POSTPUBERTAL STRESS SELECTIVELY ACTIVATES DOPAMINE NEURONS PROJECTING TO THE VENTRAL STRIATUM VIA DISRUPTION OF RETICULAR THALAMIC NUCLEUS-NUCLEUS REUNIENS-VENTRAL HIPPOCAMPAL ACTIVITY

Abstract Background Stress is a major risk factor for psychiatric disorders, particularly when occuring during the sensitive period of adolescence. We showed previously that male rats exposed to major stressors during prepuberty exhibit amygdala-driven loss of parvalbumin neurons in the ventral hippocampus, hippocampal hyperactivity, and an increase in ventral tegmental area (VTA) dopamine (DA) neuron activity. In contrast, we now find that female rats are resilient to the effects of prepubertal stress, but are uniquely sensitive to postpubertal (PostP) stress that impacts the system via a unique pathway involving the nucleus reuniens. Aims & Objectives Using a combined stress paradigm, we examine the mechanism by which PostP stress in females activates medial VTA DA neuron activity, which are the DA neurons projecting to the affect-associated ventral nucleus accumbens.Method: Female rats were subjected to a combination of footshock/restraint stress during PostP (PD41-50). single-unit extracellular recordings of RE neurons 1-2 and 5-6 weeks were done after stress. RTN local field potentials were recorded in the RTN for at PD41, PD51, PD61, and PD85. Low (30-50Hz) and high gamma (60-120Hz) were analyzed. Immunohistochemistry analysis of PV/PNN content was evaluated in the posterior RTN one week after PostP stress (PD61). Another cohort of female rats received a retrograde inhibitory AAV-DREADDs virus (AAVrg-hSyn-hM4D(Gi)-mCherry, 500nL) at PD 31 followed by a cannula implantation in the nucleus reunions. Females were injected with Clozapine N-oxide (CNO, 1mM/200nL) in the nucleus reunions 15 min before stress during PD41-50. The rats were recorded for DA activity in the VTA during adulthood (PD>65). Results Although female rats failed to show activation of the amygdala after PostP stress, another region that also projects to ventral hippocampal parvalbumin neurons, the nucleus reuniens, shows selective activation 1-2 weeks and 5-6 weeks after PostP stress only in females. This is accompanied by a loss of parvalbumin interneurons in the ventral hippocampus. This loss of hippocampal parvalbumin neurons leads to ventral hippocampal activation and DA neuron overdrive; an effect that is attenuated by inhibition of the reuniens-hippocampal pathway via inhibitory retrograde DREADD injection into the ventral hippocampus and CNO injection into the nucleus reuniens. One region that potently regulates primary thalamic nuclei, including the nucleus reuniens, is the reticular nucleus of the thalamus (RTN), a region consisting of parvalbumin-containing GABAergic neurons. We found that after postpubertal stress there is first an activation of low gamma oscillations one day after stress (consistent with parvalbumin neuron overdrive) followed one week later by a loss of parvalbumin neurons in the region of the RTN associated with the nucleus reuniens. Discussion & Conclusion These data support that female rats that are resilient to prepubertal stress but show sensitivity to PostP stress that leads to parvalbumin loss in the RTN, decreased RTN inhibition of the nucleus reuniens, parvalbumin loss in the ventral hippocampus, and activation of the affect-related ventromedial striatum. These data are consistent with human studies, in which, females tend to be exposed more often to PostP stress in terms of e.g. sexual abuse, and are more susceptible to affect-related disorders.