Biology subjects

Schetters, D.

Publications and source records attributed to Schetters, D..

4 recordsLinked to original sources

bioRxiv2026

Anterior insula activity during alcohol and social reward self-administration and choice in male and female rats

Alcohol use disorder (AUD) is characterized by the prioritization of alcohol over healthier non-alcohol rewards, posing significant challenges for addiction treatment. Understanding the neural mechanisms driving this maladaptive preference is crucial for effective intervention. We previously showed that rats will choose alcohol over social reward in a discrete-choice task. Here, we used fiber photometry to investigate how anterior insula cortex (aIC) activity relates to choice and employed Linear Ballistic Accumulator (LBA) modelling to dissect the underlying decision processes. Male and female rats, transfected with calcium indicator jGCaMP7f in aIC, were trained to lever-press for either social reward or alcohol (20% ethanol) in alternating sessions, followed by discrete-choice sessions, and then punishment of alcohol choices. Rats developed a preference for alcohol over social reward, which was reversed when alcohol choices were punished. Model output successfully described this behaviour with the model-derived decision bias tracking preference across all phases. Photometry recordings showed that, as alcohol preference emerged, increased aIC activity during the cue period preceding alcohol choices (relative to social choices) was significantly correlated with decision bias towards alcohol. During punishment, aIC activity bias was no longer related to decision bias, despite the preference shift. These results demonstrate that aIC activity is linked to alcohol reward and choice and suggest that aIC contributes to alcohol preference by encoding a bias in the evidence accumulation process. This highlights a specific role of aIC in the cognitive mechanisms of alcohol-seeking, and its potential as a target for therapeutic interventions. SignificanceUnderstanding the neural basis of prioritizing alcohol over natural rewards is critical for combating alcohol use disorder. This study investigates how anterior insula cortex (aIC) activity in rats relates to choices between alcohol and social reward. Using fiber photometry and cognitive modelling, we found that aIC activity is not only consistently higher for alcohol-related actions but also, during the decision period prior to choice. Differential activity for alcohol versus social choices significantly correlates with a model-derived "decision bias", the speed of evidence accumulation, favouring alcohol, once preference is established. This provides novel mechanistic insight, suggesting aIC contributes to alcohol preference by encoding a bias in the decision-making process, highlighting its role in alcohol seeking and as a potential therapeutic target.

neuroscience↗

bioRxiv2025

Dual Role of LH-GABA Neurons in Encoding Alcohol Reward and Aversive Memories

One of the core aspects of alcohol use disorder is continued use despite negative consequences. Individuals with an alcohol use disorder typically engage in behaviors which represent a failure to integrate the aversive consequences of their actions. The neural mechanisms of learning about conflicting experiences remain poorly understood. Previous research has highlighted the critical role of GABAergic neurons in the Lateral Hypothalamus (LH-GABA) in rewarding memories. However, whether this role extends to aversive outcomes, and competition between rewarding and aversive outcomes remains unexplored. In this study, we sought to elucidate the role of LH-GABA neurons in encoding and expressing alcohol reward and aversive memories using fiber photometry calcium imaging. We used a dual-virus approach to confine expression of jGCaMP7f to GABAergic neurons in LH of male and female Long-Evans rats. In our first experiment, following acquisition of a cue-alcohol association, a mild foot shock was introduced on 50% of the trials. In the second experiment, we used three different cues to signal alcohol, foot-shock, or no consequence. Subsequently, we combined these conditioned stimuli in pairs to evoke motivational conflict. Our results reveal that LH-GABA activity is associated with cues predictive of both appetitive and aversive outcomes and is highest to a cue predictive of an aversive outcome. Additionally, the response of LH-GABA activity to an aversive shock stimulus is attenuated in the presence of alcohol. In summary, our findings show the activity of LH-GABA neurons is involved in learning both appetitive and aversive associations, and their interaction in conflict. Significance statement.This study addresses a critical knowledge gap in understanding the neural mechanisms behind learning in conflicting situations. Focusing on the GABAergic neurons in Lateral Hypothalamus, which have previously been associated with rewarding memories and motivation, we explore their role in the competition between rewarding and aversive motivation. We used fiber photometry to record LH-GABA neurons and found that their activity is heightened for aversive outcomes, irrespective of certainty. Notably, in situations of motivational conflict, this activity to the shock is dampened in the presence of alcohol. These insights not only enhance our understanding of the neural basis of emotional adaptation but also hold implications for psychiatric disorders like alcohol use disorder, depression, and anxiety, providing potential avenues for therapeutic interventions.

neuroscience↗

bioRxiv2023

Lateral hypothalamic GABAergic neurons encode alcohol memories.

In alcohol use disorder the alcohol memories persist during abstinence, and exposure to stimuli associated with alcohol use can lead to relapse. This highlights the importance of investigating the neural substrates underlying not only relapse, but also encoding and expression of alcohol memories. GABAergic neurons in the Lateral Hypothalamus (LH- GABA) have been shown to be critical for food-cue memories and motivation, however the extent to which this role extends to alcohol-cue memories and motivations remains unexplored. In this study, we aimed to describe how alcohol related memories are encoded and expressed in LH GABAergic neurons. Our first step was to monitor LH-GABA calcium transients during acquisition, extinction, and reinstatement of an alcohol-cue memory using fiber photometry. We trained the rats on a Pavlovian conditioning task where one conditioned stimulus (CS+) predicted alcohol (20% EtOH) and another conditioned stimulus (CS-) had no outcome. We then extinguished this association through non-reinforced presentations of the CS+ and CS-, finally in two different groups we measured relapse under non-primed and alcohol primed induced reinstatement. Our results show that initially both cues caused increased LH-GABA activity, and after learning only the alcohol-cue increased LH-GABA activity. After extinction this activity decreases, and we found no differences in LH- GABA activity during reinstatement in either group. Next, inhibited LH-GABA neurons with optogenetics to show that activity of these neurons is necessary for the formation of an alcohol-cue associations. These findings suggest that LH-GABA might be involved in attentional processes modulated by learning.

neuroscience↗

bioRxiv2021

Role of anterior insula cortex in context-induced relapse of nicotine-seeking

Tobacco use is the leading cause of preventable death worldwide, and relapse during abstinence remains the key barrier to successful treatment of tobacco addiction. During abstinence, environmental contexts associated with nicotine use can induce craving and contribute to relapse. The insular cortex (IC) is thought to be a critical substrate of nicotine addiction and relapse. However, its specific role in context-induced relapse of nicotine-seeking is not fully known. In this study, we report a novel rodent model of context-induced relapse to nicotine-seeking after punishment-imposed abstinence, which models self-imposed abstinence through increasing negative consequences of excessive drug use. Using the neuronal activity marker Fos we find that the anterior (aIC), but not the middle or posterior IC, shows increased activity during context-induced relapse. Combining Fos with retrograde labelling of aIC inputs, we show projections to aIC from contralateral aIC and basolateral amygdala exhibit increased activity during context-induced relapse. Next, we used fiber photometry in aIC and observed phasic increases in aIC activity around nicotine-seeking responses during self-administration, punishment, and the context-induced relapse tests. Next, we used chemogenetic inhibition in both male and female rats to determine whether activity in aIC is necessary for context-induced relapse. We found that chemogenetic inhibition of aIC decreased context-induced nicotine-seeking after either punishment- or extinction-imposed abstinence. These findings highlight the critical role nicotine-associated contexts play in promoting relapse, and they show that aIC activity is critical for this context-induced relapse following both punishment and extinction imposed abstinence.

neuroscience↗