Intranasal Administration of Oxytocin Attenuates Social Recognition Deficits and Increases Prefrontal Cortex Inhibitory Postsynaptic Currents following Traumatic Brain Injury

Abstract

Pediatric traumatic brain injury (TBI) results in heightened risk for social deficits that can emerge during adolescence and adulthood. A moderate TBI in male and female rats on postnatal day 11 (equivalent to children below the age of 3) resulted in impairments in social novelty recognition, defined as the preference for interacting with a novel rat compared to a familiar rat, but not sociability, defined as the preference for interacting with a rat compared to an object in the three-chamber test when tested at 4-weeks (adolescence) and 8-weeks (adulthood) postinjury. The deficits in social recognition were not accompanied by deficits in novel object recognition memory and were associated with a decrease in the frequency of spontaneous inhibitory postsynaptic currents (IPSC) recorded from pyramidal neurons within layer II/III of the medial prefrontal cortex (mPFC). Whereas TBI did not affect the expression of oxytocin (OXT) or the oxytocin Receptor (OXT-R) mRNAs in the hypothalamus and mPFC respectively, intranasal administration of OXT prior to behavioral testing was found to reverse impairments in social novelty recognition and increase IPSC frequency in the mPFC in brain-injured animals.These results suggest that TBI-induced deficits in social behavior may be linked to increased excitability of neurons in the mPFC and suggests that the regulation of GABAergic neurotransmission in this region as a potential mechanism underlying these deficits. 3 Significance StatementTraumatic brain injury (TBI) occurs in approximately half a million children below the age of 14 each year, with children younger than 4 years old at heightened risk. A younger age at injury is associated with worse behavioral and psychosocial outcomes in pediatric TBI patients, particularly as children age into adolescence and adulthood. In this study, we explored the role of oxytocin in the long-term effects of pediatric TBI on social behaviors in adolescence and adulthood. The results indicate that intranasal administration of oxytocin (OXT) improves social outcomes following pediatric TBI, potentially by increasing inhibitory neurotransmission within the medial prefrontal cortex (mPFC) and provide novel support for the use of intranasal OXT treatment to mitigate social deficits in pediatric TBI patients.

A Pro-social Pill? The Potential of Pharmacological Treatments to Improve Social Outcomes After Pediatric Traumatic Brain Injury

“…In mice, mutations in the oxytocin or oxytocin receptor genes manifest in social recognition deficits (46)(47)(48); whereas in humans, genetic variations in the oxytocin receptor gene are associated with individual variability in social behaviors (49). In contrast to these findings, moderate TBI in the neonatal rat did not reduce expression of mRNA for oxytocin in the paraventricular nucleus of the hypothalamus despite the presence of deficits in social recognition behavior (24). However, potential changes in protein levels of oxytocin after pediatric TBI were not investigated.…”

“…Therapeutic targeting to improve social outcomes in experimental models are very limited to date. Findings regarding endogenous oxytocin treatment in the immature injured rat brain are promising ( 24 ), and several studies in models of early life HI provide avenues for future research in neurotrauma. Ultimately, the goals of such research should be two-fold: to both increase our understanding of the fundamental neurobiology underlying social impairments after pediatric TBI, and to identify novel therapeutic strategies that can ameliorate or prevent social behavior deficits.…”

“…Similarly, severe TBI in p14 rats led to deficits in social interaction and social novelty in adolescence ( 23 ). More recently, Runyan et al reported that a moderate TBI in the p11 rat resulted in deficits in social recognition memory at adolescence and adulthood in both male and female rats ( 24 ). A similar trajectory is commonly seen in patients after childhood TBI, where deficits may emerge and evolve with developmental maturation ( 25 , 26 ).…”

“…In pediatric TBI, Runyan et al have recently investigated the potential of oxytocin treatment to ameliorate social behavior deficits following moderate TBI in p11 rats ( 24 ). Intranasal administration of oxytocin reduced deficits in social recognition in a dose-dependent manner at 4–5 weeks after injury (equivalent to adolescence); brain-injured animals receiving 60 μg of oxytocin at 30–45 min prior to behavior testing exhibited social recognition behavior similar to sham-injured rats.…”

Traumatic Brain Injury: An Age-Dependent View of Post-Traumatic Neuroinflammation and Its Treatment

“…Few studies have examined the impacts of neonatal TBI in terms of functional deficits. Neonatal TBI induces cognitive deficits in adolescents, at 28 dpi, through an impairment in novel object recognition memory [ 151 ] along with an increase in the time spent in the open arms of the elevated-plus maze, suggestive of risk-taking behavior [ 148 ]. These functional deficits are still present in adulthood [ 146 , 151 ].…”