Sex differences in the effects of deep brain stimulation on traumatic brain injury-induced cognitive deficits in rats

Traumatic brain injury (TBI) is often associated with cognitive impairments, with episodic memory deficits among the most prevalent sequelae. While clinical evidence indicates that females tend to experience worse long-term cognitive outcomes following TBI, biological sex remains poorly characterized in preclinical neuromodulation studies. Deep brain stimulation (DBS) has emerged as a promising neuromodulatory approach for cognitive rehabilitation, but its sex-dependent efficacy following TBI remains poorly understood. We investigated the effects of chronic anterior nucleus of the thalamus (ANT) DBS on spatial learning and recognition memory following moderate-severe fluid percussion injury in male and female rats. DBS-treated animals underwent ANT electrode implantation and received either active stimulation or sham treatment. TBI produced sex- and domain-specific cognitive impairments, with females showing greater deficits in novelty-based recognition memory and males exhibiting more pronounced impairments in spatial acquisition. ANT-DBS improved cognitive outcomes in a manner that tracked these vulnerabilities, most robustly restoring recognition memory in females. Animals receiving sham stimulation also showed improvements across several outcomes, suggesting substantial electrode insertion effects. DBS increased the use of spatial search strategies in the Barnes maze, with broadly similar effects across sexes. In females, TBI selectively upregulated the expression of hippocampal estrogen receptor alpha (ERα), while estrogen receptor beta (ERβ) was largely unaffected. ERα levels were normalized in DBS-treated animals. Our findings demonstrate the potential of ANT-DBS to improve cognitive outcomes following TBI in a sex- and task-dependent manner and highlight the importance of considering biological sex in the development of neuromodulatory therapies for post-injury cognitive dysfunction.