Basolateral amygdala to ventral subiculum network plasticity in alcohol dependent male and female rats

Project Summary/Abstract
Aside from exploring highly relevant scientific questions, the goal of this K01 extends to providing the
candidate with mentored training to facilitate her transition to an independent investigator. This encompasses
the acquisition of new, sophisticated state-of-the-art techniques as well as career development with the
ultimate aim of providing the candidate with a multidisciplinary toolkit to study alcohol use disorder and
enhanced mentoring/training skills to relay her expertise to the next generation of mentees interested in alcohol
research. Under the mentorship of Dr. Weiner, the candidate will explore the role of posterior basolateral
amygdala (BLA) inputs to the ventral subiculum (vSub) of the ventral hippocampus in alcohol dependent male
and female rats. Specific Aim 1 of this project will focus on the circuitry and neuroadaptations of pBLA-vSub
circuits using the well-validated chronic intermittent ethanol exposure (CIE) paradigm. Based on preliminary
findings and growing evidence that the pBLA plays a central role in mediating affective behavior and alcohol
drinking-related behaviors, we advance the working hypothesis that CIE initially increases pBLA-vSub
excitability in males but that a disproportionate strengthening of inhibitory elements of this circuitry
initially protects females from this maladaptive change. However, we predict that this protective effect
is either lost or overcome after a longer CIE exposure, leading to similar levels of network excitability
and anxiety-like behavior in both sexes. These experiments will focus on two novel inhibitory pBLA-vSub
projections that we have begun to characterize, including a monosynaptic GABAergic projection from the pBLA
onto vSub glutamatergic neurons. Experiments, using ex vivo optogenetics, and fiber photometry will examine
the integrated functional plasticity of glutamatergic and GABAeregic synapses within these pBLA-vSub circuits.
To further establish the cellular identity and distribution pattern within the BLA of a novel monosynaptic
GABAergic projection neuron population of male and female rats, we will use FISH RNAScope. Additional
chemogenetic experiments will then test whether CIE-dependent pBLA-vSub adaptations of synaptic
communication (hypoexcitability or hyperexcitability) play a causal role in the anxiety-like phenotypes that
emerge during withdrawal from CIE. Together, these findings will significantly advance our understanding of
the neural mechanisms responsible for the negative affective symptoms associated with alcohol withdrawal
and potentially shed light on novel neural substrates for the development of better treatments for alcohol use
disorder.

Grant Number: 5K01AA030081-05
NIH Institute/Center: NIH
Principal Investigator: Eva Bach