Featured Publications

Sensory processing assigns salience to environmental and internal stimuli, shaping behavior through learned associations. In alcohol use disorder (AUD), this process is dysregulated, causing sensory cues to perpetuate excessive drinking and negative affect in abstinence. While visual, olfactory, and taste cues are known to influence AUD progression, the neurocircuit mechanisms that regulate sensory information in addiction remain poorly understood. The primary somatosensory cortex (S1) encodes tactile, thermal, proprioceptive, and nociceptive inputs, and projects to higher-order regions involved in motor and emotional processing. One such target is the insula, a hub for interoceptive integration and affective regulation. We previously identified that insula neurons receiving S1 projections extend into the extended amygdala, implicating this projection in emotional processing. Here, we map S1-insula collateralizations in downstream motor and sensory processing regions, suggesting a unique role for this circuit in AUD-related behavior. Using chemogenetics, fiber photometry, and two complementary mouse models of AUD (binge-like drinking and chronic drinking with forced abstinence), we demonstrate that the S1-insula circuit is selectively recruited during ethanol drinking and aversive behaviors. Chronic ethanol exposure disrupts this circuit’s engagement, suggesting a maladaptive shift in sensory-affective integration. Notably, S1-insula neurons show both immediate and delayed activity increases in response to an ethanol lick, indicating temporally distinct roles. These findings reveal a unique cortico-cortical mechanism by which somatosensory signaling modulates both external cue reactivity and internal affective states in AUD. This work underscores the role of sensory networks in addiction and identifies a potential circuit-level target for future diagnostic and therapeutic strategies.

Stress is central to many neuropsychiatric conditions, including alcohol use disorder (AUD). Stress influences alcohol initiation, escalation, progression to AUD, and relapse. Identifying stress-activated neurocircuits and individual variability in these responses is critical for developing new AUD treatment targets. This study investigates the relationship between adult stress response and AUD hyperkatifeia, a prolonged negative emotional state in protracted abstinence. In C57BL/6J mice, repeated restraint stress did not alter ethanol consumption but heightened aversive behavior during abstinence. We examined the mid-insula, a key network hub for emotional regulation and stress response, as a potential mechanism driving this effect. Mid-insula GCaMP activity was higher during active stress-coping behavior, and negatively correlated with ethanol consumption, and positively correlated with GCaMP activity during the novelty-suppressed feeding test in abstinence. Next, we assessed whether stress-induced activity in the stress-sensitive insula-BNST circuit is sufficient to alter ethanol drinking behavior and abstinence-induced avoidance behavior. Chemogenetically inhibiting mid-insula-BNST neurons during stress had sex-specific effects, reducing ethanol consumption in males and abstinence-induced aversive behavior in females. Clustering analysis revealed two distinct phenotypes, one characterized by high active coping during stress, low ethanol consumption, and low avoidance behavior in abstinence, and a second cluster with the opposite pattern. Insula-BNST inhibition during stress shifted female mice toward the former cluster, but had no impact on male cluster identity. Collectively, this study implicates the insula-BNST circuit as a key mediator of stress response, stress-induced drinking, and abstinence-related affective vulnerability, positioning this circuit as a potential biomarker and therapeutic target for hyperkatifeia.

