The hippocampus has a crucial role in learning and memory processes.


EVOLUTION AND DEVELOPMENT

The cerebral cortex evolves from the telencephalic pallium by the arrangement of neurons in a single layer (cortical plate), which is present in reptiles and mammals but not in fishes, amphibians and birds. The telencephalic pallium of vertebrates can be subdivided into a lateral, dorsal and medial pallium, which will give rise to the olfactory cortices, neocortex, and hippocampal region, respectively, of the mammalian cerebral cortex.

The hippocampal region (archicortex) and olfactory cortex (paleocortex) of mammals consist of three layers, similar to the cerebral cortex of reptiles. In contrast to the mammalian iso- or neocortex that underwent lateral expansion and differentiated into a multi six -layered cortex. The human hippocampus follows the progress of the lateral telencephalic pallium forming the temporal lobe. This development is incomplete in most mammals, the hippocampus is involved only a partial hemispheric rotation. Thus, the hippocampus remains dorsal to the thalamus, whereas the human hippocampus is ventral, curves beneath the thalamus and the relation of CA1 and CA3 is inversed as compared with rats. (Figure 1.)

The human hippocampus bulges into the temporal horn of the lateral ventricle arching around the mesencephalon forming a shape like sea-horse. It is formed by two interlocking sheets of cortex and has laminar structure. In early development the two laminae (cornu ammonis and gyrus dentatus) are continuous. Then the cornu ammonis bulges into the ventricular cavity, and the gyrus dentatus becomes concave and slips beneath the cornu ammonis. In the final position the cornu ammonis and the gyrus dentatus resemble two U-shaped interlocking laminae fitting into each other separated by the hippocampal sulcus and the arteries and veins.

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STRUCTURE (Figure 2.)

The cornu ammonis (CA) is divided into 6 layers:

1. alveus (intracentricular surface): axons of the hippocampal neurons entering the fimbria (main output)
   
2. stratum oriens: scattered basket neurons; crossed by pyramidal cell axons
   
3. stratum pyramidale: pyramidal neurons, soma is surronded by a dense arborizations of basket cell axons; marked vascular density
   
4. stratum radiatum: apical dendrits of pyramidal neurons connecting with Schaffer collaterals
   
5. stratum lacunosum: axonal fasciculi formed of perforant fibers and Schaffer collaterals
   
6. stratum moleculare: apical dendrites of pyramidal neurons contacting with the collateral of the perforant fibers; most intense vascular density.
   

A heterogenous structure appears in frontal sections of the cornu ammonis due to the different appearances of the pyramidal neurons. It has four regions:

• CA1- (continues from the subiculum) small, triangular pyramidal soma, scattered distribution (in rats the pyramidal layer of CA1 is narrow and dense)
  
• CA2 – large, ovoid, densely packed soma
  
• CA3 – similar to CA2, but density is less marked (CA2 and CA3 zone is distinguished by fine unmyelinated fibers of the mossy fibers in CA3 surrounding the pyramidal soma forming a supplementary layer between stratum radiatum and pyramidale – str. lucidum- a characteristic of CA3)
  
• CA4 – large, ovoid, scattered soma (mossy and large myelinated fibers are the characteristic of CA4)
  

The gyrus dentatus is divided into 3 layers:

1. stratum moleculare: fibers of the perforant path, commissural and septal fibers
   
2. stratum granulosum: small, rounded, densely packed granular neurons
   
3. polymorphic layer: crossed by axons of granular neurons (mossy fibers)
   

Subiculum: the end of the stratum radiatum of CA1 is considered to mark the limit between the cornu ammonis and subiculum

Entorhinal cortex: the uni-directional inputs of the hippocampus originate mainly in this adjacent area. It is hypothesized that this area filters all information before memorization in the neocortex.

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PATHWAYS
Principle pathways

1. Perforant Path (glutaminergic)
   It is the major input to the hippocampus. The axons in the entorhinal cortex and project to the dendrites of granule cells of the dentate gyrus and pyramidal cells of the CA3, CA1 and the subiculum.
   
   
2. Mossy Fibre Pathway (glutaminergic, Zn2+)
   The mossy fibres are the axons of DG granule cells and extend to CA3 (and CA4) pyramidal cells, forming their major input. LTP is NMDA receptor-independent in this pathway, but instead appears to involve pre-synaptic kainate receptors.
   
