Hippocampal formation

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The hippocampus proper (Ammon,s horn) appears as a curved cortical structure in the floor and medial wall of the temporal horn of the lateral ventricle largely behind the amygdaloid body. The hippocampus, the dentate gyrus and some closely related cortical areas in the parahippocampal gyrus, including the subicular complex (which itself is divided into the subiculum, presubiculum and parasubiculum) and the entorhinal cortex, are together referred to as the hippocampal formation.
1. Gross Antomical Features and Development

Ammon's horn and the dentate gyrus can be recognized quite early in embryonic development, where they form a thin band along the medial edge of the pallium. The dentate gyrus is the most medial component of the hippocampal formation, and it lies along the "free edge" of the cortical mantle during early embryogenesis, since it is bordered along its medial aspect by the tela choroidea of the lateral ventricle caudally, and the septum ependymale and lamina terminalis rostrally. As development progresses, caudal (temporal) parts of the hippocampal region undergo considerable enlargement, whereas rostral (septal) parts develop little and come to form the indusium griseum dorsal to the genu of the corpus callosum. As the cortical mantle expands during development, the hippocampal region remains medial, and its main body comes to lie along the medial aspect of the inferiotr horn of the lateral ventricle in the temporal region. However, because of tremendous cellular proliferation, Ammon's horn folds back upon itself along the hippocampal fissure, as does the DG, which eventually forms a wedge-shaped structure. As a result, the hippocampal formation is perhaps best viewed as a series of adjacent cortical stripes that begin laterally at the rhinal fissure and consist, in order, of the lateral and medial entorhinal areas: the parasubiculum, presubiculum, and subiculum; fields CA1, CA2, and CA3 of Ammon’s horn; and the dentate gyrus.

2. Cytoarchltectonic Organization
Fig. in the documentation summarizes the nomenclature most commonly used today for the various cortical fields that make up the hippocampal formation, and for their lamination in rat. Fig. summarizes the main cell types of the hippocampus proper and dentate gyrus and the topographic distribution of the major inputs to the pyramidal and granular cells, respectively. In addition to these pyramidal and granule cells, the hippocampal formation contains a relatively large population of interneurons. While the pyramidal and granule cells seem to contain glutamate as transmitters, the interneurons represent a neurochemically heterogeneous population, containing

GABA, CCK, VIP, SP, CRF, Somatostatin, NPY, enkephalin, dynorphin, acetylcholine, etc.
3. Summary of Hippocampal Connectivity

    1. Extrinsic Connections

Until the mid 1970s, the prevailing view of the extrinsic connectivity of the hippocampal formation was largely that enunciated by Papez (1937). Papez suggested that the hippocampus was the recipient of sensory information from a variety of cortical regions. The hippocampus was thought to funnel this sensory information through the fimbria and fornix to the mammillary nuclei where it could marshal appropriate emotional responses.

It is now clear, however, that the subicular complex, rather than the hippocampus proper, gives rise to the postcommissural projection to the mammillary bodies. Moreover, recent studies conducted mainly in the primate brain have shown that the fornix is not the sole output pathway of the hippocampal system. Both the subicular complex and the entorhinal cortex project to neighbouring cortices such as the perirhinal cortex and to more distant regions such as the orbitofrontal cortex. The concept has emerged that the interaction of the hippocampal formation with the neocortex is at least as important to its normal functions as its subcortical interactions. The hippocampal formation can also influence a variety of brain regions through nonfimbrial projections to the amygdaloid complex and striatum.
3.1.1. Cortical Inputs/outputs
Several cortical areas, what are usually regarded as multimodal association areas in the temporal (TF,TH,TG, dorsal bank of the superior temporal gyrus) , prefrontal (dorsolateral, infralimbic, prelimbic, posterior orbitofrontal) cingulate (areas 24 and 23), retrosplenial (area 29, 30) and insular (ventral or agranular) regions project to the entorhinal cortex. In addition, the lateral entorhinal cortex receive a massive input from the olfactory bulb. Although the available evidence indicates that the entorhinal cortex receives the most prominent cortical innervation, the subicular cortex also receive direct cortical input from the tempolar polar pole. The presubiculum also receive information from the primary visual cortex and multimodal visuo-spatial information from the inferior parietal lobule. The presubiculum receives additional inputs from the caudal cingulated cortex, the superior temporal gyrus and the dorsolateral prefrontal cortex. The perirhinal area, which lies deep to the rhinal sulcus, along the lateral edge of the lateral entorhinal area, appears to receive inputs from many of the cortical fields that project directly to the entorhinal cortex and presubiculum and project to the entorhinal area, therefore it may provide an additional route for cortical information reaching the hippocampus.

