Two models of inescapable stress increase tph2 mRNA expression in the anxiety-related dorsomedial part of the dorsal raphe nucleus

Donner, Nina C.; Kubala, Kenneth H.; Hassell, James E.; Lieb, Margaret W.; Nguyen, Kadi T.; Heinze, Jared D.; Drugan, Robert C.; Maier, Steven F.; Lowry, Christopher A.

doi:10.1016/j.ynstr.2018.01.003

Cited by 24 publications

(26 citation statements)

References 95 publications

(132 reference statements)

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“…The increase in number of TPH2ϩ neurons in the anhedonic condition (susceptible rats) is consistent with increased TPH2 immunoreactivity and mRNA expression observed after exposure to stress in animals (Poeggel et al, 2003;Amat et al, 2010;Donner et al, 2018) and in brains of depressed patients who committed suicide (Underwood et al, 1999;Boldrini et al, 2005;Bach-Mizrachi et al, 2008). Our findings are the first evidence in an animal model, that stress-induced increase in TPH2 in the DR does not result merely from an increased expression within preexisting serotonergic neurons, but is a result of previously nonserotonergic neurons gaining TPH2 expression.…”

Section: Discussionsupporting

confidence: 86%

“…Studies in rodent models have shown that serotonergic molecular machinery is upregulated in the DR after both chronic (Adell et al, 1988;Zhang et al, 2012;Donner et al, 2016) and acute stress (Donner et al, 2018). However, they did not specifically address differences between rodents that are susceptible or resilient to chronic stress-induced anhedonia, or whether this upregulation occurs in identified classes of neurons expressing specific neurotransmitters.…”

Section: Discussionmentioning

confidence: 99%

“…Knock-out mice lacking key components of serotonergic machinery show altered stress-related behaviors (Holmes et al, 2003;Lira et al, 2003;Adamec et al, 2006;Gutknecht et al, 2015). Extracellular levels of serotonin (Kawahara et al, 1993;Mokler et al, 2007), expression of serotonin-related molecules (Adell et al, 1988;Zhang et al, 2012;Issler et al, 2014;Donner et al, 2018), serotonergic activity (Grahn et al, 1999;Paul et al, 2011;Grandjean et al, 2019), and innervation (Natarajan et al, 2017) have been shown to change in response to both acute and chronic stress. Such regulation is linked to behavioral changes including anhedonia (Berton et al, 1997;Wood et al, 2013;Lopes et al, 2016;Natarajan et al, 2017) and is altered by treatment with antidepressants and anxiolytics (Benmansour et al, 1999;Abumaria et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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 (VGLUT3ϩ) 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)ϩ neurons abolished the increase in DRv TPH2ϩ neurons and ameliorated stress-induced anhedonia in susceptible rats. These findings show that activation of amygdalar CRHϩ 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.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…Previous studies in rodent models have shown that serotonergic molecular machinery is upregulated in the DR after both chronic (Adell et al, 1988;Zhang et al, 2012;Donner et al, 2016) and acute stress (Donner et al, 2018). However, these studies did not specifically address differences between animals that are susceptible or resilient to chronic stress-induced anhedonia, or whether this upregulation occurs in identified classes of neurons expressing specific neurotransmitters.…”

Section: Discussionmentioning

confidence: 98%

Serotonergic plasticity in the dorsal raphe nucleus characterizes susceptibility and resilience to anhedonia

Prakash

Stark

Keisler

et al. 2019

Preprint

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critical feedback on the research and Dr.Byung Kook Lim for his valuable feedback and the use of his slide-scanning microscope. ABSTRACTChronic 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 SIGNIFICANCE STATEMENTDepression 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.

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“…The DR and MnR contain the major serotonergic (5-HT) populations (Pollak Dorocic et al, 2014). Both of the nuclei and 5-HT are involved in anxiety and depression, and they are crucial and central drug targets (Lanzenberger et al, 2012;An et al, 2013An et al, , 2016Lopez Hill et al, 2013;Campos et al, 2018;de Souza et al, 2018;Donner et al, 2018). The LC is the major noradrenergic system with regard to stress and major depressive disorder (Chandley and Ordway, 2012;Fan et al, 2018).…”

Section: Emotionmentioning

confidence: 99%

Connection Input Mapping and 3D Reconstruction of the Brainstem and Spinal Cord Projections to the CSF-Contacting Nucleus

Song

Zhai

et al. 2020

Front. Neural Circuits

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Objective: To investigate whether the CSF-contacting nucleus receives brainstem and spinal cord projections and to understand the functional significance of these connections. Methods: The retrograde tracer cholera toxin B subunit (CB) was injected into the CSF-contacting nucleus in Sprague-Dawley rats according the previously reported stereotaxic coordinates. After 7-10 days, these rats were perfused and their brainstem and spinal cord were sliced (thickness, 40 µm) using a freezing microtome. All the sections were subjected to CB immunofluorescence staining. The distribution of CBpositive neuron in different brainstem and spinal cord areas was observed under fluorescence microscope. Results: The retrograde labeled CB-positive neurons were found in the midbrain, pons, medulla oblongata, and spinal cord. Four functional areas including one hundred and twelve sub-regions have projections to the CSF-contacting nucleus. However, the density of CB-positive neuron distribution ranged from sparse to dense. Conclusion: Based on the connectivity patterns of the CSF-contacting nucleus receives anatomical inputs from the brainstem and spinal cord, we preliminarily conclude and summarize that the CSF-contacting nucleus participates in pain, visceral activity, sleep and arousal, emotion, and drug addiction. The present study firstly illustrates the broad projections of the CSF-contacting nucleus from the brainstem and spinal cord, which implies the complicated functions of the nucleus especially for the unique roles of coordination in neural and body fluids regulation.

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Two models of inescapable stress increase tph2 mRNA expression in the anxiety-related dorsomedial part of the dorsal raphe nucleus

Cited by 24 publications

References 95 publications

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

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

Serotonergic plasticity in the dorsal raphe nucleus characterizes susceptibility and resilience to anhedonia

Connection Input Mapping and 3D Reconstruction of the Brainstem and Spinal Cord Projections to the CSF-Contacting Nucleus

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