Biology subjects

Lefevre, E. M.

Publications and source records attributed to Lefevre, E. M..

5 recordsLinked to original sources

bioRxiv2024

Mu opioid receptor expression by nucleus accumbens inhibitory interneurons promotes affiliative social behavior

Mu opioid receptors in the nucleus accumbens regulate motivated behavior, including pursuit of natural rewards like social interaction as well as exogenous opioids. We used a suite of genetic and viral strategies to conditionally delete mu opioid receptor expression from all major neuron types in the nucleus accumbens. We pinpoint inhibitory interneurons as an essential site of mu opioid receptor expression for typical social behavior, independent from exogenous opioid sensitivity.

neuroscience↗

bioRxiv2022

Differential Patterns of Synaptic Plasticity in the Nucleus Accumbens Caused by Continuous and Interrupted Morphine Exposure

Opioid exposure and withdrawal both cause adaptations in brain circuits that may contribute to abuse liability. These adaptations vary in magnitude and direction following different patterns of opioid exposure, but few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological impact. In this study, we compared cellular and synaptic adaptations in the nucleus accumbens shell caused by morphine exposure that was either continuous, or interrupted by daily bouts of naloxone-precipitated withdrawal. At the behavioral level, continuous morphine administration caused psychomotor tolerance, which was reversed when the continuity of morphine action was interrupted by naloxone-precipitated withdrawal. Using ex vivo slice electrophysiology in female and male mice, we investigated how these patterns of morphine administration altered intrinsic excitability and synaptic plasticity of medium spiny neurons (MSNs) expressing the D1 or D2 dopamine receptor. We found that morphine-evoked adaptations at excitatory synapses were predominately conserved between patterns of administration, but there were divergent effects on inhibitory synapses and the subsequent balance between excitatory and inhibitory synaptic input. Overall, our data suggest that continuous morphine administration produces adaptations that dampen the output of D1-MSNs, which are canonically thought to promote reward-related behaviors. Interruption of otherwise continuous morphine exposure does not dampen D1-MSN functional output to the same extent, which may enhance behavioral responses to subsequent opioid exposure. Our findings support the hypothesis that maintaining continuity of opioid administration could be an effective therapeutic strategy to minimize the vulnerability to opioid use disorders.

neuroscience↗

bioRxiv2020

Mu Opioid Receptor Gene Dosage Influences Reciprocal Social Behaviors and Nucleus Accumbens Microcircuitry

The mu opioid receptor regulates reward derived from both drug use and natural experiences, including social interaction. Homozygous genetic knockout of the mu opioid receptor (Oprm1-/-) causes social deficits in mice, whereas partial dysregulation of mu opioid signaling has been documented in several neuropsychiatric disorders. Here, we investigated the social behavior of male and female mice with heterozygous genetic knockout of the mu opioid receptor (Oprm1+/-), modeling partial reduction of mu opioid signaling. Reciprocal social interaction and social conditioned place preference were diminished in Oprm1+/- and Oprm1-/- mutants of both sexes. Interaction with Oprm1 mutants also altered the social behavior of genotypical test partners. We corroborated this latter result using a social preference task, in which genotypical mice preferred interactions with another typical mouse over Oprm1 mutants. We also analyzed inhibitory synapses in the nucleus accumbens, a key brain region for mu opioid regulation of social behavior, 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 density of inhibitory synaptic puncta at the cell body of D2-MSNs was increased in both male and female mutants. These changes in nucleus accumbens microcircuitry were more robust in Oprm1+/- mutants than Oprm1-/- mutants, demonstrating that partial reductions of mu opioid signaling can have large effects on brain function and behavior. Our results support a role for partial dysregulation of mu opioid signaling in social deficits associated with neuropsychiatric conditions.

neuroscience↗

bioRxiv2019

Interruption of Continuous Opioid Exposure Exacerbates Drug-Evoked Adaptations in Brain Function and Behavior

Drug-evoked adaptations in the mesolimbic dopamine system are postulated to drive opioid abuse and addiction. These adaptations vary in magnitude and direction following different patterns of opioid exposure, but few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological and behavioral impact. We exposed male and female mice to morphine for one week, with administration patterns that were either intermittent (daily injections) or continuous (osmotic minipump infusion). We then interrupted continuous morphine exposure with either naloxone-precipitated or spontaneous withdrawal. Continuous morphine exposure caused tolerance to the psychomotor-activating effects of morphine, whereas both intermittent and interrupted morphine exposure caused long-lasting psychomotor sensitization. Given links between locomotor sensitization and mesolimbic dopamine signaling, we used fiber photometry and a genetically encoded dopamine sensor to conduct longitudinal measurements of dopamine dynamics in the nucleus accumbens. Locomotor sensitization caused by interrupted morphine exposure was accompanied by enhanced dopamine signaling in the nucleus accumbens. To further assess downstream consequences on striatal gene expression, we used next-generation RNA sequencing to perform genome-wide transcriptional profiling in the nucleus accumbens and dorsal striatum. The interruption of continuous morphine exposure exacerbated drug-evoked transcriptional changes in both nucleus accumbens and dorsal striatum, dramatically increasing differential gene expression and engaging unique signaling pathways. Our study indicates that opioid-evoked adaptations in brain function and behavior are critically dependent on the pattern of drug administration, and exacerbated by interruption of continuous exposure. Maintaining continuity of chronic opioid administration may therefore represent a strategy to minimize iatrogenic effects on brain reward circuits.

neuroscience↗

bioRxiv2019

Nucleus Accumbens Fast-Spiking Interneurons Constrain Impulsive Action

BackgroundThe nucleus accumbens (NAc) controls multiple facets of impulsivity, but is a heterogeneous brain region with diverse microcircuitry. Prior literature links impulsive behavior in rodents to gamma aminobutyric acid (GABA) signaling in the NAc. Here, we studied the regulation of impulsive behavior by fast-spiking interneurons (FSIs), a strong source of GABA-mediated synaptic inhibition in the NAc.\n\nMethodsMale and female transgenic mice expressing Cre recombinase in FSIs allowed us to identify these sparsely distributed cells in the NAc. We used a 5-choice serial reaction time task (5-CSRTT) to measure both impulsive action and sustained attention. During the 5-CSRTT, we monitored FSI activity with fiber photometry calcium imaging, and manipulated FSI activity with chemogenetic and optogenetic methodology. We used electrophysiology, optogenetics, and fluorescent in situ hybridization to confirm these methods were robust and specific to FSIs.\n\nResultsIn mice performing the 5-CSRTT, NAc FSIs showed sustained activity on trials ending with correct responses, but declined over time on trials ending with premature responses. The number of premature responses increased significantly after sustained chemogenetic inhibition or temporally delimited optogenetic inhibition of NAc FSIs, without any changes in response latencies or general locomotor activity.\n\nConclusionsThese experiments provide strong evidence that NAc FSIs constrain impulsive actions, most likely through GABA-mediated synaptic inhibition of medium spiny projection neurons. Our findings may provide insight into the pathophysiology of disorders associated with impulsivity, and inform the development of circuit-based therapeutic interventions.

neuroscience↗