There are indications that most, if not all, of the cortical areas that project to the entorhinal cortex and subicular complex receive return projections. In addition, it has been shown that field CAI project to prefrontal infralimbic and prelimbic areas and the perirhinal areas in rodents.

3.1.2. Subcortical Afferents
Amygdala. In the rat, cat and monkey the basolateral complex of the amygdala give rise to prominent projection to LIII of the lateral entorhinal cortex and the subicular complex. It is interesting to note that the basolateral complex receive also multimodal sensory information from the same cortical areas that also project to the subiculum and entorhinal cortex. The amygdalo-hippocampal connections are likely to provide part of the anatomical substrate for the well known effect of emotion on memory functions.
Septum. In addition to the amygdala, a number of other subcortical structures project to the hippocampal formation. Most prominent among these are the septal complex and the supramammillary area. The septal projection arises from cells of the medial septal nucleus and the nucleus of the diagonal band of Broca and, in the rat brain, travels to the hippocampal formation via four routes: the fimbria, dorsal fornix, supracallosal stria and via a ventral route through the amygdala. Septal fibers terminate in essentially all fields of the hippocampal formation but are most prominment in the dentate gyrus and the CA3 field. Lewis and Shute (1967) first proposed that the septohippocampal projection was cholinergic after showing that fibrial sections led to a substantial loss of histochemical staining of the degradative enzyme acetylcholine esterase. More recently, several groups, using immunocytochenmistry against choline acetyltransferase in combination with retrograde tracer techniques, confirmed that a substantial proportion (30-70%) of the septohippocampal neurons are cholinergic, the rest is GABAergic and peptidergic. Subpopulation of cholinergic neurons also contain a peptide galanin. The entorhinal cortex is also innervated by cells of the medial septal nucleus and nucleus of the diagonal band of Brcca. Using electronmicroscopic double immunolabeling technique, it has been identified that cholinergic terminals form synapses with pyramidal, granule cells and GABAergic and peptidergic nonpyramidal neurons. In contrast GABAergic septohippocampal fibers terminate exclusively on GABAergic interneurons.
Hypothalamus. The major hypothalamic projection to the hippocampal formation arises from a population of large cells which cap and partially surround the mammillary nuclei in a zone that has been named the supramammillary area. The supramammillary projection terminates in many of the fields of the hippocampal formation but most heavily in fields CA2 and CA3 of the hippocampus and in the rostral entorhinal cortex. A pathway containing claretinin and substance P has been reported to originate in the supramammillary nucleus and terminates as a desne band in the inner one-fourth of the molecular layer and uppermost granule cell layer of the dentate gyrus. This pathway has been proposed to play a role in the regulation of theta activity (Berger et al., 2001). In addition, scattered cells in different parts of the lateral and medial hypothalamus, including the tuberomammillary nucleus and zona incerta also project to the hippocampus. A subset of these cells demonstrate alfa-melanocyte-stimulating hormone-like immunoreactivity.
Thalamus. The hippocampal formation also receive a substantial innervation from several thalamic nuclei. All divisions of the anterior thalamic complex and associated lateral dorsal nucleus project primarily to the subicular complex. The midline thalamic nuclei (paratenial, paraventricular, reuniens) also project to the hippocampal formation. The entorhinal cortex receives a particularly heavy projection from the paraventricular thalamic nucleus and a minor input from the pulvinar. The nucleus reuniens projection terminates primarily in the stratum lacunosum-moleculare of CAI, in portions of the subicular complex and the entorhinal cortex.
Brainstem. The hippocampal formation receives minor projections from several brainsten regions, including the ventral tegmental area, periaqueductal gray matter, dorsal tegmental nucleus and the laterodorsal tegmental nucleus. Most hippocampally directed brainstem fibers, however, arise in the locus coeruleus and in the raphe nuclei. The locus coeruleus gives rise to the major noradrenergic input to the hippocampal formation, while the raphe nuclei give rise to its major serotoninergic innerration. Dopaminergic fibers originate in the ventral tegmental area.
3.1.3. Subcortical efferent connections
Hippocampal efferents enter the fimbria and dorsal fornix passing the septal pole of the hippocampus. In posterior parts of the septal region many axons (from the dentate hilar region and field CA3 on both sides of the brain) cross in the ventral hippocampal commissure and a short distance later the remaining axons have become segregated into 2 distinct components, the pre-and postcommissural fornix. The precommissural fornix, which innervates primarily the lateral septal nucleus, arises mainly from cells of the hippocampus proper and to a lesser extent from the subiculum and entorhinal cortex. The cells of CA3, which project bilaterally to the septal complex, are the same cells that give rise to the Schaffer collaterals to CA1. The nucleus accumbens also receives a projection through the fornix which arises in the subicular complex and entorhinal cortex. The subiculum and entorhinal cortex give rise to additional projections to the caudate nucleus and putamen. Upon reaching the diencephalon, the postommissural fornix gives rise to the medial corticohvtothalamic and subiculo-thalamic tracts before continuing on to the mammillary body as the column of the fornix. Subicular fibers innervate the midline and anterior thalamic nuclei, and fibers originating in the subiculum and presubiculum provide the major extrinsic input to the mammillary body. In the rat and cat, the ventromedial nucleus of the hypothalamus receives fibers from the ventral subiculum through the medial corticohypothalamic tract, though this connection has not yet been confirmed in the primate.
The hippocampal formation is also interconnected with several regions of the amygdala. In the monkey, the subiculum project to the basal nucleus and the entorhinal cortex projects to both the basal and the lateral nuclei. In the rat, the ventral portion of CA1 is reported to project to the lateral, basal and cortical amygdaloid nuclei. The hippocampo-amygdaloid fibers take more direct routes through adjacent temporal white matter.

