Hippocampus#Role in general memory
{{Short description|Vertebrate brain region involved in memory consolidation}}
{{About|the section in the brain|the fish genus Hippocampus|Seahorse|the mythological creature Hippocampus|Hippocampus (mythology)|other uses}}
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{{Infobox Brain
| Name = Hippocampus
| Latin = hippocampus
| Image = Gray739-emphasizing-hippocampus.png
| Caption = Humans have two hippocampi, one in each hemisphere of the brain. They are located in the medial temporal lobe of the brain. In this lateral view of the human brain, the frontal lobe is at the left, the occipital lobe at the right, and the temporal and parietal lobes have largely been removed to reveal one of the hippocampi underneath.
| Image2 = 1511 The Limbic Lobe.jpg
| Caption2 = Hippocampus (lowest pink region) as part of the limbic system
| Width2 = 180px
| IsPartOf = Temporal lobe
| Components =
| Artery =
| Vein =
}}
The hippocampus ({{plural form}}: hippocampi; via Latin from Greek {{lang|grc|ἱππόκαμπος}}, 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the subiculum are components of the hippocampal formation located in the limbic system.
The hippocampus plays important roles in the consolidation of information from short-term memory to long-term memory, and in spatial memory that enables navigation. In humans, and other primates the hippocampus is located in the archicortex, one of the three regions of allocortex, in each hemisphere with direct neural projections to, and reciprocal indirect projections from the neocortex. The hippocampus, as the medial pallium, is a structure found in all vertebrates.
In Alzheimer's disease (and other forms of dementia), the hippocampus is one of the first regions of the brain to suffer damage; short-term memory loss and disorientation are included among the early symptoms. Damage to the hippocampus can also result from oxygen starvation (hypoxia), encephalitis, or medial temporal lobe epilepsy. People with extensive, bilateral hippocampal damage may experience anterograde amnesia: the inability to form and retain new memories.
Since different neuronal cell types are neatly organized into layers in the hippocampus, it has frequently been used as a model system for studying neurophysiology. The form of neural plasticity known as long-term potentiation (LTP) was initially discovered to occur in the hippocampus and has often been studied in this structure. LTP is widely believed to be one of the main neural mechanisms by which memories are stored in the brain.
In rodents as model organisms, the hippocampus has been studied extensively as part of a brain system responsible for spatial memory and navigation. Many neurons in the rat and mouse hippocampi respond as place cells: that is, they fire bursts of action potentials when the animal passes through a specific part of its environment. Hippocampal place cells interact extensively with head direction cells, whose activity acts as an inertial compass, and conjecturally with grid cells in the neighboring entorhinal cortex.
Name
File:Hippocampus and seahorse cropped.JPG (left) compared with a seahorse (right)Preparation by László Seress in 1980.]]
The earliest description of the ridge running along the floor of the inferior horn of the lateral ventricle comes from the Venetian anatomist Julius Caesar Aranzi (1587), who likened it first to a silkworm and then to a seahorse (Latin hippocampus, from Greek ἱππόκαμπος, from ἵππος, 'horse' + κάμπος, 'sea monster').{{cite journal |vauthors=Tatu L, Bogousslavsky J |title=Beasts and Gods: Hippocampal quarrels before memory |journal=Rev Neurol (Paris) |volume=178 |issue=10 |pages=991–995 |date=December 2022 |pmid=35927101 |doi=10.1016/j.neurol.2022.03.022 |url=}} The German anatomist Duvernoy (1729), the first to illustrate the structure, also wavered between "seahorse" and "silkworm". "Ram's horn" was proposed by the Danish anatomist Jacob Winsløw in 1732; and a decade later his fellow Parisian, the surgeon de Garengeot, used cornu Ammonis – horn of Amun,{{cite book | vauthors = Duvernoy HM | title = The Human Hippocampus | edition = 3rd | year = 2005 | publisher = Springer-Verlag | location = Berlin | isbn = 978-3-540-23191-2 | page = 1 | chapter = Introduction | chapter-url = https://books.google.com/books?id=5GkpPjk5z1IC&pg=PP1 | ref = refDuvernoy2005 | access-date = 2016-03-05 | archive-date = 2016-08-28 | archive-url = https://web.archive.org/web/20160828091605/https://books.google.com/books?id=5GkpPjk5z1IC&pg=PP1 | url-status = live }} after the ancient Egyptian god who was often represented as having a ram's head.{{cite journal |last1=Iniesta |first1=I. |title=On the origin of Ammon's horn |journal=Neurología (English Edition) |date=October 2014 |volume=29 |issue=8 |pages=490–496 |doi=10.1016/j.nrleng.2012.03.024}} Ammon is the Greek name for Amun.{{cite journal | vauthors = Pearce JM | title = Ammon's horn and the hippocampus | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 71 | issue = 3 | pages = 351 | date = September 2001 | pmid = 11511709 | pmc = 1737533 | doi = 10.1136/jnnp.71.3.351 | ref = refPearce2001 | department = Historical Note }}
The head region of the hippocampus is enlarged, and presents two or three rounded elevations or foot-like digitations, and hence it was named the pes hippocampi (pes meaning foot).{{cite web|title=BrainInfo|url=http://braininfo.rprc.washington.edu/centraldirectory.aspx?ID=2283|website=braininfo.rprc.washington.edu}}{{cite journal |vauthors=Anand KS, Dhikav V |title=Hippocampus in health and disease: An overview |journal=Ann Indian Acad Neurol |volume=15 |issue=4 |pages=239–46 |date=October 2012 |pmid=23349586 |pmc=3548359 |doi=10.4103/0972-2327.104323 |doi-access=free |url=}} Later this part was described as pes hippocampi major, with an adjacent bulge in the occipital horn of the lateral ventricle, described as pes hippocampi minor later renamed as the calcar avis.{{cite journal | vauthors = Owen CM, Howard A, Binder DK | title = Hippocampus minor, calcar avis, and the Huxley-Owen debate | journal = Neurosurgery | volume = 65 | issue = 6 | pages = 1098–1104; discussion 1104–1105 | date = December 2009 | pmid = 19934969 | doi = 10.1227/01.neu.0000359535.84445.0b | s2cid = 19663125 }} In 1786 Félix Vicq-d'Azyr published an authoritative description naming just the hippocampus but the term remained largely unused with no description of any function proposed until in the middle of the 20th century it was associated with memory.
Mayer mistakenly used the term hippopotamus in 1779, and was followed by some other authors until Karl Friedrich Burdach resolved this error in 1829. In 1861 the hippocampus minor became the center of a dispute over human evolution between Thomas Henry Huxley and Richard Owen, satirized as the Great Hippocampus Question. The term hippocampus minor fell from use in anatomy textbooks and was officially removed in the Nomina Anatomica of 1895.{{cite journal | vauthors = Gross CG | title = Hippocampus minor and man's place in nature: a case study in the social construction of neuroanatomy | journal = Hippocampus | volume = 3 | issue = 4 | pages = 403–415 | date = October 1993 | pmid = 8269033 | doi = 10.1002/hipo.450030403 | ref = refGross1993 | s2cid = 15172043 }}
Today, the structure is just called the hippocampus, with the term cornu Ammonis (that is, 'Ammon's horn') surviving in the names of the hippocampal subfields CA1–CA4.{{cite journal | vauthors = Pang CC, Kiecker C, O'Brien JT, Noble W, Chang RC | title = Ammon's Horn 2 (CA2) of the Hippocampus: A Long-Known Region with a New Potential Role in Neurodegeneration | journal = The Neuroscientist | volume = 25 | issue = 2 | pages = 167–180 | date = April 2019 | pmid = 29865938 | doi = 10.1177/1073858418778747 | s2cid = 46929253 | url = https://kclpure.kcl.ac.uk/portal/en/publications/0547351a-ef50-44ac-b15d-e192706f446b }}{{cite web |title=Search Results for ammon's horn |url=https://www.oxfordreference.com/search?q=ammon%27s+horn&searchBtn=Search&isQuickSearch=true |website=Oxford Reference |access-date=9 December 2021}}{{cite web | vauthors = Colman AM |title=dentate gyrus |url=https://www.oxfordreference.com/view/10.1093/acref/9780199657681.001.0001/acref-9780199657681-e-2184?rskey=auIwwd&result=10 |website=A Dictionary of Psychology |publisher=Oxford University Press |access-date=10 December 2021 |language=en |doi=10.1093/acref/9780199657681.001.0001 |date=21 May 2015|isbn=978-0-19-965768-1 }}
In the limbic system
File:Blausen 0614 LimbicSystem.png]]
The hippocampus is one of the structures of the limbic lobe, first described by Broca in 1878, as the cortical areas that line the deep edge of the cortex.{{cite book|title=Neuroscience|date=2012|publisher=Sinauer|isbn=978-0-87893-695-3 |edition=5th|location=Sunderland, MA|page=652| vauthors = Purves D }} The limbic lobe is the main component of the limbic system.{{cite journal | vauthors = Roxo MR, Franceschini PR, Zubaran C, Kleber FD, Sander JW | title = The limbic system conception and its historical evolution | journal = TheScientificWorldJournal | volume = 11 | pages = 2428–2441 | year = 2011 | pmid = 22194673 | pmc = 3236374 | doi = 10.1100/2011/157150 | doi-access = free }} The cingulate gyrus, and the parahippocampal gyrus are the two main parts of the described lobe, which had been largely associated with olfaction. Many studies later culminating in work by Papez, and MacLean, the involvement of other interacting brain regions associated with emotion was recognized. The hippocampus is anatomically connected to parts of the brain that are involved with emotional behavior, including the septal area, the hypothalamic mammillary bodies, and the anterior nuclear complex in the thalamus. MacLean proposed that the associated structures of the limbic lobe be included in what he termed as the limbic system.
Anatomy
{{See also |Hippocampus anatomy}}
File:Sobo 1909 639.png showing structure and location of hippocampus]]
File:Brainmaps-macaque-hippocampus.jpg section of the brain of a macaque monkey, showing hippocampus (circled)]]
The hippocampus is a five centimeter long ridge of gray matter tissue within the parahippocampal gyrus that can only be seen when the gyrus is opened up.{{cite journal |last1=Fogwe |first1=Leslie A. |last2=Reddy |first2=Vamsi |last3=Mesfin |first3=Fassil B. |title=Neuroanatomy, Hippocampus |url=https://www.ncbi.nlm.nih.gov/books/NBK482171/#:~:text=The%20hippocampus%20has%20three%20distinct,and%20entorhinal%20and%20other%20cortices. |website=StatPearls |publisher=StatPearls Publishing |date=2025|pmid=29489273 }}{{cite book|title=Neuroscience|date=2011|publisher=Sinauer|isbn=978-0-87893-695-3 |edition=5th|location=Sunderland, MA|pages=730–735| vauthors = Purves D }} The hippocampus is an inward fold of three-layered archicortex (one of three regions of the allocortex) into the medial temporal lobe of the brain, where it elevates into the floor of each lateral ventricle inferior horn.{{cite book |last1=Morris |first1=Richard |last2=Amaral |first2=David |title=The Hippocampus Book |date=2024 |pages= 49–50|publisher=Oxford University Press, Incorporated |location=Oxford |isbn=9780190065324 |edition=2nd}}{{cite journal |last1=Creutzfeldt |first1=O.D. |title=The allocortex and limbic system |journal=Cortex Cerebri: Performance, Structural and Functional Organisation of the Cortex |date=27 April 1995 |pages=486–540 |doi=10.1093/acprof:oso/9780198523246.003.0009|isbn=978-0-19-852324-6 }}{{cite journal | vauthors = Bachevalier J | title = Nonhuman primate models of hippocampal development and dysfunction | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 116 | issue = 52 | pages = 26210–26216 | date = December 2019 | pmid = 31871159 | pmc = 6936345 | doi = 10.1073/pnas.1902278116 | doi-access = free | bibcode = 2019PNAS..11626210B }} The hippocampus stretches along its anterior-posterior axis, from the amygdala to the splenium of the corpus callosum, with the head, body, and tail regions as subdivisions of this axis.{{cite journal |vauthors=Sun F, Shuai Y, Wang J, Yan J, Lin B, Li X, Zhao Z |title=Hippocampal gray matter volume alterations in patients with first-episode and recurrent major depressive disorder and their associations with gene profiles |journal=BMC Psychiatry |volume=25 |issue=1 |pages=134 |date=February 2025 |pmid=39955494 |doi=10.1186/s12888-025-06562-4 |doi-access=free |pmc=11829352 |url=}} The dentate gyrus, CA subfields, fimbria, and subiculum are divisions across the short axis, the proximal-distal axis.
