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

Abstract

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.

Involvement of brain cell phenotypes in stress-vulnerability and resilience

“…Those findings indicate that increased serotonergic neuron expression or activity is associated with stress resilience. However, pointing in the opposite direction, another work verified that susceptible individuals to CSDS exhibited an increased number of serotonergic neurons in the ventral subnucleus of the DRN relative to control and resilient subjects (Prakash et al, 2020).…”

Brain circuit dysfunction in specific symptoms of depression

“…Furthermore, the DRv is mainly innervated by the central amygdaloid nucleus (CeA). Recent findings indicate that the activation of corticotropin‐releasing hormone‐expressing neurons in the CeA reduces TPH2 + neurons in the dorsal raphe nucleus (DRN) of susceptible mice, thereby alleviating stress‐induced anhedonia (Prakash et al., 2020). Another experiment found the upstream region of the DRN, VTA, which is also involved in regulating the reward‐related circuits.…”

Decoding Neurotransmitter Switching: The Road Forward

“…Excitatory transmitters generally have inhibitory transmitters as switch partners and vice versa (Spitzer, 2017), although the ultimate determinants of synaptic sign are the receptors. Classical low-molecular-weight transmitters have been observed to switch with other classical transmitters (Grant et al, 1995;Godavarthi and Spitzer, 2017;Spitzer, 2019, 2020;Pratelli and Spitzer, 2019;Romoli et al, 2019;Prakash et al, 2020) and with peptide transmitters (Dulcis et al, 2013;Zambetti et al, 2017). There does not presently seem to be a reason to anticipate that members of any class of transmitters are forbidden switch partners.…”

“…In combination with Hebbian and homeostatic plasticity, switching forms a triumvirate of forms of plasticity that enables changes in synaptic strength (Penn and Shatz, 1999), synaptic scaling (Turrigiano, 2008) and reversal of synaptic sign (Spitzer, 2017). Transmitter switching has been studied in many species, including Caenorhabditis elegans (Pocock and Hobert, 2010;Serrano-Saiz et al, 2013), zebrafish (Bertuzzi et al, 2018), Xenopus (Borodinsky et al, 2004;Dulcis and Spitzer, 2008;Demarque and Spitzer, 2010;Dulcis et al, 2017), and rats and mice (Patterson and Chun, 1977;Schotzinger and Landis, 1988;Dulcis et al, 2013;Meng et al, 2018;Spitzer, 2019, 2020;Romoli et al, 2019;Prakash et al, 2020).…”