Biology subjects

Retzlaff, C. L.

Publications and source records attributed to Retzlaff, C. L..

4 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

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

Inhibitory interneurons represent less than 5% of neurons within the nucleus accumbens, but are critical for proper microcircuit function within this brain region. In the dorsal striatum, neuropeptide Y is expressed by two interneuron subtypes (low-threshold spiking interneurons and neurogliaform interneurons) that exhibit mu opioid receptor sensitivity in other brain regions. However, few studies have assessed the molecular and physiological properties of neuropeptide Y interneurons within the nucleus accumbens. We used a transgenic reporter mouse to identify and characterize neuropeptide Y interneurons in acute nucleus accumbens brain slices. Nearly all cells exhibited electrophysiological properties of low-threshold spiking interneurons, with almost no neurogliaform interneurons observed among neuropeptide Y interneurons. We corroborated this pattern using fluorescent in situ hybridization, and also identified a high level of mu opioid receptor expression by low-threshold spiking interneurons, which led us to examine the functional consequences of mu opioid receptor activation in these cells using electrophysiology. Mu opioid receptor activation caused a reduction in the rate of spontaneous action potentials in low-threshold spiking interneurons, as well as a decrease in optogenetically-evoked GABA release onto medium spiny neurons. The latter effect was more robust in female versus male mice, and when the postsynaptic medium spiny neuron expressed the Drd1 dopamine receptor. This work is the first to examine the physiological properties of neuropeptide Y interneurons in the nucleus accumbens, and show they may be an important target for mu opioid receptor modulation by endogenous and exogenous opioids.

neuroscience↗

bioRxiv2022

Neuroligin-3 in Dopamine Neurons Promotes Behavioral and Neurobiological Adaptations to Chronic Morphine Exposure

Chronic opioid exposure causes structural and functional changes in brain circuits, which may contribute to opioid use disorders. Synaptic cell-adhesion molecules are prime candidates for mediating this opioid-evoked plasticity. Neuroligin-3 (NL3) is an X-linked postsynaptic adhesion protein that shapes synaptic function at multiple sites in the mesolimbic dopamine system. We therefore studied how genetic knockout of NL3 alters responses to chronic morphine in male mice. Constitutive NL3 knockout caused a persistent reduction in psychomotor sensitization after chronic morphine exposure and changed in the topography of locomotor stimulation produced by morphine. This latter change was recapitulated by conditional genetic deletion of NL3 from cells expressing the Drd1 dopamine receptor, whereas reduced psychomotor sensitization was recapitulated by conditional genetic deletion from dopamine neurons. Without NL3 expression, dopamine neurons in the ventral tegmental area exhibited diminished activation following chronic morphine exposure, by measuring in vivo calcium signals with fiber photometry. This altered pattern of dopamine neuron activity may be driven by aberrant forms of opioid-evoked synaptic plasticity in the absence of NL3: dopamine neurons lacking NL3 showed weaker synaptic inhibition at baseline, which was subsequently strengthened after chronic morphine. In total, our study highlights neurobiological adaptations in dopamine neurons of the ventral tegmental area that correspond with increased behavioral sensitivity to opioids, and further suggests that NL3 expression by dopamine neurons provides a molecular substrate for opioid-evoked adaptations in brain function and behavior.

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↗