AlSubaie, Rawan; (2021) Control of Parallel Hippocampal Output Pathways by Amygdalar Long-Range Inhibition. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The ventral hippocampus (vHPC), the main output region of the hippocampus re-ceives dense input from the amygdala (Pitkanen et al., 2000; McDonald and Mott, 2016). The vHPC has been implicated in a range of functions from anxiety to reward learning. Increasingly, it has been shown that these diverse functions are controlled through the activity of populations of neurons that project to distinct downstream targets. Thus, amygdalar input, centred in the vH is well positioned to control output populations and contribute to behavioural output. The BA:vHPC circuit is a candidate circuit for contextual learning, that is able to integrate information regarding the nature of environmental cues, whether rewarding or threatening to support goal directed behaviour. However, despite the large body of literature investigating each region individually little is known regarding the interaction and behavioural consequence of the BA:vHPC circuit. Using, ChR2-assisted circuit mapping (CRACM), I found that BA input is composed of two parallel projections, an excitatory and inhibitory projection that directly targeted pyramidal cells and interneurons in the vHPC. Furthermore, these two pathways selectivity target projection population in the vH. Specifically, ex-citatory input from the BA targeted both BA (vHPC-BA) and NAc projecting cells (vHPC-NAc) equally but avoided PFC projecting cells (vHPC-PFC). In contrast, long-range inhibitory input preferentially targeted vHPC-BA cells over vHPC-NAc and avoided vHPC-PFC cells. Next, using a simple leaky integrate-and-fire model I combined our circuit physiology to show that preferential targeting of vHPC-BA cells by long-range inhibition results in the activation of vHPC-NAc cells by reducing feed-forward and lateral inhibition onto this population. We demonstrate that the relative amount of long-range inhibition within this circuit creates a gating mechanism that alters the amount of inhibition within the hippocampus and ultimately switched activity from vHPC-BA to vHPC-NAc cells. Furthermore, I show that stimulation of both excitatory and inhibitory BA terminals in the vH is necessary to support place preference. Using a combination opto and chemo genetics in vivo, I show that the induction of place preference is reliant on long-range inhibitory input from the BA as well as the activity of vHPC-NAc cells. Overall, I identify a novel long-range inhibitory projection from the BA that is able to control activity of vHPC-BA and vHPC-NAc cells to promote place preference

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