Developmental origin and local signals cooperate to determine septal astrocyte identity

Abstract

Astrocyte specification during development is influenced by both intrinsic and extrinsic factors, but the precise contribution of each remains poorly understood. Here we show that septal astrocytes from Nkx2.1 and Zic4 expressing progenitor zones are allocated into non-overlapping domains of the medial (MS) and lateral septal nuclei (LS) respectively. Astrocytes in these areas exhibit distinctive molecular and morphological features tailored to the unique cellular and synaptic circuit environment of each nucleus. Using single-nucleus (sn) RNA sequencing, we trace the developmental trajectories of cells in the septum and find that neurons and astrocytes undergo region and developmental stage-specific local cell-cell interactions. We show that expression of the classic morphogens Sonic hedgehog (Shh) and Fibroblast growth factors (Fgfs) by MS and LS neurons respectively, functions to promote the molecular specification of local astrocytes in each region. Finally, using heterotopic cell transplantation, we show that both morphological and molecular specifications of septal astrocytes are highly dependent on the local microenvironment, regardless of developmental origins. Our data highlights the complex interplay between intrinsic and extrinsic factors shaping astrocyte identities and illustrates the importance of the local environment in determining astrocyte functional specialization.

Multimodal classification of neurons in the lateral septum

“…Consistent with previous studies, we found that the majority of MSNs (93.6%) have a history of Nkx2.1 expression ( Figure S2C ) (Magno et al, 2017; Wei et al, 2012). Notably, we observed a sharp contrast in Nkx2.1 lineage between medial and lateral septal astrocytes—at 87.2% and 10.8% respectively—indicating that astrocytes in the septum have distinct developmental origins (Xie et al, 2023).…”

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 .…”