Molecular characterization of depression trait and state

Shukla, Rammohan; Newton, Dwight F.; Sumitomo, Akiko; Zare, Habil; McCullumsmith, Robert E.; Lewis, David A.; Tomoda, Toshifumi; Sibille, Etienne

doi:10.1038/s41380-021-01347-z

Cited by 29 publications

(29 citation statements)

References 69 publications

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“…In our previous study, an immune function-related gene module associated with CRH+ cells showed the highest probabilistic association to MDD (16), suggesting a causal role of elevated immune response in CRH+ cells on the disease trajectory. It is unclear how these elevated immune response-and inflammation-related gene expression in CRH+ interneurons is associated with the pathophysiology of MDD.…”

Section: Discussionmentioning

confidence: 80%

“…Recent animal and human studies implicate CRH and CRH+ cells in the stress response and trajectory of MDD across episode and remission phases (15,16,45), however, the molecular characteristics and pathological features of cortical CRH+ cells in the human brain are largely unknown. Here, we report that CRH is mostly expressed in GABAergic interneurons and that it overlaps with the major classes of interneurons in the human ACC, specifically VIP+ interneurons (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

“…CRH+ neurons and released CRH peptide were shown to modulate cognitive-and moodrelated behaviors (14,15). The association of CRH+ neurons with MDD is also implied by a subsequent RNA sequencing (RNAseq) study performed in the subgenual anterior cingulate cortex (sgACC) of MDD patients (16). In that study, we performed cell-type deconvolution of bulk tissue RNAseq data, which suggested that CRH-expressing (CRH+) neurons are affected by the disease and their transcriptomic changes are synchronized with the episode and remission phases of the illness.…”

Section: Introductionmentioning

confidence: 99%

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Lower Levels of GABAergic Function Markers in Corticotropin-Releasing Hormone-Expressing Neurons in the sgACC of Human Subjects With Depression

Newton

Lewis

et al. 2022

Front. Psychiatry

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RationaleA previous transcriptome meta-analysis revealed significantly lower levels of corticotropin-releasing hormone (CRH) mRNA in corticolimbic brain regions in major depressive disorder (MDD) subjects, suggesting that cortical CRH-expressing (CRH+) cells are affected in MDD. Rodent studies show that cortical CRH is mostly expressed in GABAergic interneurons; however, the characteristic features of CRH+ cells in human brain cortex and their association with MDD are largely unknown.MethodsSubgenual anterior cingulate cortex (sgACC) of human subjects without brain disorders were labeled using fluorescent in situ hybridization (FISH) for CRH and markers of excitatory (SLC17A7), inhibitory (GAD1) neurons, as well as markers of other interneuron subpopulations (PVALB, SST, VIP). MDD-associated changes in CRH+ cell density and cellular CRH expression (n = 6/group) were analyzed. RNA-sequencing was performed on sgACC CRH+ interneurons from comparison and MDD subjects (n = 6/group), and analyzed for group differences. The effect of reduced BDNF on CRH expression was tested in mice with blocked TrkB function.ResultsAbout 80% of CRH+ cells were GABAergic and 17.5% were glutamatergic. CRH+ GABAergic interneurons co-expressed VIP (52%), SST (7%), or PVALB (7%). MDD subjects displayed lower CRH mRNA levels in GABAergic interneurons relative to comparison subjects without changes in cell density. CRH+ interneurons show transcriptomic profile suggesting lower excitability and less GABA release and reuptake. Further analyses suggested that these molecular changes are not mediated by altered glucocorticoid feedback and potentially occur downstream for a common modulator of neurotrophic function.SummaryCRH+ cells in human sgACC are a heterogeneous population of GABAergic interneurons, although largely co-expressing VIP. Our data suggest that MDD is associated with reduced markers of inhibitory function in sgACC CRH+ interneurons, and provide further evidence for impaired GABAergic function in the cortex in MDD.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lower Levels of GABAergic Function Markers in Corticotropin-Releasing Hormone-Expressing Neurons in the sgACC of Human Subjects With Depression

Newton

Lewis

et al. 2022

Front. Psychiatry

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“…More recently, insights into the transcriptional signatures associated with depressive traits and states have been made (Shukla et al, 2021 ). Using RNAseq from the anterior cingulate gyrus, Shukla and colleagues investigated transcriptional signatures from four different cohorts during: a first depressive episode; remission after the first episode; recurrent episodes, or remission after recurrent episodes.…”

Section: Sex-specific Molecular Alterations In Mddmentioning

confidence: 99%

Sex-Specific Brain Transcriptional Signatures in Human MDD and Their Correlates in Mouse Models of Depression

Touchant

Labonté

2022

Front. Behav. Neurosci.

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Major depressive disorder (MDD) is amongst the most devastating psychiatric conditions affecting several millions of people worldwide every year. Despite the importance of this disease and its impact on modern societies, still very little is known about the etiological mechanisms. Treatment strategies have stagnated over the last decades and very little progress has been made to improve the efficiency of current therapeutic approaches. In order to better understand the disease, it is necessary for researchers to use appropriate animal models that reproduce specific aspects of the complex clinical manifestations at the behavioral and molecular levels. Here, we review the current literature describing the use of mouse models to reproduce specific aspects of MDD and anxiety in males and females. We first describe some of the most commonly used mouse models and their capacity to display unique but also shared features relevant to MDD. We then transition toward an integral description, combined with genome-wide transcriptional strategies. The use of these models reveals crucial insights into the molecular programs underlying the expression of stress susceptibility and resilience in a sex-specific fashion. These studies performed on human and mouse tissues establish correlates into the mechanisms mediating the impact of stress and the extent to which different mouse models of chronic stress recapitulate the molecular changes observed in depressed humans. The focus of this review is specifically to highlight the sex differences revealed from different stress paradigms and transcriptional analyses both in human and animal models.

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“…Somatostatin-expressing (SST) GABAergic neurons can provide powerful inhibitions in both local and long-range brain networks [ 65 ]. Evidence suggests that somatostatin deficits are involved in depression pathophysiology [ 66 , 67 ]. MDD patients show reduced SST neurotransmission [ 68 ].…”

Section: Introductionmentioning

confidence: 99%

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

Sung

Lau

2022

Pharmaceutics

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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.

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Molecular characterization of depression trait and state

Cited by 29 publications

References 69 publications

Lower Levels of GABAergic Function Markers in Corticotropin-Releasing Hormone-Expressing Neurons in the sgACC of Human Subjects With Depression

Lower Levels of GABAergic Function Markers in Corticotropin-Releasing Hormone-Expressing Neurons in the sgACC of Human Subjects With Depression

Sex-Specific Brain Transcriptional Signatures in Human MDD and Their Correlates in Mouse Models of Depression

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

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