Summary: Drugs of abuse, like alcohol, modulate gene expression in reward circuits and consequently alter behavior. However, the in vivo cellular mechanisms through which alcohol induces lasting transcriptional changes are unclear. We show that Drosophila Notch/Su(H) signaling, and the secreted fibrinogen-related protein Scabrous, in mushroom body (MB) memory circuitry, is important for the enduring preference of cues associated with alcohol’s rewarding properties. Alcohol exposure affects Notch responsivity in the adult MB and alters Su(H) targeting at the dopamine-2-like receptor (Dop2R). Alcohol-cue training also caused lasting changes to the MB nuclear transcriptome, including changes in the alternative splicing of Dop2R and newly implicated transcripts like Stat92E. Together, our data suggest that alcohol-induced activation of the highly conserved Notch pathway and accompanying transcriptional responses in memory circuitry contribute to addiction. Ultimately this provides mechanistic insight into the etiology and pathophysiology of Alcohol Use Disorder.

A single, severe episode of stress can bring about myriad responses amongst individuals, ranging from cognitive enhancement to debilitating and persistent anxiety; however, the biological mechanisms that contribute to resilience versus susceptibility to stress are poorly understood. The dentate gyrus (DG) of the hippocampus and the basolateral nucleus of the amygdala (BLA) are key limbic regions that are susceptible to the neural and hormonal effects of stress. Previous work has also shown that these regions contribute to individual variability in stress responses; however, the molecular mechanisms underlying the role of these regions in susceptibility and resilience are unknown. In this study, we profiled the transcriptomic signatures of the DG and BLA of rats with divergent behavioral outcomes after a single, severe stressor. We subjected rats to three hours of immobilization with exposure to fox urine and conducted a behavioral battery one week after stress to identify animals that showed persistent, high anxiety-like behavior. We then conducted bulk RNA sequencing of the DG and BLA from susceptible, resilient, and unexposed control rats. Differential gene expression analyses revealed that the molecular signatures separating each of the three groups were distinct and non-overlapping between the DG and BLA. In the amygdala, key genes associated with insulin and hormonal signaling corresponded with vulnerability. Specifically, Inhbb, Rab31, and Ncoa3 were upregulated in the amygdala of stress-susceptible animals compared to resilient animals. In the hippocampus, increased expression of Cartpt - which encodes a key neuropeptide involved in reward, reinforcement, and stress responses - was strongly correlated with vulnerability to anxiety-like behavior. However, few other genes distinguished stress-susceptible animals from control animals, while a larger number of genes separated stress-resilient animals from control and stress-susceptible animals. Of these, Rnf112, Tbx19, and UBALD1 distinguished resilient animals from both control and susceptible animals and were downregulated in resilience, suggesting that an active molecular response in the hippocampus facilitates protection from the long-term consequences of severe stress. These results provide novel insight into the mechanisms that bring about individual variability in the behavioral responses to stress and provide new targets for the advancement of therapies for stress-induced neuropsychiatric disorders.

Recent studies revealed mechanisms by which the microbiome affects its host’s brain, behavior and wellbeing, and that dysbiosis – persistent microbiome-imbalance – is associated with the onset and progress of various chronic diseases, including addictive behaviors. Yet, understanding of the ecological and evolutionary processes that shape the host-microbiome ecosystem and affect the host state, is still limited. Here we propose that competition dynamics within the microbiome, associated with host-microbiome mutual regulation, may promote dysbiosis and aggravate addictive behaviors. We construct a mathematical framework, modeling the dynamics of the host-microbiome ecosystem in response to alterations. We find that when this ecosystem is exposed to substantial perturbations, the microbiome may shift towards a composition that reinforces the new host state. Such a positive feedback loop augments post-perturbation imbalances, hindering attempts to return to the initial equilibrium, promoting relapse episodes and prolonging addictions. We show that the initial microbiome composition is a key factor: a diverse microbiome enhances the ecosystem’s resilience, whereas lower microbiome diversity is more prone to lead to dysbiosis, exacerbating addictions. This framework provides evolutionary and ecological perspectives on host-microbiome interactions and their implications for host behavior and health, while offering verifiable predictions with potential relevance to clinical treatments.

Recent studies revealed mechanisms by which the microbiome affects its host’s brain, behavior and wellbeing, and that dysbiosis – persistent microbiome-imbalance – is associated with the onset and progress of various chronic diseases, including addictive behaviors. Yet, understanding of the ecological and evolutionary processes that shape the host-microbiome ecosystem and affect the host state, is still limited. Here we propose that competition dynamics within the microbiome, associated with host-microbiome mutual regulation, may promote dysbiosis and aggravate addictive behaviors. We constructed a mathematical framework, modeling the dynamics of the host-microbiome ecosystem in response to alterations. We find that when this ecosystem is exposed to substantial perturbations, the microbiome may shift towards a composition that reinforces the new host state. Such positive feedback loop augments post-perturbation imbalances, hindering attempts to return to the initial equilibrium, thus promoting relapse episodes and prolonged addictions. We also find that the initial microbiome composition is a key factor: a diverse microbiome enhances the ecosystem’s resilience, whereas lower microbiome diversity is more prone to reach dysbiosis, exacerbating addictions. This framework provides novel evolutionary and ecological perspectives on host-microbiome interactions and their implications for host behavior and health, while offering verifiable predictions with potential relevance to clinical treatments.