Inhibition of hippocampal or thalamic inputs to the nucleus accumbens reverses stress-induced alterations in dopamine system function

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.

Keywords: dopamine; hippocampus; psychosis; thalamus.

Figure 1.

Inescapable foot shock has no effect on the firing rate of vHipp pyramidal neurons (A) but does significantly decrease the percentage of action potentials occurring in bursts (B). Representative traces from vHipp control (C), vHipp stress (D) are shown. The firing rate of PVT neurons was not significantly different following inescapable foot shock stress (E). The percentage of action potentials occurring in bursts is significantly reduced in PVT neurons after foot shock stress. Representative traces from PVT control (G) and PVT stress animals (H) are shown. * P < .05 compared to control. *** P < .001 compared to control.

Figure 2.

Foot shock stress increases coordinated activity between the PVT and NAc but not between the PVT and mPFC. Histological verification of electrode placement for the PVT (A), NAc (B), and mPFC (C) are shown. Arrows denote the electrode track. Foot shock stress significantly increased delta synchrony (D) and theta coherence (E) between the PVT and NAc. * P < .05 compared to control. No significant changes were observed in delta synchrony (F) or theta synchrony (G) between the PVT and mPFC.

Figure 3.

Inhibition of PVT–NAc projections restores dopamine system function following foot shock stress. (A) Schematic representation of concurrent injections of an AAV retrograde Cre virus into either the NAc or mPFC and Cre-dependent inhibitory Gi DREADD into the PVT. (B) Verification of retrograde Cre (left; scale bar represents 200 µm) and Gi DREADD (right; scale bar represents 50 µm) expression in the PVT. (C) The number of spontaneously active dopamine neurons per electrode track (population activity) was increased following foot shock stress. Chemogenetic inhibition of PVT-NAc projections restored dopamine system function. In control animals, inhibition of PVT-mPFC projections significantly increased population activity. Representative traces from control (D) and stress animals (G). (E) Significant differences in firing rate were observed between control/PVT–mPFC animals and stress/PVT–mPFC animals. (F) There were no significant differences in bursting pattern. *P < .05 compared to stress/vehicle. **P < .01 compared to control/vehicle.

Figure 4.

Inhibition of vHipp–NAc projections restores dopamine system function following foot shock stress. (A) Schematic representation of concurrent injections of an AAV retrograde Cre virus into either the NAc or mPFC and Cre-dependent inhibitory Gi DREADD into the vHipp. (B) Representative image of retrograde Cre (left; scale bar represents 500 µm) and Gi DREADD (right; scale bar represents 100 µm) expression in the vHipp. (C) The number of spontaneously active dopamine neurons per electrode track (population activity) was increased following foot shock stress. Chemogenetic inhibition of vHipp-NAc projections restored dopamine system function. Representative traces from control (D) and stress animals (G). (E) There were no significant differences in firing rate. (F) Bursting pattern was significantly increased in vHipp–mPFC animals compared to stress/vehicle while the bursting activity of vHipp-NAc animals was significantly decreased from stress/vehicle. *P < .05 compared to stress/vehicle. **P < .01 compared to stress/vehicle. ***P < .001 compared to control/vehicle.