Converging innervation of somatostatin neurons in the lateral septum by the prefrontal cortex and hippocampus

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Converging innervation of somatostatin neurons in the lateral septum by the prefrontal cortex and hippocampus Abstract The lateral septum (LS) is a central hub in regulating various affective behaviors, including feeding, anxiety, fear, reward, sociability, and memory. The LS predominantly comprises heterogeneous GABAergic spiny neurons that receive inputs from various cortical and subcortical regions. However, how the LS integrates the information from different inputs remains unknown. Recent studies suggest that the LS's diverse functions may be attributable to both heterogeneous subpopulations and topographically organized structures that exhibit different input and output connections. Notably, the dorsal and ventral poles of the LS (dLS and vLS) have distinct and often opposing roles. This functional heterogeneity may be partially explained by distinct dorsal and ventral inputs from the hippocampus (e.g., dCA1 and vCA1), as well as competitive inputs from the infralimbic (IL) region of the prefrontal cortex (PFC). However, evidence is lacking for how these diverse inputs differentially innervate diverse cell types in the LS subregions. Recent studies indicated that somatostatin (SST) is highly expressed in the LS, and SST neurons are activated by diverse stressors, gating distinct fear responses. Given the topographic projections from the hippocampus and IL to LS subregions, a fundamental question raised is whether SST neurons in the dLS and vLS are convergently innervated by both the hippocampus and IL. In this proposal, we hypothesize that SST neurons within sub-circuits of the LS (i.e., dLS and vLS) exhibit distinct physiological properties and synaptic connections from their upstream IL and CA1 inputs. Specifically, while SST neurons in the dLS and vLS are selectively driven by dCA1 or vCA1 inputs, respectively, the vLS activity can be overridden by IL inputs through an IL-dLS-vLS disynaptic pathway. To test this hypothesis, we will utilize in vitro and in vivo physiological recording combined with intersectional viral approach and optostimulation. In Aim 1, we will determine how SST neurons within the LS subcircuits are innervated by IL and CA1 inputs in vitro. In Aim 2, we will determine the synaptic and functional responses of SST neurons within LS subcircuits to IL and CA1 inputs in vivo. We expect this study will provide novel information about the neural circuity that comprises the basis of affective functions, which may elucidate the pathophysiology of various disorders in which these processes are dysregulated.