The hippocampal formation refers to the hippocampus, and its related adjoining parts to include the dentate gyrus, the subiculum, the presubiculum, parasubiculum, and the entorhinal cortex. Sometimes the subiculum, presubiculum, and parasubiculum are grouped together as the subicular complex, but the regions are neuroanatomically distinct. Some sources may only include the hippocampus, dentate gyrus, and subiculum, being regions of the hippocampal three-layered archicortex. But the six regions are linked together serially by almost unidirectional neural pathways. Other sources include the indusium griseum, gyrus fasciolaris, the medial and longitudinal striae, and uncus, and exclude subicular regions.{{cite book |last1=Singh |first1=Vishram |title=Textbook. of Anatomy Vol III |date=2017 |publisher=Elsevier |isbn=9788131237274 |page=402}}{{cite journal |last1=Chauhan |first1=Pradip |last2=Jethwa |first2=Kinjal |last3=Rathawa |first3=Ashish |last4=Chauhan |first4=Girish |last5=Mehra |first5=Simmi |title=The Anatomy of the Hippocampus |url=https://www.ncbi.nlm.nih.gov/books/NBK575732/ |website=Cerebral Ischemia |publisher=Exon Publications |access-date=19 March 2025 |date=2021|pmid=34905307 }} The neural layout and pathways within the hippocampal formation are very similar in all mammals.{{cite book|vauthors= Anderson P, Morris R, Amaral, Bliss T, O'Keefe J|veditors= Anderson P, Morris R, Amaral, Bliss T, O'Keefe J|title= The hippocampus book|edition= first|year= 2007|publisher= Oxford University Press|location= New York|isbn= 978-0195100273|pages=3–77 |chapter = The hippocampal formation|chapter-url= https://books.google.com/books?id=zg6oyF1DziQC&pg=PA3|access-date= 2016-12-15|archive-date= 2020-03-15|archive-url= https://web.archive.org/web/20200315125212/https://books.google.com/books?id=zg6oyF1DziQC&pg=PA3|url-status= live}}
The hippocampus has a generally similar appearance across the range of mammals, from egg-laying mammals such as the echidna, to humans and other primates.{{cite book | ref=refWest1990 | vauthors = West MJ | title = Stereological studies of the hippocampus: a comparison of the hippocampal subdivisions of diverse species including hedgehogs, laboratory rodents, wild mice and men | volume = 83 | pages = 13–36 | year = 1990 | pmid = 2203095 | doi = 10.1016/S0079-6123(08)61238-8 | isbn = 978-0-444-81149-3 | series = Progress in Brain Research | chapter = Chapter 2 Stereological studies of the hippocampus: A comparison of the hippocampal subdivisions of diverse species including hedgehogs, laboratory rodents, wild mice and men }} The hippocampal-size-to-body-size ratio broadly increases, being about twice as large for primates as for the echidna. It does not, however, increase at anywhere close to the rate of the neocortex-to-body-size ratio. Therefore, the hippocampus takes up a much larger fraction of the cortical mantle in rodents than in primates. In adult humans the volume of the hippocampus on each side of the brain is about 3.0 to 3.5 cm3 as compared to 320 to 420 cm3 for the volume of the neocortex.* {{cite journal | vauthors = Suzuki M, Hagino H, Nohara S, Zhou SY, Kawasaki Y, Takahashi T, Matsui M, Seto H, Ono T, Kurachi M | title = Male-specific volume expansion of the human hippocampus during adolescence | journal = Cerebral Cortex | volume = 15 | issue = 2 | pages = 187–193 | date = February 2005 | pmid = 15238436 | doi = 10.1093/cercor/bhh121 | ref = refSuzuki2005 | doi-access = free }} There is also a general relationship between the size of the hippocampus and spatial memory. When comparisons are made between similar species, those that have a greater capacity for spatial memory tend to have larger hippocampal volumes.{{cite journal | vauthors = Jacobs LF | title = The evolution of the cognitive map | journal = Brain, Behavior and Evolution | volume = 62 | issue = 2 | pages = 128–139 | year = 2003 | pmid = 12937351 | doi = 10.1159/000072443 | ref = refJacobs2003 | s2cid = 16102408 }}
Neuroanatomy
The hippocampus, and dentate gyrus that is folded into the hippocampal archicortex have the shape of a curved, rolled-up tube. The curve of the hippocampus (known as cornu Ammonis) uses the initial letters CA to name the hippocampal subfields CA1-CA4. CA4 is in fact the polymorphic layer or hilus of the dentate gyrus, but CA4 is still sometimes in use to describe the part of CA3 that inserts between the dentate gyrus regions or blades.{{cite journal |vauthors=Chen HJ, Qiu J, Qi Y, Fu L, Fu Q, Wu W, Dai G, Chen F |title=Hippocampal subfield morphology in regular hemodialysis patients |journal=Nephrol Dial Transplant |volume=38 |issue=4 |pages=992–1001 |date=March 2023 |pmid=36124763 |pmc=10064839 |doi=10.1093/ndt/gfac263 |url=}}
It can be distinguished as an area where the cortex narrows into a single layer of densely packed pyramidal neurons, which curl into a tight U shape. One edge of the "U," – (CA4) the hilus of the dentate gyrus, is embedded into the backward-facing, flexed dentate gyrus. In humans the hippocampus is described as having an anterior and posterior part; in other primates they are termed rostral and caudal, and in rodent literature they are the ventral and dorsal part. Both parts are of similar composition but belong to different neural circuits.{{cite journal | vauthors = Moser MB, Moser EI | title = Functional differentiation in the hippocampus | journal = Hippocampus | volume = 8 | issue = 6 | pages = 608–619 | year = 1998 | pmid = 9882018 | doi = 10.1002/(SICI)1098-1063(1998)8:6<608::AID-HIPO3>3.0.CO;2-7 | ref = refMoser1998 | s2cid = 32384692 }} The dentate gyrus combined with other hippocampal regions form a banana-like structure, with the two hippocampi joined at the stems by the commissure of fornix (also called the hippocampal commissure).{{cite book |vauthors=Amaral DG, Scharfman HE, Lavenex P |chapter=The dentate gyrus: Fundamental neuroanatomical organization (Dentate gyrus for dummies) |title=The Dentate Gyrus: A Comprehensive Guide to Structure, Function, and Clinical Implications |series=Progress in Brain Research |volume=163 |issue= |pages=3–22 |date=2007 |pmid=17765709 |pmc=2492885 |doi=10.1016/S0079-6123(07)63001-5 |isbn=978-0-444-53015-8 |chapter-url=}} In primates, the part of the hippocampus at the bottom, near the base of the temporal lobe, is much broader than the part at the top. This means that in cross-section the hippocampus can show a number of different shapes, depending on the angle and location of the cut.{{cite book | vauthors = Duvernoy H, Cattin F, Risold PY | chapter = Vascularization | pages = 69–105 | veditors = Duvernoy HM, Cattin F, Risold PY | title = The human hippocampus: functional anatomy, vascularization and serial sections with MRI. | location = Berlin | publisher = Springer | date = June 2005 | isbn = 978-3-642-33603-4 | doi = 10.1007/978-3-642-33603-4_5 }}
In a cross-section of the hippocampus, including the dentate gyrus, several layers will be shown. The dentate gyrus has three layers of cells – the outer molecular layer, the middle granular layer, and the inner polymorphic layer also known as the hilus.{{cite journal |vauthors=Jinde S, Zsiros V, Nakazawa K |title=Hilar mossy cell circuitry controlling dentate granule cell excitability |journal=Front Neural Circuits |volume=7 |issue= |pages=14 |date=2013 |pmid=23407806 |pmc=3569840 |doi=10.3389/fncir.2013.00014 |doi-access=free |url=}} The CA3 subfield has the following cell layers known as strata: lacunosum-moleculare, radiatum, lucidum, pyramidal, and oriens. CA2 and CA1 also have these layers except the lucidum stratum.{{cite journal | vauthors = Murakami G, Tsurugizawa T, Hatanaka Y, Komatsuzaki Y, Tanabe N, Mukai H, Hojo Y, Kominami S, Yamazaki T, Kimoto T, Kawato S | title = Comparison between basal and apical dendritic spines in estrogen-induced rapid spinogenesis of CA1 principal neurons in the adult hippocampus | journal = Biochemical and Biophysical Research Communications | volume = 351 | issue = 2 | pages = 553–558 | date = December 2006 | pmid = 17070772 | doi = 10.1016/j.bbrc.2006.10.066 | quote = CA1 neurons consist of four regions, i.e., the stratum oriens, the cell body, the stratum radiatum, and the stratum lacunosum-moleculare }}
The input to the hippocampus (from varying cortical and subcortical structures) comes from the entorhinal cortex via the perforant path.{{cite journal | vauthors = Witter M | title = Entorhinal cortex | journal = Scholarpedia | date = October 2011 | volume = 6 | issue = 10 | pages = 4380 | doi = 10.4249/scholarpedia.4380 | doi-access = free | bibcode = 2011SchpJ...6.4380W }} The entorhinal cortex (EC) is strongly and reciprocally connected with many cortical and subcortical structures as well as with the brainstem. Different thalamic nuclei, (from the anterior and midline groups), the medial septal nucleus,{{cite journal | vauthors = Takeuchi Y, Nagy AJ, Barcsai L, Li Q, Ohsawa M, Mizuseki K, Berényi A | title = The Medial Septum as a Potential Target for Treating Brain Disorders Associated With Oscillopathies | journal = Frontiers in Neural Circuits | volume = 15 | issue = | pages = 701080 | date = 2021 | pmid = 34305537 | pmc = 8297467 | doi = 10.3389/fncir.2021.701080 | doi-access = free | url = }} the supramammillary nucleus of the hypothalamus, and the raphe nuclei and locus coeruleus of the brainstem all send axons to the EC, so that it serves as the interface between the neocortex and the other connections, and the hippocampus.
The EC is located in the parahippocampal gyrus, a cortical region adjacent to the hippocampus. This gyrus conceals the hippocampus. The parahippocampal gyrus is adjacent to the perirhinal cortex, which plays an important role in the visual recognition of complex objects. There is also substantial evidence that it makes a contribution to memory, which can be distinguished from the contribution of the hippocampus. It is apparent that complete amnesia occurs only when both the hippocampus and the parahippocampus are damaged.{{cite journal | vauthors = Eichenbaum H, Yonelinas AP, Ranganath C | title = The medial temporal lobe and recognition memory | journal = Annual Review of Neuroscience | volume = 30 | pages = 123–152 | year = 2007 | pmid = 17417939 | pmc = 2064941 | doi = 10.1146/annurev.neuro.30.051606.094328 }}
=Circuitry=
File:CajalHippocampus (modified).png. DG: dentate gyrus. Sub: subiculum. EC: entorhinal cortex]]
The major input to the hippocampus is through the entorhinal cortex (EC), whereas its major output is via CA1 to the subiculum.{{Cite book | ref=refKandel2012 | title = Principles of Neural Science | vauthors = Kandel ER, Schwartz JH, Jessell TM, Siegelbaum SA, Hudspeth AJ | publisher = McGraw-Hill Medical | year = 2012 | isbn = 978-0-07-139011-8 | edition = 5th | location = New York | pages = 1490–1491 | oclc = 820110349}} Information reaches CA1 via two main pathways, direct and indirect. Axons from the EC that originate in layer III are the origin of the direct perforant pathway and form synapses on the very distal apical dendrites of CA1 neurons. Conversely, axons originating from layer II are the origin of the indirect pathway, and information reaches CA1 via the trisynaptic circuit. In the initial part of this pathway, the axons project through the perforant pathway to the granule cells of the dentate gyrus (first synapse). From then, the information follows via the mossy cell fibers to CA3 (second synapse). From there, CA3 axons called Schaffer collaterals leave the deep part of the cell body and loop up to the apical dendrites and then extend to CA1 (third synapse). Axons from CA1 then project back to the entorhinal cortex, completing the circuit.{{cite book | vauthors = Purves D |title=Neuroscience |date=2011 |publisher=Sinauer |location=Sunderland, Mass. |isbn=978-0-87893-695-3 |page=171 |edition=5th}}
Basket cells in CA3 receive excitatory input from the pyramidal cells and then give an inhibitory feedback to the pyramidal cells. This recurrent inhibition is a simple feedback circuit that can dampen excitatory responses in the hippocampus. The pyramidal cells give a recurrent excitation which is an important mechanism found in some memory processing microcircuits.{{cite book | vauthors = Byrne JH | title = Introduction to Neurons and Neuronal Networks | chapter = Section 1, Intro Chapter | series = Neuroscience Online: An Electronic Textbook for the Neurosciences | publisher = Department of Neurobiology and Anatomy – The University of Texas Medical School at Houston | chapter-url = http://neuroscience.uth.tmc.edu/s1/introduction.html |url-status=dead|archive-url=https://web.archive.org/web/20131203010009/http://neuroscience.uth.tmc.edu/s1/introduction.html|archive-date=2013-12-03}}
Several other connections play important roles in hippocampal function. Beyond the output to the EC, additional output pathways go to other cortical areas including the prefrontal cortex. A major output goes via the fornix to the lateral septal area and to the mammillary body of the hypothalamus (which the fornix interconnects with the hippocampus). The hippocampus receives modulatory input from the serotonin, norepinephrine, and dopamine systems, and from the nucleus reuniens of the thalamus to field CA1. A very important projection comes from the medial septal nucleus, which sends cholinergic, and gamma amino butyric acid (GABA) stimulating fibers (GABAergic fibers) to all parts of the hippocampus. The inputs from the medial septal nucleus play a key role in controlling the physiological state of the hippocampus; destruction of this nucleus abolishes the hippocampal theta rhythm and severely impairs certain types of memory.{{cite journal | vauthors = Winson J | title = Loss of hippocampal theta rhythm results in spatial memory deficit in the rat | journal = Science | volume = 201 | issue = 4351 | pages = 160–163 | date = July 1978 | pmid = 663646 | doi = 10.1126/science.663646 | ref = refWinson1978 | bibcode = 1978Sci...201..160W }}
=Subfields=
File:Hippocampus coronal section176157.fig.004.jpg]]
File:Golgi Hippocampus.jpg of a hippocampus stained using silver nitrate]]
Hippocampal subfields, and subregions, head, body, and tail, are functionally and anatomically differentiated, and connect differently to other brain regions.{{cite journal |vauthors=Xiao Y, Hu Y, Huang K |title=Atrophy of hippocampal subfields relates to memory decline during the pathological progression of Alzheimer's disease |journal=Front Aging Neurosci |volume=15 |issue= |pages=1287122 |date=2023 |pmid=38149170 |pmc=10749921 |doi=10.3389/fnagi.2023.1287122 |doi-access=free |url=}}{{cite journal |vauthors=Canada KL, Botdorf M, Riggins T |title=Longitudinal development of hippocampal subregions from early- to mid-childhood |journal=Hippocampus |volume=30 |issue=10 |pages=1098–1111 |date=October 2020 |pmid=32497411 |pmc=8500647 |doi=10.1002/hipo.23218 |url=}} Their cells are morphologically different.{{cite journal |vauthors=Ezama L, Hernández-Cabrera JA, Seoane S, Pereda E, Janssen N |title=Functional connectivity of the hippocampus and its subfields in resting-state networks |journal=Eur J Neurosci |volume=53 |issue=10 |pages=3378–3393 |date=May 2021 |pmid=33786931 |pmc=8252772 |doi=10.1111/ejn.15213 |url=}} They also have different levels of vulnerability to disease.
