Social Stress Alters InhibitorySynaptic Input to Distinct Subpopulations of Raphe Serotonin Neurons

摘要

Anxiety disorders are among the most prevalent psychiatric disorders, yet much is unknown about the underlying mechanisms. The dorsal raphe (DR) is at the crux of the anxiety-inducing effects of uncontrollable stress, a key component of models of anxiety. Though DR serotonin (5-HT) neurons play a prominent role, anxiety-associated changes in the physiology of 5-HT neurons remain poorly understood. A 5-day social defeat model of anxiety produced a multifaceted, anxious phenotype in intruder mice that included increased avoidance behavior in the open field test, increased stress-evoked grooming, and increased bladder and heart weights when compared to control mice. Intruders were further compared to controls using electrophysiology recordings conducted in midbrain slices wherein recordings targeted 5-HT neurons of the ventromedial (vmDR) and lateral wing (lwDR) subfields of the DR. Though defining membrane characteristics of 5-HT neurons were unchanged, γ-aminobutyric-acid-mediated (GABAergic) synaptic regulation of 5-HT neurons was altered in a topographically specific way. In the vmDR of intruders, there was a decrease in the frequencyand amplitude of GABAergic spontaneous inhibitory postsynaptic currents(sIPSCs). However, in the lwDR, there was an increase in the strengthof inhibitory signals due to slower sIPSC kinetics. Synaptic changeswere selective for GABAergic input, as glutamatergic synaptic inputwas unchanged in intruders. The distinct inhibitory regulation ofDR subfields provides a mechanism for increased 5-HT output in vmDRtarget regions and decreased 5-HT output in lwDR target regions, divergentresponses to uncontrollable stress that have been reported in theliterature but were previously poorly understood.