Toward dysfunctional brain circuitry in schizophrenia and alcohol use disorder: A preclinical neuroimaging study

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ABSTRACT Rates of alcohol use disorder (AUD) are significantly higher in patients with schizophrenia (SCZ) compared to the general population. My primary mentor (Dr. Alan I. Green) has developed a theoretical neurobiological formulation suggesting that dysfunctional “brain reward circuity” underpins increased substance use (including alcohol use) in SCZ, and that such substances may at least partially ameliorate this dysfunction. Supporting this theory, studies assessing resting-state functional connectivity (rs-fc) via magnetic resonance imaging have shown that patients with SCZ and co-occurring cannabis use disorder show dysfunctional connectivity between the nucleus accumbens (NAc) and prefrontal cortical (PFC) regions (NAc-PFC), as well as between the default mode network (DMN) and the executive control network (ECN). In line with the theory, these circuit dysfunctions are partially ameliorated by smoking cannabis, but it is currently unknown whether alcohol would have the same effect in patients with SCZ and AUD. Furthermore, while clinical studies show that the antipsychotic drug clozapine decreases alcohol use in patients with SCZ, direct evidence of clozapine’s effect on dysfunctional neural circuitry in SCZ is currently lacking. Here, I propose to use the neonatal ventral hippocampal lesion (NVHL) rat model to investigate the brain circuit underpinnings of SCZ and AUD. NVHL rats exposed to alcohol in adolescence (NVHL-AE) drink more alcohol in adulthood compared to sham (control) rats, and their alcohol intake is reduced by clozapine treatment. Preliminary data suggests that NVHL-AE rats have reduced NAc-PFC connectivity (similar to what is observed clinically in patients with SCZ), but whether these rats have DMN-ECN dysfunction is unknown. It is also unknown how either alcohol or clozapine will alter brain connectivity in the NVHL-AE rat. This F31 proposal, which assesses rs-fc in the NVHL-AE rat, will: 1) confirm NAc-PFC dysfunction; 2) determine if there is dysfunctional DMN-ECN connectivity; and 3) determine the effect of alcohol or clozapine on connectivity in this animal model. Data from the proposed aims will help assess whether dysfunctional brain circuitry underpins increased alcohol use in a rodent model used to study SCZ and AUD and, whether alcohol exposure or clozapine treatment will at least partially ameliorate some of the circuit dysfunction. These studies will be impactful because they will test the relationship of candidate biomarkers of connectivity (dysfunctional NAc-PFC and/or DMN-ECN connectivity) and increased alcohol use in SCZ. The results generated from these Aims will lay the groundwork for future investigations in which dysfunctional connectivity is selectively targeted to develop novel treatments for SCZ and AUD. Completion of these studies will allow me to apply my training in advanced neuroimaging and analytic techniques and, by doing so, prepare me to address important questions in the field of co-occurring mental illness and AUD.