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The Role of S1-Insula Neurons in Mediating Affective Behaviors in Alcohol Abstienence

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title
The Role of S1-Insula Neurons in Mediating Affective Behaviors in Alcohol Abstienence
author
Salazar, Amanda Liliana
abstract
Alcohol Use Disorder (AUD) is a growing problem in our nation and worldwide. COVID-19 has led to a significant rise in alcohol use, with many people relapsing due to the negative affective states correlated with abstinence. An understanding of the functional connectivity network of abstinence-induced negative affect is needed. Previous work in our lab has elucidated parts of this network, identifying an insula-bed nucleus of the stria terminalis (BNST) pathway activated during stress and negative affect in abstinence. Therefore, my master’s thesis focuses on elucidating the control network for insula-BNST pathway mediation of abstinence-induced negative affect. We mapped 2nd order inputs into this pathway and identified the somatosensory cortex (S1) as a dense population of neurons that project to the insula-BNST pathway. In the context of drug addiction, sensory cortical areas possibly generate the recall or imagine the feeling of using drugs to induce cravings and decrease inhibitory control, and the S1 and insula may be particularly important in the initial euphoric feelings of drug-taking, and the subsequent re-exposure to drugs and related cues. To test this potential pathway in alcohol abstinence, we injected specific viral loads into the S1 and insula of 3 separate cohorts of female mice to isolate and manipulate S1 cells that project to the insula. We then subjected the mice to a chronic alcohol drinking forced abstinence (CDFA) model. After 6 weeks of drinking and 2 weeks of abstinence, mice were subjected to multiple behavioral tests (Novelty Suppressed Feeding Test (NSFT), Acoustic Startle, Foot Shock Startle, and Air Puff Startle). We found that chemogenetic activation of these S1-insula neurons caused increased negative affect-like behavior regardless of ethanol abstinence. The inclusion of ethanol abstinence, however, caused lower negative affect-like behaviors in S1-insula activated mice, showing a dampening effect of ethanol abstinence despite S1-insula activation. This data was corroborated with completely inverse data when chemogenetically inhibiting the same pathway in a separate cohort. A separate study was also done on female mice to understand the effects of S1-insula activation during drinking in a drinking-in-the-dark paradigm. We found that S1-insula activation causes an increase in drinking levels. Overall, our findings demonstrate a strong possibility of the S1 servings as a critical regulator of the insula to BNST pathway, and an overall contributor to alcohol drinking and alcohol abstinence-induced negative affect. These advances will be leveraged in future studies to better understand the neurobiological substrates underlying behaviors that develop following abstinence from alcohol in patients with AUD.
subject
Alcohol
Brain
Circuitry
Insula
Sensory
contributor
Centanni, Samuel W (advisor)
Maier, Joost X (committee member)
Holleran, Katherine M (committee member)
date
2024-05-23T08:36:33Z (accessioned)
2024 (issued)
degree
Neuroscience (discipline)
embargo
2029-05-18 (terms)
2029-05-18 (liftdate)
identifier
http://hdl.handle.net/10339/109466 (uri)
language
en (iso)
publisher
Wake Forest University
type
Thesis

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