Blast‐induced Traumatic Brain Injury Elicits Sociability Deficits and Aggressive Behaviors Coinciding with Transient Variations in CNS 5‐HT Levels and 5‐HT2A Hypersensitivity
Authors: Collins Sean M. , Reeder Evan L. , O’Connell Christopher J. , Gudelsky Gary A. , Robson Matthew J. 
Published: April 2020

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity. In the United States alone, TBI accounts for 2.8 million emergency department visits and an economic cost of nearly $80 billion annually. The lack of any FDA‐approved therapies for treatment of acute or chronic symptoms of TBI necessitates the identification and characterization of novel drug targets. TBI often results in the generation of neuropsychiatric disorders including major depressive disorder (MDD), anxiety, aggression, and social withdrawal within the first 12 months following injury, disorders linked to altered serotonin (5‐HT) signaling. Currently, the effects of TBI on physiologic function of the 5‐HT signaling system within the CNS are poorly understood. We hypothesize that TBI drives the formation of aberrant behavioral states linked to neuropsychiatric disorders through alterations of normal, physiologic 5‐HT signaling. To test this hypothesis, adult, wild type C57Bl/6J mice were subjected to a single, blast‐induced TBI or sham treatment, followed by behavioral and/or molecular analyses 0–30 days post‐injury (dpi). High performance liquid chromatography (HPLC) revealed a time‐dependent increase and subsequent decrease in total 5‐HT and 5HIAA levels within the dorsal raphe nucleus (DRN) 10 and 30 dpi, respectively. No effect of TBI on 5‐HT levels was found in prefrontal cortex (PFC) or somatosensory cortex (SSC), areas of high 5‐HT innervation. Using the tube test for social dominance, time‐dependent alterations in DRN 5‐HT levels were found to correlate with altered social dominance behavior. TBI resulted in decreased social dominance/aversion 10 dpi, but an increase in dominance behavior 30 dpi. Using the Crawley Three Chamber Sociability Assay, TBI‐induced decreases in sociability were observed 10 dpi, an effect not present at 30 dpi. To investigate alterations in 5‐HT receptor pharmacology associated with TBI, 5‐HT2A receptor sensitivity was determined using DOI‐induced head twitch response (HTR) assays. TBI rapidly increased 5‐HT2A receptor sensitivity, effects persisting for 10 dpi. TBI‐elicited increases in DOI‐induced HTR were attenuated by administration of the 5‐HT2A antagonist M100907, indicating a dependence on intact 5‐HT2A receptor signaling. [3H]Ketanserin receptor binding studies revealed an increase in cortical 5‐HT2A receptor binding at 3 and 10 dpi. Collectively, these data provide evidence that TBI elicits time‐dependent alterations in the 5‐HT architecture of the CNS, effects that coincide with altered social function. A more thorough understanding of specifically how neurotrauma alters 5‐HT signaling will allow for the informed clinical utilization of available 5‐HT‐oriented pharmacotherapies and may provide drug discovery targets for TBI‐elicited neuropsychiatric sequelae.

Support or Funding Information

Studies were supported by the Brain & Behavior Research Foundation, PhRMA Foundation, and the University of Cincinnati