Nucleus reuniens, chronic ethanol and cognitive deficits - PROJECT SUMMARY
Approximately 29.5 million people over the age of 12 in the US had alcohol use disorder (AUD) according to the
2021 National Survey on Drug Use and Health. Chronic alcohol use can lead to the emergence of cognitive
deficits, particularly working memory, which persist during alcohol withdrawal and abstinence increasing the
odds of relapse. Approved treatments for alcohol use disorder are not designed to treat alcohol-induced cognitive
dysfunction, so understanding potential mechanisms is necessary to develop new treatments. The nucleus
reuniens of the thalamus (RE) is a ventral midline thalamic nucleus that plays a key role in cognitive function,
such as spatial working memory, attention, and behavioral flexibility. The RE is also bidirectionally connected to
the medial prefrontal cortex (mPFC) and the hippocampus, which have been highly studied in AUD and cognition.
Despite its interconnectedness, the RE is understudied in the alcohol field. In my preliminary studies, I induced
alcohol dependence using chronic intermittent ethanol (CIE) vapor exposure (4 cycles) in male and female
C57BL/6J mice. Following CIE, mice were either tested on a T-maze delayed alternation spatial working memory
task or sacrificed for whole cell patch clamp electrophysiology to measure intrinsic excitability in the RE. Mice
used in the T-maze task were trained prior to CIE and tested following 2 and 4 cycles, to track cognitive decline
across the development of dependence. Both male and female mice exhibited significant deficits in performance
after CIE. Despite this similar behavioral phenotype, CIE had divergent effects on intrinsic excitability, causing
an increase in firing in females and a decrease in males. I also found that firing in the RE in the absence of
alcohol exposure appeared to be sex-dependent, where males have significantly greater excitability than
females. These results indicated that the RE could be an exciting new target for the study of chronic alcohol-
induced cognitive deficits. The overall hypothesis of this research proposal is that chronic alcohol exposure
causes sex-dependent functional adaptations to the RE and that regulating RE activation will improve cognitive
performance. To achieve this, the proposal uses a multi-technical approach to study the RE in vivo and in slice
physiology. Aim 1 of this proposal will determine if chronic alcohol exposure alters the function of the RE using
fiber photometry during performance on a spatial working memory task and whether normalizing aberrant activity
using optogenetics will improve cognitive performance in CIE-exposed mice. Aim 2 of this proposal will
characterize the effect of CIE exposure on the physiology of RE neurons involved in mPFC and hippocampal
circuitry by recording intrinsic excitability and synaptic transmission from neurons that project to the mPFC, the
hippocampus, or both. The results of these experiments will serve as landmark studies for the role of the RE in
alcohol-induced cognitive dysfunction and allow us to further understand the underlying mechanisms of cognitive
deficits following chronic alcohol.