Sex-Dependent Differences in Anterior Insular Cortex Inputs to the Dorsolateral Striatum During Binge Alcohol Drinking

Core Concepts

Binge alcohol consumption induces sex-dependent neuroadaptations in the anterior insular cortex (AIC) inputs to the dorsolateral striatum (DLS), with male AIC inputs to the left DLS showing the strongest encoding of binge alcohol drinking behaviors.

Abstract

The study investigated sex differences in binge alcohol drinking behaviors and the underlying neuroadaptations in the anterior insular cortex (AIC) to dorsolateral striatum (DLS) circuitry in male and female mice. Key findings: Male and female mice consumed similar levels of alcohol during the Drinking in the Dark (DID) paradigm, but displayed different behavioral strategies to achieve these intakes. Female mice were more efficient in their alcohol consumption, requiring less time and fewer drinking events to reach similar intake levels as males. Inter-session water intake predicted future alcohol intake in females, but not males, suggesting sex differences in thirst state regulation. Calcium imaging of AIC inputs to the DLS revealed that male AIC inputs to the left DLS showed the strongest encoding of binge alcohol drinking behaviors, with increased magnitude and altered temporal dynamics of the calcium signals. As binge drinking history increased, the engagement of male left AIC inputs to the DLS decreased, suggesting decreased left AIC input engagement with increased drinking experience. These sex-dependent neuroadaptations in the AIC-DLS circuit provide targets for future pharmacotherapies and therapeutic modalities to treat alcohol use disorder.

Stats

Females displayed decreased alcohol event durations and number of alcohol drinks compared to males. Females showed increased inter-drink intervals during alcohol DID sessions compared to males. Male AIC inputs to the left DLS showed the largest magnitude increase in calcium signals during binge alcohol drinking events. The time to peak calcium signal in left AIC inputs increased in males but decreased in females when transitioning from water to alcohol drinking.

Quotes

"Binge alcohol consumption induces sex-dependent neuroadaptations in the anterior insular cortex (AIC) inputs to the dorsolateral striatum (DLS), with male AIC inputs to the left DLS showing the strongest encoding of binge alcohol drinking behaviors." "Female mice were more efficient in their alcohol consumption, requiring less time and fewer drinking events to reach similar intake levels as males." "As binge drinking history increased, the engagement of male left AIC inputs to the DLS decreased, suggesting decreased left AIC input engagement with increased drinking experience."

Key Insights Distilled From

Sex-dependent, lateralized engagement of anterior insular cortex inputs to the dorsolateral striatum in binge alcohol drinking

by Haggerty,D. ... at www.biorxiv.org 08-24-2023

https://www.biorxiv.org/content/10.1101/2023.08.23.554484v3

Deeper Inquiries

How do the sex-dependent neuroadaptations in the AIC-DLS circuit evolve over longer timescales of binge alcohol exposure?

The sex-dependent neuroadaptations in the AIC-DLS circuit evolve over longer timescales of binge alcohol exposure by displaying distinct patterns of calcium dynamics and synaptic activity. In males, there is an increase in calcium activity at AIC inputs into the left DLS during the transition from water to alcohol consumption, indicating a heightened engagement of this circuit. This increased engagement is particularly evident during drinking events, where alcohol consumption leads to larger peak amplitudes and altered time to peak values. On the other hand, females show a decrease in time to peak values during alcohol consumption, suggesting a quicker response of the circuit to alcohol intake. These sex-specific changes in calcium dynamics reflect the differential adaptation of the AIC-DLS circuit in response to binge alcohol exposure over time.

What are the potential mechanisms underlying the sex differences in thirst state regulation and its influence on future alcohol intake?

The sex differences in thirst state regulation and its influence on future alcohol intake may be attributed to various factors, including hormonal fluctuations, neural circuitry differences, and behavioral strategies. Females, who tend to consume more water between alcohol drinking sessions, may have a different sensitivity to thirst cues or a more efficient way of quenching their thirst compared to males. This could be influenced by sex hormones like estrogen, which have been shown to impact alcohol intake patterns. Additionally, the neural circuitry involved in thirst regulation, such as the AIC-DLS pathway, may function differently in males and females, leading to distinct responses to thirst states and subsequent alcohol consumption. These sex-specific mechanisms contribute to the observed correlations between inter-session water intake and future alcohol intake, highlighting the complex interplay between thirst regulation, behavioral strategies, and sex differences in alcohol consumption.

Could targeting the lateralized encoding of binge alcohol drinking in the AIC-DLS circuit lead to the development of novel, sex-specific pharmacotherapies for alcohol use disorder?

Targeting the lateralized encoding of binge alcohol drinking in the AIC-DLS circuit holds promise for the development of novel, sex-specific pharmacotherapies for alcohol use disorder. By understanding how the AIC inputs into the DLS encode binge alcohol consumption behaviors differently in males and females, researchers can identify potential targets for intervention. For example, modulating the activity of specific receptors or neurotransmitters involved in this circuit may offer a sex-specific approach to reducing alcohol intake. Additionally, leveraging the lateralization of the circuit could allow for targeted interventions that address the unique neuroadaptations seen in male and female binge drinkers. By tailoring pharmacotherapies to the sex-specific mechanisms underlying alcohol consumption, more effective and personalized treatments for alcohol use disorder may be developed.