Altered CNS Serotonin Signaling and Social Deficits Elicited by Blast‐Induced Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States, accounting for approximately 2.8 million emergency room visits and an economic burden of nearly $30 billion annually. The lack of any FDA approved medications to treat the acute or chronic effects of TBI contributes greatly to the societal and economic costs. The most common enduring comorbidity of mild to moderate TBI is the generation of neuropsychiatric disorders including major depressive disorder (MDD), anxiety, and aberrant behaviors such as social withdrawal. These disorders/behaviors are linked to altered serotonin (5‐HT) signaling within the CNS. However, the effects of neurotrauma on the normal, physiologic function of the serotonergic system are currently not well defined. We hypothesize that TBI results in specific alterations of 5‐HT signaling, ultimately impacting mood and behavioral states mediated by 5‐HT signaling. To test this hypothesis, adult, wild type C57Bl/6J mice were subjected to either a single, moderate blast‐induced TBI or sham treatment. Ten days post‐injury (dpi) or sham treatments, high performance liquid chromatography (HPLC) revealed a significant increase in total 5‐HT and 5‐HIAA levels within the raphe nucleus of TBI subjects compared to their sham counterparts, an effect not found in the prefrontal cortex (PFC) or somatosensory cortex (SSC), areas of high 5‐HT innervation. TBI subjects (10 dpi) exhibited a significant potentiation in head twitch response (HTR) elicited by administration of the 5‐HT precursor, 5‐hydroxytryptophan (5‐HTP, 100 mg/kg, i.p.) as compared to their sham counterparts, an effect mediated by the activation of cortical 5‐HT2A receptors. To ascertain 5‐HT2A or 5‐HT1A receptor sensitivity changes elicited by TBI, DOI‐induced head twitch assays and 8‐OH‐DPAT‐induced hypothermia assays were utilized, respectively. No changes in 5‐HT1A receptor sensitivity were detected in TBI subjects following administration of the 5‐HT1A agonist 8‐OH‐DPAT (0.1 mg/kg, s.c., 10 dpi), however administration of the 5‐HT2A agonist DOI (1 mg/kg, i.p., 3 and 10 dpi) resulted in a significant potentiation of HTR in TBI subjects as compared to their sham counterparts, indicative of increased 5‐HT2A receptor sensitivity. As 5‐HT signaling is a major determinant of complex social behavior, we hypothesized that TBI‐induced changes in homeostatic 5‐HT signaling would coincide with behaviors reminiscent of social withdrawal. Using the Crawley Three Chamber Sociability Assay, significant social deficits were found in TBI subjects (10 dpi) as compared to their sham counterparts. Collectively, our studies suggest that TBI acts to alter specific aspects of 5‐HT signaling within the CNS, effects that may drive TBI‐induced changes in behavior and the generation of neuropsychiatric disorders. A greater understanding of how various forms of neurotrauma causes altered 5‐HT signaling may lead to the discovery of pharmacotherapies aimed at ameliorating the chronic neuropsychiatric complications of TBI.Support or Funding InformationThis work was supported in part by the Brain and Behavioral Research Foundation (Grant No. 25230).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.