Biology subjects

Hofford, R. S.

Publications and source records attributed to Hofford, R. S..

7 recordsLinked to original sources

bioRxiv2026

Granulocyte colony-stimulating factor acts through calcium-permeable AMPA receptors to potentiate cocaine reward

Neuroimmune interactions have emerged as critical modulators of substance use disorders and may represent promising translational therapeutic targets. In prior work, we demonstrated that the cytokine granulocyte colony stimulating factor (G-CSF) is elevated in mice following cocaine exposure, with circulating levels correlating with cocaine intake and locomotor sensitization. Additionally, exogenous G-CSF enhances cocaine reward and increases low-dose cocaine self-administration. We have further shown that repeated G-CSF administration alters expression of glutamatergic synapse-associated proteins following cocaine-seeking behavior. Building on these findings, the present studies examined the molecular consequences of repeated administration of G-CSF, cocaine, or their combination, with a focus on glutamatergic signaling pathways. We also tested whether altered glutamate receptor expression contributes to G-CSF-mediated enhancement of cocaine reward. Repeated combined administration of G-CSF and cocaine produced robust changes in glutamate-associated and synapse-related protein expression within the nucleus accumbens and medial prefrontal cortex. These molecular adaptations were accompanied by increased synaptic density in the nucleus accumbens. Finally, pharmacological inhibition of calcium-permeable AMPA receptors within the nucleus accumbens reversed the G-CSF-induced enhancement of cocaine conditioned place preference. Together, these findings indicate that G-CSF enhances cocaine reward at least in part by promoting glutamatergic synaptic remodeling in the nucleus accumbens, identifying a neuroimmune-glutamate mechanism that may be leveraged for therapeutic intervention.

neuroscience↗

bioRxiv2025

Brief disruption of the microbiome has age-dependent effects on morphine reward and gene expression in the medial prefrontal cortex of adolescent and adult mice

Adolescence is a critical period for the initiation of problematic drug use, which significantly increases the risk of developing substance use disorders later in life. This heightened vulnerability is partly attributed to the immaturity of the prefrontal cortex, a brain region both essential for decision-making and implicated in drug reward. During adolescence, peripheral systems, such as the gut microbiome, also undergo substantial changes. Emerging evidence suggests that disruptions to the gut microbiome can influence gene expression and drug reward behaviors in rodent models. In this study, we investigated the effects of microbiome disruption on morphine reward and prefrontal cortical gene expression in adolescent and adult mice. Using oral antibiotics to transiently disrupt the microbiome, we found that short-term antibiotic exposure reduced morphine place preference specifically in adolescent mice. In a separate cohort, we observed that antibiotic treatment altered the transcriptomic response to morphine in the medial prefrontal cortex across all age groups. Notably, the transcriptomic changes induced by antibiotics and morphine were age-specific, with distinct gene expression patterns observed in adolescents compared to adults. These findings establish a foundation for future research into the role of the gut microbiome in opioid reward and highlight potential gene pathways underlying age-dependent differences in opioid sensitivity.

neuroscience↗

bioRxiv2023

Microbial short-chain fatty acids regulate drug seeking and transcriptional control in a model of cocaine seeking

Cocaine use disorder represents a public health crisis with no FDA-approved medications for its treatment. A growing body of research has detailed the important connections between the brain and the resident population of bacteria in the gut, the gut microbiome in psychiatric disease models. Acute depletion of gut bacteria results in enhanced reward in a mouse cocaine place preference model, and repletion of bacterially-derived short-chain fatty acid (SCFA) metabolites reverses this effect. However, the role of the gut microbiome and its metabolites in modulating cocaine-seeking behavior after prolonged abstinence is unknown. Given that relapse prevention is the most clinically challenging issue in treating substance use disorders, studies examining the effects of microbiome manipulations in relapse-relevant models are critical. Here, Sprague-Dawley rats received either untreated water or antibiotics to deplete the gut microbiome and its metabolites. Rats were trained to self-administer cocaine and subjected to either within-session threshold testing to evaluate motivation for cocaine or 21 days of abstinence followed by a cue-induced cocaine-seeking task to model relapse behavior. Microbiome depletion did not affect cocaine acquisition on an FR1 schedule. However, microbiome-depleted subjects exhibited significantly enhanced motivation for low dose cocaine on a within-session threshold task. Similarly, microbiome depletion increased cue-induced cocaine-seeking following prolonged abstinence. In the absence of a normal microbiome, repletion of bacterially-derived SCFA metabolites reversed the behavioral and transcriptional changes associated with microbiome depletion. These findings suggest that gut bacteria, via their metabolites, are key regulators of drug-seeking behaviors, positioning the microbiome as a potential translational research target.

neuroscience↗

bioRxiv2022

Changes in gut microbiome composition drive fentanyl intake and striatal proteomic changes

