Neural pathways

Hippocampal Pathways


The hippocampus is perhaps the most studied structure in the brain. together with the adjacent Amygdyla, it forms the central axis of the Limbic System. It is critical to spatial learning and awareness, navigation, episodic/event memory, associational recollection .... and much more.

The hippocampus is formed by two interlocking sheets of cortex and in cross-section has a very defined laminar structure with layers visible where rows of pyramidal cells are arranged. The connections within the hippocampus generally follow this laminar format and, as a rule, are uni-directional. They form well-characterised closed loops that originate mainly in the adjacent entorhinal cortex. Thus there are defined routes for information flow making the hippocampus a very popular target for the study of synaptic function. The different cell layers and sections are defined by the series of connections made. The main pyramidal cell layers are the CA1-4 regions (principally CA1 and CA3) and the dentate gyrus.

Perforant Path

The perforant path is the major input to the hippocampus. The axons of the perforant path arise principally in layers II and III of the entorhinal cortex (EC), with minor contributions from the deeper layers IV and V. Axons from layers II/IV project to the granule cells of the dentate gyrus (DG) and pyramidal cells of the CA3 region, while those from layers III/V project to the pyramidal cells of the CA1 and the subiculum. The perforant path can be segregated into lateral and medial pathways (LPP and MPP, respectively), depending on whether the fibres arise from the lateral or medial entorhinal cortex. Iit was in this pathway that long-term potentiation (LTP) was first discovered.

Mossy Fibre Pathway

hippocampal pathwaysThe hippocampal Network: The hippocampus forms a principally uni-directional network, with input from the Entorhinal Cortex (EC) tht forsms connections with the Dentate Gyrus (DG) and CA3 pyramidal neurons via the Perforant Path (PP - split into lateral and medial). CA3 neurons also receive input from the DG via the Mossy Fibres (MF). They send axons to CA1 pyramidal cells via the Schaffer Collateral Pathway (SC), as well as to CA1 cells in the contralateral hippocampus via the Associational Commisural (AC) Pathway. CA1 neurons also receive inputs direct from the Perforant Path and send axons to the Subiculum (Sb). These neurons in turn send the main hippocampal output back to the EC, forming a loop.

The mossy fibres are the axons of DG granule cells. They extend from the dendate gyrus to CA3 pyramidal cells, forming their major input. MF synapses on CA neurons are large aggregations of termini, with multiple transmitter release sites and post-synaptic densities. Multiple granule cells can synapse onto a single CA3 pyramidal cell. This pathway is studied extensively as a model for the functional roles of kainate receptors in synaptic plasticity. For instance, LTP is NMDA receptor-independent in this pathway, but instead appears to involve pre-synaptic kainate receptors. See here for more information.

Schaffer Collateral/Associational Commissural Pathway

This pathway is derived from axons that project from the CA3 region of then hippocampus to the CA1 region. The axons either come from neurons in the same hippocampus (ipsilateral) or from the other hippocampus (contralateral). These latter fibres are termed commissural fibres, as they cross from one hemisphere of the brain to the other. This pathway is utilised very extensively exhibits to study NMDA receptor-dependent LTP and LTD.

CA1 - Subiculum - EC

The pathway from CA1 to Subiculum (Sb) and on to the entorhinal cortex forms the principal output from the hippocampus. However, it is not a straightforward uni-directional pathway. The connection from CA1 - Sb follows a strict anatomical layout. The distal end of the CA1 region projects to the proximal end of the Sb, i.e. those cells nearest to the CA1 - Sb junction are connected, and those furthest apart are connected. Projections to EC follow a similar pattern, with distal CA1/proximal Sb projecting to the lateral EC while proximal CA1/distal Sb project to the medial EC. It should also be noted that the input to these cells from the EC follows the same pattern i.e., distal CA1/proximal Sb receives input from the lateral EC while proximal CA1/distal Sb receives input from medial EC. Thus two closed loop networks are present within the overall hippocampal network. These loops are further extended to perirhinal and post-rhinal cortices, as the Perirhinal Cortex projects to the lateral EC and receives returning projections while the post-rhinal cortex projects to and receives inputs from the medial EC.

Perirhinal and Post-Rhinal Cortices

hippocampal and para-hippocampal regionsThe perirhinal and postrhinal cortices are part of the cortical region that surround the hippocampal formation (in the human brain, the 'postrhinal cortex' is made up of areas TH and TF of the parahippocampal cortex). They lie adjacent to the hippocampus within the temporal lobe. Unlike the hippocampus itself, these regions are much less structured in terms of having a strict organisation of neurons into distinct layers, but are functionally separate. The perirhinal and postrhinal cortices receive incoming sensory information from the visual, olfactory and somato-sensory cortices (among many other inputs) and they are closely involved in the interpretation of novelty and familiarity, e.g in visual recognition memory.

The connectivity within these areas is complex, but can be simplified to two main loops; perirhinal-LEC-hippocampus and postrhinal-MEC-hippocampus.

parahippocampal pathwaysPerirhinal-LEC-hippocampus

The perirhinal cortex sends projections to the lateral entorhinal cortex (LEC). This innervation runs from and to the superficial layers (layers II and III). These in turn project to the CA1-subiculum junction as part of the LEC projection to the hippocampus, part of the perforant path. Reciprocal projections return to the LEC, but to deeper layers (layer V), with intra-LEC connections closing the loops.


Similar to the perirhinal cortex, the postrhinal cortex sends also projections to the entorhinal cortex, but in this case to the medial entorhinal cortex (MEC). This innervation again runs from and to the superficial layers (layers II and III). These in turn project to the proximal CA1 (nearer to CA3) and the distal subiculum as part of the perforant path. Reciprocal projections return to layer V of the MEC, with intra-MEC connections closing the loops.

Other networks

There is some evidence from retrograde filling that the perirhinal and postrhinal cortices also innervate the hippocampus directly, producing a more focussed projection to the relevant region y, although given the difficulties of defining the precise extent of any of these regions, it is still unclear whether these projections actually arise in the entorhinal cortex. Connections between the LEC and MEC and between the perirhinal and postrhinal cortices add further loops in which the inputs to either cortex can modulate the processing of the other.