Exposure to traumatic stressors can have detrimental effects on one’s well-being. Alcohol is often used as a coping mechanism to alleviate stress, leading to the development of alcohol use disorder (AUD). Furthermore, sex dimorphisms in stress and AUD alter their progression and sustenance. To investigate these interactions for effective treatment strategies, validated and exhaustive preclinical models are necessary. Here, we designed a comprehensive study that examines how traumatic stress influences ethanol drinking patterns and PTSD-like phenotypes in male and female mice with Single Prolonged Stress (SPS). Male and female C57BL/6J mice underwent SPS, a model of traumatic stress consisting of a series of consecutive stressors, followed by a 7-day stress incubation period. Mice then underwent a series of tests for aversive state, fear discrimination, and drinking patterns during continuous and limited ethanol access. SPS selectively increased negative affect and startle responses in male mice, while females were unaffected. SPS disrupted discrimination adjustment between fear and safety cues during extinction, while ethanol exposure attenuated overall fear responses. SPS maintained baseline sex differences in consumption. Furthermore, female consumption increased when access was provided prior to and continuously throughout SPS and fear conditioning, contrasting with groups exposed to ethanol afterwards. In summary, we identified a distinct sex specific relationship between traumatic stress, fear memory, and the timing of ethanol consumption. We highlight SPS as a robust translational model for exploring the sex-specific neurobiological mechanisms driving traumatic stress-induced affective disturbances.

Alcohol Use Disorder (AUD) is a growing problem worldwide, causing an incredible burden on health and the economy. Though AUD impacts people of all backgrounds and demographics, increasing evidence has suggested robust sex differences in alcohol drinking patterns and AUD-induced negative emotionality or hyperkatifeia. Rates of problematic drinking have significantly risen among women, and women face more severe negative emotional consequences in abstinence such as increased risk of comorbidity with an anxiety or mood disorder and more severe symptoms of depression. As such, a bevy of preclinical literature using contingent methods of alcohol (ethanol) consumption has amassed in recent years to better understand sex as a biological variable in alcohol drinking and abstinence-induced negative emotionality. Mice are widely used to model alcohol drinking, as they are conducive to genetic manipulation strategies, and many strains will voluntarily consume alcohol. Sex-specific results from these mouse studies, however, have been inconsistent. Therefore, this review aims to summarize the current knowledge on sex differences in AUD-related contingent ethanol drinking and abstinence-induced negative emotionality in mice. Various contingent mouse drinking models and negative emotional-based behavioral paradigms are introduced and subsequently discussed in the context of sex differences to show increasing indications of sex specificity in mouse preclinical studies of AUD. With this review, we hope to inform future research on potential sex differences in preclinical mouse models of AUD and provide mounting evidence supporting the need for more widespread inclusion of preclinical female subjects in future studies.

Background: Negative emotional states are associated with the initiation and maintenance of alcohol use and drive relapse to drinking during withdrawal and protracted abstinence. Physical exercise is correlated with decreased negative affective symptoms, although a direct relationship between drinking patterns and exercise level has not been fully elucidated.
Methods: We incorporated intermittent running wheel access into a chronic continuous access, two-bottle choice alcohol drinking model in female C57BL/6J mice. Wheel access was granted intermittently once mice established a preference for alcohol over water. After 6weeks, alcohol was removed (forced abstinence) and mice were given continuous access to unlocked or locked wheels. Negative affect-like behavior, home cage behavior, and metabolic activity were measured during protracted abstinence.
Results: Wheel access shifted drinking patterns in the mice, increasing drinking when the wheel was locked, and decreasing drinking when unlocked. Moreover, alcohol preference and consumption were strongly negatively correlated with the amount of running. An assessment of negative affect-like behavior in abstinence via the novelty suppressed feeding and saccharin preference tests (SPT) showed that unlimited wheel access mitigated abstinence-induced latency increases. Mice in abstinence also spent more time sleeping during the active dark cycle than control mice, providing additional evidence for abstinence-induced anhedonia- and depression-like behavior. Furthermore, running wheel access in abstinence decreased dark cycle sleep to com-parable alcohol- and wheel-naïve mice. Given the positive impact of exercise and the negative impact of alcohol on metabolic health, we compared metabolic phenotypes of alcohol-abstinent mice with and without wheel access. Wheel access increased energy expenditure, carbon dioxide production, and oxygen consumption, providing a potential metabolic mechanism through which wheel access improves affective state.
Conclusions: This study suggests that including exercise in AUD treatment regimens has the potential to reduce drinking, improve affective state during abstinence and could serve as a non-pharmacological approach to prevent the development of an AUD in high-risk individuals.