3.2. Intrinsic Connections
3.2.1. Intrahippocampal Association Pathways
Current views of intrahippocampal information processing are all based on the concept of trisynaptic-circuit, which was first clearly outlined in the anatomical studies of Ramon y Cajal (1911) and shown to consist of a series of transversaly oriented excitatory pathways that begins with a projection from the entorhinal cortex (EC) to the dentate gyrus (the perforant pathway), continues with the mossy fiber pathway from the dentate gyrus (DG) to field CA3, and ends with the Schaffer collaterals from CA3 to CA1. Anatomical evidence (see Amaral’s Fig.) now suggests that the trisynaptic circuit is more complex than this and includes a further projection from field CA1 (and subiculum) back to the entorhinal area. In addition, it has been found that perhaps the densest input to the medial entorhinal area arises in another component of the hippocampal formation, in the pre, and parasubiculum, which are conspicuous in that they are the only parts of the hippocampal formation that are usually not thought of as a component of the 'trisynaptic circuit', but instead give rise to the postcommissural fornix. Layer II EC fibers terminate in the molecular layer of the dentate gyrus and st. lacunosum-moleculare of CA3, while layer III EC neurons project exclusively to CA1 and subiculum.
Cells of the DG do not project outside of the hippocampus. The dentate granule cells project via their distinctive axons, the mossy fibers, upon cells of the dentate gyrus's own polymorphic layer and onto the proximal dendrites of the pyramidal cells of the CA3 region of the hippocampus. The other main constituent of the granule layer is the dentate basket cell that give rise to a dense plexus of GABAergic fibers and terminals that surround the granule cell bodies. The deep, or polymorphic layer of the dentate gyrus has a mixture of neuronal types that give rise to local and associational connections. In nonprimates, cells in the polymorphic layer also contribute a commissural projection to the contralateral DG, but this connection is negligible in monkey. The axons of class of cell, the mossy cell, project to the inner one third of the molecular layer. This projection serves to associate different septotemporal (in rodents or rostrocaudal in humans) levels of the DG. There is a second population of cells in the polymorphic layer, immunoreactive for GABA and somatostatin that terminate in the outer two-thirds of the molecular layer.
Field CA3 of Ammon's horn constitutes the third link in the classical trisynaptic circuit because it receives the dentate mossy fiber input and in turn projects to the adjacent field CA1. Collaterals of single CA3 pyramidal cells project to other levels of CA3, to CA1 and to subcortical regions, especially the septal nuclei. CA3 cells also contribute the major input system to CA1 (the Schaffer collaterals), which terminates throughout stratum radiatum and stratum oriens.
CA1 pyramidal cells project predominantly to the subiculum, but do not project to other levels of CA1. The subiculum, in turn, projects to the pre and parasubiculum and all three components of the subicular complex project to the entorhinal cortex.
The most striking featureof the intrinsic circuitry of the hippocampal formation is that it is largely unidirectional. The CA3 field does not project back to the dentate granule cells, nor do CA1 pyramidal cells project back to CA3. Thus, aside from the initial entorhinal input that reaches all hippocampal fields in parallel, information flow from the DG through the other fields follows a serial and largely unidirectional flow.
3.2.2. Commissural Connection
Since the classical studies of Kolliker, Ramon y Cajal and Lorernte de No, the presence of hippocampal commissures are well known. The organization of commissural connections was experimentally analyzed first by Blackstad in 1956 in rodents and later also in monkeys. In the monkey, only the rostral (or uncal) part of the hippocampus and associated dentate gyrus are connected by commissural fibers. This contrasts markedly with the rodent brain, where both CA3 and CA1 of the entire hippocampus receive strong, topographically organized projection from the opposite CA3. The dentate gyrus receives a major input from the cells of the contralateral polymorphic layer of the DG. As in the rat, the monkey presubiculum gives rise to a substantial commissural projection which terminates in LIII of the contralateral entorhinal cortex. This projection constitutes the major link between the hippocampal formation of the two sides in primates.