   
3. Schaffer Collateral/Associational Commissural Pathway
   Before the axons from CA3-CA4 enter the fimbria, they emit the Schaffer collaterals derived from CA3 neurons in the ipsilateral hippocampus or from an equivalent structure in the contralateral hemisphere (commissural fibres) to the CA1 region. In primates, commissural fibers are only few and only reach limited regions of the hippocampus. However, in rodents, all hippocampal regions are connected to the corresponding contralateral regions. LTP and LTD are NMDA receptor-dependent in this pathway.
   
   
4. CA1 - Subiculum – entorhinal cortex
   This pathway forms the principal output of the hippocampus. It follows the fimbira, the fornix and reach the anterior thalamic nucleus directly or via the mamillary bodies. From the thalamus impulses could reach the cerebral cortex (particularly the cingulate cortex).
   
   

Regulatory circuits

Basket interneurons (GABA) localized in the str. oriens of cornu ammonis and the str. moleculare and the porymorphic layers of the gyrus dentatus. They receive impulses from pyramidal neurons (from mossy fibers in gyrus dentatus) and their long axons returns to and inhibit pyramidal neurons (granular neurons in dentate gyrus) forming basket arborization around their soma.

Other interneurons producing neuromediators such as substance P, VIP, CCK, CRF, neuropeptide Y, encephalin, dynorphin,

Extrahippocampal fibers: noradrenergic fibers from locus coeruleus, serotoninergic fibers from nuclei of raphe, dopamine from substantia nigra, cholinergic fibers of septal nuclei (they recieve information from the brain stem-formatio reticularis and project to and excite pyramidal and granular neurons), neuropeptidergic terminals (vasopressin, somatostatin, substance P, neuropeptide Y, MSH).

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FUNCTIONS
The hippocampus is critical in spatial learning, navigation, awareness, episodic/event memory. Hippocampal damage produce disorders of memory, particularly in short-term memory, defects remembering of events, deficits in spatial memory. Selective damage to certain hippocampal areas occurs from certain diseases:

Temporal lobe epilepsy affect CA1 field, whereas CA2 and CA3 remain healthy, and CA4 is partially affected (Sommer, 1880; Spielmeyer, 1927; Bratz, 1899).

• Hippocampal sclerosis (classic Ammon`s horn sclerosis) involves lesions of CA1 and CA4 (Zola-Morgan, 1986).
  
• Transient cerebral ischemia produces delayed (2-4 days) and irreversible damage to CA1 region, whereas the damage in CA4 is rapid and reversible, and (Kirino, 1982, 1986). Interestingly, previous destruction of CA3 prevent delayed neuronal damage in CA1, may be due to the toxic effect of glutaminergic effect of the Schaffer collaterals (Onodera, 1986).
• Kainate acid administration cause selective damage in CA3 due to synaptic dysfunction of mossy fibers on pyramidal neurons (Collins, 1986)
  
• Hypoglicemia cause damage to the gyrus dentatus (Collins, 1986).
  
• Aging affect the CA4 region.
  
• Altzheimer disease affets CA1 region and subiculum.

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LTP (Long-Term Potentiation)
The discovery of long-lasting potentiated synapses in the hippocampus provided a possible biological basis for learning and memory (1973). LTP is rapidly induced, strengthened by repetition, and lasts for several hours in vitro to several weeks in vivo.

The experimental setup is the following: a high-frequency train of stimuli applied to fibers afferent to the hippocampus (Schaffer collaterals of CA3 neurons) increase the amplitude of EPSPs in the target neurons (CA1 neurons).

Mechanism:
During the early phase of LTP, the high-frequency stimulation opens non-NMDA glutamate channels leading to hypopolarization. This dislodges Mg from the NMDA glutamate channels, and Ca enters the cells. The calcium triggers the activity of Ca-dependent kinases, PKC and Cacalmodulin, and tyrosine kinase. Ca-calmodulin kinase phosphorylates non-NMDA channels, increasing their sensitivity to glutamate and a messenger is sent retrogradely to the presynaptic terminal to increase the release of transmitter substance.
In the late phase of LTP, calcium enters the cell and triggers Ca-calmodulin, which in turn activates adenylyl cyclase and cAMP kinase. The latter translates to the nucleus of the cell and starts processes that lead to protein synthesis and to structural changes, i.e., the formation of new synapses.

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