Peripubertal Stress Exerts Differential Impacts on Thalamic Reticular and Reuniens Nuclei in Male vs Female Rats

Background Stress can have a major impact on the risk and development of pathology in the adult and can differ substantially between males and females, with early stress increasing male susceptibility to schizophrenia whereas females are more susceptible to affective disorders as adults. We have shown previously that prepubertal stress (PeriP; postnatal days, PD31-40) exerts long-term effects specifically in male rats through alterations in the amygdala-hippocampal pathway, whereas females were resilient. We now report that females are selectively sensitive to the long-term effects of postpubertal stress (PostP; PD41-50), but in this case acts via the thalamic-hippocampal projection. Aims & Objectives We examined if the nucleus reuniens of thalamus (RE) and thalamic reticular nucleus (TRN) play a role in female susceptibility, as these regions have been linked to dopaminergic activity and cognitive regulation. Method Male and female rats were subjected to either daily handling or daily footshock + 3 restraint sessions over 10 days from PD31-40 (prepubertal, PreP) or from PD41-50 (postpubertal, PostP) and tested as adults (>PD65). Dopamine (DA) neurons were recorded in the VTA in a cells/track protocol, and recordings were made from ventral hippocampal (vHip) and nucleus reuniens. Results Sex differences were observed with males having more active RE neurons at baseline (PeriP, F1,20=21.56, p<0.05; PostP, F1,36=5.28, p<0.05; ANOVA). A separate cohort of male and female Sprague-Dawley rats were exposed to footshock/restraint stress during PeriP and PostP. PostP stress increased the number of active RE neurons only in females 5-6 weeks after stress (n=6; Sex-Stress, F1,36=16.74, p<0.05, ANOVA) with no effect of PeriP stress on either sex (n=8-12). PeriP stress increased low gamma power only in females (n=5-9) at PD51 (F1,35=5.48, p<0.05, ANOVA) and PostP stress (n=3-8) increased low gamma at PD51 (Stress-age interaction, F2,29=6.10, p<0.05, ANOVA), consistent with an impact on PV neurons. High gamma was not changed in females after PeriP or PostP stress. No effect was observed in males for all time points (PeriP, n=6-7; PostP, n=3-7). For PV/PNN staining, PostP stress decreased the number of PV in the TRN at PD61 only in females (n=2-9; sex-stress interaction, F1,16=7.53, p<0.05, ANOVA). Females were found to have more PV+ interneurons than males (sex, F1,16=5.94, p<0.05, ANOVA). Therefore, females exhibit sensitivity to PostP stress, potentially mediated by RE and TRN activity. PostP stress increased the adult RE activity, increased low and high gamma immediately after stress, and decreased PV+ cells one week after stress. Stress affects PV-TRN transmission during PostP stress, leading to impaired PV content and disrupted inhibitory drive to RE, resulting in increased RE activity. This selectively increased activity in the medial VTA DA neurons via an alteration of the hippocampus. TRN gamma oscillations and RE activity were unaffected by PeriP or PostP stress, suggesting that they do not underlie male vulnerability. Discussion & Conclusions TRN and RE seem to be involved in the sex-dependent neurobiological circuit disruption underlying early-life stress vulnerability, especially in females via the RE-hippocampal projection. The impact on the affect-related medial VTA could account for the greater vulnerability of females to affective disorders as adults.