Insula function is considered critical for many motivated behaviors, with proposed functions ranging from attention, behavioral control, emotional regulation, goal-directed and aversion-resistant responding. Further, the insula is implicated in many neuropsychiatric conditions including substance abuse. More recently, multiple insula subregions have been distinguished based on anatomy, connectivity, and functional contributions. Generally, posterior insula is thought to encode more somatosensory inputs, which integrate with limbic/emotional information in middle insula, that in turn integrate with cognitive processes in anterior insula. Together, these regions provide rapid interoceptive information about the current or predicted situation, facilitating autonomic recruitment and quick, flexible action. Here, we seek to create a robust foundation from which to understand potential subregion differences, and provide direction for future studies. We address subregion differences across humans and rodents, so that the latter’s mechanistic interventions can best mesh with clinical relevance of human conditions. We first consider the insula’s suggested roles in humans, then compare subregional studies, and finally describe rodent work. One primary goal is to encourage precision in describing insula subregions, since imprecision (e.g. including both posterior and anterior studies when describing insula work) does a disservice to a larger understanding of insula contributions. Additionally, we note that specific task details can greatly impact recruitment of various subregions, requiring care and nuance in design and interpretation of studies. Nonetheless, the central ethological importance of the insula makes continued research to uncover mechanistic, mood, and behavioral contributions of paramount importance and interest.

Active responses to stressors involve motor planning, execution, and feedback. Here we identify an insular cortex to BNST (insula→BNST) circuit recruited during restraint stress induced active struggling that modulates affective behavior. We demonstrate that activity in this circuit tightly follows struggling behavioral events and that the size of the fluorescent sensor transient reports the duration of the struggle event, an effect that fades with repeated exposure to the homotypic stressor. Struggle events are associated with enhanced glutamatergic-and decreased GABAergic signaling in the insular cortex, indicating the involvement of a larger circuit. We delineate the afferent network for this pathway, identifying substantial input from motor-and premotor cortex, somatosensory cortex, and the amygdala. To begin to dissect these incoming signals, we examine the motor cortex input, and show that the cells projecting from motor regions to insular cortex are engaged shortly before struggle event onset. This study thus demonstrates a role for the insula→BNST pathway in monitoring struggling activity and regulating affective behavior.

Negative affect is a core symptom domain associated with an array of neurological and psychiatric disorders and is only partially targeted by current therapies, highlighting the need for better, more targeted treatment options. This study focuses on negative affective symptoms associated with prolonged alcohol abstinence, one of the leading causes of relapse. Using a mouse model of chronic alcohol consumption followed by forced abstinence (CDFA), prolonged alcohol abstinence increased c-fos expression and spontaneous glutamatergic neurotransmission in the dorsal bed nucleus of the stria terminalis (dBNST), a region heavily implicated in negative affect in both humans and rodents. Further, pharmacologically enhancing endogenous cannabinoids (eCB) with JZL184 prevents abstinence-induced increases in dBNST neuronal activity, underscoring the therapeutic potential of drugs targeting the brain’s eCB system. Next, we used a channelrhodopsin-assisted mapping strategy to identify excitatory inputs to the dBNST that could contribute to CDFA-induced negative affect. We identified the insular cortex (insula), a region involved in regulating interoception, as a dense, functional, eCB-sensitive input to the dBNST. Using a chemogenetic strategy to locally mimic eCB signaling, we demonstrate that the insula strongly influences the CDFA behavioral phenotype and dBNST neuronal activity. Lastly, we used an anterograde strategy for transynaptic targeting of Cre expression in combination with a Gq-DREADD to selectively recruit dBNST neurons receiving insula projections. Chemogenetic recruitment of these neurons mimicked behavioral and c-fos responses observed in CDFA. Collectively, this study supports a role for the insula-BNST neural circuit in negative affective disturbances and highlights the therapeutic potential of the eCB system for treating negative affective disorders.