Mechanisms and circuits underlying the role of the lateral septum brain region in learning and memory

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The hippocampus processes spatial information for generating spatial contextual maps for navigation and episodic memory. The lateral septum (LS) is the main subcortical target of the hippocampal formation, receiving massive projections from the pyramidal neurons of CA3, CA2, CA1 and subiculum neurons. Despite receiving massive projections from the hippocampus, the nature of the information the LS is receiving, and the organization of hippocampal-LS circuits remains largely unknown. The LS is part of an extensive outer layer covering the medial septum (MS) which contains neurons that use GABA as their neurotransmitter. Because of its anatomical position, the LS may be involved in the integration of spatial and rewarding signals which is then passed on to the MS. Using cutting edge viral tracing techniques, optogenetics, new calcium imaging techniques with miniaturized fluorescence microscopy, and electrophysiology, we aim to characterize the spatial firing properties of cells in the LS based upon their anatomical connections and hypothesized functional relationship with the hippocampal formation and their output to the MS. All experiments in open field, goal directed navigation tasks, as well as memory-dependent tasks in freely behaving mice. General objective: The research program will determine the spatial coding properties of the different sub nuclei of the lateral septum, in reference to their anatomical connections and hypothesized functional relationship with the hippocampus and define the behavioral correlates of these projections in spatial navigation and reward seeking. We will determine using optogenetics how the LS causally contributes to these functions. Specific objectives: We will determine the specific role of this microcircuit in building, maintaining and updating the necessary associations between context and reward, focusing on the integrative role of the lateral septum. 1. Investigate the anatomical subdivisions of the LS with respect to its incoming projections, focusing on the different areas of the hippocampal formation, as well as their output to specific neuronal types in the medial septum. 2. Establish the spatial firing characteristics of these lateral septal cells in reference to their functional relationship with the hippocampus. We will use state-of-the-art calcium imaging techniques with miniature microscope combined with recently developed viral tracing strategies. 3. Using optogenetics, we will manipulate the LS circuits to provide causal evidence that LS neurons have an essential role in spatial navigation and memory as well as integrating space and reward. The results of this research program will reveal for the first time the functional features of LS neurons in direct relation to the incoming input from the hippocampus and independently from the different hippocampal subregions. The combination of these powerful techniques will provide a clear understanding of the role of LS neurons in memory.