RGD Reference Report - Serotonergic Plasticity in the Dorsal Raphe Nucleus Characterizes Susceptibility and Resilience to Anhedonia. - Rat Genome Database

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Serotonergic Plasticity in the Dorsal Raphe Nucleus Characterizes Susceptibility and Resilience to Anhedonia.

Authors: Prakash, Nandkishore  Stark, Christiana J  Keisler, Maria N  Luo, Lily  Der-Avakian, Andre  Dulcis, Davide 
Citation: Prakash N, etal., J Neurosci. 2020 Jan 15;40(3):569-584. doi: 10.1523/JNEUROSCI.1802-19.2019. Epub 2019 Dec 2.
RGD ID: 597830157
Pubmed: PMID:31792153   (View Abstract at PubMed)
PMCID: PMC6961996   (View Article at PubMed Central)
DOI: DOI:10.1523/JNEUROSCI.1802-19.2019   (Journal Full-text)

Chronic stress induces anhedonia in susceptible but not resilient individuals, a phenomenon observed in humans as well as animal models, but the molecular mechanisms underlying susceptibility and resilience are not well understood. We hypothesized that the serotonergic system, which is implicated in stress, reward, and antidepressant therapy, may play a role. We found that plasticity of the serotonergic system contributes to the differential vulnerability to stress displayed by susceptible and resilient animals. Stress-induced anhedonia was assessed in adult male rats using social defeat and intracranial self-stimulation, while changes in serotonergic phenotype were investigated using immunohistochemistry and in situ hybridization. Susceptible, but not resilient, rats displayed an increased number of neurons expressing the biosynthetic enzyme for serotonin, tryptophan-hydroxylase-2 (TPH2), in the ventral subnucleus of the dorsal raphe nucleus (DRv). Further, a decrease in the number of DRv glutamatergic (VGLUT3+) neurons was observed in all stressed rats. This neurotransmitter plasticity is activity-dependent, as was revealed by chemogenetic manipulation of the central amygdala, a stress-sensitive nucleus that forms a major input to the DR. Activation of amygdalar corticotropin-releasing hormone (CRH)+ neurons abolished the increase in DRv TPH2+ neurons and ameliorated stress-induced anhedonia in susceptible rats. These findings show that activation of amygdalar CRH+ neurons induces resilience, and suppresses the gain of serotonergic phenotype in the DRv that is characteristic of susceptible rats. This molecular signature of vulnerability to stress-induced anhedonia and the active nature of resilience could be targeted to develop new treatments for stress-related disorders like depression.SIGNIFICANCE STATEMENT Depression and other mental disorders can be induced by chronic or traumatic stressors. However, some individuals are resilient and do not develop depression in response to chronic stress. A complete picture of the molecular differences between susceptible and resilient individuals is necessary to understand how plasticity of limbic circuits is associated with the pathophysiology of stress-related disorders. Using a rodent model, our study identifies a novel molecular marker of susceptibility to stress-induced anhedonia, a core symptom of depression, and a means to modulate it. These findings will guide further investigation into cellular and circuit mechanisms of resilience, and the development of new treatments for depression.




  
Object Symbol
Species
Term
Qualifier
Evidence
With
Notes
Source
Original Reference(s)
TPH2Humanstress-related disorder treatmentISOTph2 (Rattus norvegicus) RGD 
Tph2Ratstress-related disorder treatmentIEP  RGD 
Tph2Mousestress-related disorder treatmentISOTph2 (Rattus norvegicus) RGD 


Genes (Rattus norvegicus)
Tph2  (tryptophan hydroxylase 2)

Genes (Mus musculus)
Tph2  (tryptophan hydroxylase 2)

Genes (Homo sapiens)
TPH2  (tryptophan hydroxylase 2)