Synaptic and neuronal mechanisms of fear control: the role of hippocampal-amygdalar interactions

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Projections from the ventral hippocampus (vHPC) to the amygdala, its basolateral nucleus (BLA), specifically, play an essential role in context representation in the amygdala during encoding of fear memory extinction. However, synaptic and network-level mechanisms by which vHPC-amygdala projections may control the function of the amygdala and amygdala-dependent fear-related behaviors are largely unknown. Combining the use of chemogenetic and optogenetic techniques with ex vivo and in vivo electrophysiology, tract tracing with viral vectors and behavioral training and testing, we will explore the functional roles of vHPC-amygdala projections in conditioned fear and fear extinction at synaptic and circuitry-specific levels. In Aim 1 we will investigate how the mechanisms of synaptic plasticity in vHPC projections to subnuclei of the amygdala affect the signal flow in neural circuits of fear conditioning and extinction. Optogeneticaly activating vHPC-amygdala projections, we will record from neurons in different subdivisions of the amygdala in slices from control, fear-conditioned and fear- extinguished mice and assay the effects of behavioral training on both excitatory and inhibitory drive in recorded neurons and their synaptically-driven spike firing output. We will then explore the role of the vHPC-amygdala pathway in control of fear-related behaviors (Aim 2). Specifically, we will examine the contributions of behaviorally-induced synaptic plasticity at vHPC inputs to the amygdala, specifically focusing on long-range GABAergic vHPC-BLA projections (identified by us), to the encoding of context-dependency of fear extinction memory using chemogenetic tools. We will also systematically explore whether extinction-associated potentiation of GABAergic synaptic transmission at vHPC-BLA projections may satisfy criteria of synaptic plasticity and memory (SPM) hypothesis, thus possibly linking these plastic synaptic modifications to the encoding of context-dependency of fear extinction. Finally (Aim 3), we will investigate the synaptic and neural circuit-level mechanisms in vHPC-amygdala projections implicated in fear renewal triggered by repeated stress in fear extinguished mice. We hypothesize that repeated stress may affect the mechanisms of extinction- triggered synaptic plasticity in vHPC-BLA projections, impairing context representation, and, therefore, possibly resulting in fear renewal. Our studies could identify specific synaptic mechanisms and neural projections which could potentially be targeted for therapeutic treatments of disorders implicating dysfunctions of the fear system of the brain.