Influence of Sex and Muscarinic Activity on Memory Retrieval in Mouse Model of Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is a serious global risk factor leading to the onset of cognitive impairment and neurodegenerative diseases. Cognitive and memory impairment following a TBI is associated with the dysregulation of cholinergic neurotransmission in the brains of subjects. The extent of memory impairment following a TBI is linked with the sex of the subject. This study aimed to identify the sex-dimorphic role of muscarinic cholinergic modulation in neurological functioning and episodic memory retrieval in a mouse model of TBI. Balb/c mice were divided into four groups of males and four groups of females (i.e., Sham, TBI, TBI + Scopolamine 1 mg/kg, and TBI + Donepezil 1 mg/kg). After training with the Morris water maze test and fear conditioning, all groups were subjected to brain injury (7.84 × 10−5 J impact force) except for the Sham mice. Following brain injury, scopolamine or donepezil was administered to the respective groups for 5 days. Acute scopolamine immediately after brain trauma showed a neuroprotective effect in the males only, while subchronic donepezil significantly impaired neurological functioning in both sexes. Subchronic scopolamine and donepezil treatment reversed the TBI-induced retrograde amnesia for spatial memory in male mice. Contextual fear memory retrieval was not affected by the TBI and treatments in both sexes. Thus, we concluded that the sex-dimorphic response of the muscarinic receptors in TBI-induced memory impairment depends on the type of memory. This study highlights the potential for therapeutic modalities in TBI subjects.