The role of the septum in social memory

点击翻译按钮获取中文摘要

Project summary Social memory impairment is one of the most debilitating symptoms of autism spectrum disorder (ASD). Although the hippocampus has been well established to be the key player in social memory, hippocampal input regions that may regulate social memory have not been explored. The septum sends strong direct and indirect projections to the hippocampus and has been heavily implicated in emotional processing and social interactions. However, it is unclear which synaptic changes and cell-types drive the septum’s role in social memory. Further, the impact of the septum in social memory-related disorders such as ASD is understudied. Therefore, investigating the mechanism of social memory and the associated synaptic and cellular changes will be critical for creating additional and potentially improved treatment options. My long-term goal is to use integrative approaches to study the mechanisms of social dysfunction. The overall objective is to identify circuit and synaptic underpinnings of social memory regulation by the septum and develop rescue strategies for social memory deficits in mouse models with social memory impairments. Based on my preliminary results, I hypothesize that synaptic plasticity in certain septal cell-types occurs after social exposure and that these synaptic changes are likely to be the critical factor in enhancing social memory. Therefore, I will pursue two specific aims: 1) Dissect the circuit and synaptic mechanisms of social memory modulation by the septum; and 2) Develop rescue strategies for social memory deficits in ASD-associated mouse models with social memory impairment. In the first aim I will systematically identify the septal cell-types involved in social memory using a combination of viral tracing and immunohistochemistry. I will then determine social memory- induced input changes from septal neurons onto hippocampal neurons with ex vivo slice electrophysiology in FosTRAP2 mice. Finally, I will determine the septum’s role in social memory acquisition, consolidation and recall via in vivo optogenetics. In the second aim, I plan to identify the synaptic alterations in two ASD-associated mouse models, Neuroligin-3R451C and SynGAP1het lines, which display social memory deficiency. Moreover, I will develop strategies for the improvement of social memory in these mouse lines via in vivo optogenetic stimulation and micro-infusion of neuromodulators. The approach detailed in this proposal is innovative, because it harnesses new technological advances by integrating viral-tracing with in vivo and ex vivo optogenetics to examine the mechanisms governing social memory. Preliminary studies suggest that the septum to hippocampal projection plays a role in regulating social memory and that the control of social memory by the septum is bi-directional. The proposed research is therefore highly significant, as the bi-directional control of social memory offers immense therapeutic potential. Ultimately, the outcome will likely provide a framework for translational research towards the improvement of social memory deficits.