Circuit-Specific Inhibition of Dopaminergic Signaling Associated with Phantom Gustatory Sensations in Disrupted-in-Schizophrenia-1 Mice

Schizophrenia is a severe neuropsychiatric disorder characterized by a suite of symptoms occurring across cognitive (delayed processing, paraphasia, attentional deficits), negative (anhedonia, blunted affect, catatonia), and positive (hallucinations, delusions) domains. Antipsychotics are the most commonly prescribed medication to treat positive symptoms, however their use is complicated by substantial side-effects and inadequate efficacy. This reflects a lack of progress in understanding the precise neurobiological mechanisms underlying these symptoms, due in part to a lack of appropriate preclinical animal models. Here, I used an animal model of genetic vulnerability for neuropsychiatric illness known as Disrupted-in-schizophrenia-1 (DISC-1) to examine impaired reality testing, which reflects an aberrant internal representation of an absent event. In mice, this can be observed by an associatively evoked perception of an absent sweet taste. This effect is dopaminergically-dependent and associated with elevated activity in the insular cortex (IC). By combining sophisticated Pavlovian behavioral procedures with chemogenetic inhibition of dopamine neurons projecting from the ventral tegmental area (VTA) to the IC, I show that inactivation of the VTA --> IC dopaminergic circuitry leads to impaired reality testing in wild-type mice, and that DISC-1 mice have significantly less dopamine neurons which send projections to the IC, specifically. These data yield new insights with regard to the neurobiology underlying reality testing and the functional anatomical outcomes following perturbations of the DISC-1 genetic locus. My studies also suggest potential targets for the development of novel pharmacological treatments in humans with schizophrenia.