4. Overview
The direct inputs, intrinsic circuitry, and direct outputs of the hippocampal formation in the rat are summarized in Fig. , and a simplified version of this information is presented in Fig. .The basic connectional relationships that emerge from this analysis can be summarized as follows.
1) The hippocampal formation consists of 2 fundamentally different parts, the parahippocampal and the hippocampal regions, on the basis of differential input and outputs. However, the seven major cortical fields that comprise the hippocampal formation are extensively interconnected by the parallel, though somewhat divergent transversaly oriented intrahippocampal circuits. Thus, inputs to the parahippocampal region influence the output of the hippocampal region and vice versa.
2) It is tempting to generalize that the hippocampal formation receives 2 classes of inputs: one from all parts of the cerebral cortex that is cognitive in nature, and another from the medial septum and parts of the hypothalamus and brain stem that is related in a general way to behavioral state.
As illustrated in Fig. all sensory regions of the cerebral cortex have direct or indirect access to the hippocampal formation, and the vast majority of these intracortical association pathways end in the entorhinal cortex and the subicular complex. In addition, these same areas receive inputs from the lateral and basolateral nuclei of the amygdala, which also receive a variety of cortical inputs, and from the anterior and midline nuclei of the thalamus.
The second class of inputs ascends from the basal forebrain and brainstem through componets of the MFB, and is distributed throughout the hippocampal formation. As a broad generalization, these projections may be thought of as modulating activity in the intrahippocampal circuitry in the context of behavioral state.
3)The direct output of the hippocampal formation is confined to the forebrain and there are again major differences between the hippocampal and parahippocampal regions as a whole. The parahippocampal region projects back to widespread parts of the cortical mantle, as well as the basolateral amygdala, the anterior and midline nuclei of the thalamus, the mammillary body and the nucleus accumbens, whereas the hippocampal region projects almost exclusively to the septum. The dentate gyrus appears to give rise to few if any extrahippocampal projections. Ventral parts of the subiculum and adjacent field CA1 are special in that sense that they project to the ventralmost part of the septum and to the basomedial hypothalamus.
The hippocampal formation is thus in a position to influence a wide range of motor control systems. Pathways from the parahippocampal region to the rest of the cortical mantle may influence projections to the striatum; inputs to the nucleus accumbens may influence locomotor behavior; and projection to the hypothalamus are in a position to influence the expression of a variety of ingestive and reproductive behaviors as well as associated autonomic and neuroendocrine responses.
The intimate two-way relations that the hippocampus has with the rest of the cerebral cortex are consistent with its role in memory functions. The intrahippocampal circuit is in an ideal position to subserve mechanisms underlying short-term memory. In this context, the ascending control pathways from the brainstem and basal forebrain, which are in a position to monitor ongoing consequences of behavior, may be involved in reinforcement mechanisms.
5. Functional Aspects
For much of the first half of this century, the hippocampal formation was thought to he primarily related to olfactory function and was considered to be a prominent component of what was called
the rhinencephalon or olfactory brain. Little evidence supported this view, however, since anosmic animals may have a well developed hippocampus, too. Papez (1937) proposed that the hippocampal formation and its connections with the mammillary body, anterior thalamic nuclei and cingulate cortex constitute a closed neural system responsible for the elaboration of emotional experience and responses. There has been relatively little substantiation of Papez's theory, and the role of modulator of emotional expression is now more closely linked to the amygdaloid complex than the hippocampal


