Activation of Somatostatin-Expressing Neurons in the Lateral Septum Improves Stress-Induced Depressive-like Behaviors in Mice

Abstract

Depression is a debilitating mood disorder with highly heterogeneous pathogenesis. The limbic system is well-linked to depression. As an important node in the limbic system, the lateral septum (LS) can modulate multiple affective and motivational behaviors. However, the role of LS in depression remains unclear. By using c-Fos expression mapping, we first screened and showed activation of the LS in various depression-related behavioral tests, including the forced swim test (FST), tail suspension test (TST), and sucrose preference test. In the LS, more than 10% of the activated neurons were somatostatin-expressing (SST) neurons. We next developed a microendoscopic calcium imaging method in freely moving mice and revealed that LSSST neural activity increased during mobility in the TST but not open field test. We hypothesize that LSSST neuronal activity is linked to stress and depression. In two mouse models of depression, repeated lipopolysaccharide (LPS) injection and chronic restraint stress (CRS), we showed that LS neuronal activation was suppressed. To examine whether the re-activation of LSSST neurons can be therapeutically beneficial, we optogenetically activated LSSST neurons and produced antidepressant-like effects in LPS-injected mice by increasing TST motility. Moreover, chemogenetic activation of LSSST neurons increased FST struggling in the CRS-exposed mice. Together, these results provide the first evidence of a role for LSSST neurons in regulating depressive-like behaviors in mice and identify them as a potential therapeutic target for neuromodulation-based intervention in depression.

A neuronal coping mechanism linking stress-induced anxiety to motivation for reward

“…Previous studies indicate that SST can mediate inhibitory responses primarily at dendritic sites within excitatory neuronal networks (67-69) and also at axonal sites within the MHb-IPN pathway (62). In addition, SST function is implicated in anxiety-like behavior (70,71) and behavioral responses mediated by chronic stress (72)(73)(74). Our scRNAseq data identified IPN stress-activated neurons as highly enriched for SST, suggesting that the IPN is part of the SSTergic network underlying self-grooming.…”

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

“…We identified 14 molecularly defined cell types in the septum (2 glutamatergic and 12 GABAergic), which we determined by evaluating cluster stability over multiple clustering granularities (Figure 1C, S1G). Among these neurons, we found clusters that corresponded to previously-identified LS cell types, including neurotensin-(Nts+; Gaba8), somatostatin-(Sst+; Gaba11), corticotropin-releasing hormone receptor 2-(Crhr2+; Gaba5) and dopamine receptor 3expressing (Drd3+) neurons [19][20][21][32][33][34][35] . Crhr2 expression was limited to the Gaba5 subcluster, but Nts and Sst expression were more promiscuous.…”

“…Using in situ , in vivo , and ex vivo approaches, we demonstrated that spontaneous withdrawal induces LS- Nts activity in vivo, likely due to opioid-driven increases in glutamatergic signaling onto LS- Nts neurons. Opioid withdrawal is arguably a chronic stress state 1,3,22,61 , and other states of chronic distress, such as pain and chronic social defeat, elevate neuronal activity in the LS, including in LS- Nts , LS- Sst , and general LS GABAergic neurons 34,62,63 . We originally hypothesized that prolonged LS- Nts activation would be maladaptive, but our results indicated the opposite.…”

Multimodal classification of neurons in the lateral septum

“…Recently, groups of functionally distinct LS neurons have been characterized based on differences in the expression of neuropeptides and neurotransmitter receptors. For instance, somatostatin ( Sst) expressing neurons in the LSd have been implicated in the regulation of context-associated fear behaviors and are thought to be anxiolytic (An et al, 2022; Besnard et al, 2019; Li et al, 2022). In contrast, neurons expressing the corticotropin releasing hormone receptor 2 ( Crhr2 ) in the LSi are activated by threatening stimuli and are anxiogenic (Anthony et al, 2014; Hashimoto et al, 2022).…”