Role of Muscarinic Receptors in Memory Retrieval

Abstract

Learning and memory is essential for successful survival of humans and animals. Memory retrieval is the phenomenon of utilizing memories and information acquired in the past to make decision and performance in present. It is crucial for survival and day to day activities of humans and animals. Inability to retrieve memories is known as retrograde amnesia. Cholinergic receptors are important for regulation of learning and memory processes. Impaired cholinergic transmission is a leading cause of cognitive deficit and amnesia. Cholinergic receptors, i.e. muscarinic and nicotinic receptors, have established role in memory acquisition and consolidation but their involvement in memory retrieval is not much investigated. This study was conducted to explore the role of muscarinic cholinergic receptors in memory retrieval and the effect of gender. Gender dependent role of muscarinic receptors in memory retrieval was assessed in young Balb/c mice under normal conditions, sub-chronic stress, post traumatic brain injury and sub-chronic D2 dopamine receptor antagonism. Mice were trained for spatial and fear memories, using Morris water maze test and contextual fear conditioning, respectively. After training they were subjected to cholinergic drug treatment i.e, 1mg/kg scopolamine (muscarinic receptor antagonist) and 1mg/kg donepezil (acetylcholine esterase inhibitor), under normal conditions, following sub-chronic restrain stress, traumatic brain injury and dopamine D2 receptor antagonism by risperidone (2.5 mg/kg). Memory retrieval was accessed using probe trial and context retention. Further, the involvement of hippocampal and entorhinal cortex muscarinic receptors in memory retrieval was also explored. Under normal conditions acute (30 minutes before test) and Abstract vii sub-chronic (for five days) muscarinic blockade impaired spatial memory retrieval in male (P < 0.05) but not in female mice (P > 0.05). Acute and sub-chronic scopolamine treatment impaired retrieval of contextual fear memory in male and female mice (P < 0.05), except sub-chronic treated female mice (P > 0.05). There was no effect of acute and sub-chronic cholinergic receptor antagonism on object memory retrieval in male and female mice. Sub-chronic stress impaired spatial memory retrieval in both male and female mice (P < 0.05) but the impaired spatial recall was not effected by muscarinic activity. However, muscarinic receptor activation by donepezil reversed stress induced fear memory retrieval in mice irrespective of gender (P < 0.005). Sub-chronic muscarinic modulation affected trauma induced neurological damage in gender dependent manner but their effect was not significant in reversing trauma induced fear and spatial memory retrieval deficit in both genders. Gender and task dependent effect of muscarinic receptors were observed in memory retrieval under sub-chronic dopamine antagonism. In male mice muscarinic modulation impaired spatial memory retrieval under dopaminergic antagonism (P < 0.05). Muscarinic antagonism impaired fear retrieval in males but significantly enhanced fear recall in females (P < 0.005) under sub-chronic antagonism. Hippocampal and medial entorhinal cortex muscarinic receptors were found to mediate spatial and fear memory retrieval but not the object memory retrieval. It is concluded that muscarinic receptors are important for memory retrieval. Under physiological conditions muscarinic activity displays gender dependent involvement in memory retrieval. Muscarinic activation enhanced emotional memory recall in both genders under stress condition. Sub-chronic muscarinic modulation Abstract viii gender dependently reversed trauma induced impaired spatial memory recall. Furthermore, muscarinic receptors in hippocampus and entorhinal are required for emotional and spatial memory retrieval. These findings suggest that role of muscarinic receptor activity in retrieving different types of memories depends on gender of subjects and the conditions during which memories are retrieved. Findings of this study emphasize on the importance of considering gender as crucial variable in exploring underlying mechanisms and potential therapeutic options for dementia and neurological disorders.