Raphe GABAergic Neurons Mediate the Acquisition of Avoidance after Social Defeat

Abstract

Serotonin (5-HT) modulates neural responses to socioaffective cues and can bias approach or avoidance behavioral decisions, yet the cellular mechanisms underlying its contribution to the regulation of social experiences remain poorly understood. We hypothesized that GABAergic neurons in the dorsal raphe nucleus (DRN) may participate in socioaffective regulation by controlling serotonergic tone during social interaction. We tested this hypothesis using whole-cell recording techniques in genetically identified DRN GABA and 5-HT neurons in mice exposed to social defeat, a model that induces long-lasting avoidance behaviors in a subset of mice responsive to serotonergic antidepressants. Our results revealed that social defeat engaged DRN GABA neurons and drove GABAergic sensitization that strengthened inhibition of 5-HT neurons in mice that were susceptible, but not resilient to social defeat. Furthermore, optogenetic silencing of DRN GABA neurons disinhibited neighboring 5-HT neurons and prevented the acquisition of social avoidance in mice exposed to a social threat, but did not affect a previously acquired avoidance phenotype. We provide the first characterization of GABA neurons in the DRN that monosynaptically inhibit 5-HT neurons and reveal their key role in neuroplastic processes underlying the development of social avoidance.

Monoamine-Sensitive Developmental Periods Impacting Adult Emotional and Cognitive Behaviors

“…Manipulations evoking hypo-5-HTergic states such as tryptophan depletion exert prodepressive effects (Blokland et al, 2002;Feder et al, 2011), whereas selective 5-HT reuptake inhibitors (SSRIs) that block the 5-HTT and hence enhance synaptic 5-HT levels have antidepressant and anxiolytic efficacy (Fuller and Wong, 1990). Preclinical research mirrors this relationship, as reduced firing of 5-HTergic neurons is often observed in animal models of depression and anxiety (Bambico et al, 2009;Challis et al, 2013). Although genome-wide association studies (GWAS) have thus far not identified genetic risk loci for depression (Flint and Kendler, 2014), the relationship between perturbed 5-HTergic signaling and affective behavior is further supported by genetic linkage and association studies.…”

Reward processing by the dorsal raphe nucleus: 5-HT and beyond

“…First, activation of DRN neurons strongly drives reward behaviors primarily in a glutamate-dependent manner. Optogenetic suppression of DRN GABA neuron activity disinhibits non-GABA neurons and prevents mice from acquiring social avoidance (Challis et al 2013), which gives the initial hint that the activity of DRN non-GABA neurons may reduce the aversiveness of social defeat. Our group examined the behavioral effects of optogenetic stimulation of mouse DRN Pet-1 neurons (Liu et al 2014), which consist of mostly 5-HT neurons ( 90%) and some purely glutamate neurons ( 10%).…”

Gq/5-HT 2c receptor signals activate a local GABAergic inhibitory feedback circuit to modulate serotonergic firing and anxiety in mice

“…These two neuronal types, which most likely represent GABAergic and 5-HT neurons, were identified by their cell type-specific firing pattern and firing frequencies (9,10). responses in HEK cells transiently expressing vMo, supplemented with 10 μM 9-cis retinal (white circles; n = 6), all-trans retinal (black triangles; n = 6) and without supplementation (black circles; n = 6) after repeated light stimulation (2-s light pulse, 1-s delay, 60 repeats), with HEK cells transfected with mCherry as control (white diamonds; n = 6); and (C) heterologous expression of vMo-CT 5-HT2c C-terminally tagged with mCherry fused to the C-terminal domain of the human 5-HT 2c -R in HEK cells and Ca 2+ responses in HEK cells transiently expressing vMo-CT 5-HT2c , supplemented with 10 μM 9-cis retinal (white circles; n = 6), all-trans retinal (black triangles; n = 6) and without any supplements (black circles; n = 6) after repeated light stimulation (2-s light pulse, 1-s delay, 60 repeats; 485 nm) with HEK cells transfected with mCherry (white diamonds; n = 6) as a control.…”