The most widely accepted and long-lived proposal of hippocampal function relates to its role in memory (Bechterew, 1900; Scoville and Milner, 1957; Mishkin, 1978: Zola-Morgan and squire, 1986). Indeed, selective populations of hippocampal neurons degenerate in Alzheimer's disease and in certain types of amnesia. A role for the hippccampal formation in learning and memory has also been strengthened by demonstrations of LTP of synaptic efficacy in most components of intrahippocampal circuitry.
From studies of HM, and especially RB it can be concluded that the hippocampal formation is necessary for producing anterograde amnestic syndrome (Spiers et al., 2001). A postmortem histological analysis of the entire brain of RB revealed a complete and bilateral loss of CA1 pyramidal cells. No other fields of the hippocampal formation showed damage. Haist et al (2001) have used fMRI and the famous faces task to generate data indicating that the hippocampus proper may be involved only in the retrieval of memories that go back a few years. The entorhinal cortex, in contrast, demonstrates temporally graded changes in activity when viewing and identifying faces that extend back up to 20 years. New imaging data also support that the anterior hippocampus is activated during encoding and retrieval predominatly activate the posterior hippocampus.

6. Clinical Anatomy
There are various clinical conditions that result in morphological alterations of the human hippocampal formation. In ischemia and temporal lobe epilepsy, for example, field CA1 of the hippocampus (Sommer sector=CA1) suffers the greatest neuronal loss. In other neuropathological conditions, such as Alzheimer's disease (AD), the pathological insult may actually demonstrate laminar specificity.
AD is associated with four neuropathological correlates in the hippocampal formation: neuronal cell loss, neurofibrillary tangles, neuritic plaques and granulevacuolar degeneration. There is a substantial cell loss in CA1 the subiculum and LII and LV of the entorhinal cortex. Neurofibrillary tangles, while occasionally observed in the normal aged brain, are more numerous in AD and are located in the same regions that undergo the greatest amount of cell loss. Neuritic plaques show a preferetial localization in the molecular layer of the DG. Given the cell loss and other pathological sequale of AD, especially in the EC, it has been suggested that, as the disease develops, the hippocampal formation becomes, in essence functionally disconnected from its major afferent and efferent interactions. Given the important role the hippocampal formation is known to play in certain forms of memory, it is likely that at least a portion of the problems with memory function observed in AD is attributable to hippocampal damage.
Temporal lobe or complete partial epilepsy is another neurological disorder in which the hippocampal formation is severely affected. As Sommer (1880) initially described , cell loss is most consistently found in CA1 field. In some cases of long term epilepsy, cell loss is so striking that Ammon's horn sclerosis is applied at this stage.
There are a number of other pathological conditions in which the hippocampal formation is preferentially damaged. Among these is the loss of neurons, primarily in CA1, consequent to the ischemia associated with cardiorespiratory arrest.

