Transcriptional and Spatial Resolution of Cell Types in the Mammalian Habenula

Hashikawa, Yoshiko; Hashikawa, Koichi; Rossi, Mark A.; Basiri, Marcus L.; Liu, Yuejia; Johnston, Nathan L.; Ahmad, Omar R.; Stuber, Garret D.

doi:10.1016/j.neuron.2020.03.011

Cited by 113 publications

(141 citation statements)

References 111 publications

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“…Both our study ( Supplementary Fig. 4 ) and previous reports showed that OxR2 has a larger population in the LHb than OxR1 ( Hashikawa et al, 2020 ; Zhang et al, 2018 ), indicating that OxR2 is more likely involved in the modulation of LHb function. However, the regulatory effect of OxR1 signaling in the LHb is worth investigating in the future.…”

Section: Discussionsupporting

confidence: 76%

“…Exposure to chronic social stress significantly increases the excitability of LHb neurons ( Huang et al, 2019 ). LHb neurons encode mRNA for both OxR1 and OxR2, but with higher proportion of OxR2 ( Hashikawa et al, 2020 ). These studies suggest that orexinergic projections from the LHA to the LHb may also mediate depression-like behavior induced by social stress.…”

Section: Introductionmentioning

confidence: 99%

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Lateral hypothalamus orexinergic inputs to lateral habenula modulate maladaptation after social defeat stress

Wang

Dong

et al. 2021

Neurobiology of Stress

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Social stress, a common stressor, causes multiple forms of physical and mental dysfunction. Prolonged exposure to social stress is associated with a higher risk of psychological disorders, including anxiety disorders and major depressive disorder (MDD). The orexinergic system is involved in the regulation of multiple motivated behaviors. The current study examined the regulatory effect of orexinergic projections from the lateral hypothalamic area (LHA) to the lateral habenula (LHb) in depression- and anxiety-like behaviors after chronic social defeat stress. When mice were defeated during social interaction, both orexinergic neurons in the LHA and glutamatergic neurons in the LHb were strongly activated, as indicated by the FosTRAP strategy. Infusion of orexin in the LHb significantly alleviated social avoidance and depression-like behaviors induced by chronic social defeat stress. Administration of an orexin receptor 2 antagonist in the LHb further aggravated the depressive phenotype. Photoactivation of orexinergic cell bodies in the LHA or terminals in the LHb relieved anxiety-like behaviors induced by chronic social defeat stress. Collectively, we identified the antidepressant and anxiolytic effects of the circuit from LHA orexinergic neurons to the LHb in response to chronic social stress, providing new evidence of the antidepressant properties of LHA orexin circuits.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Lateral hypothalamus orexinergic inputs to lateral habenula modulate maladaptation after social defeat stress

Wang

Dong

et al. 2021

Neurobiology of Stress

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“…To link the molecular and physiological properties of single cells, researchers applied a combined method of whole-cell recording and single-cell RNA sequencing (scRNA-seq) to individual neurons in acute slices in early studies and named this method “patch-seq” [ 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 ]. The basic protocol of patch-seq is as follows: researchers perform whole-cell recording from individual neurons from living tissue slices or even intact animals and aspirate the cell contents through a patch pipette for subsequent RNA sequencing.…”

Section: Hybrid Methodologies With In Vivo Whole-cell Recording Tementioning

confidence: 99%

In Vivo Whole-Cell Patch-Clamp Methods: Recent Technical Progress and Future Perspectives

Noguchi

Ikegaya

Matsumoto

2021

Sensors

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Brain functions are fundamental for the survival of organisms, and they are supported by neural circuits consisting of a variety of neurons. To investigate the function of neurons at the single-cell level, researchers often use whole-cell patch-clamp recording techniques. These techniques enable us to record membrane potentials (including action potentials) of individual neurons of not only anesthetized but also actively behaving animals. This whole-cell recording method enables us to reveal how neuronal activities support brain function at the single-cell level. In this review, we introduce previous studies using in vivo patch-clamp recording techniques and recent findings primarily regarding neuronal activities in the hippocampus for behavioral function. We further discuss how we can bridge the gap between electrophysiology and biochemistry.

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“…Wagner, et al 25 used in situ hybridization images from the Allen Brain Atlas to map transcript expression throughout the LHb and its subregions, finding ten distinct anatomical patterns of expression. Recent single cell RNAseq profiles of the habenular nuclei identified several types of distinct neurons 26,27 , although none of these appeared to be pathway-specific. However, these studies did not explicitly examine gene expression between the three major LHb outputs.…”

mentioning

confidence: 99%

“…Given the heterogeneity of the LHb transcriptome and the functional differences between its anatomically segregated output pathways, it seems plausible that gene expression in these pathways respond differentially to stress. Additionally, while both Hashikawa, et al 27 and Wallace, et al 26 studied the murine habenula, this is the first study examining the genetic profile of LHb neurons in the rat.…”

mentioning

confidence: 99%

Stress induces divergent gene expression among lateral habenula efferent pathways

Levinstein

Coffey

Marx

et al. 2020

Preprint

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The lateral habenula (LHb) integrates critical information regarding aversive stimuli that shapes decision making and behavioral responses. The three major LHb outputs innervate dorsal raphe nucleus (DRN), ventral tegmental area (VTA), and the rostromedial tegmental nucleus (RMTg). LHb neurons that project to these targets are segregated and nonoverlapping, and this led us to consider whether they have distinct molecular phenotypes and adaptations to stress exposure. In order to capture a time-locked profile of gene expression after repeated forced swim stress, we used intersectional expression of RiboTag in rat LHb neurons and next-gen RNA sequencing to interrogate the RNAs actively undergoing translation from each of these pathways. The "translatome" in the neurons comprising these pathways was similar at baseline, but diverged after stress, especially in the neurons projecting to the RMTg. Using weighted gene co-expression network analysis, we found one module comprising genes downregulated after stress in the RMTg-projecting LHb neurons; there was an overrepresentation of genes associated with phosphoinositide 3 kinase (PI3K) signaling in this module. Reduced PI3K signaling in RMTg-projecting LHb neurons may be a compensatory adaptation that alters the functional balance of LHb outputs to GABAergic vs. monoaminergic neurons following repeated stress exposure.

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Transcriptional and Spatial Resolution of Cell Types in the Mammalian Habenula

Cited by 113 publications

References 111 publications

Lateral hypothalamus orexinergic inputs to lateral habenula modulate maladaptation after social defeat stress

Lateral hypothalamus orexinergic inputs to lateral habenula modulate maladaptation after social defeat stress

In Vivo Whole-Cell Patch-Clamp Methods: Recent Technical Progress and Future Perspectives

Stress induces divergent gene expression among lateral habenula efferent pathways

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