Sex-Specific Role for Dopamine Receptor D2 in Dorsal Raphe Serotonergic Neuron Modulation of Defensive Acoustic Startle and Dominance Behavior

Abstract

Brain networks underlying states of social and sensory alertness are normally adaptive, influenced by serotonin and dopamine (DA), 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 <i>Drd2-Pet1</i>, distinguished by expression of the type-2 DA receptor (<i>Drd2</i>) 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 <i>Pet1</i> neurons contributes to their capacity for shaping defensive behaviors. To address this, we generated mice in which <i>Drd2</i> gene sequences were deleted selectively in <i>Pet1</i> neurons. We found that <i>Drd2^Pet1-CKO</i> males, but not females, demonstrated increased winning against sex-matched controls in a social dominance assay. <i>Drd2^Pet1-CKO</i> females, but not males, exhibited blunting of the acoustic startle response, a protective, defensive reflex. Indistinguishable from controls were auditory brainstem responses (ABRs), locomotion, cognition, and anxiety-like and depression-like behaviors. Analyzing wild-type <i>Drd2-Pet1</i> neurons, we found sex-specific differences in the proportional distribution of axonal collaterals, in action potential (AP) duration, and in transcript levels of <i>Gad2,</i> important for GABA synthesis. <i>Drd2^Pet1-CKO</i> cells displayed sex-specific differences in the percentage of cells harboring <i>Gad2</i> transcripts. Our results suggest that DRD2 function in <i>Drd2-Pet1</i> 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.