Neuropeptidergic modulation of synaptic circuits in fear and anxiety

Introduction

Fear and anxiety are essential for survival. Adequate reactions to anticipated and perceived threats strongly depend on the current state, context, and previous experience.

Neurobiological Mechanisms

What are the neurobiological mechanisms that underlie these adaptive behaviors? While synaptic circuits are the backbone to process threat signals and transform them into behavioral responses, increasing evidence suggests that neuropeptides tune these synaptic circuits in a state- and context-dependent manner. This tuning allows for temporal control of excitability and plasticity.

Neuropeptide Receptors

Neuropeptide receptors are abundantly expressed in neuronal circuits that regulate fear and anxiety. Recent evidence suggests that most neurons synthesize multiple neuropeptides and, in turn, are regulated by multiple neuropeptide receptors that are expressed in highly cell type-specific patterns.

Genetic and Pharmacological Evidence

Indeed, genetic alterations in humans, as well as pharmacological and genetic experiments in mice, indicate important roles for multiple neuropeptides in regulating fear and anxiety. If dysfunctional, these neuropeptides can increase the risk for multiple neuropsychiatric disorders. However, due to the lack of specificity of existing tools, the circuit mechanisms underlying these effects are largely unknown.

Proposal Objectives

In this proposal, I aim to reveal cell type-specific neuropeptidergic signaling mechanisms for context-dependent regulation of cortical circuit activity, cellular excitability, and synaptic plasticity.

Methodology

I will use cutting-edge in vivo imaging and circuit manipulation tools combined with region- and cell type-specific CRISPR/Cas9-mediated genetic ablation to reveal how these neuropeptidergic signaling mechanisms regulate behavioral responses in the context of fear and anxiety.

Expected Outcomes

This multidisciplinary approach will allow me to gain unprecedented mechanistic insights into how neuropeptides drive adaptive circuit computations and how their dysfunction underlies maladaptive behavioral and emotional responses to external cues.