Sex-dependent effects of angiotensin II type 1 receptor blocker on molecular and behavioral changes induced by single prolonged stress.

Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder that not only entails alterations in fear behavior and anxiety but also includes neuroendocrine dysfunctions involving the hypothalamic pituitary adrenal (HPA) axis and the renin-angiotensin system. Recent preclinical studies demonstrate that activation of the angiotensin type 1 receptor (AT1R) in the paraventricular region of the hypothalamus (PVR) promotes anxiety-like behaviors and enables microglia proliferation. An increase in microglia and anxiety-like behavior also occurs in the PTSD animal model single-prolonged stress (SPS). In the present study, we tested whether AT1Rs contribute to the effects of SPS on behavior and microglia in brain structures important for HPA axis regulation and fear behavior. To test this, male and female animals were exposed to SPS and then given the oral AT1R antagonist candesartan beginning one week later. Candesartan did not alter auditory fear conditioning or extinction in SPS-exposed male or female animals. However, we found that the male animals exposed to SPS showed increased anxiety-like behavior, which was reversed by candesartan. In contrast, neither SPS nor candesartan altered anxiety-like behavior in the female animals. At the molecular level, SPS increased the cellular expression of AT1Rs in the PVR of male animals and candesartan reversed this effect, whereas AT1Rs in the PVR of females were unaltered by either SPS or candesartan. Iba1-expressing microglia increased in the PVR after SPS exposure and was reversed by candesartan in both sexes suggesting that SPS stimulates AT1Rs to increase microglia in the PVR. Collectively, these results suggest that the contribution of AT1Rs to the molecular and behavioral effects of SPS is sex-dependent.

Infusion of C20:0 ceramide into ventral hippocampus triggers anhedonia-like behavior in female and male rats.

Increased long-chain C20:0 ceramides have been found in the serum of patients with depression. Moreover, ceramides are linked with increased microglia reactivity and inflammatory cytokine production, which are associated with depression. Since ceramides can readily cross the blood brain barrier, peripheral C20:0 ceramides could enter the brain, activate microglia, and induce depressive-like behavior. In this study, we determined whether localized infusion of C20:0 ceramides into the ventral hippocampus (VH) of rats is sufficient to activate microglia and induce depressive-like behaviors. Adult male and female rats received infusions of C20:0 ceramides or vehicle solution every other day for 2 weeks. After the third infusion, C20:0-infused animals showed reduced sucrose preference suggesting anhedonia-like behavior. In contrast, infusions of C20:0 ceramides did not affect immobility in the forced swim test or sucrose grooming suggesting that the behavioral effects of ceramides are task dependent. Furthermore, C20:0-infusions did not increase Iba-1 + microglia or inflammatory markers in the VH suggesting that localized increases in C20:0 ceramides in the VH are sufficient to induce anhedonia-like behavior without microglia activation.