Biology subjects

Kalivas, P. W.

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

6 recordsLinked to original sources

bioRxiv2026

Deep transcriptomic analysis of molecular mediators of complex traits in heterogeneous stock (HS) rats

Rats are a powerful model organism for genome-wide association studies (GWAS) of physiological and behavioral traits. Heterogeneous Stock (HS) rats, which were created by intercrossing 8 inbred rat strains, are heavily used for this purpose because of their genetic diversity and accumulated recombinations due to over 100 generations of outbreeding, which improves mapping precision. However, functional genomics resources for post-GWAS interpretation of genomic findings have been limited. We processed 3,160 RNA-seq samples, 1,932 of which were previously unpublished, from 13 tissues as part of RatGTEx. We used Pantry to quantify six modalities of transcriptome regulation (expression, isoform ratio, intron excision ratio, alternative transcription start site (TSS), alternative poly(A), and RNA stability) in each sample, which allowed us to identify 144,876 independent quantitative trait loci (QTL) for 22,599 genes. We performed a transcriptome-wide association study (TWAS) with 19,796 unique genes across tissues and transcriptional modalities and 308 traits collected from 14 studies using FUSION, which identified 7,473 significant gene-trait associations. This work presents a significant expansion of the RatGTEx resource in terms of samples, modes of transcriptome regulation, and genetic analyses. Our findings provide molecular evidence for the involvement of specific genes in mediating GWAS signals through a range of transcriptome regulatory mechanisms. These gene-to-phenotype relationships can be easily applied to genetic analyses in humans and other species. Further experiments can use this evidence to confirm these molecular mediators and target them for the treatment of behavioral and physiological traits and disorders. To facilitate use of these results, we have updated results on RatGTEx.org and provided a new interactive TWAS web portal (twas.ratgtex.org).

genetics↗

bioRxiv2024

Formation of an Enduring Ensemble of Accumbens Neurons Leads to Prepotent Seeking for Cocaine Over Natural Reward Cues

Neuronal activity in the nucleus accumbens core (NAcore) is necessary for reward-seeking behaviors. We hypothesized that the differential encoding of natural and drug rewards in the NAcore contributes to substance use disorder. We leveraged single-cell calcium imaging of dopamine D1- and D2-receptor-expressing medium spiny neurons (MSNs) in the NAcore of mice to examine differences between sucrose and cocaine rewarded (self-administration) and unrewarded (abstinent and cue-induced) seeking. Activity was time-locked to nose-poking for reward, clustered, and compared between sucrose and cocaine. Only in cocaine-trained mice were excited D1-MSNs securely stable, capable of decoding nose-poking in all rewarded and unrewarded sessions and correlated with the intensity of nose-poking for unrewarded seeking. Furthermore, D1-MSNs formed a stable ensemble predictive of seeking behavior after extended cocaine, but not sucrose abstinence. The excited D1-MSN ensemble uniquely drives cue-induced cocaine seeking and may contribute to why drug seeking is prepotent over natural reward seeking in cocaine use disorder.

neuroscience↗

bioRxiv2022

Matrix Metalloproteinase Activity During Methamphetamine Cued Relapse

Relapse to drug seeking involves transient synaptic remodeling that occurs in response to drug associated cues. This remodeling includes activation of matrix metalloproteinases (MMPs) to initiate catalytic signaling in the extracellular matrix (ECM) in the nucleus accumbens core (NAcore). We hypothesized that MMP activity would be increased in the NAcore during cue-induced methamphetamine (meth) seeking in a rat model of meth use and relapse. Male and female rats had indwelling jugular catheters and bilateral intracranial cannula targeting the NAcore surgically implanted. Following recovery, rats underwent meth or saline self-administration (6hr/day for 15 days) in which active lever responding was paired with a light+tone stimulus complex, followed by home cage abstinence. Testing occurred after 7 or 30 days of abstinence. On test day, rats were microinjected with a FITC-quenched gelatin substrate that fluoresces following cleavage by MMPs, allowing for the quantification of gelatinase activity by MMP-2 and -9 during cued relapse testing. MMP-2,9 activity was significantly increased in the NAcore by meth cues presentation after 7 and 30 days of abstinence, indicating that remodeling by MMPs occurs during presentation of meth associated cues. Surprisingly, while cue-induced seeking increased between days 7 and 30, suggesting behavioral incubation, MMP-2,9 activity did not increase. These findings indicate that while MMP activation is elicited during meth cue-induced seeking, MMP activation did not parallel the behavioral incubation that occurs during extended drug abstinence.

neuroscience↗

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↗