In humans the head of the hippocampus is termed the anterior hippocampus, the body is the intermediate hippocampus, and the tail the posterior hippocampus. The subregions all serve different functions, project with different neural pathways, and have varying numbers of place cells.{{cite journal | vauthors = Fanselow MS, Dong HW | title = Are the dorsal and ventral hippocampus functionally distinct structures? | journal = Neuron | volume = 65 | issue = 1 | pages = 7–19 | date = January 2010 | pmid = 20152109 | pmc = 2822727 | doi = 10.1016/j.neuron.2009.11.031 | ref = refFanselow2010 }} (In other primates the terms used are rostral and caudal, and in rodents they are termed ventral and dorsal).{{cite journal |vauthors=Dalton MA, D'Souza A, Lv J, Calamante F |title=New insights into anatomical connectivity along the anterior-posterior axis of the human hippocampus using in vivo quantitative fibre tracking |journal=eLife |volume=11 |issue= |pages= |date=November 2022 |pmid=36345716 |pmc=9643002 |doi=10.7554/eLife.76143 |doi-access=free |url=}} The posterior hippocampus serves for spatial memory, verbal memory, and learning of conceptual information. Using the radial arm maze in rats, lesions in the dorsal hippocampus were shown to cause spatial memory impairment. Its projecting pathways include the medial septal nucleus, and supramammillary nucleus.{{cite journal | vauthors = Pothuizen HH, Zhang WN, Jongen-Rêlo AL, Feldon J, Yee BK | title = Dissociation of function between the dorsal and the ventral hippocampus in spatial learning abilities of the rat: a within-subject, within-task comparison of reference and working spatial memory | journal = The European Journal of Neuroscience | volume = 19 | issue = 3 | pages = 705–712 | date = February 2004 | pmid = 14984421 | doi = 10.1111/j.0953-816X.2004.03170.x | ref = refPothuizen2004 | s2cid = 33385275 }} In the rat the dorsal hippocampus also has more place cells than both the ventral and intermediate hippocampal regions.{{cite journal | vauthors = Jung MW, Wiener SI, McNaughton BL | title = Comparison of spatial firing characteristics of units in dorsal and ventral hippocampus of the rat | journal = The Journal of Neuroscience | volume = 14 | issue = 12 | pages = 7347–7356 | date = December 1994 | pmid = 7996180 | pmc = 6576902 | doi = 10.1523/JNEUROSCI.14-12-07347.1994 | ref = refJung1994 }}
In the early 20th century, the widely held view was that olfaction was a major hippocampal function.{{cite book |last1=Morris |first1=Richard |last2=Amaral |first2=David |title=The Hippocampus Book |date=2024 |pages= 8–9|publisher=Oxford University Press, Incorporated |location=Oxford |isbn=9780190065324 |edition=2nd}} This view was argued against, pointing out that the hippocampus was present in some animals such as dolphins and whales, that did not have a sense of smell; and further that lesions in the temporal lobe in dogs had been shown to have no effect on their sense of smell. These arguments were concluded in 1947 and held for a few more decades. In 1984, and 1987, studies in the rat showed that the entorhinal cortex receives substantial input from the olfactory bulb, with part of the EC being directly innervated by the lateral olfactory tract. Secondary inputs to the EC were also shown to include some from the periamygdaloid and piriform cortices, and CA1 in the ventral hippocampus was shown to sends axons to the main olfactory bulb.{{cite journal | vauthors = van Groen T, Wyss JM | title = Extrinsic projections from area CA1 of the rat hippocampus: olfactory, cortical, subcortical, and bilateral hippocampal formation projections | journal = The Journal of Comparative Neurology | volume = 302 | issue = 3 | pages = 515–528 | date = December 1990 | pmid = 1702115 | doi = 10.1002/cne.903020308 | s2cid = 7175722 }} It is evident that the hippocampus does have an involvement in memory for odors.{{cite book | vauthors = Eichenbaum H, Otto TA, Wible CG, Piper JM | veditors = Davis JL, Eichenbaum H | title=Olfaction | year=1991 | chapter=Ch 7. Building a model of the hippocampus in olfaction and memory | publisher=MIT Press | isbn=978-0-262-04124-9 |ref=refEichenbaum1991}}{{cite book |vauthors=Eichenbaum H, Cohen NJ| title = Memory, Amnesia, and the Hippocampal System | year =1993 | publisher =MIT Press | ref = refEichenbaum1993 }}
The intermediate hippocampus has overlapping characteristics with both the ventral and dorsal hippocampus. Studies in 2002, showed that alterations to the ventral hippocampus reduced the amount of information sent to the amygdala by the dorsal and ventral hippocampus, consequently altering fear conditioning in rats.{{cite journal | vauthors = Anagnostaras SG, Gale GD, Fanselow MS | title = The hippocampus and Pavlovian fear conditioning: reply to Bast et al | journal = Hippocampus | volume = 12 | issue = 4 | pages = 561–565 | year = 2002 | pmid = 12201641 | doi = 10.1002/hipo.10071 | url = http://homepage.mac.com/sanagnos/19bastreply2002.pdf | ref = refAnagnostaras2002 | url-status = dead | s2cid = 733197 | archive-url = https://web.archive.org/web/20050216104718/http://homepage.mac.com/sanagnos/19bastreply2002.pdf | archive-date = 2005-02-16 }} In 2007, studies using anterograde tracing methods, located the moderate projections to two primary olfactory cortical areas and prelimbic areas of the medial prefrontal cortex. This region has the smallest number of place cells. The ventral hippocampus functions in fear conditioning and affective processes.{{cite journal | vauthors = Cenquizca LA, Swanson LW | title = Spatial organization of direct hippocampal field CA1 axonal projections to the rest of the cerebral cortex | journal = Brain Research Reviews | volume = 56 | issue = 1 | pages = 1–26 | date = November 2007 | pmid = 17559940 | pmc = 2171036 | doi = 10.1016/j.brainresrev.2007.05.002 | ref = refCenquizca2007 }}
Function
=Theories=
Three main theories of hippocampal function have been in dominance: response inhibition, episodic memory, and spatial cognition. The response inhibition theory (caricatured by John O'Keefe and Lynn Nadel as "slam on the brakes!") was very popular up to the 1960s.{{cite journal | vauthors = Nadel L, O'Keefe J, Black A | title = Slam on the brakes: a critique of Altman, Brunner, and Bayer's response-inhibition model of hippocampal function | journal = Behavioral Biology | volume = 14 | issue = 2 | pages = 151–162 | date = June 1975 | pmid = 1137539 | doi = 10.1016/S0091-6773(75)90148-0 | ref = refNadel1975 }} It was based largely on two observations: first, that animals with hippocampal damage tend to be hyperactive; second, that animals with hippocampal damage often have difficulty learning to inhibit previously learnt responses, especially if the response requires remaining quiet as in a passive avoidance test. British psychologist Jeffrey Gray developed this line of thought into a complete theory of the role of the hippocampus in anxiety, called the behavioral inhibition system.{{cite book | vauthors = Gray JA, McNaughton N | title = The Neuropsychology of Anxiety: An Enquiry into the Functions of the Septo-Hippocampal System | year = 2000 | publisher = Oxford University Press | ref = refGray2000 }}{{cite journal |vauthors=Bosecke C, Ng M, Dastgheib Z, Lithgow BJ |title=Perspective: Hippocampal theta rhythm as a potential vestibuloacoustic biomarker of anxiety |journal=Eur J Neurosci |volume=61 |issue=1 |pages=e16641 |date=January 2025 |pmid=39662900 |pmc=11664906 |doi=10.1111/ejn.16641 |url=}}
The second major line of thought relates the hippocampus to memory. Although it had historical precursors, this idea derived its main impetus from a famous report by American neurosurgeon William Beecher Scoville and British-Canadian neuropsychologist Brenda Milner.{{cite journal | vauthors = Scoville WB, Milner B | title = Loss of recent memory after bilateral hippocampal lesions | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 20 | issue = 1 | pages = 11–21 | date = February 1957 | pmid = 13406589 | pmc = 497229 | doi = 10.1136/jnnp.20.1.11 | ref = refScoville1957 }} It described the results of surgical destruction of the hippocampi when trying to relieve epileptic seizures in an American man Henry Molaison, known until his death in 2008 as "Patient H.M."{{cite journal |vauthors=Squire LR |title=The legacy of patient H.M. for neuroscience |journal=Neuron |volume=61 |issue=1 |pages=6–9 |date=January 2009 |pmid=19146808 |pmc=2649674 |doi=10.1016/j.neuron.2008.12.023 |url=}}{{cite news | vauthors = Carey B | title=H. M., an Unforgettable Amnesiac, Dies at 82 | work=The New York Times | date=2008-12-04 | url=https://www.nytimes.com/2008/12/05/us/05hm.html | access-date=2009-04-27 | ref=refhMObit | archive-date=2018-06-13 | archive-url=https://web.archive.org/web/20180613184944/https://www.nytimes.com/2008/12/05/us/05hm.html | url-status=live }} The unexpected outcome of the surgery was severe anterograde, and partial retrograde amnesia; Molaison was unable to form new episodic memories after his surgery and could not remember any events that occurred just before his surgery, but he did retain memories of events that occurred many years earlier extending back into his childhood. This case attracted such widespread professional interest that Molaison became the most intensively studied subject in medical history.
File:Rats_and_cognitive_maps_and_maze.pngs]]
The third important theory of hippocampal function relates the hippocampus to space, and spatial memory, with the idea of a cognitive map first proposed by American psychologist E.C. Tolman. This theory was followed further by O'Keefe, and in 1971, he and his student Dostrovsky discovered neurons, in the rat hippocampus that seemed to show activity related to the rat's location within its environment. The neurons were described as place cells.{{cite journal | vauthors = O'Keefe J, Dostrovsky J | title = The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat | journal = Brain Research | volume = 34 | issue = 1 | pages = 171–175 | date = November 1971 | pmid = 5124915 | doi = 10.1016/0006-8993(71)90358-1 | ref = refOKeefe1971 }} A book was later produced in 1978, The Hippocampus as a Cognitive Map written by O'Keefe and Nadel.{{cite book | vauthors = O'Keefe J, Nadel L | title = The Hippocampus as a Cognitive Map | year = 1978 | publisher = Oxford University Press | url = http://www.cognitivemap.net/HCMpdf/HCMChapters.html | ref = refOKeefe1978 | access-date = 2008-10-23 | archive-date = 2011-03-24 | archive-url = https://web.archive.org/web/20110324042731/http://www.cognitivemap.net/HCMpdf/HCMChapters.html | url-status = live }} It has been generally agreed that the hippocampus plays a key role in spatial coding but the details are widely debated.{{cite journal | vauthors = Moser EI, Kropff E, Moser MB | title = Place cells, grid cells, and the brain's spatial representation system | journal = Annual Review of Neuroscience | volume = 31 | pages = 69–89 | year = 2008 | pmid = 18284371 | doi = 10.1146/annurev.neuro.31.061307.090723 | ref = refMoser2008 | s2cid = 16036900 }}
Research has focused on trying to bridge the disconnect between the two main views of hippocampal function as being split between memory and spatial cognition. In some studies, these areas have been expanded to the point of near convergence. In an attempt to reconcile the two disparate views, it is suggested that a broader view of the hippocampal function is taken and seen to have a role that encompasses both the organization of experience (mental mapping, as per Tolman's original concept in 1948) and the directional behavior seen as being involved in all areas of cognition, so that the function of the hippocampus can be viewed as a broader system that incorporates both the memory and the spatial perspectives in its role that involves the use of a wide scope of cognitive maps.{{cite journal | vauthors = Schiller D, Eichenbaum H, Buffalo EA, Davachi L, Foster DJ, Leutgeb S, Ranganath C | title = Memory and Space: Towards an Understanding of the Cognitive Map | journal = The Journal of Neuroscience | volume = 35 | issue = 41 | pages = 13904–13911 | date = October 2015 | pmid = 26468191 | pmc = 6608181 | doi = 10.1523/JNEUROSCI.2618-15.2015 }}{{Cite journal |last1=Tse |first1=Dorothy |last2=Langston |first2=Rosamund F. |last3=Kakeyama |first3=Masaki |last4=Bethus |first4=Ingrid |last5=Spooner |first5=Patrick A. |last6=Wood |first6=Emma R. |last7=Witter |first7=Menno P. |last8=Morris |first8=Richard G. M. |date=2007-04-06 |title=Schemas and Memory Consolidation |url=https://www.science.org/doi/10.1126/science.1135935 |journal=Science |volume=316 |issue=5821 |pages=76–82 |doi=10.1126/science.1135935|pmid=17412951 |bibcode=2007Sci...316...76T }}{{Cite journal |last1=Tse |first1=Dorothy |last2=Takeuchi |first2=Tomonori |last3=Kakeyama |first3=Masaki |last4=Kajii |first4=Yasushi |last5=Okuno |first5=Hiroyuki |last6=Tohyama |first6=Chiharu |last7=Bito |first7=Haruhiko |last8=Morris |first8=Richard G. M. |date=2011-08-12 |title=Schema-dependent gene activation and memory encoding in neocortex |url=https://pubmed.ncbi.nlm.nih.gov/21737703/ |journal=Science |volume=333 |issue=6044 |pages=891–895 |doi=10.1126/science.1205274 |issn=1095-9203 |pmid=21737703|bibcode=2011Sci...333..891T }}{{Cite journal |last1=Miller |first1=Adam M. P. |last2=Jacob |first2=Alex D. |last3=Ramsaran |first3=Adam I. |last4=De Snoo |first4=Mitchell L. |last5=Josselyn |first5=Sheena A. |last6=Frankland |first6=Paul W. |date=2023-06-21 |title=Emergence of a predictive model in the hippocampus |journal=Neuron |volume=111 |issue=12 |pages=1952–1965.e5 |doi=10.1016/j.neuron.2023.03.011 |pmid=37015224 |issn=0896-6273|pmc=10293047 }} This relates to the purposive behaviorism born of Tolman's original goal of identifying the complex cognitive mechanisms and purposes that guided behavior.{{cite journal | vauthors = Eichenbaum H | title = The hippocampus and declarative memory: Cognitive mechanisms and neural codes | journal = Behavioural Brain Research | volume = 127 | issue = 1–2 | pages = 199–207 | date = December 2001 | pmid = 11718892 | doi = 10.1016/s0166-4328(01)00365-5 | s2cid = 20843130 }}
It has also been proposed that the spiking activity of hippocampal neurons is associated spatially, and it was suggested that the mechanisms of memory and planning both evolved from mechanisms of navigation and that their neuronal algorithms were basically the same.{{cite journal | vauthors = Buzsáki G, Moser EI | title = Memory, navigation and theta rhythm in the hippocampal-entorhinal system | journal = Nature Neuroscience | volume = 16 | issue = 2 | pages = 130–138 | date = February 2013 | pmid = 23354386 | pmc = 4079500 | doi = 10.1038/nn.3304 }}
Many studies have made use of neuroimaging techniques such as functional magnetic resonance imaging (fMRI), and a functional role in approach-avoidance conflict has been noted. The anterior hippocampus is seen to be involved in decision-making under approach-avoidance conflict processing. It is suggested that the memory, spatial cognition, and conflict processing functions may be seen as working together and not mutually exclusive.{{cite journal | vauthors = Ito R, Lee AC | title = The role of the hippocampus in approach-avoidance conflict decision-making: Evidence from rodent and human studies | journal = Behavioural Brain Research | volume = 313 | pages = 345–357 | date = October 2016 | pmid = 27457133 | doi = 10.1016/j.bbr.2016.07.039 | doi-access = free }}
= Role in memory =
{{See also|Amnesia|Epigenetics in learning and memory}}
The hippocampus is essential for the formation of explicit memory, also known as declarative memory. Episodic memory, and semantic memory are the two components of explicit memory.
