Hypothalamus-habenula potentiation encodes chronic stress experience and drives depression onset

Zheng, Zhiwei; Guo, Chunguang; Li, Min; Yang, Liang; Liu, Pengyang; Zhang, Xuliang; Liu, Yiqin; Guo, Xiaonan; Cao, Shu-Xia; Dong, Yiyan; Zhang, Chunlei; Chen, Min; Xu, Jiamin; Hu, Hailan; Cui, Yihui

doi:10.1016/j.neuron.2022.01.011

Cited by 75 publications

(73 citation statements)

References 63 publications

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“…2Bi and Bii; p = 0.0009; Chi-square test), which appeared to be specific for tonically active neurons. This was an interesting observation as bursting activity of LHb neurons is believed to be the primary driver of depressive behaviour (Yang et al ., 2018; Zheng et al ., 2022).…”

Section: Resultsmentioning

confidence: 99%

“…The lateral habenula (LHb) is an evolutionarily conserved brain structure located within the epithalamus which encodes aversive events (Matsumoto and Hikosaka, 2007; Lecca et al ., 2017), and depressive behaviour (Li et al ., 2011; Yang et al ., 2018; Hu et al ., 2020; Zheng et al ., 2022). Specifically, the LHb becomes hyperactive in depression (Li et al ., 2011; Lecca et al ., 2016; Tchenio et al ., 2017; Cui et al ., 2018; Yang et al ., 2018), thus enhancing output to the midbrain reward circuitry, for which the LHb acts as an inhibitory modulator (Wang and Aghajanian, 1977; Ji and Shepard, 2007; Jhou et al ., 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, many studies have employed the use of a variety of different animal models of depressive behaviour including chronic mild stress (Cerniauskas et al ., 2019), chronic restraint stress (Yang et al ., 2018; Zheng et al ., 2022), social defeat (Golden et al ., 2016; Knowland et al ., 2017), learned helplessness (Li et al ., 2011) and various models of early life stress (Tchenio et al ., 2017; Authement et al ., 2018; Simmons et al ., 2020; Langlois et al ., 2022), and have independently reached this conclusion that the LHb becomes hyperactive in depression. However, the majority of these studies have carried out experimentation shortly after exposure to the relevant stressor, and as such there is comparatively little evidence as to the long-term persistence of depressive phenotype, and the corresponding synaptic and physiological alterations within the LHb (Langlois et al ., 2022).…”

Section: Introductionmentioning

confidence: 99%

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Effects of early life stress and subsequent re-exposure to stress on neuronal activity in the lateral habenula

Webster

Beerens

Wozny

2022

Preprint

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Early life stress can result in depression in humans and depressive-like behaviour in rodents. In various animal models of depression, the lateral habenula (LHb) has been shown to become hyperactive immediately after early life stress. However, whether these pathological changes persist into adulthood is less well understood. Hence, we utilised the maternal separation (MS) model of depression to study how early life stress alters LHb physiology and depressive behaviour in adult mice. We find that only a weak depressive phenotype persists into adulthood which surprisingly is underpinned by LHb hypoactivity in acute slices, accompanied by alterations in both excitatory and inhibitory signalling. However, while we find the LHb to be less active at rest, we report that the neurons reside in a sensitised state where they are more responsive to re-exposure to stress in adulthood in the form of acute restraint, thus priming them to respond to aversive events with an increase in neuronal activity mediated by changes in glutamatergic transmission. These findings thus suggest that in addition to LHb hyperactivity, hypoactivity likely also promotes an adverse phenotype. Re-exposure to stress results in the reappearance of LHb hyperactivity offering a possible mechanism to explain how depression relapses occur following previous depressive episodes.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of early life stress and subsequent re-exposure to stress on neuronal activity in the lateral habenula

Webster

Beerens

Wozny

2022

Preprint

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“…Recent findings have identified the effects that CRS shares with other paradigms and that mirror those observed in humans ( Yuen et al, 2012 ; Seewoo et al, 2020 ; Yoo et al, 2022 ). For example both CRS and CSDS induce elevated firing in the projection from the lateral hypothalamus to the LHb which causes the onset of depressive-like symptoms ( Zheng et al, 2022 ). Additional studies will further confirm the usefulness of this practical and efficient paradigm.…”

Section: Modelling Pathogenesismentioning

confidence: 99%

Encore: Behavioural animal models of stress, depression and mood disorders

Petković

Chaudhury

2022

Front. Behav. Neurosci.

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Animal studies over the past two decades have led to extensive advances in our understanding of pathogenesis of depressive and mood disorders. Among these, rodent behavioural models proved to be of highest informative value. Here, we present a comprehensive overview of the most popular behavioural models with respect to physiological, circuit, and molecular biological correlates. Behavioural stress paradigms and behavioural tests are assessed in terms of outcomes, strengths, weaknesses, and translational value, especially in the domain of pharmacological studies.

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“…However, many characterized regions in this study were previously underappreciated as potential mediators of psilocybin's action. Preferential effect for psilocybin in insular area, which is implicated in interoception and emotional awareness (69), area postrema, which is involved in vomiting for humans, and lateral habenula, which is maladaptively affected by stress and depressive state (70)(71)(72), are a few examples of potential interest.…”

Section: Psilocybin and Ketamine Induce Convergent And Distinct Diffe...mentioning

confidence: 99%

Shared and distinct brain regions targeted for immediate early gene expression by ketamine and psilocybin

Davoudian

Shao

Kwan

2022

Preprint

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Background: Psilocybin is a psychedelic with therapeutic potential. While there is growing evidence that psilocybin exerts its beneficial effects through enhancing neural plasticity, the exact brain regions involved are not completely understood. Determining the impact of psilocybin on plasticity-related gene expression throughout the brain can broaden our understanding of the neural circuits involved in psychedelic-evoked neural plasticity. Methods: Whole-brain serial two-photon microscopy and light sheet microscopy were employed to map the expression of the immediate early gene, c-Fos, in male and female mice. The drug-induced c-Fos expression following psilocybin administration was compared to that of subanesthetic ketamine and saline control. To gain insights into the contributions of receptors and cell types, the c-Fos expression maps were related to brain-wide in situ hybridization data. Results: Psilocybin and ketamine produced acutely comparable elevations in c-Fos expression in numerous brain regions, including anterior cingulate cortex, locus coeruleus, primary visual cortex, central and basolateral amygdala, and claustrum. Select regions exhibited drug-preferential differences, such as dorsal raphe, lateral habenula, and insular cortex for psilocybin and retrosplenial cortex for ketamine. Correlation of psilocybin's effects with gene expression highlighted potential roles of 5-HT2A and GluN2B subunit of NMDA receptors. Conclusions: The systematic mapping approach produced an unbiased list of brain regions impacted by psilocybin and ketamine. The data are a valuable resource that highlights previously underappreciated regions for future investigations. By identifying regions with similar and disparate effects, the results provide insights into how psilocybin and ketamine may produce their rapid-acting and long-lasting therapeutic effects.

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Hypothalamus-habenula potentiation encodes chronic stress experience and drives depression onset

Cited by 75 publications

References 63 publications

Effects of early life stress and subsequent re-exposure to stress on neuronal activity in the lateral habenula

Effects of early life stress and subsequent re-exposure to stress on neuronal activity in the lateral habenula

Encore: Behavioural animal models of stress, depression and mood disorders

Shared and distinct brain regions targeted for immediate early gene expression by ketamine and psilocybin

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