Writing these notes the chapter by Insausti and Amaral (2004) Hippocampal Formation. In: Paxinos Mai and (*eds) The Human Nervous Ssystem. 2nd edition, Elsevier-Academic Press, was heavily used and paraphrases were taken without quotation.


 The septum pellucidum is a thin lamina of glia and fibers that stretches between the anterior part of the corpus callosum and the fornix, thereby separating the anterior parts of the two lateral ventricles. This part of the septum is generally devoid of nerve cells. However, the ventral parts of the septum, the true septum (septum verum) contains important cell groups which merge rostroventrally with the nucleus of the diagonal band. The diagonal bad nucleus, and its accompaning fiber tract, the diagonal
band, sweeps downward in front of the anterior commissure on the medial side of the hemisphere and, then proceeds caudally and laterally into an ill-defined but extensive basal forebrain region traditionally referred to as the substantia innominata. This region contains a heterogeneous population of neurons and is traversed by a variety of fiber tracts. It extends laterally and caudally deep to the optic tract, between the basal surface of the brain and the lateral extension of the anterior commissure.

     The septal region (septum verum or precommissural septum) forms part of the medial wall of the cerebral hemispheres. It is situated directly rostral to the lamina terminalis within the paraterminal gyrus. It is bordered dorsally by the corpus callosum, rostrally by the precommissural

portion of the hippocampus (tenia tecta), and caudally by the anterior commissure and preoptic region. Ventrolaterally it borders on the nucleus accumbens. In human it contains a mnumber of rather poorly determined cell groups, among which the medial and lateral septal nuclei can be mentioned. The ventromedial part of the septum is the diagonal band of Broca.

In the rat the septal region can be parcellated into 4 divisions on the basis of cytoarchitecture and connections. The lateral division (lateral septal n.); the medial division (medial septal nucleus = MS and the nucleus of the diagonal band of Broca = DB); the posterior division consists of the septofimbrial and triangular nuclei; and the ventral division consists of the bed nucleus of the stria terminalis. As a broad generalization, the lateral, medial and posterior divisions of the septal region are particularly associated with the hippocampal formation, whereas the ventral division is related primarily to the amygdala and substantia innominata.

     Through extensive and reciprocal interconnections with telencephalic and diencephalic areas and to a lesser extent, with mesencephalic, lower brainstem and spinal cord regions, the septum is involved in the control of a variety of physiological and behavioral processes related to higher
cognitive functions (learning and memory, emotions, fear, aggression, stress) and autonomic regulation (water/food intake, temperature and osmoregulation). The septal area can be viewed as an interface between limbic telencephalic regions associated with cognition and motivation, on one hand, and hypothalamic and brainstem areas related to endocrine and autonomic functions on the other hand. The medial septal division primarily relays ascending pathways to telencephalic regions, whereas the lateral septal division mainly mediates descending limbic cortical pathways to diencephalic areas.

