Biology subjects

Hurd, Y. L.

Publications and source records attributed to Hurd, Y. L..

5 recordsLinked to original sources

bioRxiv2026

Ketamine Modulates Endogenous Opioid Peptide Signaling and Reduces Heroin-Seeking in Male Long-Evans Rats

Opioid Use Disorder (OUD) continues to be a pressing public health crisis, marked by high relapse rates and limited treatment options. Ketamine, a non-competitive N-Methyl-D-Aspartate receptor (NMDAR) antagonist, has emerged as a promising therapeutic for numerous psychiatric illnesses due to its robust antidepressant properties and glutamate-mediated synaptic plasticity. However, ketamine's therapeutic mechanisms remain elusive, with emerging evidence implicating the endogenous opioid system. Furthermore, few studies have investigated ketamine's potential as an intervention for OUD. Accordingly, this study assessed ketamine's ability to rewire endogenous opioid and glutamatergic circuitry and reduce heroin-seeking activity in male Long-Evans rats. Using a multi-cohort design, we investigated ketamine's effects on opioid-related transcriptional, protein, and signaling properties in key brain regions associated with reward and addiction, and subsequently on heroin-seeking using a self-administration paradigm. To investigate mechanisms of plasticity, we also quantified transcriptional changes to NMDAR subunits. Molecular analyses demonstrated increased expression of endogenous opioid system-related genes and endogenous opioid peptides at the protein level, elevated mu-opioid receptor protein levels, and enhanced G protein activity, suggesting increased receptor function. Notably, transcriptional changes were particularly prominent in the shell subregion of the nucleus accumbens (NAc). We also revealed that ketamine altered NMDAR subunit expression in the medial prefrontal cortex and NAc, indicating circuit-level synaptic remodeling. Behavioral analyses revealed that ketamine significantly reduced heroin-primed, but not cue-induced, seeking activity. Together, these findings suggest ketamine reduces acute relapse vulnerability to opioids through coordinated modulation of opioid and glutamatergic systems, highlighting its potential as a novel intervention for OUD.

neuroscience↗

bioRxiv2026

Protracted abstinence from heroin, but not cocaine, is associated with profound medial prefrontal cortex synaptic bioenergetic remodeling and lasting neural hypofunction

Relapse following prolonged abstinence is a primary challenge in the treatment of opioid and cocaine use disorders, driven in part by enduring dysfunction of medial prefrontal cortex (mPFC) circuits that impair inhibitory control over drug-seeking. The molecular substrates underlying this dysfunction, and whether they differ across drug classes, remain unknown. Here, we performed label-free quantitative proteomics of mPFC synaptosomes isolated from rats after 30-day abstinence following intravenous heroin or cocaine self-administration to profile synaptic adaptations that may contribute to relapse vulnerability. Heroin abstinence induced extensive synaptic proteomic remodeling characterized by coordinated downregulation of mitochondrial proteins involved in oxidative phosphorylation, including pyruvate dehydrogenase complex subunits that regulate carbon entry into mitochondrial metabolism. Targeted metabolomic profiling of whole mPFC revealed accumulation of upstream glycolytic and pentose phosphate pathway intermediates, consistent with altered pyruvate utilization and mitochondrial oxidation. Several bioenergetic metabolites also correlated positively with the severity of escalation of heroin intake. Consistent with the bioenergetic remodeling observed during protracted heroin abstinence, whole-cell patch-clamp recordings from layer V mPFC pyramidal neurons revealed lasting suppression of intrinsic excitability and a decreased spontaneous excitatory synaptic activity. Cocaine abstinence, by contrast, produced limited changes in synaptic bioenergetics while inducing a distinct cytoskeletal remodeling signature. Overall, these findings identify synaptic bioenergetic remodeling as a previously underappreciated feature of prolonged heroin abstinence and reveal a marked divergence in the molecular adaptations induced by heroin versus cocaine within the mPFC. These results implicate mitochondrial bioenergetic pathways as therapeutic targets for reducing relapse vulnerability specifically associated with opioid use disorder.

neuroscience↗

bioRxiv2023

Shared and divergent transcriptomic regulation in nucleus accumbens D1 and D2 medium spiny neurons by cocaine and morphine