The hippocampus also encodes emotional context from the amygdala. This is partly why returning to a location where an emotional event occurred may evoke that emotion. There is a deep emotional connection between episodic memories and places.{{Cite book|title=Learning and Memory From Brain to Behavior | edition = Second | vauthors = Gluck M, Mercado E, Myers C |publisher=Kevin Feyen|year=2014|isbn=978-1-4292-4014-7|location=New York|pages=416}}
Due to bilateral symmetry the brain has a hippocampus in each cerebral hemisphere. If damage to the hippocampus occurs in only one hemisphere, leaving the structure intact in the other hemisphere, the brain can retain near-normal memory functioning.{{cite journal | vauthors = Di Gennaro G, Grammaldo LG, Quarato PP, Esposito V, Mascia A, Sparano A, Meldolesi GN, Picardi A | title = Severe amnesia following bilateral medial temporal lobe damage occurring on two distinct occasions | journal = Neurological Sciences | volume = 27 | issue = 2 | pages = 129–133 | date = June 2006 | pmid = 16816912 | doi = 10.1007/s10072-006-0614-y | s2cid = 7741607 }} Severe damage to the hippocampi in both hemispheres results in profound difficulties in forming new memories (anterograde amnesia) and often also affects memories formed before the damage occurred (retrograde amnesia). Although the retrograde effect normally extends many years back before the brain damage, in some cases older memories remain. This retention of older memories leads to the idea that consolidation over time involves the transfer of memories out of the hippocampus to other parts of the brain.{{cite book | vauthors = Squire LR, Schacter DL | title = The Neuropsychology of Memory | year =2002 | publisher = Guilford Press | ref = refSquire2002}}{{rp|Ch. 1}} Experiments using intrahippocampal transplantation of hippocampal cells in primates with neurotoxic lesions of the hippocampus have shown that the hippocampus is required for the formation and recall, but not the storage, of memories.{{cite journal | vauthors = Virley D, Ridley RM, Sinden JD, Kershaw TR, Harland S, Rashid T, French S, Sowinski P, Gray JA, Lantos PL, Hodges H | title = Primary CA1 and conditionally immortal MHP36 cell grafts restore conditional discrimination learning and recall in marmosets after excitotoxic lesions of the hippocampal CA1 field | journal = Brain: A Journal of Neurology | volume = 122 | issue = 12 | pages = 2321–2335 | date = December 1999 | pmid = 10581225 | doi = 10.1093/brain/122.12.2321 | doi-access = free }} It has been shown that a decrease in the volume of various parts of the hippocampus leads to specific memory impairments. In particular, efficiency of verbal memory retention is related to the anterior parts of the right and left hippocampus. The right head of the hippocampus is more involved in executive functions and regulation during verbal memory recall. The tail of the left hippocampus tends to be closely related to verbal memory capacity.{{cite journal| vauthors = Sozinova EV, Kozlovskiy SA, Vartanov AV, Skvortsova VB, Pirogov YA, Anisimov NV, Kupriyanov DA |date=September 2008|title=The role of hippocampal parts in verbal memory and activation processes|journal=International Journal of Psychophysiology|volume=69|issue=3|pages=312|doi=10.1016/j.ijpsycho.2008.05.328}}
Damage to the hippocampus does not affect some types of memory, such as the ability to learn new skills (playing a musical instrument or solving certain types of puzzles, for example). This fact suggests that such abilities depend on different types of memory such as procedural memory in implicit memory function, implicating different brain regions. Furthermore, amnesic patients frequently show implicit memory for experiences even in the absence of conscious knowledge. For example, patients asked to guess which of two faces they have seen most recently may give the correct answer most of the time in spite of stating that they have never seen either of the faces before. Some researchers distinguish between conscious recollection, which depends on the hippocampus, and familiarity, which depends on portions of the medial temporal lobe.{{cite journal | vauthors = Diana RA, Yonelinas AP, Ranganath C | title = Imaging recollection and familiarity in the medial temporal lobe: a three-component model | journal = Trends in Cognitive Sciences | volume = 11 | issue = 9 | pages = 379–386 | date = September 2007 | pmid = 17707683 | doi = 10.1016/j.tics.2007.08.001 | ref = refDiana2007 | s2cid = 1443998 }} A study claims to have confirmed that the hippocampus is not associated with implicit memory.{{cite journal |vauthors=Steinkrauss AC, Slotnick SD |title=Is implicit memory associated with the hippocampus? |journal=Cogn Neurosci |volume=15 |issue=2 |pages=56–70 |date=April 2024 |pmid=38368598 |doi=10.1080/17588928.2024.2315816 |url=}} But other sources say the question is still up for debate (as of 2024).{{cite journal |vauthors=Slotnick SD |title=The hippocampus and implicit memory |journal=Cogn Neurosci |volume=15 |issue=2 |pages=25–26 |date=April 2024 |pmid=38767113 |doi=10.1080/17588928.2024.2354706 |url=}}
When rats are exposed to an intense learning event, they may retain a life-long memory of the event even after a single training session. The memory of such an event appears to be first stored in the hippocampus, but this storage is transient. Much of the long-term storage of the memory seems to take place in the anterior cingulate cortex.{{cite journal | vauthors = Frankland PW, Bontempi B, Talton LE, Kaczmarek L, Silva AJ | title = The involvement of the anterior cingulate cortex in remote contextual fear memory | journal = Science | volume = 304 | issue = 5672 | pages = 881–883 | date = May 2004 | pmid = 15131309 | doi = 10.1126/science.1094804 | s2cid = 15893863 | bibcode = 2004Sci...304..881F }} When such an intense learning event was experimentally applied, more than 5,000 differently methylated DNA regions appeared in the hippocampus neuronal genome of the rats at one hour and at 24 hours after training.{{cite journal | vauthors = Duke CG, Kennedy AJ, Gavin CF, Day JJ, Sweatt JD | title = Experience-dependent epigenomic reorganization in the hippocampus | journal = Learning & Memory | volume = 24 | issue = 7 | pages = 278–288 | date = July 2017 | pmid = 28620075 | pmc = 5473107 | doi = 10.1101/lm.045112.117 }} These alterations in methylation pattern occurred at many genes that were down-regulated, often due to the formation of new 5-methylcytosine sites in CpG rich regions of the genome. Furthermore, many other genes were upregulated, likely often due to the removal of methyl groups from previously existing 5-methylcytosines (5mCs) in DNA. Demethylation of 5mC can be carried out by several proteins acting in concert, including TET enzymes{{cite journal | vauthors = Rasmussen KD, Helin K | title = Role of TET enzymes in DNA methylation, development, and cancer | journal = Genes & Development | volume = 30 | issue = 7 | pages = 733–750 | date = April 2016 | pmid = 27036965 | pmc = 4826392 | doi = 10.1101/gad.276568.115 }}{{cite journal | vauthors = Melamed P, Yosefzon Y, David C, Tsukerman A, Pnueli L | title = Tet Enzymes, Variants, and Differential Effects on Function | journal = Frontiers in Cell and Developmental Biology | volume = 6 | issue = | pages = 22 | date = 2018 | pmid = 29556496 | doi = 10.3389/fcell.2018.00022 | doi-access = free | pmc = 5844914 }} as well as enzymes of the DNA base excision repair pathway.{{cite journal | vauthors = Drohat AC, Coey CT | title = Role of Base Excision "Repair" Enzymes in Erasing Epigenetic Marks from DNA | journal = Chemical Reviews | volume = 116 | issue = 20 | pages = 12711–12729 | date = October 2016 | pmid = 27501078 | pmc = 5299066 | doi = 10.1021/acs.chemrev.6b00191 }}
==Between systems model==
The between-systems memory interference model describes the inhibition of non-hippocampal systems of memory during concurrent hippocampal activity.{{cite journal | vauthors = Packard MG, Goodman J | title = Factors that influence the relative use of multiple memory systems | journal = Hippocampus | volume = 23 | issue = 11 | pages = 1044–1052 | date = November 2013 | pmid = 23929809 | doi = 10.1002/hipo.22178 }} Specifically it was found that when the hippocampus was inactive, non-hippocampal systems located elsewhere in the brain were found to consolidate memory in its place. However, when the hippocampus was reactivated, memory traces consolidated by non-hippocampal systems were not recalled, suggesting that the hippocampus interferes with long-term memory consolidation in other memory-related systems.{{cite journal | vauthors = Sparks FT, Lehmann H, Sutherland RJ | title = Between-systems memory interference during retrieval | journal = The European Journal of Neuroscience | volume = 34 | issue = 5 | pages = 780–786 | date = September 2011 | pmid = 21896061 | doi = 10.1111/j.1460-9568.2011.07796.x | s2cid = 25745773 }}
One of the major implications that this model illustrates is the dominant effects of the hippocampus on non-hippocampal networks when information is incongruent. With this information in mind, future directions could lead towards the study of these non-hippocampal memory systems through hippocampal inactivation, further expanding the labile constructs of memory. Additionally, many theories of memory are holistically based around the hippocampus. This model could add beneficial information to hippocampal research and memory theories such as the multiple trace theory.{{cite journal | vauthors = Moscovitch M, Rosenbaum RS, Gilboa A, Addis DR, Westmacott R, Grady C, McAndrews MP, Levine B, Black S, Winocur G, Nadel L | title = Functional neuroanatomy of remote episodic, semantic and spatial memory: a unified account based on multiple trace theory | journal = Journal of Anatomy | volume = 207 | issue = 1 | pages = 35–66 | date = July 2005 | pmid = 16011544 | pmc = 1571502 | doi = 10.1111/j.1469-7580.2005.00421.x | department = Review }}{{cite book | vauthors = Moscovitch M, Gilboa A | chapter = Systems consolidation, transformation and reorganization: Multiple trace theory, trace transformation theory and their competitors. | veditors = Kahana MJ, Wagner AD | title = The Oxford Handbook of Human Memory, Two Volume Pack: Foundations and Applications | publisher = Oxford University Press | date = June 2024 | isbn = 978-0-19-091798-2 | doi = 10.1093/oxfordhb/9780190917982.013.43 | department = Review }} Lastly, the between-system memory interference model allows researchers to evaluate their results on a multiple-systems model, suggesting that some effects may not be simply mediated by one portion of the brain.{{cite journal | vauthors = Ferbinteanu J | title = Memory systems 2018 - Towards a new paradigm | journal = Neurobiology of Learning and Memory | volume = 157 | issue = | pages = 61–78 | date = January 2019 | pmid = 30439565 | pmc = 6389412 | doi = 10.1016/j.nlm.2018.11.005 | department = Review }}
=Role in approach-avoidance conflict processing=
{{Further |Reward system}}
Approach-avoidance conflict happens when a situation is presented that can either be rewarding or punishing, and the ensuing decision-making has been associated with anxiety.{{cite journal | vauthors = O'Neil EB, Newsome RN, Li IH, Thavabalasingam S, Ito R, Lee AC | title = Examining the Role of the Human Hippocampus in Approach-Avoidance Decision Making Using a Novel Conflict Paradigm and Multivariate Functional Magnetic Resonance Imaging | journal = The Journal of Neuroscience | volume = 35 | issue = 45 | pages = 15039–15049 | date = November 2015 | pmid = 26558775 | pmc = 6605357 | doi = 10.1523/jneurosci.1915-15.2015 }} fMRI findings from studies in approach-avoidance decision-making found evidence for a functional role that is not explained by either long-term memory or spatial cognition. Overall findings showed that the anterior hippocampus is sensitive to conflict, and that it may be part of a larger cortical and subcortical network seen to be important in decision-making in uncertain conditions.
A review makes reference to a number of studies that show the involvement of the hippocampus in conflict tasks. The authors suggest that one challenge is to understand how conflict processing relates to the functions of spatial navigation and memory and how all of these functions need not be mutually exclusive.
=Role in social memory=
{{Further|Collective memory}}
The hippocampus has received renewed attention for its role in social memory. Epileptic human subjects with depth electrodes in the left posterior, left anterior or right anterior hippocampus demonstrate distinct, individual cell responses when presented with faces of presumably recognizable famous people.{{cite journal | vauthors = Quiroga RQ, Reddy L, Kreiman G, Koch C, Fried I | title = Invariant visual representation by single neurons in the human brain | journal = Nature | volume = 435 | issue = 7045 | pages = 1102–1107 | date = June 2005 | pmid = 15973409 | doi = 10.1038/nature03687 | bibcode = 2005Natur.435.1102Q | s2cid = 1234637 | url = https://resolver.caltech.edu/CaltechAUTHORS:20130816-103222719 }} Associations among facial and vocal identity were similarly mapped to the hippocampus of rheseus monkeys. Single neurons in the CA1 and CA3 responded strongly to social stimulus recognition by MRI. The CA2 was not distinguished, and may likely comprise a proportion of the claimed CA1 cells in the study.{{cite journal | vauthors = Sliwa J, Planté A, Duhamel JR, Wirth S | title = Independent Neuronal Representation of Facial and Vocal Identity in the Monkey Hippocampus and Inferotemporal Cortex | journal = Cerebral Cortex | volume = 26 | issue = 3 | pages = 950–966 | date = March 2016 | pmid = 25405945 | doi = 10.1093/cercor/bhu257 }} The dorsal CA2 and ventral CA1 subregions of the hippocampus have been implicated in social memory processing. Genetic inactivation of CA2 pyramidal neurons leads to pronounced loss of social memory, while maintaining intact sociability in mice.{{cite journal | vauthors = Hitti FL, Siegelbaum SA | title = The hippocampal CA2 region is essential for social memory | journal = Nature | volume = 508 | issue = 7494 | pages = 88–92 | date = April 2014 | pmid = 24572357 | pmc = 4000264 | doi = 10.1038/nature13028 | bibcode = 2014Natur.508...88H }} Similarly, ventral CA1 pyramidal neurons have also been demonstrated as critical for social memory under optogenetic control in mice.{{cite journal | vauthors = Okuyama T, Kitamura T, Roy DS, Itohara S, Tonegawa S | title = Ventral CA1 neurons store social memory | journal = Science | volume = 353 | issue = 6307 | pages = 1536–1541 | date = September 2016 | pmid = 27708103 | pmc = 5493325 | doi = 10.1126/science.aaf7003 | bibcode = 2016Sci...353.1536O }}{{cite journal | vauthors = Meira T, Leroy F, Buss EW, Oliva A, Park J, Siegelbaum SA | title = A hippocampal circuit linking dorsal CA2 to ventral CA1 critical for social memory dynamics | journal = Nature Communications | volume = 9 | issue = 1 | pages = 4163 | date = October 2018 | pmid = 30301899 | pmc = 6178349 | doi = 10.1038/s41467-018-06501-w | bibcode = 2018NatCo...9.4163M }}
Physiology
File:Rat-hippocampal-activity-modes.png and CA1 neural activity in the theta (awake/behaving) and LIA (slow-wave sleep) modes. Each plot shows 20 seconds of data, with a hippocampal EEG trace at the top, spike rasters from 40 simultaneously recorded CA1 pyramidal cells in the middle (each raster line represents a different cell), and a plot of running speed at the bottom. The top plot represents a time period during which the rat was actively searching for scattered food pellets. For the bottom plot the rat was asleep.]]
The hippocampus shows two major modes of activity, each associated with a distinct pattern of neural population activity and waves of electrical activity as measured by an electroencephalogram (EEG). These modes are named after the EEG patterns associated with them: theta and large irregular activity (LIA). The main characteristics described below are for the rat, which is the animal most extensively studied.