Medial Septal Region

The medial septal complex gives rise to both ascending and descending projections. Ascending cholinergic and GABAergic fibers appear to innervate all parts of the hippocampal formation and other allo- and periallocortical areas, including the cingulate gyrus, infralimbic, pyriform and insular cortices. Descending fibers from the medial septal nucleus pass through (and perhaps innervate) the median and medial preoptic nuclei before entering the medial forebrain bundle (distributing fibers to the lateral hypothalamus) and ending in the medial mammillary nucleus, the supramammillary nucleus, the ventral tegmental area, the interpeduncular nucleus and the dorsal and median raphe nuclei. Double retrograde tracer experiments indicate that separate groups of neurons in the medial septal complex project to the hippocampal formation and brainstem. The descending projections of neurochemically defined MSDB neurons are largely unexplored. The interpeduncular nucleus receive cholinergic input.
     Some hippocampofugal axons also contact MS cells, however, more significantly, the medial septal nucleus receive ascending fibers in the medial forebrain bundle (MFB). The latter appears to consist of fibers arising in the lateral preoptic and lateral hypothalamic areas, the magnocellular preoptic nucleus, the midbrain raphe nuclei, the parabrachial nucleus and the locus coeruleus. The MS receives also spinal input. The neurochemical character of afferents to septohippocampal cholinergic neurons is only partially identified. So far GABAegic, dopaminergic, noradrenergic, few
cholinergic and NPY synapses were identified on MS cholinergic neurons. Cholinergic MSDB projection neurons innervate hippocampal pyramidal, dentate granule and interneurons rather nonselectively, while the GABAergic
parvalbumin-containing component is involved in disinhibitory mechanisms by selectively targeting hippocampal interneurons.

Functional aspects: Large rhytmic field potentials (rhythmic slow activity or theta rhythm) are commonly associated' with the hippocampal formation. It is postulated that MS is, the pacemaker of this rhythm and the population rhythmicity and frequency of MSDB neurons is regulated by subcortical afferents. The septohippocampal system, via its projective cholinergic and GABAergic neurons may be critically involved in memory and learning. Administration of cholinerqic and GABAergic compunds into the MS impair performance in memory-related behavioral tasks. Simultaneous stimulation of
the medial perforant path and the MS enhances the induction of LTP in the dentate gyrus and cholinergic agents influence the induction of LTP. Lesions of MSDB neurons results in memory and learning impairments, similarly to AD,
where there is a decrease of ChAT in the cortex and hippocampus and a loss of cholinerg,ic and non-cholinergic projecting cells in the basal foreebrain with concomitant loss of memory.

Lateral Septal Nucleus

 The major connections of the lateral septal nucleus include a topographically organized input from the Ammon's horn and subiculum, and a projection to the medial septal nucleus (although this projection is questioned in the light of new tracing studies). Like the medial septal complex, the LS also shares bidirectional connections with areas that contribute to

the MFB. In particular, lateral and anterior hypothalamic areas are prominent targets of LS efferents. In addition to the hippocampal formation, cingulate, infralimbic cortex, ventral pallidum, nucleus accumbens, bed nucleus of the stria terminalis, anterior and medial amygdaloid nucleus, midline thalamic nuclei are prominent targets of lateral septal efferents. A few LS fibers reach different brainstem areas, including the periaqueductal gray, the substantia nigra, and raphe nuclei.
     The organization of ascending projections to the lateral septal nucleus is exceedingly complex: some 30 sources of possible afferents have been described. Since fibers in most - of these pathways continue rostrally to medial prefrontal areas and other parts of the cortical mantle including the hippocampal formation, it is often not clear whether certain regions in fact give rise to terminal fields in the lateral septal nucleus.
     Most of the medial and lateral hypothalamic cells contribute to the innervation of the lateral septal nucleus. These afferents are topographically organized and contain thyrotropin-releasing hormone, substance P,enkephalin, dopamine and other substances and often terminate in pericellular baskets in the LS. Midline thalamic nuclei also project to the LS.
     A number of cell groups in the midbrain project to the lateral septal nucleus: dopaminergic and non-dopaminergic fibers from the ventral tegmental area; serotoninergic and non-serotoninergic fibers from the raphe nuclei, noradrenergic axons from the locus coeruleus. Cells in the laterodorsal and pedunculopontine tegmental nuclei, the parabrachial region, from the nucleus of the solitary tract and the ventrolateral medulla also send ascending fibers to the septum.

