μ-Opioid Receptor (Oprm1) Copy Number Influences Nucleus Accumbens Microcircuitry and Reciprocal Social Behaviors

Abstract

The l-opioid receptor regulates reward derived from both drug use and natural experiences, including social interaction, through actions in the nucleus accumbens. Here, we studied nucleus accumbens microcircuitry and social behavior in male and female mice with heterozygous genetic knockout of the l-opioid receptor (Oprm1 1/2 ). This genetic condition models the partial reduction of l-opioid receptor signaling reported in several neuropsychiatric disorders. We first analyzed inhibitory synapses in the nucleus accumbens, using methods that differentiate between medium spiny neurons (MSNs) expressing the D1 or D2 dopamine receptor. Inhibitory synaptic transmission was increased in D2-MSNs of male mutants, but not female mutants, while the expression of gephyrin mRNA and the density of inhibitory synaptic puncta at the cell body of D2-MSNs was increased in mutants of both sexes. Some of these changes were more robust in Oprm1 1/2 mutants than Oprm1 2/2 mutants, demonstrating that partial reductions of l-opioid signaling can have large effects. At the behavioral level, social conditioned place preference and reciprocal social interaction were diminished in Oprm1 1/2 and Oprm1 2/2 mutants of both sexes. Interaction with Oprm1 mutants also altered the social behavior of wild-type test partners. We corroborated this latter result using a social preference task, in which wild-type mice preferred interactions with another typical mouse over Oprm1 mutants. Surprisingly, Oprm1 2/2 mice preferred interactions with other Oprm1 2/2 mutants, although these interactions did not produce a conditioned place preference. Our results support a role for partial dysregulation of l-opioid signaling in social deficits associated with neuropsychiatric conditions. Significance StatementActivation of the m-opioid receptor plays a key role in the expression of normal social behaviors. In this study, we examined brain function and social behavior of female and male mice, with either partial or complete genetic deletion of m-opioid receptor expression. We observed abnormal social behavior following both genetic manipulations, as well as changes in the structure and function of synaptic input to a specific population of neurons in the nucleus accumbens, which is an important brain region for social behavior. Synaptic changes were most robust when m-opioid receptor expression was only partially lost, indicating that small reductions in m-opioid receptor signaling can have a large impact on brain function and behavior.

Chronic sodium bromide treatment relieves autistic-like behavioral deficits in three mouse models of autism

“…In the current study, we tested whether bromide ions would relieve autistic-like symptoms in mouse models of ASD. We first assessed bromide effects in the Oprm1 -/mouse model of ASD, which recapitulates a wide range of autistic-like core and secondary symptoms, including severe deficits in social interaction and communication (51,(58)(59)(60)(61), stereotypic behavior, exacerbated anxiety (51,60) and increased susceptibility to seizures (51,62) but displays preserved cognitive performance (52).…”

Neuroligin-3 in Dopaminergic Circuits Promotes Behavioral and Neurobiological Adaptations to Chronic Morphine Exposure

“…Quantitative RT-PCR was performed on tissue punches containing the dorsal and ventral striatum, as previously described (Lefevre et al, 2020; Toddes et al, 2021). Tissue was snap frozen on dry ice and stored at −80°C.…”

“…Morphine hydrochloride (Mallinckrodt) was dissolved in sterile 0.9% saline and delivered subcutaneously (5 mL/kg) by bolus injection at one of several doses (2, 6.32, or 20 mg/kg). We have previously used this series of doses to measure the acute psychomotor response to morphine (Toddes et al, 2021), as well as long-lasting psychomotor sensitization (Lefevre et al, 2020). The day prior to the first acute morphine injection, animals were habituated to the behavior apparatus and given an equivalent volume of 0.9% saline subcutaneously.…”

Characterization and mu opioid receptor sensitivity of neuropeptide Y interneurons in the nucleus accumbens

“…As previously described (Toddes et al, 2021), mice were anesthetized with isoflurane and perfused with ice cold sucrose solution containing (in mM): 228 sucrose, 26 NaHCO3, 11 glucose, 2.5 KCl, 1 NaH2PO4-H2O, 7 MgSO4-7H20, 0.5 CaCl2-2H2O. Brains were then rapidly dissected and placed in cold sucrose.…”