Transcriptional profiling of sequentially generated septal neuron fates

García, Miguel Turrero; Stegmann, Sarah K.; Lacey, Tiara E; Reid, C.; Hrvatin, Siniša; Weinreb, Caleb; Adam, Manal A; Nagy, Martina; Harwell, Corey C.

doi:10.1101/2021.06.29.450296

Cited by 4 publications

(17 citation statements)

References 70 publications

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“…In line with our hypothesis, a recent study found that AHA GABAergic neurons mediate avoidance behavior via their projection to the vlPAG [ 59 ]. Although few studies have focused on LS neuronal populations expressing specific molecular determinants [ 60 ], it is likely that discrete populations integrating information from similar cortical areas exert complementary yet non-overlapping roles on physiological and behavioral responses.…”

Section: Possible Interactions Between Ls Circuitsmentioning

confidence: 99%

Top-down regulation of motivated behaviors via lateral septum sub-circuits

Besnard

Leroy

2022

Mol Psychiatry

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How does cognition regulate innate behaviors? While the cognitive functions of the cortex have been extensively studied, we know much less about how cognition can regulate innate motivated behaviors to fulfill physiological, safety and social needs. Selection of appropriate motivated behaviors depends on external stimuli and past experiences that helps to scale priorities. With its abundant inputs from neocortical and allocortical regions, the lateral septum (LS) is ideally positioned to integrate perception and experience signals in order to regulate the activity of hypothalamic and midbrain nuclei that control motivated behaviors. In addition, LS receives numerous subcortical modulatory inputs, which represent the animal internal states and also participate in this regulation. In this perspective, we argue that LS sub-circuits regulate distinct motivated behaviors by integrating neural activity from neocortical, allocortical and neuromodulatory inputs. In addition, we propose that lateral inhibition between LS sub-circuits may allow the emergence of functional units that orchestrates competing motivated behaviors.

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Section: Possible Interactions Between Ls Circuitsmentioning

confidence: 99%

Top-down regulation of motivated behaviors via lateral septum sub-circuits

Besnard

Leroy

2022

Mol Psychiatry

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“…We performed in situ hybridization for Crhr2 and found an almost complete depletion of this mRNA throughout the LS of cKO mice (Figure 2A). We found that Crhr2expressing cells were largely confined to the tdTomato+ Nkx2.1-lineage (Figure 2B), providing the first direct evidence that their developmental origin is the septal eminence 10 . The lateral septum is densely innervated by axons positive for urocortin-3 (UCN-3), a neuropeptide within the corticotropin-releasing factor family with high affinity for the CRHR2 receptor 20,21 .…”

Section: Reduced Innervation Of the Lateral Septum In The Absence Of ...mentioning

confidence: 56%

“…In the MGE/PoA, expression of Prdm16 is confined to progenitors, where it controls their proliferative capacity 15 . In the developing septum, Prdm16 expression is sustained in postmitotic neurons 10,41 , potentially reflecting a specific need for this gene in the survival of septal neurons. The Nkx2.1-lineage in the LS is largely derived from the septal eminence, which produces sequential cohorts of neurons with diverse morphologies and anatomical locations over the neurogenic period 10 .…”

Section: Discussionmentioning

confidence: 99%

“…Nkx2.1-lineage cells constitute a significant proportion of the medial and lateral septal nuclei 7,10,11 . Since newborn septal neurons express high levels of Prdm16 10 , we decided to examine the effect of Prdm16 deletion within the Nkx2.1 lineage 15 in the septa of control (Nkx2.1Cre;Ai14, hereafter labeled as 'WT') and mutant (Nkx2.1Cre;Prdm16 f/f ;Ai14, labeled as 'cKO') mice (Figure 1A).…”

Section: Deletion Of Nkx21-lineage Neurons In the Lateral Septummentioning

confidence: 99%

“…To understand how the septum controls specific behavioral responses, it is necessary to study defined neuronal populations and their connectivity. Developmental lineage is often a good predictor of mature neuron identity, as neurons with shared developmental origins tend to share aspects of their circuitry and functional features [7][8][9][10][11] . Nkx2.1 is a transcription factor expressed during embryonic development in forebrain progenitors within the medial ganglionic eminence / preoptic area (MGE/PoA) and the septal eminence (SE); the latter proliferative area is distinguished as part of the developing septal complex by its expression of transcription factors of the Zic family [12][13][14] .…”

Section: Introductionmentioning

confidence: 99%

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

García,

Tran,

Peterson

et al. 2023

Preprint

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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.

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TrkB-dependent regulation of molecular signaling across septal cell types

Rodriguez

Tran

Garcia-Flores

et al. 2023

Preprint

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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.

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Transcriptional profiling of sequentially generated septal neuron fates

Cited by 4 publications

References 70 publications

Top-down regulation of motivated behaviors via lateral septum sub-circuits

Top-down regulation of motivated behaviors via lateral septum sub-circuits

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

TrkB-dependent regulation of molecular signaling across septal cell types

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