Role of intestinal serotonin transporter in post traumatic stress disorder

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Post traumatic stress disorder (PTSD) a devastating psychiatric disorder and one of the most difficult service- related disabilities in Veterans, nonetheless without a consistently effective therapy. The only FDA-approved drugs for the treatment of PTSD are the selective serotonin reuptake inhibitors (SSRIs); the response rate to these drugs, however, is relatively small requiring development of more specific and individually effective therapies. In this regard, the neurotransmitter and hormone, serotonin (5-HT) is well-recognized for its role in depression, anxiety, aggression, impulsivity, and suicidal behaviors, which are frequently found in PTSD patients. Serotonin transporter, (SERT; SLC6A4), regulates the extracellular availability of 5-HT, and is a common target for SSRIs. Linkage of the short allele of the SERT gene polymorphism has been implicated in increasing the vulnerability to develop PTSD and predicting poor treatment outcome. In this regard, SERT is abundantly expressed in the gut and its dysfunction has been shown to cause gut microbiota alterations; albeit its role in the predisposition or progression of PTSD is not fully understood. To gain insights into the role of gut- microbiota and SERT interactions in PTSD, we utilized our recently developed novel transgenic model with inducible overexpression of SERT restricted to intestinal epithelial cells (SOEIEC) that exhibits low fecal 5-HT levels (LC/MS). The mouse model of protracted social isolation (SI), was used as chronic stressor important to elicit PTSD-like increased aggression in resident intruder assays. Interestingly, males with SOEIEC under SI exhibited increase in aggression while females were resilient as compared to wild type counterparts. To understand the sex-dependent differences, we correlated the aggression with structure of gut microbial communities. The data demonstrated a strong negative association of aggression with genus Desulfovibrio (sulfate reducing bacteria) and positive associations with Bacteroidales, Gastranaerophilales, and genus- Anaerotruncus. How 5-HT pools in the gut impact upstream factors affecting gut microbiota and triggers downstream factors in the gut and brain leading to PTSD like behavior in a sex-dependent manner is not known. Thus, our proposed studies will use cell specific SOE (in IEC and in neurons) to further elucidate PTSD related fear conditioning responses and aggression behavior and elucidate the underlying molecular mechanisms across gut-brain axis (Aim 1). Additional studies utilizing SOE and SERT KO are needed to assess the causal role of SERT induced gut-microbiota changes in predisposing mice (M/F) to fear deficits/increased aggression (Aim 2). This will be achieved by fecal microbial transplant and assessing the functional role of gut microbial changes by integrating the PTSD-like behavior with downstream targets (single cell RNA seq) and selected metabolites along gut-brain axis. The outcome of the studies will provide novel insights into the role of intestinal SERT in PTSD predisposition and will pave the way for microbial based therapeutics for PTSD management.