TrkB-dependent regulation of molecular signaling across septal cell types

Abstract

The lateral septum (LS), a GABAergic structure located in the basal forebrain, is implicated in social behavior, learning, and memory. We previously demonstrated that expression of tropomyosin kinase receptor B (TrkB) in LS neurons is required for social novelty recognition. To better understand molecular mechanisms by which TrkB signaling controls behavior, we locally knocked down TrkB in LS and used bulk RNA-sequencing to identify changes in gene expression downstream of TrkB. TrkB knockdown induces upregulation of genes associated with inflammation and immune responses, and downregulation of genes associated with synaptic signaling and plasticity. Next, we generated one of the first atlases of molecular profiles for LS cell types using single nucleus RNA-sequencing (snRNA-seq). We identified markers for the septum broadly, and the LS specifically, as well as for all neuronal cell types. We then investigated whether the differentially expressed genes (DEGs) induced by TrkB knockdown map to specific LS cell types. Enrichment testing identified that downregulated DEGs are broadly expressed across neuronal clusters. Enrichment analyses of these DEGs demonstrated that downregulated genes are uniquely expressed in the LS, and associated with either synaptic plasticity or neurodevelopmental disorders. Upregulated genes are enriched in LS microglia, associated with immune response and inflammation, and linked to both neurodegenerative disease and neuropsychiatric disorders. In addition, many of these genes are implicated in regulating social behaviors. In summary, the findings implicate TrkB signaling in the LS as a critical regulator of gene networks associated with psychiatric disorders that display social deficits, including schizophrenia and autism, and with neurodegenerative diseases, including Alzheimer’s.

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 .…”