Building emotional circuits: interfacing intrinsic programs with early-life experiences

Introduction

Emotion regulation and responses to fear and stress are vital for survival and interactions with the environment. Within the brain, the amygdala governs emotional states through specialised nuclei and connectivity, controlling anxiety, fear reactions, and emotional learning.

Background

In mammals, amygdala circuits mature postnatally and are influenced by mother-offspring bonding, which impairment causes early-life stress and leads to lasting consequences on anxiety. However, the molecular and cellular mechanisms underlying amygdala neuron differentiation and wiring, their reliance on intrinsic programs, potential sex differences, and impact of early-life experiences remain poorly understood.

Hypothesis

Here, I hypothesise that the differentiation of amygdala neurons relies on transcriptional programs, which vary between sexes and are modulated by early-life stress.

Methodology

Building on advanced technologies and expertise for single-cell gene expression, spatial position, and connectivity analyses that I developed in my prior work, I propose to test this in the amygdalae of female and male mice, by:

1. Identifying transcriptional programs guiding neuron differentiation using single-nucleus and spatial transcriptomics.
2. Characterizing projection development and intrinsic programs using barcoded axon tracings combined with transcriptomics.
3. Determining the role of intrinsic determinants and the impact of early-life stress on projection development and function using CRISPR-Cas9-mediated gene manipulation, maternal separation, 3D axon tracings, and anxiety/emotional memory tests.

Expected Outcomes

These experiments will reveal transcriptional programs governing amygdala circuit development and sex dimorphisms. They will identify amygdala neuron types sensitive to the environment, potentially more prone to be affected in diseases.

Significance

This research will contribute to understanding the genetic and environmental aspects of emotional dysregulation, a common feature in neuropsychiatric disorders, including anxiety disorders.