Downregulated Kcnd3 in the PSTh is vital for CSDS-induced anxiety-like behavior
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ABSTRACT:
PROVIDER: PRJNA1269456 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33745392_1.fastq.gz | Fastqsanger.gz | |||
| SRR33745392_2.fastq.gz | Fastqsanger.gz | |||
| SRR33745393_1.fastq.gz | Fastqsanger.gz | |||
| SRR33745393_2.fastq.gz | Fastqsanger.gz | |||
| SRR33745394_1.fastq.gz | Fastqsanger.gz |
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Project description:Anxiety disorders seriously damage our mental health, with chronic stress identified as a major etiologic factor. However, the precise neural mechanisms underlying the transition from chronic stress to anxiety remain unclear. In this study, with the chronic social defeat stress (CSDS) paradigm in mice, we verified a critical role of the parasubthalamic nucleus (PSTh) in anxiety regulation and found that CSDS results in a lasting increase in PSTh neuronal activity. Here, we explored the molecular substrates responsible for the increased intrinsic excitability of PSTh neurons following CSDS by RNA-sequence experiments. We found that CSDS downregulated Kcnd3 in PSTh neurons. Kcnd3 knockdown enhanced PSTh neuronal activity and produced anxiogenic effects in unstressed naïve mice, whereas overexpression of Kcnd3 in PSTh neurons dampened neuronal over-excitability and alleviated anxiety-like behavior in CSDS animals. Taken together, our results provide a cellular mechanism that the downregulated Kcnd3 induced by CSDS mediates intrinsic excitability of PSTh neurons, leading to anxiety-like behavior.
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Project description:MAP kinase signaling has been implicated in brain development, long-term memory, and the response to antidepressants. Inducible Braf knockout mice enabled us to unravel a new role of neuronal MAPK signaling for emotional behavior. Braf mice that were induced during adulthood showed normal anxiety but increased depression-like behavior, in accordance with pharmacological findings. In contrast, the inactivation of Braf in the juvenile brain leads to normal depression-like behavior but decreased anxiety in adults. In these mutants we found no alteration of GABAergic neurotransmission but reduced neuronal arborization in the dentate gyrus. Analysis of gene expression in the hippocampus revealed nine downregulated MAPK target genes that represent candidates to cause the mutant phenotype. Our results reveal the differential function of MAPK signaling in juvenile and adult life phases and emphasize the early postnatal period as critical for the determination of anxiety in adults. Moreover, these results validate inducible gene inactivation as new valuable approach, allowing to discriminate between gene function in the adult and the developing postnatal brain. Five male Braf-cko, six male homozygous Braf-flox littermates, six male heterozygous CamkII-Cre, and six male wildtype littermates were killed with CO2, the complete hippocampal tissue was prepared, and total RNA was extracted with the Trizol protocol. The integrity and quality of the RNA samples were analyzed with an RNA electrophoresis chip (RNA 6000 Nano Kit, Agilent, Boeblingen, Germany). RNA samples of high integrity and quality (RIN ≥ 7.5) were further processed with the TotalPrep RNA Amplification Kit (Ambion, Austin, TX, USA) and hybridized onto MouseWG-6 v1.1 Expression Bead-Chips (Illumina, San Diego, CA, USA) following manufacturer’s instructions. Data were analyzed using the software R (used packages: beadarray, limma, and vsn).
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Project description:Investigating the molecular basis and correlates of anxiety-related and depression-like behaviors, we generated a mouse model consisting of high (HAB), normal (NAB) and low (LAB) anxiety-related behavior mice. We utilized the elevated plus-maze for testing the genetic predisposition to anxiety-related behavior and, consequently, used this as selection criterion for the inbreeding of our animals. In depression-related tests, HAB mice display a more passive, depression-like coping strategy than LAB mice, resembling clinical comorbidity of anxiety and depression as observed in psychiatric patients. Using a microarray approach, the hypothalamic paraventricular nucleus (PVN), the basolateral (BLA) and central amygdala (CeA), the cingulate cortex (Cg) and the dentate gyrus (DG) – centers of the central nervous anxiety and fear circuitries – were investigated and screened for differences between HAB, NAB and LAB mice. Analysis was performed from four to six animals per line (HAB, NAB and LAB from generation 25, respectively) per brain region, giving a total of 78 individual arrays analyzed. The LAB mouse line is referred to as reference.
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