A developmentally defined population of neurons in the lateral septum controls responses to aversive stimuli

Abstract

When interacting with their environment, animals must balance exploratory and defensive behavior to evaluate and respond to potential threats. The lateral septum (LS) is a structure in the ventral forebrain that calibrates the magnitude of behavioral responses to stress-related external stimuli, including the regulation of threat avoidance. The complex connectivity between the LS and other parts of the brain, together with its largely unexplored neuronal diversity, makes it difficult to understand how defined LS circuits control specific behaviors. Here, we describe a mouse model in which a population of neurons with a common developmental origin (Nkx2.1-lineage neurons) are absent from the LS. Using a combination of circuit tracing and behavioral analyses, we found that these neurons receive inputs from the perifornical area of the anterior hypothalamus (PeFAH) and are specifically activated in stressful contexts. Mice lacking Nkx2.1-lineage LS neurons display increased exploratory behavior even under stressful conditions. Our study extends the current knowledge about how defined neuronal populations within the LS can evaluate contextual information to select appropriate behavioral responses. This is a necessary step towards understanding the crucial role that the LS plays in neuropsychiatric conditions where defensive behavior is dysregulated, such as anxiety and aggression disorders.

A dorsal hippocampus-prodynorphinergic dorsolateral septum-to-lateral hypothalamus circuit mediates contextual gating of feeding

“…Sst-expressing cells, such as in the cortex 42,[66][67][68][69] , exhibit a wide range of neuropeptides. Sequencing experiments have noted the expression of various neuropeptides in the septum [36][37][38][39][40][41][42][43] , including Sst, neurotensin (Nts), proenkephalin (Penk), neuropeptide Y (Npy), and Pdyn, but the extent of their overlap and localization within the LS isn't well-defined. Moreover, while LS(Nts) circuits have been linked to a variety of motivated behaviors 63,65,70,71 , little to nothing is known of other LS neuropeptidergic populations, such as Pdyn, Penk, or Npy.…”

“…The dorsolateral subregion of the lateral septum (DLS) sits at the top of the LS and is well-positioned to regulate context-dependent behaviors, such as feeding, given its considerable DHPC input and robust targeting of hypothalamic regions, including the LHA 36 . A myriad of cell-types exists within the LS [37][38][39][40][41][42][43] , distinguished by their input-output connectivity, physiology and neuropeptidergic expression, and this diversity likely contributes to the various behaviors now associated with LS function [44][45][46][47][48][49] , including cell-type-specific contributions of LS neurons to stress-responding and conditioned fear 36,[50][51][52][53] , social interactions [54][55][56][57] , and drug-and food-seeking or consumption 43,[58][59][60][61][62][63][64][65] . A predominant cell-type in the DLS is somatostatin (Sst)-expressing inhibitory neurons 36,43,53 .…”