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bioRxiv · 10.1101/2025.10.16.682872

Depression-like behavior following mild traumatic brain injury in adolescent rats: a role for limbic neuropeptides

Martin, C. R.·Giacometti, L. L.·Barson, J. R.·Raghupathi, R.
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Abstract

Mild traumatic brain injury (mTBI) is common among adolescents because of their participation in contact sports and mTBI is more likely to lead to depression-related behaviors in girls than boys. Various neuropeptides, often within the limbic system, have been implicated in the regulation of depression-related behaviors. To identify potential neuropeptide involvement in behavioral effects of mTBI, this study used adolescent-age male and female rats to compare the effects of single and repetitive mTBI on depression-like behavior and limbic neuropeptide expression. Female but not male rats displayed increased immobility in the forced swim test compared to sham-injured rats at 5-weeks (chronic), but not 2-weeks (acute) following closed-head injury, and this effect was estrous cycle-dependent following single but not repetitive injury. In the nucleus accumbens (NAc), a major limbic nucleus, mRNA expression of corticotropin-releasing factor (CRF) and dynorphin (DYN) was decreased after single injury only in female rats, particularly during the estrus phase, while expression of enkephalin (ENK) was decreased after repetitive injury. In the paraventricular nucleus of the thalamus (PVT), another limbic nucleus, mRNA expression of pituitary adenylate cyclase-activating polypeptide (PACAP) was increased in repetitively injured female but not male rats at 2- and 5-weeks but was unchanged in single injured female rats compared to sham-injured rats. These data suggest that depression-like behavior emerges in the chronic phase following adolescent mTBI only in females, being estrous cycle-dependent following single-injury. Moreover, reduced ENK in the NAc and elevated PACAP in the PVT may contribute to depression-like behavior in females following repetitive mTBI.

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Martin, C. R., Giacometti, L. L., Barson, J. R., Raghupathi, R.. 2025-10-17. Depression-like behavior following mild traumatic brain injury in adolescent rats: a role for limbic neuropeptides. https://doi.org/10.1101/2025.10.16.682872

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