The theta mode appears during states of active, alert behavior (especially locomotion), and also during REM sleep (dreaming).{{cite book | ref=refBuzsaki1990 | vauthors = Buzsáki G, Chen LS, Gage FH | title = Spatial organization of physiological activity in the hippocampal region: relevance to memory formation | volume = 83 | pages = 257–268 | year = 1990 | pmid = 2203100 | doi = 10.1016/S0079-6123(08)61255-8 | isbn = 978-0-444-81149-3 | series = Progress in Brain Research | chapter = Chapter 19 Chapter Spatial organization of physiological activity in the hippocampal region: Relevance to memory formation }} In the theta mode, the EEG is dominated by large regular waves with a frequency range of 6 to 9 Hz, and the main groups of hippocampal neurons (pyramidal cells and granule cells) show sparse population activity, which means that in any short time interval, the great majority of cells are silent, while the small remaining fraction fire at relatively high rates, up to 50 spikes in one second for the most active of them.{{Cite book| vauthors = Squire LR | chapter = Learning and Memory: Brain Systems |url=https://www.worldcat.org/oclc/830351091 | veditors = Ghosh A, Berg D, Bloom FE, Squire L, Spitzer NC, du Lac S |title=Fundamental Neuroscience|date=17 December 2012|isbn=978-0-12-385871-9|edition=4th |publisher=Elsevier/Academic Press |location=Amsterdam|pages=1038|oclc=830351091}}{{cite journal | vauthors = Colgin LL | title = Rhythms of the hippocampal network | journal = Nature Reviews. Neuroscience | volume = 17 | issue = 4 | pages = 239–249 | date = April 2016 | pmid = 26961163 | pmc = 4890574 | doi = 10.1038/nrn.2016.21 }} An active cell typically stays active for half a second to a few seconds. As the rat behaves, the active cells fall silent and new cells become active, but the overall percentage of active cells remains more or less constant. In many situations, cell activity is determined largely by the spatial location of the animal,{{cite journal | vauthors = Radvansky BA, Oh JY, Climer JR, Dombeck DA | title = Behavior determines the hippocampal spatial mapping of a multisensory environment | journal = Cell Reports | volume = 36 | issue = 5 | pages = 109444 | date = August 2021 | pmid = 34293330 | pmc = 8382043 | doi = 10.1016/j.celrep.2021.109444 }} but other behavioral variables also clearly influence it.
The LIA mode appears during slow-wave sleep (non-dreaming), and also during states of waking immobility such as resting or eating. In the LIA mode, the EEG is dominated by sharp waves that are randomly timed large deflections of the EEG signal lasting for 25–50 milliseconds. Sharp waves are frequently generated in sets, with sets containing up to 5 or more individual sharp waves and lasting up to 500 ms. The spiking activity of neurons within the hippocampus is highly correlated with sharp wave activity. Most neurons decrease their firing rate between sharp waves; however, during a sharp wave, there is a dramatic increase in firing rate in up to 10% of the hippocampal population.{{cite journal | vauthors = Buzsáki G | title = Hippocampal sharp wave-ripple: A cognitive biomarker for episodic memory and planning | journal = Hippocampus | volume = 25 | issue = 10 | pages = 1073–188 | date = October 2015 | pmid = 26135716 | pmc = 4648295 | doi = 10.1002/hipo.22488 }}
These two hippocampal activity modes can be seen in primates as well as rats, with the exception that it has been difficult to see robust theta rhythmicity in the primate hippocampus. There are, however, qualitatively similar sharp waves and similar state-dependent changes in neural population activity.{{cite journal | vauthors = Skaggs WE, McNaughton BL, Permenter M, Archibeque M, Vogt J, Amaral DG, Barnes CA | title = EEG sharp waves and sparse ensemble unit activity in the macaque hippocampus | journal = Journal of Neurophysiology | volume = 98 | issue = 2 | pages = 898–910 | date = August 2007 | pmid = 17522177 | doi = 10.1152/jn.00401.2007 | ref = refSkaggs2007 | s2cid = 941428 }}
= Hippocampal theta rhythm =
{{Main|Theta wave}}
The underlying currents producing the theta wave are generated mainly by densely packed neural layers of the entorhinal cortex, CA3, and the dendrites of pyramidal cells. The theta wave is one of the largest signals seen on EEG, and is known as the hippocampal theta rhythm.{{cite journal | vauthors = Buzsáki G | title = Theta oscillations in the hippocampus | journal = Neuron | volume = 33 | issue = 3 | pages = 325–340 | date = January 2002 | pmid = 11832222 | doi = 10.1016/S0896-6273(02)00586-X | ref = refBuzsaki2002 | s2cid = 15410690 | doi-access = free }} In some situations the EEG is dominated by regular waves at 3 to 10 Hz, often continuing for many seconds. These reflect subthreshold membrane potentials and strongly modulate the spiking of hippocampal neurons and synchronize across the hippocampus in a travelling wave pattern.{{cite journal | vauthors = Lubenov EV, Siapas AG | title = Hippocampal theta oscillations are travelling waves | journal = Nature | volume = 459 | issue = 7246 | pages = 534–539 | date = May 2009 | pmid = 19489117 | doi = 10.1038/nature08010 | url = https://authors.library.caltech.edu/14755/2/Lubenov2009p4508Nature_supp.pdf | ref = refLubenov2009 | access-date = 2019-07-13 | url-status = live | s2cid = 4429491 | bibcode = 2009Natur.459..534L | archive-url = https://web.archive.org/web/20180723181835/https://authors.library.caltech.edu/14755/2/Lubenov2009p4508Nature_supp.pdf | archive-date = 2018-07-23 }} The trisynaptic circuit is a relay of neurotransmission in the hippocampus that interacts with many brain regions. From rodent studies it has been proposed that the trisynaptic circuit generates the hippocampal theta rhythm.{{cite journal | vauthors = Komisaruk BR | title = Synchrony between limbic system theta activity and rhythmical behavior in rats | journal = Journal of Comparative and Physiological Psychology | volume = 70 | issue = 3 | pages = 482–492 | date = March 1970 | pmid = 5418472 | doi = 10.1037/h0028709 | author1-link = Barry Komisaruk }}
Theta rhythmicity previously clearly shown in rabbits and rodents has also been shown in humans.{{cite journal | vauthors = Cantero JL, Atienza M, Stickgold R, Kahana MJ, Madsen JR, Kocsis B | title = Sleep-dependent theta oscillations in the human hippocampus and neocortex | journal = The Journal of Neuroscience | volume = 23 | issue = 34 | pages = 10897–10903 | date = November 2003 | pmid = 14645485 | pmc = 6740994 | doi = 10.1523/JNEUROSCI.23-34-10897.2003 | ref = refCantero2003 }} In rats (the animals that have been the most extensively studied), theta is seen mainly in two conditions: first, when an animal is walking or in some other way actively interacting with its surroundings; second, during REM sleep.{{cite journal | vauthors = Vanderwolf CH | title = Hippocampal electrical activity and voluntary movement in the rat | journal = Electroencephalography and Clinical Neurophysiology | volume = 26 | issue = 4 | pages = 407–418 | date = April 1969 | pmid = 4183562 | doi = 10.1016/0013-4694(69)90092-3 }} The function of theta has not yet been convincingly explained although numerous theories have been proposed.{{cite book | vauthors = Buzsáki G | title = Rhythms of the Brain | publisher = Oxford University Press | year = 2006 | isbn = 978-0-19-530106-9 | ref = refBuzsaki2006 }} The most popular hypothesis has been to relate it to learning and memory. An example would be the phase with which theta rhythms, at the time of stimulation of a neuron, shape the effect of that stimulation upon its synapses. What is meant here is that theta rhythms may affect those aspects of learning and memory that are dependent upon synaptic plasticity.{{cite journal | vauthors = Huerta PT, Lisman JE | title = Heightened synaptic plasticity of hippocampal CA1 neurons during a cholinergically induced rhythmic state | journal = Nature | volume = 364 | issue = 6439 | pages = 723–725 | date = August 1993 | pmid = 8355787 | doi = 10.1038/364723a0 | ref = refHuerta1993 | s2cid = 4358000 | bibcode = 1993Natur.364..723H }} It is well established that lesions of the medial septum{{snd}}the central node of the theta system{{snd}}cause severe disruptions of memory.{{cite journal | vauthors = Numan R, Feloney MP, Pham KH, Tieber LM | title = Effects of medial septal lesions on an operant go/no-go delayed response alternation task in rats | journal = Physiology & Behavior | volume = 58 | issue = 6 | pages = 1263–1271 | date = December 1995 | pmid = 8623030 | doi = 10.1016/0031-9384(95)02044-6 | url = https://www.sciencedirect.com/science/article/abs/pii/0031938495020446 | ref = refNuman1995 | access-date = 2020-03-09 | url-status = live | s2cid = 876694 | archive-url = https://web.archive.org/web/20210427200148/https://www.sciencedirect.com/science/article/abs/pii/0031938495020446 | archive-date = 2021-04-27 }} However, the medial septum is more than just the controller of theta; it is also the main source of cholinergic projections to the hippocampus. It has not been established that septal lesions exert their effects specifically by eliminating the theta rhythm.{{cite journal | vauthors = Kahana MJ, Seelig D, Madsen JR | title = Theta returns | journal = Current Opinion in Neurobiology | volume = 11 | issue = 6 | pages = 739–744 | date = December 2001 | pmid = 11741027 | doi = 10.1016/S0959-4388(01)00278-1 | ref = refKahana2001 | s2cid = 43829235 }}
= Sharp waves =
{{Main|Sharp waves and ripples}}
During sleep or during resting, when an animal is not engaged with its surroundings, the hippocampal EEG shows a pattern of irregular slow waves, somewhat larger in amplitude than theta waves. This pattern is occasionally interrupted by large surges called sharp waves.{{cite journal | vauthors = Buzsáki G | title = Hippocampal sharp waves: their origin and significance | journal = Brain Research | volume = 398 | issue = 2 | pages = 242–252 | date = November 1986 | pmid = 3026567 | doi = 10.1016/0006-8993(86)91483-6 | ref = refBuzsaki1986 | s2cid = 37242634 }} These events are associated with bursts of spike activity lasting 50 to 100 milliseconds in pyramidal cells of CA3 and CA1. They are also associated with short-lived high-frequency EEG oscillations called "ripples", with frequencies in the range 150 to 200 Hz in rats, and together they are known as sharp waves and ripples. Sharp waves are most frequent during sleep when they occur at an average rate of around 1 per second (in rats) but in a very irregular temporal pattern. Sharp waves are less frequent during inactive waking states and are usually smaller. Sharp waves have also been observed in humans and monkeys. In macaques, sharp waves are robust but do not occur as frequently as in rats.
Sharp waves appear to be associated with memory.{{cite journal | vauthors = Wilson MA, McNaughton BL | title = Reactivation of hippocampal ensemble memories during sleep | journal = Science | volume = 265 | issue = 5172 | pages = 676–679 | date = July 1994 | pmid = 8036517 | doi = 10.1126/science.8036517 | ref = refWilson1994 | s2cid = 890257 | bibcode = 1994Sci...265..676W }} Numerous later studies, have reported that when hippocampal place cells have overlapping spatial firing fields (and therefore often fire in near-simultaneity), they tend to show correlated activity during sleep following the behavioral session. This enhancement of correlation, commonly known as reactivation, has been found to occur mainly during sharp waves.{{cite journal | vauthors = Jackson JC, Johnson A, Redish AD | title = Hippocampal sharp waves and reactivation during awake states depend on repeated sequential experience | journal = The Journal of Neuroscience | volume = 26 | issue = 48 | pages = 12415–12426 | date = November 2006 | pmid = 17135403 | pmc = 6674885 | doi = 10.1523/JNEUROSCI.4118-06.2006 | ref = refJackson2006 }} It has been proposed that sharp waves are, in fact, reactivations of neural activity patterns that were memorized during behavior, driven by strengthening of synaptic connections within the hippocampus.{{cite journal | vauthors = Sutherland GR, McNaughton B | title = Memory trace reactivation in hippocampal and neocortical neuronal ensembles | journal = Current Opinion in Neurobiology | volume = 10 | issue = 2 | pages = 180–186 | date = April 2000 | pmid = 10753801 | doi = 10.1016/S0959-4388(00)00079-9 | ref = refSutherland2000 | s2cid = 146539 | authorlink1 = Grant Robert Sutherland }} This idea forms a key component of the "two-stage memory" theory,{{cite journal | vauthors = Buzsáki G | title = Two-stage model of memory trace formation: a role for "noisy" brain states | journal = Neuroscience | volume = 31 | issue = 3 | pages = 551–570 | date = January 1989 | pmid = 2687720 | doi = 10.1016/0306-4522(89)90423-5 | s2cid = 23957660 }} advocated by Buzsáki and others, which proposes that memories are stored within the hippocampus during behavior and then later transferred to the neocortex during sleep. Sharp waves in Hebbian theory are seen as persistently repeated stimulations by presynaptic cells, of postsynaptic cells that are suggested to drive synaptic changes in the cortical targets of hippocampal output pathways. Suppression of sharp waves and ripples in sleep or during immobility can interfere with memories expressed at the level of the behavior,{{cite journal | vauthors = Girardeau G, Benchenane K, Wiener SI, Buzsáki G, Zugaro MB | title = Selective suppression of hippocampal ripples impairs spatial memory | journal = Nature Neuroscience | volume = 12 | issue = 10 | pages = 1222–1223 | date = October 2009 | pmid = 19749750 | doi = 10.1038/nn.2384 | s2cid = 23637142 }}{{cite journal | vauthors = Ego-Stengel V, Wilson MA | title = Disruption of ripple-associated hippocampal activity during rest impairs spatial learning in the rat | journal = Hippocampus | volume = 20 | issue = 1 | pages = 1–10 | date = January 2010 | pmid = 19816984 | pmc = 2801761 | doi = 10.1002/hipo.20707 }} nonetheless, the newly formed CA1 place cell code can re-emerge even after a sleep with abolished sharp waves and ripples, in spatially non-demanding tasks.{{cite journal | vauthors = Kovács KA, O'Neill J, Schoenenberger P, Penttonen M, Ranguel Guerrero DK, Csicsvari J | title = Optogenetically Blocking Sharp Wave Ripple Events in Sleep Does Not Interfere with the Formation of Stable Spatial Representation in the CA1 Area of the Hippocampus | journal = PLOS ONE | volume = 11 | issue = 10 | pages = e0164675 | date = 19 Nov 2016 | pmid = 27760158 | pmc = 5070819 | doi = 10.1371/journal.pone.0164675 | doi-access = free | bibcode = 2016PLoSO..1164675K }}
= Long-term potentiation =
{{See also|Long-term potentiation|Sleep and learning}}
Since at least the time of Ramon y Cajal (1852–1934), psychologists have speculated that the brain stores memory by altering the strength of connections between neurons that are simultaneously active.{{cite journal | vauthors = Ramón y Cajal S | title = The Croonian Lecture: La Fine Structure des Centres Nerveux | journal = Proceedings of the Royal Society | volume = 55 | pages = 444–468 | year = 1894 | doi = 10.1098/rspl.1894.0063 | issue = 331–335 | ref = refCajal1894 | bibcode = 1894RSPS...55..444C | doi-access = free }} This idea was formalized by Donald Hebb in 1949,{{cite book |last1=Hebb |first1=Donald O. |title=The organization of behavior: a neuropsychological theory |date=1974 |publisher=Wiley |location=New York |isbn=0-471-36727-3 |edition=11. [print.]}} but for many years remained unexplained. In 1973, Tim Bliss and Terje Lømo described a phenomenon in the rabbit hippocampus that appeared to meet Hebb's specifications: a change in synaptic responsiveness induced by brief strong activation and lasting for hours or days or longer.{{cite journal | vauthors = Bliss TV, Lomo T | title = Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path | journal = The Journal of Physiology | volume = 232 | issue = 2 | pages = 331–356 | date = July 1973 | pmid = 4727084 | pmc = 1350458 | doi = 10.1113/jphysiol.1973.sp010273 | ref = refBliss1973 }} This phenomenon was soon referred to as long-term potentiation (LTP). As a candidate mechanism for long-term memory, LTP has since been studied intensively, and a great deal has been learned about it. However, the complexity and variety of the intracellular signaling cascades that can trigger LTP is acknowledged as preventing a more complete understanding.{{cite journal | vauthors = Malenka RC, Bear MF | title = LTP and LTD: an embarrassment of riches | journal = Neuron | volume = 44 | issue = 1 | pages = 5–21 | date = September 2004 | pmid = 15450156 | doi = 10.1016/j.neuron.2004.09.012 | ref = refMalenka2004 | s2cid = 79844 | doi-access = free }}
The hippocampus is a particularly favorable site for studying LTP because of its densely packed and sharply defined layers of neurons, but similar types of activity-dependent synaptic change have also been observed in many other brain areas.{{cite journal | vauthors = Cooke SF, Bliss TV | title = Plasticity in the human central nervous system | journal = Brain | volume = 129 | issue = Pt 7 | pages = 1659–1673 | date = July 2006 | pmid = 16672292 | doi = 10.1093/brain/awl082 | ref = refCooke2006 | doi-access = free }} The best-studied form of LTP has been seen in CA1 of the hippocampus and occurs at synapses that terminate on dendritic spines and use the neurotransmitter glutamate. The synaptic changes depend on a special type of glutamate receptor, the N-methyl-D-aspartate (NMDA) receptor, a cell surface receptor which has the special property of allowing calcium to enter the postsynaptic spine only when presynaptic activation and postsynaptic depolarization occur at the same time.{{cite journal | vauthors = Nakazawa K, McHugh TJ, Wilson MA, Tonegawa S | title = NMDA receptors, place cells and hippocampal spatial memory | journal = Nature Reviews. Neuroscience | volume = 5 | issue = 5 | pages = 361–372 | date = May 2004 | pmid = 15100719 | doi = 10.1038/nrn1385 | ref = refNakazawa2004 | s2cid = 7728258 }} Drugs that interfere with NMDA receptors block LTP and have major effects on some types of memory, especially spatial memory. Genetically modified mice that are modified to disable the LTP mechanism, also generally show severe memory deficits.
