Abstract
BACKGROUND: Symptoms of psychosis are often observed in patients with post-traumatic stress disorder (PTSD) and are driven by aberrant regulation of the mesolimbic dopamine system. We have previously shown that targeting upstream brain regions that regulate dopamine neuron activity, the ventral hippocampus (vHipp), and paraventricular nucleus of the thalamus (PVT) maybe a novel approach to restore dopamine system function. The vHipp and PVT work in concert to regulate ventral tegmental area (VTA) dopamine neuron activity through a multisynaptic circuit that begins with inputs to the nucleus accumbens (NAc). Therefore, we hypothesized that inhibition of projections from either the vHipp or PVT to the NAc would reverse stress-induced alterations in dopamine system function. METHODS: In this study, we induced stress-related pathophysiology in rats using a 2-day inescapable foot shock procedure. We then examined if foot shock stress altered the firing patterns and coordinated neuronal activity within vHipp and PVT circuits. Finally, we examined if chemogenetic inhibition of NAc afferents could reverse stress-induced alterations in dopamine system function. RESULTS: We observed a significant increase in coherence between the PVT and NAc up to 48 hours after foot shock stress. In addition, stress increased VTA dopamine neuron population activity, which was reversed following chemogenetic inhibition of either vHipp-NAc or PVT-NAc projections. CONCLUSIONS: Taken together, these results suggest that increased coherence between the PVT and NAc, following stress, may contribute to psychosis-like symptoms but targeting either the PVT or vHipp may be viable options for the treatment of comorbid psychosis related to PTSD.