Editing Hippocampus (section)

== Physiology ==
[[File:Rat-hippocampal-activity-modes.png|thumb|300px| Examples of rat hippocampal [[EEG]] and CA1 neural activity in the [[Theta wave|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 waves|theta]] and [[large irregular activity]] (LIA). The main characteristics described below are for the rat, which is the animal most extensively studied.<ref name="Buzsaki2006"/>

The theta mode appears during states of active, alert behavior (especially locomotion), and also during [[Rapid eye movement sleep|REM sleep]] (dreaming).<ref name=Buzsaki1990>{{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 }}</ref> In the theta mode, the EEG is dominated by large regular waves with a [[frequency range]] of 6 to 9 [[Hertz|Hz]], and the main groups of hippocampal neurons ([[pyramidal cell]]s and [[granule cell]]s) 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.<ref>{{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}}</ref><ref name="Colgin_2016">{{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 }}</ref> 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,<ref name="Radvansky_2021">{{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 }}</ref> 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.<ref name=Buzsaki1990 /> 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.<ref name="Buzsáki_2015">{{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 }}</ref>

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.<ref name=Skaggs2007>{{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 }}</ref>

=== Hippocampal theta rhythm ===
{{Main|Theta wave}}
[[File:eeg theta.svg|thumb|Example of a one-second EEG theta wave|350px|right]]
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.<ref name=Buzsaki2002>{{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 }}</ref> In some situations the EEG is dominated by regular waves at 3 to 10&nbsp;Hz, often continuing for many seconds. These reflect subthreshold [[membrane potential]]s and strongly modulate the spiking of hippocampal neurons and synchronize across the hippocampus in a travelling wave pattern.<ref>{{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 }}</ref> The [[trisynaptic circuit]] is a relay of [[neurotransmission]] in the hippocampus that interacts with many brain regions. From [[animal testing on rodents|rodent studies]] it has been proposed that the trisynaptic circuit generates the hippocampal theta rhythm.<ref>{{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 }}</ref>

Theta rhythmicity previously clearly shown in rabbits and rodents has also been shown in humans.<ref>{{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 }}</ref> In [[laboratory rat|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 [[Rapid eye movement sleep|REM sleep]].<ref>{{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 }}</ref> The function of theta has not yet been convincingly explained although numerous theories have been proposed.<ref name=Buzsaki2006>{{cite book | vauthors = Buzsáki G | title = Rhythms of the Brain | publisher = Oxford University Press | year = 2006 | isbn = 978-0-19-530106-9 | ref = refBuzsaki2006 }}</ref> 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]].<ref>{{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 }}</ref> It is well established that lesions of the [[medial septum]]{{snd}}the central node of the theta system{{snd}}cause severe disruptions of memory.<ref>{{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 }}</ref> However, the medial septum is more than just the controller of theta; it is also the main source of [[cholinergic]] projections to the hippocampus.<ref name="Anderson"/> It has not been established that septal lesions exert their effects specifically by eliminating the theta rhythm.<ref>{{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 }}</ref>

=== 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''.<ref>{{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 }}</ref> 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&nbsp;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.<ref name="Skaggs2007" />

Sharp waves appear to be associated with memory.<ref name="Wilson">{{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 }}</ref> 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.<ref>{{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 }}</ref> 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.<ref>{{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 }}</ref> This idea forms a key component of the "two-stage memory" theory,<ref name="Two-stage">{{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 }}</ref> 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.<ref name="Two-stage"/> Suppression of sharp waves and ripples in sleep or during immobility can interfere with memories expressed at the level of the behavior,<ref name="suppression of hippocampal ripples">{{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 }}</ref><ref name="impair spatial learning study">{{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 }}</ref> 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.<ref name="pmid27760158">{{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 }}</ref>

=== Long-term potentiation ===
{{See also|Long-term potentiation|Sleep and learning}}

Since at least the time of [[Santiago Ramon y Cajal|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.<ref>{{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 }}</ref> This idea was formalized by [[Donald O. Hebb|Donald Hebb]] in 1949,<ref name="Hebb">{{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.]}}</ref> 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.<ref>{{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 }}</ref> 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.<ref name="ReferenceC">{{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 }}</ref>

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.<ref>{{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 }}</ref> The best-studied form of LTP has been seen in CA1 of the hippocampus and occurs at synapses that terminate on [[dendritic spine]]s and use the [[neurotransmitter]] [[glutamate]].<ref name="ReferenceC"/> The synaptic changes depend on a special type of [[glutamate receptor]], the [[NMDA receptor|''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.<ref name=Nakazawa2004>{{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 }}</ref> Drugs that interfere with NMDA receptors block LTP and have major effects on some types of memory, especially spatial memory. [[Genetically modified mouse|Genetically modified mice]] that are [[Genetic engineering|modified]] to disable the LTP mechanism, also generally show severe memory deficits.<ref name=Nakazawa2004 />