Research
A brain implant for use as a hippocampal prosthesis has been the subject of research since the early 2000s.{{cite book | vauthors = Berger TW, Brinton RD, Marmarelis VZ, Sheu BJ, Tanguay AR | chapter = Brain-implantable biomimetic electronics as a neural prosthesis for hippocampal memory function. | title = Toward replacement parts for the brain: implantable biomimetic electronics as neural prostheses. | chapter-url = https://books.google.com/books?id=8axpjcE0bqUC&pg=PA241 | publisher = MIT Press | location = Cambridge | date = 2005 | isbn = 978-0-262-02577-5 }} It was reported in 2018 that a nonlinear multi-input multi-output model (MIMO) had been developed that in some studies, had been shown to restore and improve memory function.{{cite journal |vauthors=Hampson RE, Song D, Robinson BS, Fetterhoff D, Dakos AS, Roeder BM, She X, Wicks RT, Witcher MR, Couture DE, Laxton AW, Munger-Clary H, Popli G, Sollman MJ, Whitlow CT, Marmarelis VZ, Berger TW, Deadwyler SA |title=Developing a hippocampal neural prosthetic to facilitate human memory encoding and recall |journal=J Neural Eng |volume=15 |issue=3 |pages=036014 |date=June 2018 |pmid=29589592 |pmc=6576290 |doi=10.1088/1741-2552/aaaed7 |bibcode=2018JNEng..15c6014H |url=}} This has been followed by a modified version known as the memory decoding model (MDM).{{cite journal |vauthors=Roeder BM, She X, Dakos AS, Moore B, Wicks RT, Witcher MR, Couture DE, Laxton AW, Clary HM, Popli G, Liu C, Lee B, Heck C, Nune G, Gong H, Shaw S, Marmarelis VZ, Berger TW, Deadwyler SA, Song D, Hampson RE |title=Developing a hippocampal neural prosthetic to facilitate human memory encoding and recall of stimulus features and categories |journal=Front Comput Neurosci |volume=18 |issue= |pages=1263311 |date=2024 |pmid=38390007 |pmc=10881797 |doi=10.3389/fncom.2024.1263311 |doi-access=free |url=}} This model has been shown to have the potential use in significant modification of memory. A study concluded that further research could be pointed towards an evaluation of both models, in particular focusing on the hippocampal theta wave input.{{cite journal |vauthors=Roeder BM, Riley MR, She X, Dakos AS, Robinson BS, Moore BJ, Couture DE, Laxton AW, Popli G, Clary HM, Sam M, Heck C, Nune G, Lee B, Liu C, Shaw S, Gong H, Marmarelis VZ, Berger TW, Deadwyler SA, Song D, Hampson RE |title=Patterned Hippocampal Stimulation Facilitates Memory in Patients With a History of Head Impact and/or Brain Injury |journal=Front Hum Neurosci |volume=16 |issue= |pages=933401 |date=2022 |pmid=35959242 |pmc=9358788 |doi=10.3389/fnhum.2022.933401 |doi-access=free |url=}}
Clinical significance
=Aging=
{{see also|Neurobiological effects of physical exercise#Structural growth|Aging brain|Memory and aging}}
Normal aging is associated with a gradual decline in some types of memory, including episodic memory and working memory (or short-term memory). Because the hippocampus is thought to play a central role in memory, there has been considerable interest in the possibility that age-related declines could be caused by hippocampal deterioration.{{cite book | vauthors = Prull MW, Gabrieli JD, Bunge SA | veditors = Craik FI, Salthouse TA | title = The handbook of aging and cognition | year = 2000 | chapter = Ch 2. Age-related changes in memory: A cognitive neuroscience perspective |pages = 105–107| publisher = Erlbaum | isbn = 978-0-8058-2966-2 | ref = refPrull2000 }} Some early studies reported substantial loss of neurons in the hippocampus of elderly people, but later studies using more precise techniques found only minimal differences. Similarly, some MRI studies have reported shrinkage of the hippocampus in elderly people, but other studies have failed to reproduce this finding. There is, however, a reliable relationship between the size of the hippocampus and memory performance; so that where there is age-related shrinkage, memory performance will be impaired. There are also reports that memory tasks tend to produce less hippocampal activation in the elderly than in the young. Furthermore, a randomized control trial published in 2011 found that aerobic exercise could increase the size of the hippocampus in adults aged 55 to 80 and also improve spatial memory.{{cite journal | vauthors = Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, Kim JS, Heo S, Alves H, White SM, Wojcicki TR, Mailey E, Vieira VJ, Martin SA, Pence BD, Woods JA, McAuley E, Kramer AF | title = Exercise training increases size of hippocampus and improves memory | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 7 | pages = 3017–3022 | date = February 2011 | pmid = 21282661 | pmc = 3041121 | doi = 10.1073/pnas.1015950108 | ref = refErickson2011 | doi-access = free | bibcode = 2011PNAS..108.3017E }}
=Dementia=
In Alzheimer's disease (and other forms of dementia), the hippocampus is one of the first regions of the brain to suffer damage;{{cite journal | vauthors = Dubois B, Hampel H, Feldman HH, Scheltens P, Aisen P, Andrieu S, Bakardjian H, Benali H, Bertram L, Blennow K, Broich K, Cavedo E, Crutch S, Dartigues JF, Duyckaerts C, Epelbaum S, Frisoni GB, Gauthier S, Genthon R, Gouw AA, Habert MO, Holtzman DM, Kivipelto M, Lista S, Molinuevo JL, O'Bryant SE, Rabinovici GD, Rowe C, Salloway S, Schneider LS, Sperling R, Teichmann M, Carrillo MC, Cummings J, Jack CR | title = Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria | journal = Alzheimer's & Dementia | volume = 12 | issue = 3 | pages = 292–323 | date = March 2016 | pmid = 27012484 | pmc = 6417794 | doi = 10.1016/j.jalz.2016.02.002 }}
short-term memory loss and disorientation are included among the early symptoms. Amyloid beta deposits begin in the frontal lobes before the signs of neurofibrillary tangles are seen in the hippocampus.{{cite journal |vauthors=Hayat M, Syed RA, Qaiser H, Uzair M, Al-Regaiey K, Khallaf R, Albassam LA, Kaleem I, Wang X, Wang R, Bhatti MS, Bashir S |title=Decoding molecular mechanisms: brain aging and Alzheimer's disease |journal=Neural Regen Res |volume=20 |issue=8 |pages=2279–2299 |date=August 2025 |pmid=39104174 |pmc=11759015 |doi=10.4103/NRR.NRR-D-23-01403 |doi-access=free |url=}} Damage to the hippocampus can also result from oxygen starvation (hypoxia), encephalitis, or medial temporal lobe epilepsy. People with extensive, bilateral hippocampal damage may experience anterograde amnesia: the inability to form and retain new memories.
Dementia, is very often caused by cerebral ischemia, that is believed to trigger changes in the hippocampus. Changes in CA1, the hippocampal area that underlies episodic memory, cause episodic memory impairment, the earliest symptom of post-ischemic dementia.{{cite web |title=Cerebral Ischemia |url=https://www.ncbi.nlm.nih.gov/books/NBK575741/ |publisher=Exon Publications |access-date=6 January 2025 |date=2021}}
=Stress=
The hippocampus contains high levels of glucocorticoid receptors, which make it more vulnerable to long-term stress than most other brain areas.{{cite journal | vauthors = Joëls M | title = Functional actions of corticosteroids in the hippocampus | journal = European Journal of Pharmacology | volume = 583 | issue = 2–3 | pages = 312–321 | date = April 2008 | pmid = 18275953 | doi = 10.1016/j.ejphar.2007.11.064 | ref = refJoels2008 }} There is evidence that humans having experienced severe, long-lasting traumatic stress show atrophy of the hippocampus more than of other parts of the brain.{{cite journal | vauthors = Woon FL, Sood S, Hedges DW | title = Hippocampal volume deficits associated with exposure to psychological trauma and posttraumatic stress disorder in adults: a meta-analysis | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 34 | issue = 7 | pages = 1181–1188 | date = October 2010 | pmid = 20600466 | doi = 10.1016/j.pnpbp.2010.06.016 | s2cid = 34575365 }} These effects show up in post-traumatic stress disorder,{{cite journal | vauthors = Karl A, Schaefer M, Malta LS, Dörfel D, Rohleder N, Werner A | title = A meta-analysis of structural brain abnormalities in PTSD | journal = Neuroscience and Biobehavioral Reviews | volume = 30 | issue = 7 | pages = 1004–1031 | year = 2006 | pmid = 16730374 | doi = 10.1016/j.neubiorev.2006.03.004 | s2cid = 15511760 }} and they may contribute to the hippocampal atrophy reported in schizophrenia{{cite journal | vauthors = Wright IC, Rabe-Hesketh S, Woodruff PW, David AS, Murray RM, Bullmore ET | title = Meta-analysis of regional brain volumes in schizophrenia | journal = The American Journal of Psychiatry | volume = 157 | issue = 1 | pages = 16–25 | date = January 2000 | pmid = 10618008 | doi = 10.1176/ajp.157.1.16 | author2-link = Sophia Rabe-Hesketh | s2cid = 22522434 }} and severe depression.{{cite journal | vauthors = Kempton MJ, Salvador Z, Munafò MR, Geddes JR, Simmons A, Frangou S, Williams SC | title = Structural neuroimaging studies in major depressive disorder. Meta-analysis and comparison with bipolar disorder | journal = Archives of General Psychiatry | volume = 68 | issue = 7 | pages = 675–690 | date = July 2011 | pmid = 21727252 | doi = 10.1001/archgenpsychiatry.2011.60 | doi-access = free }} see also MRI database at [http://sites.google.com/site/depressiondatabase/ www.depressiondatabase.org] {{Webarchive|url=https://web.archive.org/web/20110929165423/http://sites.google.com/site/depressiondatabase/ |date=2011-09-29 }} Anterior hippocampal volume in children is positively correlated with parental family income and this correlation is thought to be mediated by income related stress.{{cite journal | vauthors = Decker AL, Duncan K, Finn AS, Mabbott DJ | title = Children's family income is associated with cognitive function and volume of anterior not posterior hippocampus | journal = Nature Communications | volume = 11 | issue = 1 | pages = 4040 | date = August 2020 | pmid = 32788583 | pmc = 7423938 | doi = 10.1038/s41467-020-17854-6 | bibcode = 2020NatCo..11.4040D }} A study has revealed atrophy as a result of depression, but this can be stopped with anti-depressants even if they are not effective in relieving other symptoms.{{cite journal | vauthors = Campbell S, Macqueen G | title = The role of the hippocampus in the pathophysiology of major depression | journal = Journal of Psychiatry & Neuroscience | volume = 29 | issue = 6 | pages = 417–426 | date = November 2004 | pmid = 15644983 | pmc = 524959 | ref = refCampbell2004 }}
Chronic stress resulting in elevated levels of glucocorticoids, notably of cortisol, is seen to be a cause of neuronal atrophy in the hippocampus. This atrophy results in a smaller hippocampal volume which is also seen in Cushing's syndrome. The higher levels of cortisol in Cushing's syndrome is usually the result of medications taken for other conditions.{{cite journal | vauthors = Starkman MN, Giordani B, Gebarski SS, Berent S, Schork MA, Schteingart DE | title = Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing's disease | journal = Biological Psychiatry | volume = 46 | issue = 12 | pages = 1595–1602 | date = December 1999 | pmid = 10624540 | doi = 10.1016/s0006-3223(99)00203-6 | s2cid = 7294913 }}{{cite book | author = Institute of Medicine (US) Forum on Neuroscience and Nervous System Disorders |title=Overview of the Glutamatergic System |url= https://www.ncbi.nlm.nih.gov/books/NBK62187/ |publisher=National Academies Press (US)|year=2011|access-date=5 February 2017|archive-date=1 September 2018|archive-url=https://web.archive.org/web/20180901114814/https://www.ncbi.nlm.nih.gov/books/NBK62187/|url-status=live}} Neuronal loss also occurs as a result of impaired neurogenesis. Another factor that contributes to a smaller hippocampal volume is that of dendritic retraction where dendrites are shortened in length and reduced in number, in response to increased glucocorticoids. This dendritic retraction is reversible. After treatment with medication to reduce cortisol in Cushing's syndrome, the hippocampal volume is seen to be restored by as much as 10%. This change is seen to be due to the reforming of the dendrites. This dendritic restoration can also happen when stress is removed. There is, however, evidence derived mainly from studies using rats that stress occurring shortly after birth can affect hippocampal function in ways that persist throughout life.{{cite book | vauthors = Garcia-Segura LM | title = Hormones and Brain Plasticity |pages=170–171| year = 2009 | publisher = Oxford University Press US | isbn = 978-0-19-532661-1 | ref = refGarciaSegura2009 }}
Sex-specific responses to stress have also been demonstrated in the rat to have an effect on the hippocampus. Chronic stress in the male rat showed dendritic retraction and cell loss in the CA3 region but this was not shown in the female. This was thought to be due to neuroprotective ovarian hormones.{{cite journal | vauthors = Conrad CD | title = Chronic stress-induced hippocampal vulnerability: the glucocorticoid vulnerability hypothesis | journal = Reviews in the Neurosciences | volume = 19 | issue = 6 | pages = 395–411 | year = 2008 | pmid = 19317179 | pmc = 2746750 | doi = 10.1515/revneuro.2008.19.6.395 }}{{cite journal | vauthors = Ortiz JB, McLaughlin KJ, Hamilton GF, Baran SE, Campbell AN, Conrad CD | title = Cholesterol and perhaps estradiol protect against corticosterone-induced hippocampal CA3 dendritic retraction in gonadectomized female and male rats | journal = Neuroscience | volume = 246 | pages = 409–421 | date = August 2013 | pmid = 23618757 | pmc = 3703463 | doi = 10.1016/j.neuroscience.2013.04.027 }} In rats, DNA damage increases in the hippocampus under conditions of stress.{{cite journal | vauthors = Consiglio AR, Ramos AL, Henriques JA, Picada JN | title = DNA brain damage after stress in rats | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 34 | issue = 4 | pages = 652–656 | date = May 2010 | pmid = 20226828 | doi = 10.1016/j.pnpbp.2010.03.004 | s2cid = 38959073 | doi-access = free }}
=Epilepsy=
File:Epilepsy- right hippocampal seizure onset.png
File:Epilepsy-left hippocampal seizure onset.png
The hippocampus is one of the few brain regions where new neurons are generated. This process of neurogenesis is confined to the dentate gyrus.{{cite journal | vauthors = Kuruba R, Hattiangady B, Shetty AK | title = Hippocampal neurogenesis and neural stem cells in temporal lobe epilepsy | journal = Epilepsy & Behavior | volume = 14 | issue = Suppl 1 | pages = 65–73 | date = January 2009 | pmid = 18796338 | pmc = 2654382 | doi = 10.1016/j.yebeh.2008.08.020 | ref = refKuruba2009 }} Neurogenesis can be positively affected by exercise or negatively affected by epileptic seizures.
