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

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 x 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.

Automated summary

Traumatic brain injury (TBI) is a significant global risk factor for cognitive impairment and neurodegenerative diseases. Cognitive and memory impairment following a TBI is associated with dysregulation of cholinergic neurotransmission. The severity of memory impairment varies by sex. This study investigated the role of muscarinic cholinergic modulation in neurological functioning and episodic memory retrieval in a TBI mouse model, revealing sex differences in the response to treatments.