PT  - JOURNAL ARTICLE
AU  - Krissy A. Lyon
AU  - Benjamin D. Rood
AU  - Lorna Wu
AU  - Rebecca A. Senft
AU  - Lisa V. Goodrich
AU  - Susan M. Dymecki
TI  - Sex-specific role for dopamine receptor D2 in dorsal raphe serotonergic neuron modulation of defensive acoustic startle and dominance behavior
AID  - 10.1523/ENEURO.0202-20.2020
DP  - 2020 Nov 19
TA  - eneuro
PG  - ENEURO.0202-20.2020
4099  - http://www.eneuro.org/content/early/2020/11/17/ENEURO.0202-20.2020.short
4100  - http://www.eneuro.org/content/early/2020/11/17/ENEURO.0202-20.2020.full
AB  - 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 Pet1 neurons. We found that Drd2Pet1-CKO males, but not females, demonstrated increased winning against sex-matched controls in a social dominance assay. Drd2Pet1-CKO 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. Drd2Pet1-CKO 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.Significance statement A subtype of dorsal raphe serotonergic neuron, denoted Drd2-Pet1, is poised for regulation by dopamine via type-2 dopamine receptor (DRD2) expression. Functional removal of DRD2 in these cells through a conditional knockout (CKO) mouse strategy resulted in sex-specific behavioral abnormalities: Drd2Pet1-CKO females exhibited reduced acoustic startle while males showed increased social dominance. Drd2-Pet1 neurons were similar in number and distribution in males versus females but exhibited sex-specific differences in neurotransmission-related mRNAs, action potential duration, and relative distribution of collaterals. Abnormalities in sensory processing and social behaviors akin to those reported here manifest in autism, schizophrenia, and post-traumatic stress disorder, in sex-specific ways. Our findings, thus, may point to novel circuits and modulatory pathways relevant to human neuropsychiatric conditions.