     The somatospiny neurons are the principal output neurons of the lateral septum and these neurons are prominent targets of convergent inputs from telencephalic regions and lower brain centers. Inputs from different

sources target different segments of the somatospiny neurons: telencephalic afferents primarily terminate on distal dendritic segments, whereas afferents from lower brain centers form pericellular baskets. The somatospiny neurons contain GABA. This isconsistent with observations that the LS controls lower limbic and autonomic functions by inhibition.

Functional considerations. The GABAergic principal LS neurons issue massive inhibitory projections to preoptic and hypothalamic regions. These projection targets include hypothalamic areas which project back to the MSDB. This topographic correlation, when considering the apparent sparsity of a direct LS input to principal MSDB neurons, highlights the possibility that a considerable component of the LS-to-MS information flow is relayed by hypothalamic neurons.
The downstream LS path can be modulated by monoaminergic, cholinergic, and peptidergic afferents arising from the hypothalamus and brainstem. The hippocampal input is excitatory and contain glutamate. Glutamate causes
strong excitation and is involved in the formation of LTP, whereas vasopressin is involved in the maintenance of fimbria-fornix evoked LTP in LS neurons. Intraseptal vasopressin enhances memory formation, whereas blockade of
endogeneous vasopressin impairs memory. Social and "reproductive" memory in the male rats is impaired by intraseptal administration of vasopressin antagonists, as well as gonadectomy. LS vasopressin system is sexually dimorphic and sex hormone sensitive: its vasopressin-immunoreactivity gradually disappears after godatectomy or during aging, and this process can-be reversed by testosterone treatment. Since the somatospiny neurons are recipients of convergent glutamatergic hippocampofugal and vasopressinergic inputs, their involvement in reproductive memory is likely. Many LS neurons posses androgen receptors and concentrate estrogen, and the somatospiny neurons are immunoreactive for the estrogen-synthesizing enzyme aromatase.
     The LS has reciprocal connections with the periventricular zone of the hypothalamus, through which autonomic and neuroendocrine functions can be influenced. On the other hand, through the extensive bidirectional connections with the lateral hypothalamus, LS participates in the control of water and salt intake, food intake and other specialized autonomic
functions, such as thermoregulation. LS neurons also modulate aggressiveness and other socially and sexually related behaviors.
     These features further suggest that LS neurons are not only relay cells, mediating the hippocampus-septum-hypothalamus information flow, but appear to be multifunctional integratory units processing convergent informations from higher cognitive centers (hippocampal formation), from sex hormone sensitive and sexually dimorphic subcortical centers, of motivation and emotion and from autonomic brain centers.

Posterior Septal Group

 Very little is known about the connections of the septofimbrial and triangular nuclei of the septum. The septofimbrial nucleus projects through the stria medullaris to the ipsilateral medial habenula, whereas the triangular nucleus project bilaterally through the stria medullaris to the medial and lateral habenula, with some fibers continuing on through the ipsilateral fasciclus retroflexus to the interpeduncular nucleus. Afferents to these nuclei may arise from Ammon's horn, the subiculum and the brainstem parabrachial nuclei.

In summary, the posterior group appears to provide the major direct route for septo-hippocampal information to reach the habenulo-interpeduncular axis. The outputs of the habenula and interpeduncular nucleus are to the midbrain raphe, Gudden's tegmental nuclei and the laterodorsal tegmental nuclei on the one hand, and to regions along the MFB (the ventral tegmental area, supramammillary nucleus, lateral zone of the hypothalamus, medial and lateral septal nuclei, substantia innominata and hippocampus) on the other. Thus, it seems reasonable to consider the stria medullaris and fasciculus retroflexus as a dorsal component (offshoot) of the MFB.

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