Neurophotonics Approaches for the Study of Pattern Separation

Abstract

Successful memory involves not only remembering over time but also keeping memories distinct. Computational models suggest that pattern separation appears as a highly efficient process to discriminate between overlapping memories. Furthermore, lesion studies have shown that the dentate gyrus (DG) participates in pattern separation. However, these manipulations did not allow identifying the neuronal mechanism underlying pattern separation. The development of different neurophotonics techniques, together with other genetic tools, has been useful for the study of the microcircuit involved in this process. It has been shown that less-overlapped information would generate distinct neuronal representations within the granule cells (GCs). However, because glutamatergic or GABAergic cells in the DG are not functionally or structurally homogeneous, identifying the specific role of the different subpopulations remains elusive. Then, understanding pattern separation requires the ability to manipulate a temporal and spatially specific subset of cells in the DG and ideally to analyze DG cells activity in individuals performing a pattern separation dependent behavioral task. Thus, neurophotonics and calcium imaging techniques in conjunction with activity-dependent promoters and high-resolution microscopy appear as important tools for this endeavor. In this work, we review how different neurophotonics techniques have been implemented in the elucidation of a neuronal network that supports pattern separation alone or in combination with traditional techniques. We discuss the limitation of these techniques and how other neurophotonic techniques could be used to complement the advances presented up to this date.

Keywords: adult born granule cells; calcium imagaing; granule cells; interneuron; memory; mossy cells; optogenetics; pattern separation.

Figure 1

Representation of the dentate gyrus (DG)-CA3 circuit. (A) Schematic representation of a coronal slice from rat brain. The hippocampus (HIP) is constituted by cornu ammonis regions 1 and 3 (CA1 and CA3, in violet) and the DG region (DG, in orange). (B) Zoom inset from the HIP. The main inputs to the HIP come from the layers 2/3 of the entorhinal cortex (EC) that constitute the perforant path (PP, light blue lines). The information coming from the EC could project to the CA3 pyramidal layer directly or indirectly by making and intermediate synapse on the granule cells (GCs, green ellipse) located in the granular layer (Gr) of the DG. Mossy cells (MCs, ligth blue rectangle) and adult-born GCs (abGC, blue circle) would be the first neurons activated and could initiate pattern separation. The abGCs can modulate the activation of GCs through a direct connection, which is excitatory or inhibitory, depending on the activity pattern of entorhinal input. On the other hand, abGCs and MCs can inhibit GCs by recruitment of parvalbumin containing interneurons (PV+, orange hexagon). Also, the activity of PV+ interneurons is modulated by somatostatin containing interneurons (SOM+, pink ellipse) and by GCs itself. SOM+ interneurons can directly inhibit GCs, specifically distal dendrites, where contextual information arrives. Thus, the interaction between the different cell types present in the DG defines the activity of GCs, which project to CA3. Finally, the CA3 pyramidal cells project through the Schaffer collaterals to the CA1 pyramidal cells forming the main hippocampal output into layer 5 of the EC.