Opioid-driven disruption of the septal complex reveals a role for neurotensin-expressing neurons in withdrawal

Abstract

Because opioid withdrawal is an intensely aversive experience, persons with opioid use disorder (OUD) often relapse to avoid it. The lateral septum (LS) is a forebrain structure that is important in aversion processing, and previous studies have linked the lateral septum (LS) to substance use disorders. It is unclear, however, which precise LS cell types might contribute to the maladaptive state of withdrawal. To address this, we used single-nucleus RNA-sequencing to interrogate cell type specific gene expression changes induced by chronic morphine and withdrawal. We discovered that morphine globally disrupted the transcriptional profile of LS cell types, but Neurotensin-expressing neurons (Nts; LS-Nts neurons) were selectively activated by naloxone. Using two-photon calcium imaging and ex vivo electrophysiology, we next demonstrate that LS-Nts neurons receive enhanced glutamatergic drive in morphine-dependent mice and remain hyperactivated during opioid withdrawal. Finally, we showed that activating and silencing LS-Nts neurons during opioid withdrawal regulates pain coping behaviors and sociability. Together, these results suggest that LS-Nts neurons are a key neural substrate involved in opioid withdrawal and establish the LS as a crucial regulator of adaptive behaviors, specifically pertaining to OUD.

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

“…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. Accordingly, we used multiplex fluorescent in situ hybridization (RNAscope 72 ) to characterize and identify whether Nts, Penk, Npy, and/or Pdyn represent overlapping or unique Sst-expressing lateral septal cell populations in male C57/BL6J mice (Figure 1A and S1A).…”

“…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 .…”

A ventral hippocampal-lateral septum pathway regulates social novelty preference

“…This study focused on ventral hippocampal projections to the lateral septum (LS) 8 . The LS, a subcortical structure primarily composed of GABAergic neurons [9][10][11] , receives dense projections from the vHPC and is well situated to orchestrate social novelty-related approach behaviors 8,[12][13][14][15][16] . For instance, LS neurons in rat pups differentially respond to sibling and non-sibling odors and are necessary for the expression of non-sibling preference in older pups 17 .…”