Seizures in temporal lobe epilepsy can affect the normal development of new neurons and can cause tissue damage. Hippocampal sclerosis specific to the mesial temporal lobe, is the most common type of such tissue damage.{{cite journal | vauthors = Thom M | title = Review: Hippocampal sclerosis in epilepsy: a neuropathology review | journal = Neuropathology and Applied Neurobiology | volume = 40 | issue = 5 | pages = 520–543 | date = August 2014 | pmid = 24762203 | pmc = 4265206 | doi = 10.1111/nan.12150 }}{{cite journal | vauthors = Chang BS, Lowenstein DH | title = Epilepsy | journal = The New England Journal of Medicine | volume = 349 | issue = 13 | pages = 1257–1266 | date = September 2003 | pmid = 14507951 | doi = 10.1056/NEJMra022308 | ref = refChang2003 | author-link2 = Daniel H. Lowenstein (physician) }} It is not yet clear, however, whether the epilepsy is usually caused by hippocampal abnormalities or whether the hippocampus is damaged by cumulative effects of seizures.{{cite journal | vauthors = Sloviter RS | title = The neurobiology of temporal lobe epilepsy: too much information, not enough knowledge | journal = Comptes Rendus Biologies | volume = 328 | issue = 2 | pages = 143–153 | date = February 2005 | pmid = 15771000 | doi = 10.1016/j.crvi.2004.10.010 | url = https://comptes-rendus.academie-sciences.fr/biologies/articles/10.1016/j.crvi.2004.10.010/ | ref = refSloviter2005 }} However, in experimental settings where repetitive seizures are artificially induced in animals, hippocampal damage is a frequent result. This may be a consequence of the concentration of excitable glutamate receptors in the hippocampus. Hyperexcitability can lead to cytotoxicity and cell death. It may also have something to do with the hippocampus being a site where new neurons continue to be created throughout life, and to abnormalities in this process.
=Schizophrenia=
The causes of schizophrenia are not well understood, but numerous abnormalities of brain structure have been reported. The most thoroughly investigated alterations involve the cerebral cortex, but effects on the hippocampus have also been described. Many reports have found reductions in the size of the hippocampus in people with schizophrenia.{{cite journal | vauthors = Harrison PJ | title = The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications | journal = Psychopharmacology | volume = 174 | issue = 1 | pages = 151–162 | date = June 2004 | pmid = 15205886 | doi = 10.1007/s00213-003-1761-y | ref = refHarrison2004 | s2cid = 12388920 }}{{cite journal | vauthors = Antoniades M, Schoeler T, Radua J, Valli I, Allen P, Kempton MJ, McGuire P | title = Verbal learning and hippocampal dysfunction in schizophrenia: A meta-analysis | journal = Neuroscience and Biobehavioral Reviews | volume = 86 | pages = 166–175 | date = March 2018 | pmid = 29223768 | pmc = 5818020 | doi = 10.1016/j.neubiorev.2017.12.001 | url = http://discovery.ucl.ac.uk/10045938/1/Antoniades_Verbal%20learning%20and%20hippocampal.pdf | access-date = 2018-11-23 | url-status = live | archive-url = https://web.archive.org/web/20180725201206/http://discovery.ucl.ac.uk/10045938/1/Antoniades_Verbal%20learning%20and%20hippocampal.pdf | archive-date = 2018-07-25 }} The left hippocampus seems to be affected more than the right. The changes noted have largely been accepted to be the result of abnormal development. Some studies in humans suggest that hippocampal alterations play a role in causing psychotic symptoms that are the most important feature of schizophrenia.{{cite journal | vauthors = Duncan LE, Li T, Salem M, Li W, Mortazavi L, Senturk H, Shahverdizadeh N, Vesuna S, Shen H, Yoon J, Wang G, Ballon J, Tan L, Pruett BS, Knutson B, Deisseroth K, Giardino WJ | title = Mapping the cellular etiology of schizophrenia and complex brain phenotypes | journal = Nature Neuroscience | volume = 28 | issue = 2 | pages = 248–258 | date = February 2025 | pmid = 39833308 | doi = 10.1038/s41593-024-01834-w | ref = refDuncan2025 | pmc = 11802450 }}{{cite journal | vauthors = Pines AR, Frandsen SB, Drew W, Meyer GM, Howard C, Palm ST, Schaper FJ, Lin C, Butenko K, Ferguson MA, Friedrich MU, Grafman JH, Kappel AD, Neudorfer C, Rost NS, Sanderson LL, Taylor JJ, Wu O, Kletenik I, Vogel JW, Cohen AL, Horn A, Fox MD, Silbersweig D, Siddiqi SH | title = Mapping Lesions That Cause Psychosis to a Human Brain Circuit and Proposed Stimulation Target | journal = JAMA Psychiatry | date = February 2025 | volume = 82 | issue = 4 | pages = 368–378 | pmid = 39937525 | doi = 10.1001/jamapsychiatry.2024.4534 | pmc = 11822627 | pmc-embargo-date = February 12, 2026 | ref = refPines2025 }} It has been suggested that on the basis of experimental work using animals, hippocampal dysfunction might produce an alteration of dopamine release in the basal ganglia, thereby indirectly affecting the integration of information in the prefrontal cortex.{{cite journal | vauthors = Goto Y, Grace AA | title = Limbic and cortical information processing in the nucleus accumbens | journal = Trends in Neurosciences | volume = 31 | issue = 11 | pages = 552–558 | date = November 2008 | pmid = 18786735 | pmc = 2884964 | doi = 10.1016/j.tins.2008.08.002 | ref = refGoto2008 }} It has also been suggested that hippocampal dysfunction might account for the disturbances in long-term memory frequently observed.{{cite journal | vauthors = Boyer P, Phillips JL, Rousseau FL, Ilivitsky S | title = Hippocampal abnormalities and memory deficits: new evidence of a strong pathophysiological link in schizophrenia | journal = Brain Research Reviews | volume = 54 | issue = 1 | pages = 92–112 | date = April 2007 | pmid = 17306884 | doi = 10.1016/j.brainresrev.2006.12.008 | ref = refBoyer2007 | s2cid = 44832178 }}
MRI studies have found a smaller brain volume and larger ventricles in people with schizophrenia{{snd}}however researchers do not know if the shrinkage is from the schizophrenia or from the medication.{{cite journal | vauthors = Ho BC, Andreasen NC, Ziebell S, Pierson R, Magnotta V | title = Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia | journal = Archives of General Psychiatry | volume = 68 | issue = 2 | pages = 128–137 | date = February 2011 | pmid = 21300943 | pmc = 3476840 | doi = 10.1001/archgenpsychiatry.2010.199 }}{{cite journal | vauthors = Fusar-Poli P, Smieskova R, Kempton MJ, Ho BC, Andreasen NC, Borgwardt S | title = Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies | journal = Neuroscience and Biobehavioral Reviews | volume = 37 | issue = 8 | pages = 1680–1691 | date = September 2013 | pmid = 23769814 | pmc = 3964856 | doi = 10.1016/j.neubiorev.2013.06.001 }} The hippocampus and thalamus have been shown to be reduced in volume; and the volume of the globus pallidus is increased. Cortical patterns are altered, and a reduction in the volume and thickness of the cortex particularly in the frontal and temporal lobes has been noted. It has further been proposed that many of the changes seen are present at the start of the disorder which gives weight to the theory that there is abnormal neurodevelopment.{{cite journal | vauthors = Haukvik UK, Hartberg CB, Agartz I | title = Schizophrenia--what does structural MRI show? | journal = Tidsskrift for den Norske Laegeforening | volume = 133 | issue = 8 | pages = 850–853 | date = April 2013 | pmid = 23612107 | doi = 10.4045/tidsskr.12.1084 | doi-access = free }}
The hippocampus has been seen as central to the pathology of schizophrenia, both in the neural and physiological effects. It has been generally accepted that there is an abnormal synaptic connectivity underlying schizophrenia. Several lines of evidence implicate changes in the synaptic organization and connectivity, in and from the hippocampus Many studies have found dysfunction in the synaptic circuitry within the hippocampus and its activity on the prefrontal cortex. The glutamatergic pathways have been seen to be largely affected. The subfield CA1 is seen to be the least involved of the other subfields,{{cite journal | vauthors = Harrison PJ, Eastwood SL | title = Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophrenia | journal = Hippocampus | volume = 11 | issue = 5 | pages = 508–519 | date = 2001 | pmid = 11732704 | doi = 10.1002/hipo.1067 | s2cid = 2502525 }} and CA4 and the subiculum have been reported elsewhere as being the most implicated areas. The review concluded that the pathology could be due to genetics, faulty neurodevelopment or abnormal neural plasticity. It was further concluded that schizophrenia is not due to any known neurodegenerative disorder. Oxidative DNA damage is substantially increased in the hippocampus of elderly patients with chronic schizophrenia.{{cite journal | vauthors = Nishioka N, Arnold SE | title = Evidence for oxidative DNA damage in the hippocampus of elderly patients with chronic schizophrenia | journal = The American Journal of Geriatric Psychiatry | volume = 12 | issue = 2 | pages = 167–175 | date = 2004 | pmid = 15010346 | doi = 10.1097/00019442-200403000-00008 }}
=Transient global amnesia=
Transient global amnesia is a dramatic, sudden, temporary, near-total loss of short-term memory. Various causes have been hypothesized including ischemia, epilepsy, migraine{{cite book | vauthors = Szabo K | title = The Hippocampus in Clinical Neuroscience | chapter = Transient global amnesia | series = Frontiers of Neurology and Neuroscience | year = 2014 | volume = 34 | issue = 5633 | pages = 143–149 | doi = 10.1159/000356431 | pmid = 24777137 | isbn = 978-3-318-02567-5 | chapter-url = http://www.bmj.com/cgi/content/short/4/5633/723-a | access-date = 2018-08-15 | archive-date = 2021-09-23 | archive-url = https://web.archive.org/web/20210923091233/https://www.bmj.com/content/4/5633/723.2 | url-status = live }} and disturbance of cerebral venous blood flow,{{cite journal | vauthors = Lewis SL | title = Aetiology of transient global amnesia | journal = Lancet | volume = 352 | issue = 9125 | pages = 397–399 | date = August 1998 | pmid = 9717945 | doi = 10.1016/S0140-6736(98)01442-1 | s2cid = 12779088 }} leading to ischemia of structures such as the hippocampus that are involved in memory.{{cite journal | vauthors = Chung CP, Hsu HY, Chao AC, Chang FC, Sheng WY, Hu HH | title = Detection of intracranial venous reflux in patients of transient global amnesia | journal = Neurology | volume = 66 | issue = 12 | pages = 1873–1877 | date = June 2006 | pmid = 16801653 | doi = 10.1212/01.wnl.0000219620.69618.9d | s2cid = 39724390 }}
There has been no scientific proof of any cause. However, diffusion-weighted MRI studies taken from 12 to 24 hours following an episode has shown there to be small dot-like lesions in the hippocampus. These findings have suggested a possible implication of CA1 neurons made vulnerable by metabolic stress.
