Biology subjects

Kalivas, P. W.

Publications and source records attributed to Kalivas, P. W..

3 recordsLinked to original sources

bioRxiv2021

Network-Based Discovery of Opioid Use Vulnerability in Rats Using the Bayesian Stochastic Block Model

Opioid use disorder is a psychological condition that affects over 200,000 people per year in the U.S., causing the Centers for Disease Control and Prevention to label the crisis as a rapidly spreading public health epidemic. It has been found that the behavioral relationship between opioid exposure and development of opioid use disorder varies greatly between individuals, implying existence of sup-populations with varying degrees of opioid vulnerability. In this study, we assessed several behavioral variables across heroin taking, refraining and seeking to establish how these factors interact with one another resulting in a heroin dependent, resilient, or vulnerable behavioral phenotype. Over 400 (male and female) heterogeneous stock rats were used in these two studies, and data were collected from two geographically distinct locations. Rats underwent heroin self-administration training, followed by a progressive ratio and heroin-primed reinstatement test. Next, rats underwent extinction training and a cue-induced reinstatement test. To assess how these variables contribute to heroin addiction vulnerability, we developed a network-based data analysis workflow. Specifically, we integrated different cohorts of rats, remove possible batch effects, and constructed a rat-rat similarity network based on their behavioral patterns. We then implemented community detection on this similarity network using a Bayesian degree-corrected stochastic block model to uncover sub-populations of rats with differing levels of opioid vulnerability. We discovered three distinct behavioral sub-populations, each with significantly different behavioral outcomes that allowed for unique characterization of each cluster in terms of vulnerability to opioid use and seeking. We implement this analysis workflow as an open source R package, named mlsbm.

animal behavior and cognition↗

bioRxiv2020

Drug self-administration in head-restrained mice for simultaneous multiphoton imaging

Multiphoton microscopy is one of several new technologies providing unprecedented insight into the activity dynamics and function of neural circuits. Unfortunately, many of these technologies require experimentation in head-restrained animals, greatly limiting the behavioral repertoire that can be studied with each approach. This issue is especially evident in drug addiction research, as no laboratories have coupled multiphoton microscopy with simultaneous intravenous drug self-administration, the gold standard of behavioral paradigms for investigating the neural mechanisms of drug addiction. Such experiments would be transformative for addiction research as one could measure or perturb an array of behavior and drug-related adaptations in precisely defined neural circuit elements over time, including but not limited to dendritic spine plasticity, neurotransmitter release, and neuronal activity. Here, we describe a new experimental assay wherein mice self-administer drugs of abuse while head-restrained, allowing for simultaneous multiphoton imaging. We demonstrate that this approach enables longitudinal tracking of activity in single neurons from the onset of drug use to relapse. The assay can be easily replicated by interested labs for relatively little cost with readily available materials and can provide unprecedented insight into the neural underpinnings of substance use disorder.

neuroscience↗

bioRxiv2020

Heroin Cues Reveal Astroglial Heterogeneity in the Nucleus Accumbens Core

Opioid use disorder (OUD) produces detrimental personal and societal consequences. Astrocytes are a major cell group in the brain that receives little attention in mediating OUD. We determined how astrocytes and the astroglial glutamate transporter, GLT-1, in the nucleus accumbens core adapt and contribute to heroin seeking in rats. Seeking heroin, but not sucrose, produced two transient forms of plasticity in different astroglial subpopulations. Increased morphological proximity to synapses occurred in one subpopulation and increased extrasynaptic GLT-1 expression in another. Augmented synapse proximity by astroglia occurred selectively at D2-dopamine receptor expressing dendrites, while changes in GLT-1 were not neuron-subtype specific. Importantly, mRNA-antisense inhibition of either morphological or GLT-1 plasticity promoted cue-induced heroin seeking. We show that heroin cues induce two distinct forms of transient plasticity in separate astroglial subpopulations that dampen heroin relapse. TEASERDifferent subpopulations of astrocytes engage with accumbens synapses to dampen heroin relapse.

animal behavior and cognition↗