Opioid use disorder (OUD) is a public health crisis currently being exacerbated by increased rates of use and overdose of synthetic opioids, primarily fentanyl. Therefore, the identification of novel biomarkers and treatment strategies to reduce problematic fentanyl use and relapse to fentanyl taking is critical. In recent years, there has been a growing body of work demonstrating that the gut microbiome can serve as a potent modulator of the behavioral and transcriptional responses to both stimulants and opioids. Here, we advance this work to define how manipulations of the microbiome drive fentanyl intake and fentanyl seeking in a translationally relevant drug self-administration model. Additionally, we utilize global proteomic analysis of the nucleus accumbens following microbiome manipulation and fentanyl administration to define how microbiome status alters the functional proteomic landscape in this key limbic substructure. These findings establish clear relevance for gut-brain signaling in OUD, and lay foundations for further translational work in this space.

neuroscience↗

bioRxiv2022

Dietary polyphenols drive alterations in behavior, transcriptional regulation, and commensal microbiota in models of opioid use.

Opioid Use Disorder (OUD) is a neuropsychiatric condition associated with tremendous medical and social consequences. Despite this burden, current pharmacotherapies for OUD are ineffective or intolerable for many patients. As such, interventions aimed at promoting overall health and resilience against OUD are of immense clinical and societal interest. Recently, treatment with a Bioactive Dietary Polyphenol Preparation (BDPP) was shown to promote behavioral resilience and adaptive neuroplasticity in multiple models of neuropsychiatric disease. Here, we assessed effects of BDPP treatment on behavioral and molecular responses to repeated morphine treatment. We find that BDPP pre-treatment alters responses across the dose range for both locomotor sensitization and conditioned place preference. Most notably, polyphenol treatment consistently reduced formation of preference at low dose (5mg/kg) morphine but enhanced it at high dose (15mg/kg). In parallel, we performed transcriptomic profiling of the nucleus accumbens, which again showed a dose x polyphenol interaction. At high dose morphine, BDPP pre-treatment potentiated gene expression changes induced by morphine particularly for genes related to synaptic function. We also profiled microbiome composition and function, as polyphenols are metabolized by the microbiome and can act as prebiotics. The profile revealed polyphenol treatment markedly altered microbiome composition and function, particularly in the low dose morphine group. Finally, we investigated involvement of the SIRT1 histone deacetylase, and the role of specific polyphenol metabolites in these behavioral phenotypes. Taken together, these results demonstrate that polyphenols have robust dose-dependent effects on behavioral and physiological responses to morphine and lay the foundation for future translational work.

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bioRxiv2020

The gut microbiome and its metabolites are necessary for morphine reward

Recent evidence has demonstrated that the gut microbiome has marked effects on neuronal function and behavior. Disturbances to microbial populations within the gut have been linked to myriad models of neuropsychiatric disorders. However, the role of the microbiome in substance use disorders remains understudied. Here we show that animals with their gut microbiome depleted by non-absorbable antibiotics (Abx) exhibit decreased formation of morphine conditioned place preference and demonstrate marked changes in gene expression within the nucleus accumbens (NAc) in response to morphine. Replacement of short-chain fatty acid (SCFA) metabolites, which are reduced by microbiome knockdown, reversed the behavioral and transcriptional effects of microbiome depletion. This identifies SCFA as the crucial mediators of microbiome-brain communication responsible for the effects on morphine reward caused by microbiome knockdown. These studies add important new behavioral, molecular, and mechanistic insight to the role of gut-brain signaling in substance use disorders.

neuroscience↗

bioRxiv2020

Granulocyte-Colony Stimulating Factor reduces cocaine-seeking and downregulates glutamatergic synaptic proteins in medial prefrontal cortex

BackgroundPsychostimulant use disorder is a major public health issue, and despite the scope of the problem there are currently no FDA approved treatments. There would be tremendous utility in development of a treatment that could help patients both achieve and maintain abstinence. Previous work from our group has identified granulocyte-colony stimulating factor (G-CSF) as a neuroactive cytokine that alters behavioral response to cocaine, increases synaptic dopamine release, and enhances cognitive flexibility. Here, we investigate the role of G-CSF in affecting extinction and reinstatement of cocaine-seeking and perform detailed characterization of its proteomic effects in multiple limbic substructures. MethodsSprague-Dawley rats were injected with PBS or G-CSF during (1) extinction or (2) abstinence from cocaine self-administration, and drug seeking behavior was measured. Quantitative assessment of changes in the proteomic landscape in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) were performed via data-independent acquisition (DIA) mass spectrometry analysis. ResultsAdministration of G-CSF during extinction accelerated the rate of extinction, and administration during abstinence attenuated cue-induced cocaine-seeking. Analysis of global protein expression demonstrated that G-CSF regulated proteins primarily in mPFC that are critical to glutamate signaling and synapse maintenance. ConclusionTaken together, these findings support G-CSF as a viable translational research target with the potential to reduce drug craving or seeking behaviors. Importantly, recombinant G-CSF exists as an FDA-approved medication which may facilitate rapid clinical translation. Additionally, using cutting-edge multi-region discovery proteomics analyses, these studies identify a novel mechanism underlying G-CSF effects on behavioral plasticity.

neuroscience↗