Sex-Specific Role For Dopamine Receptor D2 In Dorsal Raphe Serotonergic Neuron Modulation Of Defensive Acoustic Startle And Dominance Behavior

Brain networks underlying states of social and sensory alertness are normally adaptive, influenced by serotonin and dopamine, and abnormal in neuropsychiatric disorders, often with sex-specific manifestations. Underlying circuits, cells, and molecules are just beginning to be delineated. Implicated is a subtype of serotonergic neuron denoted Drd2-Pet1 distinguished by expression of the type -2 dopamine receptor (Drd2) gene, inhibited cell -autonomously by DRD2 agonism in slice, and, when constitutively silenced in male mice, affects levels of defensive and exploratory behaviors (Niederkofler et al., 2016). Unknown has been whether DRD2 signaling in these Pet1 neurons contributes to their capacity for shaping defensive behaviors. To address this, we generated mice in which Drd2 gene sequences were deleted selectively in Petl neurons. We found that Drd2(Petl-CKO) males, but not females, demonstrated increased winning against sex-matched controls in a social dominance assay. Drd2Pe"-cK females, but not males, exhibited blunting of the acoustic startle response a protective, defensive reflex. Indistinguishable from controls were auditory brainstem responses, locomotion, cognition, and anxiety- and depression -like behaviors. Analyzing wild-type Drd2-Pet1 neurons, we found sex-specific differences in the proportional distribution of axonal collaterals, in action potential duration, and in transcript levels of Gad2, important for GABA synthesis. Drd2Petl-cK cells displayed sex-specific differences in the percentage of cells harboring Gad2 transcripts. Our results suggest that DRD2 function in Drd2-Pet1 neurons is required for normal defensive/protective behaviors in a sex-specific manner, which may be influenced by the identified sex -specific molecular and cellular features. Related behaviors in humans too show sex differences, suggesting translational relevance.negatively correlated, suggesting there might exist a subgroup of Drd2-Pet1 neurons that targets the PNC and a different subgroup, the SOC. We speculate that in males, Drd2-Pet1 neurons contribute to a general level of serotonergic tone across the auditory brainstem, while in females, certain Drd2-Pet1 neurons selectively target and modulate specific nuclei.In conclusion, we found that Drd2 gene expression in a specialized subset of Petl serotonergic neurons is required for certain defensive, dominance, and protective behaviors, involving auditory processing in a sex-specific manner. Deficits in sensory processing such as altered acoustic startle and impaired social communication and dominance behaviors manifest in human disorders including autism spectrum disorder, schizophrenia, and post-traumatic stress disorder, often in sex-specific ways (King et al., 2013; Steel et al., 2014; Matsuo et al., 2016; Thye et al., 2018) and with sex-specific differences in therapeutic outcomes (Franconi et al., 2007). The presented findings, thus, may point to novel circuit nodes of relevance to human neuropsychiatric disease.