Substance use disorders (SUDs) induce widespread molecular dysregulation in the nucleus accumbens (NAc), a brain region pivotal for coordinating motivation and reward. These molecular changes are thought to support lasting neural and behavioral disturbances that promote drug-seeking in addiction. However, different drug classes exert unique influences on neural circuits, cell types, physiology, and gene expression despite the overlapping symptomatology of SUDs. To better understand common and divergent molecular mechanisms governing SUD pathology, our goal was to survey cell-type-specific restructuring of the NAc transcriptional landscape in after psychostimulant or opioid exposure. We combined fluorescence-activated nuclei sorting and RNA sequencing to profile NAc D1 and D2 medium spiny neurons (MSNs) across cocaine and morphine exposure paradigms, including initial exposure, prolonged withdrawal after repeated exposure, and re-exposure post-withdrawal. Our analyses reveal that D1 MSNs display many convergent transcriptional responses across drug classes during exposure, whereas D2 MSNs manifest mostly divergent responses between cocaine and morphine, with morphine causing more adaptations in this cell type. Utilizing multiscale embedded gene co-expression network analysis (MEGENA), we discerned transcriptional regulatory networks subserving biological functions shared between cocaine and morphine. We observed largely integrative engagement of overlapping gene networks across drug classes in D1 MSNs, but opposite regulation of key D2 networks, highlighting potential therapeutic gene network targets within MSNs. These studies establish a landmark, cell-type-specific atlas of transcriptional regulation induced by cocaine and by morphine that can serve as a foundation for future studies towards mechanistic understanding of SUDs. Our findings, and future work leveraging this dataset, will pave the way for the development of targeted therapeutic interventions, addressing the urgent need for more effective treatments for cocaine use disorder and enhancing the existing strategies for opioid use disorder.

neuroscience↗

bioRxiv2023

Transcriptional signatures of heroin intake and seeking throughout the brain reward circuit

Opioid use disorder (OUD) looms as one of the most severe medical crises currently facing society. More effective therapeutics for OUD requires in-depth understanding of molecular changes supporting drug-taking and relapse. Recent efforts have helped advance these aims, but studies have been limited in number and scope. Here, we develop a brain reward circuit-wide atlas of opioid-induced transcriptional regulation by combining RNA sequencing (RNAseq) and heroin self-administration in male mice modeling multiple OUD-relevant conditions: acute heroin exposure, chronic heroin intake, context-induced drug-seeking following prolonged abstinence, and heroin-primed drug-seeking (i.e., "relapse"). Bioinformatics analysis of this rich dataset identified numerous patterns of molecular changes, transcriptional regulation, brain-region-specific involvement in various aspects of OUD, and both region-specific and pan-circuit biological domains affected by heroin. Integrating RNAseq data with behavioral outcomes using factor analysis to generate an "addiction index" uncovered novel roles for particular brain regions in promoting addiction-relevant behavior, and implicated multi-regional changes in affected genes and biological processes. Comparisons with RNAseq and genome-wide association studies from humans with OUD reveal convergent molecular regulation that are implicated in drug-taking and relapse, and point to novel gene candidates with high therapeutic potential for OUD. These results outline broad molecular reprogramming that may directly promote the development and maintenance of OUD, and provide a foundational resource to the field for future research into OUD mechanisms and treatment strategies.

neuroscience↗

bioRxiv2021

Δ9-tetrahydrocannabinol inhibits Hedgehog-dependent patterning during development

Many birth defects are thought to arise from a multifactorial etiology; i.e., interaction between genetic and environmental risk factors. The Hedgehog (HH) signaling pathway regulates myriad developmental processes, and pathway inhibition is associated with birth defects, including holoprosencephaly (HPE). Cannabinoids are HH pathway inhibitors, but little is known of their effects on HH-dependent processes in mammalian embryos, and their mechanism of action is unclear. We report here that the psychoactive cannabinoid {Delta}9-tetrahydrocannabinol (THC) induces two hallmark HH loss-of-function phenotypes (HPE and ventral neural tube patterning defects) in Cdon mutant mice, which have a subthreshold deficit in HH signaling. THC therefore acts as a "conditional teratogen", dependent on a complementing but insufficient genetic insult. In vitro findings indicate that THC is a direct, albeit relatively weak, inhibitor of the essential HH pathway component, Smoothened. In contrast, the canonical THC receptor, cannabinoid receptor-type 1, is not required for THC to inhibit HH signaling. Cannabis consumption during pregnancy may contribute to the combination of risk factors underlying specific developmental disorders. These findings therefore have significant public health relevance.

developmental biology↗