=PTSD=
Some studies shows correlation of reduced hippocampus volume and post-traumatic stress disorder (PTSD).{{cite journal | vauthors = Bonne O, Vythilingam M, Inagaki M, Wood S, Neumeister A, Nugent AC, Snow J, Luckenbaugh DA, Bain EE, Drevets WC, Charney DS | title = Reduced posterior hippocampal volume in posttraumatic stress disorder | journal = The Journal of Clinical Psychiatry | volume = 69 | issue = 7 | pages = 1087–1091 | date = July 2008 | pmid = 18572983 | pmc = 2684983 | doi = 10.4088/jcp.v69n0707 }}{{cite journal | vauthors = Apfel BA, Ross J, Hlavin J, Meyerhoff DJ, Metzler TJ, Marmar CR, Weiner MW, Schuff N, Neylan TC | title = Hippocampal volume differences in Gulf War veterans with current versus lifetime posttraumatic stress disorder symptoms | journal = Biological Psychiatry | volume = 69 | issue = 6 | pages = 541–548 | date = March 2011 | pmid = 21094937 | pmc = 3259803 | doi = 10.1016/j.biopsych.2010.09.044 | url = http://www.biologicalpsychiatryjournal.com/article/S0006-3223(10)01013-9/fulltext | access-date = 2017-08-14 | url-status = live | archive-url = https://web.archive.org/web/20191204064536/https://www.sciencedaily.com/releases/2011/03/110322105257.htm | archive-date = 2019-12-04 }} A study of Vietnam War combat veterans with PTSD showed a 20% reduction in the volume of their hippocampus compared with veterans with no such symptoms.{{cite book| vauthors = Carlson NR |year=2014|title=Physiology of Behavior|edition=11|publisher=Pearson Education|page=624|isbn=978-1-292-02320-5}} This finding was not replicated in those with chronic PTSD, traumatized at an air show plane crash in 1988 (Ramstein, Germany).{{cite journal | vauthors = Jatzko A, Rothenhöfer S, Schmitt A, Gaser C, Demirakca T, Weber-Fahr W, Wessa M, Magnotta V, Braus DF | title = Hippocampal volume in chronic posttraumatic stress disorder (PTSD): MRI study using two different evaluation methods | journal = Journal of Affective Disorders | volume = 94 | issue = 1–3 | pages = 121–126 | date = August 2006 | pmid = 16701903 | doi = 10.1016/j.jad.2006.03.010 | url = http://dbm.neuro.uni-jena.de/pdf-files/Jatzko-JAD06.pdf | access-date = 2017-08-14 | url-status = live | archive-url = https://web.archive.org/web/20131019153804/http://dbm.neuro.uni-jena.de/pdf-files/Jatzko-JAD06.pdf | archive-date = 2013-10-19 }} It is also the case that non-combat twin brothers of Vietnam veterans with PTSD also had smaller hippocampi than other controls, raising questions about the nature of the correlation.{{cite magazine | vauthors = Stern R |date=September–October 2019 |title=The New Phrenology |url=https://skepticalinquirer.org/2019/09/the-new-phrenology/ |magazine=Skeptical Inquirer |publisher=Center for Inquiry |volume=43 |issue=5 |pages=52–56 |access-date=2020-03-20 |archive-date=2020-04-29 |archive-url=https://web.archive.org/web/20200429221719/https://skepticalinquirer.org/2019/09/the-new-phrenology/ |url-status=live }} A 2016 study strengthened the theory that a smaller hippocampus increases the risk for post-traumatic stress disorder, and a larger hippocampus increases the likelihood of efficacious treatment.{{cite journal | vauthors = Rubin M, Shvil E, Papini S, Chhetry BT, Helpman L, Markowitz JC, Mann JJ, Neria Y | title = Greater hippocampal volume is associated with PTSD treatment response | journal = Psychiatry Research: Neuroimaging | volume = 252 | pages = 36–39 | date = June 2016 | pmid = 27179314 | pmc = 4896219 | doi = 10.1016/j.pscychresns.2016.05.001 }}
= Microcephaly =
Hippocampus atrophy has been characterized in those with microcephaly.{{cite journal | vauthors = Bilgüvar K, Oztürk AK, Louvi A, Kwan KY, Choi M, Tatli B, Yalnizoğlu D, Tüysüz B, Cağlayan AO, Gökben S, Kaymakçalan H, Barak T, Bakircioğlu M, Yasuno K, Ho W, Sanders S, Zhu Y, Yilmaz S, Dinçer A, Johnson MH, Bronen RA, Koçer N, Per H, Mane S, Pamir MN, Yalçinkaya C, Kumandaş S, Topçu M, Ozmen M, Sestan N, Lifton RP, State MW, Günel M | title = Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations | journal = Nature | volume = 467 | issue = 7312 | pages = 207–210 | date = September 2010 | pmid = 20729831 | pmc = 3129007 | doi = 10.1038/nature09327 | bibcode = 2010Natur.467..207B }} Mouse models with Wdr62 mutations which recapitulate human point mutations show a deficiency in hippocampal development, and neurogenesis.{{cite journal | vauthors = Shohayeb B, Ho UY, Hassan H, Piper M, Ng DC | title = The Spindle-Associated Microcephaly Protein, WDR62, Is Required for Neurogenesis and Development of the Hippocampus | journal = Frontiers in Cell and Developmental Biology | volume = 8 | issue = | pages = 549353 | date = 2020 | pmid = 33042990 | pmc = 7517699 | doi = 10.3389/fcell.2020.549353 | doi-access = free }}
Other animals
=Other vertebrates=
Non-mammalian vertebrates lack a brain structure that looks like the mammalian hippocampus, but they have one that is considered homologous to it. The hippocampus, is in essence part of the allocortex. Only mammals have a fully developed cortex, but the structure it evolved from, called the pallium, is present in all vertebrates, even the most primitive ones such as the lamprey or hagfish.{{cite journal | vauthors = Aboitiz F, Morales D, Montiel J | title = The evolutionary origin of the mammalian isocortex: towards an integrated developmental and functional approach | journal = The Behavioral and Brain Sciences | volume = 26 | issue = 5 | pages = 535–552 | date = October 2003 | pmid = 15179935 | doi = 10.1017/S0140525X03000128 | ref = refAboitiz2003 | s2cid = 6599761 }}{{cite book | vauthors = Bingman VP, Salas C, Rodriguez F | date = 2009 | chapter = Evolution of the Hippocampus | veditors = Binder MD, Hirokawa N, Windhorst U | title = Encyclopedia of Neuroscience | pages = 1356–1360 | publisher = Springer | location = Berlin, Heidelberg | doi = 10.1007/978-3-540-29678-2_3158 | isbn = 978-3-540-29678-2 }} The pallium is usually divided into three zones: medial, lateral and dorsal. The medial pallium forms the precursor of the hippocampus. It does not resemble the hippocampus visually because the layers are not warped into an S shape or enfolded by the dentate gyrus, but the homology is indicated by strong chemical and functional affinities. There is evidence that these hippocampal-like structures are involved in spatial cognition in reptiles, and in fish.{{cite journal | vauthors = Rodríguez F, López JC, Vargas JP, Broglio C, Gómez Y, Salas C | title = Spatial memory and hippocampal pallium through vertebrate evolution: insights from reptiles and teleost fish | journal = Brain Research Bulletin | volume = 57 | issue = 3–4 | pages = 499–503 | year = 2002 | pmid = 11923018 | doi = 10.1016/S0361-9230(01)00682-7 | ref = refRodriguez2002 | s2cid = 40858078 }}
==Fish==
In teleost fish, the forebrain is everted (like an inside-out sock) with structures that lie on the outside, as contrasted with other vertebrate structures that lie in the interior, next to the ventricles.{{cite journal |vauthors=Hegarty BE, Gruenhagen GW, Johnson ZV, Baker CM, Streelman JT |title=Spatially resolved cell atlas of the teleost telencephalon and deep homology of the vertebrate forebrain |journal=Commun Biol |volume=7 |issue=1 |pages=612 |date=May 2024 |pmid=38773256 |pmc=11109250 |doi=10.1038/s42003-024-06315-1 |url=}} One of the consequences of this is that the medial pallium, the hippocampal zone of a typical vertebrate, is thought to correspond to the lateral pallium of a typical fish.{{cite journal |vauthors=Broglio C, Gómez A, Durán E, Ocaña FM, Jiménez-Moya F, Rodríguez F, Salas C |title=Hallmarks of a common forebrain vertebrate plan: specialized pallial areas for spatial, temporal and emotional memory in actinopterygian fish |journal=Brain Res Bull |volume=66 |issue=4–6 |pages=277–81 |date=September 2005 |pmid=16144602 |doi=10.1016/j.brainresbull.2005.03.021 |url=}} Several types of fish (particularly goldfish) have been shown experimentally to have strong spatial memory abilities, even forming cognitive maps of the areas they inhabit. Studies in goldfish show that damage to both the lateral pallium, and the medial pallium impairs spatial memory coding.{{cite journal |vauthors=Givon S, Altsuler-Nagar R, Oring N, Vinepinsky E, Segev R |title=Lateral and medial telencephalic pallium lesions impair spatial memory in goldfish |journal=Brain Res Bull |volume= 204|issue= |pages=110802 |date=October 2023 |pmid=39492553 |doi=10.1016/j.brainresbull.2023.110802 |url=|doi-access=free }}{{cite journal | vauthors = Vargas JP, Bingman VP, Portavella M, López JC | title = Telencephalon and geometric space in goldfish | journal = The European Journal of Neuroscience | volume = 24 | issue = 10 | pages = 2870–2878 | date = November 2006 | pmid = 17156211 | doi = 10.1111/j.1460-9568.2006.05174.x | ref = refVargas2006 | s2cid = 23884328 }} It is not clear if the medial pallium plays a similar role in basal vertebrates, such as sharks and rays, or even lampreys and hagfish.{{cite journal | vauthors = Docampo-Seara A, Lagadec R, Mazan S, Rodríguez MA, Quintana-Urzainqui I, Candal E | title = Study of pallial neurogenesis in shark embryos and the evolutionary origin of the subventricular zone | journal = Brain Structure & Function | volume = 223 | issue = 8 | pages = 3593–3612 | date = November 2018 | pmid = 29980930 | doi = 10.1007/s00429-018-1705-2 | ref = Docampo-Seara2018 | hdl-access = free | doi-access = free | hdl = 10347/17636 }} The dorsolateral pallium of the teleost is considered as homologous to the hippocampus in terrestrial vertebrates.{{cite journal |vauthors=Rodríguez F, Quintero B, Amores L, Madrid D, Salas-Peña C, Salas C |title=Spatial Cognition in Teleost Fish: Strategies and Mechanisms |journal=Animals |volume=11 |issue=8 |date=July 2021 |page=2271 |pmid=34438729 |pmc=8388456 |doi=10.3390/ani11082271 |doi-access=free |url=}} In 2023, the goldfish brain was mapped by molecular parcellization showing that its telencephalon subregions were homogeneous to the hippocampal subfields in the mouse.
==Birds==
{{See also|Avian pallium}}
In birds, the correspondence is sufficiently well established that most anatomists refer to the medial pallial zone as the "avian hippocampus".{{cite journal | vauthors = Colombo M, Broadbent N | title = Is the avian hippocampus a functional homologue of the mammalian hippocampus? | journal = Neuroscience and Biobehavioral Reviews | volume = 24 | issue = 4 | pages = 465–484 | date = June 2000 | pmid = 10817844 | doi = 10.1016/S0149-7634(00)00016-6 | ref = refColombo2000 | s2cid = 22686204 }} Numerous species of birds have strong spatial skills, in particular those that cache (store) food. There is evidence that food-caching birds have a larger hippocampus than other types of birds and that damage to the hippocampus causes impairments in spatial memory.{{cite journal | vauthors = Shettleworth SJ | title = Memory and hippocampal specialization in food-storing birds: challenges for research on comparative cognition | journal = Brain, Behavior and Evolution | volume = 62 | issue = 2 | pages = 108–116 | year = 2003 | pmid = 12937349 | doi = 10.1159/000072441 | ref = refShettleworth2003 | s2cid = 23546600 }}
=Insects and molluscs=
Some types of insects such as cockroaches, and molluscs such as the octopus, also have strong spatial learning and navigation abilities, but these appear to work differently from the mammalian spatial system, suggesting that there is no common evolutionary origin. Mushroom bodies in insect brains are associated with learning and memory carried out in the mammalian hippocampus.{{cite journal | vauthors = Mizunami M, Weibrecht JM, Strausfeld NJ | title = Mushroom bodies of the cockroach: their participation in place memory | journal = The Journal of Comparative Neurology | volume = 402 | issue = 4 | pages = 520–537 | date = December 1998 | pmid = 9862324 | doi = 10.1002/(SICI)1096-9861(19981228)402:4<520::AID-CNE6>3.0.CO;2-K | ref = refMizunami1998 | s2cid = 44384958 }} The brain of the octopus is arranged in a circle of lobes around the esophagus. The vertical lobe has been shown to be involved in forming long term memory, and is seen to be analogous to the mammalian hippocampus and cerebellum, and also to share some functional features of the mushroom bodies in insects.{{cite journal |vauthors=Jacobs RE |title=Diffusion MRI Connections in the Octopus Brain |journal=Exp Neurobiol |volume=31 |issue=1 |pages=17–28 |date=February 2022 |pmid=35256541 |pmc=8907252 |doi=10.5607/en21047 |url=}}{{cite journal |vauthors=Richter JN, Hochner B, Kuba MJ |title=Pull or Push? Octopuses Solve a Puzzle Problem |journal=PLOS ONE |volume=11 |issue=3 |pages=e0152048 |date=2016 |pmid=27003439 |pmc=4803207 |doi=10.1371/journal.pone.0152048 |doi-access=free |bibcode=2016PLoSO..1152048R |url=}}
See also
Additional images
File:Hippocampus coronal sections.gif|Hippocampus highlighted in green on coronal T1 MRI images
File:Hippocampus sagittal sections.gif|Hippocampus highlighted in green on sagittal T1 MRI images
File:Hippocampus transversal sections.gif|Hippocampus highlighted in green on transversal T1 MRI images
References
{{Academic peer reviewed|Q=Q43997714|doi-access=free}}
{{reflist|25em}}
External links
{{Commons category|Hippocampus (anatomy)|Hippocampus}}
- {{BrainMaps|hippocampus}}
- [http://www.stanford.edu/group/maciverlab/hippocampal.html Diagram of a Hippocampal Brain Slice]
- [http://ccdb.ucsd.edu/sand/main?stype=lite&keyword=hippocampus&Submit=Go&event=display&start=1 Hippocampus – Cell Centered Database]
- [http://www.temporal-lobe.com Temporal-lobe.com An interactive diagram of the rat parahippocampal-hippocampal region]
- {{cite web | url = http://www.brainnav.com/browse?highlight=8d89b5&specid=2 | title = Search Hippocampus on BrainNavigator | archive-url = https://web.archive.org/web/20120309084137/http://www.brainnav.com/browse?highlight=8d89b5&specid=2 | archive-date=2012-03-09 | work = via BrainNavigator }}
- [https://hippocampome.org/php/index.php Hippocampome.org] {{cite journal | vauthors = Wheeler DW, Kopsick JD, Sutton N, Tecuatl C, Komendantov AO, Nadella K, Ascoli GA | title = Hippocampome.org 2.0 is a knowledge base enabling data-driven spiking neural network simulations of rodent hippocampal circuits | journal = eLife | volume = 12 | issue = | pages = | date = February 2024 | pmid = 38345923 | pmc = 10942544 | doi = 10.7554/eLife.90597 | doi-access = free }}
- https://web.archive.org/web/20110722072202/http://web.sc.itc.keio.ac.jp/anatomy/Rauber-Kopsch/web/abb2/png144/440.png
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