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

Abstract

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.

A single-cell transcriptomic and anatomic atlas of mouse dorsal raphePet1neurons

“…The functional significance of 906 this variable expression can only be hypothesized at present; we speculate that it 907 may reflect a capacity for neurotransmitter plasticity -i.e. experience-dependent 908 induction or up-regulation of 5-HT phenotype, as hinted at by a recent study 909 (Prakash et al, 2019). If this is the case, cluster fourteen neurons may be 910 partially in transition, for example, from a predominately glutamatergic phenotype 911 to a 5-HT phenotype or to a glutamate-5-HT co-transmitter phenotype.…”

Roles of the Serotoninergic System in Coping with Traumatic Stress

“…This last subpopulation appears to potentiate fear via the 5-HT 1A and 5-HT 2A receptor pathways and to impair fear extinction [98]. Interestingly, in rats some DRv 5-HT+/Vglut3+ neurons are sensitive to CRH released by the AMY that induces a decrease of TPH2 in them and ameliorates stress-induced anhedonia [99]. The level of TPH2 regulation by CRH could be the signature of a resilience status [99].…”

Harnessing the Neurobiology of Resilience to Protect the Mental Well-Being of Healthcare Workers During the COVID-19 Pandemic

“…These effects are mediated both by the direct post-synaptic effects of these transmitters, and by their “cross-talk” with other pathways such as the midbrain dopaminergic pathway ( Krystal and Neumeister, 2009 ), peptides such as NPY ( Hokfelt et al, 2018 ; see section Neuropeptides), and, most significantly, the HPA “stress axis” ( Ancelin et al, 2017 ; Prakash et al, 2020 ; see section The Hypothalamic-Pituitary-Adrenal Axis). Translational evidence has identified neural “final common pathways” for these effects.…”

“…For example, the noradrenergic locus coeruleus (NOR-LC) system, connecting the brainstem with the amygdala, which modulates the formation and consolidation of memories related to stressful or traumatic events ( Haubrich et al, 2020 ). Similarly, plasticity of midbrain serotonergic neurons has been associated with resilience to stress-induced depressive symptoms ( Prakash et al, 2020 ).…”