Biology subjects

Kiraly, D. D.

Publications and source records attributed to Kiraly, D. D..

8 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↗

bioRxiv2024

Synchrony between midbrain gene transcription and dopamine terminal regulation is modulated by chronic alcohol drinking

Alcohol use disorder is marked by disrupted behavioral and emotional states which persist into abstinence. The enduring synaptic alterations that remain despite the absence of alcohol are of interest for interventions to prevent relapse. Here, 28 male rhesus macaques underwent over 20 months of alcohol drinking interspersed with three 30-day forced abstinence periods. After the last abstinence period, we paired direct sub-second dopamine monitoring via ex vivo voltammetry in nucleus accumbens slices with RNA-sequencing of the ventral tegmental area. We found persistent augmentation of dopamine transporter function, kappa opioid receptor sensitivity, and dynorphin release - all inhibitory regulators which act to decrease extracellular dopamine. Surprisingly, though transcript expression was not altered, the relationship between gene expression and functional readouts of these encoded proteins was highly dynamic and altered by drinking history. These results outline the long-lasting synaptic impact of alcohol use and suggest that assessment of transcript-function relationships is critical for the rational design of precision therapeutics.

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.

neuroscience↗

bioRxiv2021

Granulocyte-colony stimulating factor (G-CSF) enhances cocaine effects in the nucleus accumbens via a dopamine release-based mechanism

Cocaine use disorder is associated with alterations in immune function including altered expression of multiple peripheral cytokines in humans - several of which correlate with drug use. Individuals suffering from cocaine use disorder show altered immune system responses to drug-associated cues, highlighting the interaction between the brain and immune system as a critical factor in the development and expression of cocaine use disorder. We have previously demonstrated in animal models that cocaine use upregulates expression of granulocyte colony stimulating factor (G-CSF) - a pleiotropic cytokine - in the serum and the nucleus accumbens (NAc). G-CSF signaling has been causally linked to behavioral responses to cocaine across multiple behavioral domains. The goal of this study was to define whether increases in G-CSF alter the pharmacodynamic effects of cocaine on the dopamine system and whether this occurs via direct mechanisms within local NAc microcircuits. We find that systemic G-CSF injection increases cocaine effects on dopamine terminals. The enhanced dopamine levels in the presence of cocaine occur through a release-based mechanism, rather than through effects on the dopamine transporter - as uptake rates were unchanged following G-CSF treatment. Critically, this effect could be recapitulated by acute bath application of G-CSF to dopamine terminals, an effect that was occluded by prior G-CSF treatment, suggesting a similar mechanistic basis for direct and systemic exposures. This work highlights the critical interaction between the immune system and psychostimulant effects that can alter drug responses and may play a role in vulnerability to cocaine use disorder.

neuroscience↗

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

Effects of gene by microbiome interactions on behavioral and neurobiological phenotypes in a mouse model for autism spectrum disorder

Autism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder with complex pathophysiology including both genetic and environmental factors. Recent evidence demonstrates the gut microbiome and its resultant metabolome can influence brain and behavior and have been implicated in ASD. To investigate gene by microbiome interactions in a model for genetic risk of ASD, we utilize mutant mice carrying a deletion of the ASD-associated Shank3 gene (Shank3KO). Shank3KO have altered microbiome composition and function at baseline in addition to social deficits. Further depletion of the microbiome with antibiotics exacerbates social deficits in Shank3KO, and results in transcriptional changes in the frontal cortex. Supplementation with the microbial metabolite acetate leads to reversal of social behavioral phenotypes even in mice with a depleted microbiome, and significantly alters transcriptional regulation in the prefrontal cortex. These results suggest a key role for the gut microbiome and the neuroactive metabolite acetate in regulating ASD-like behaviors.

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↗

bioRxiv2018

Multi-OMIC analysis of brain and serum from chronically-stressed mice reveals network disruptions in purine metabolism, fatty acid beta-oxidation, and antioxidant activity that are reversed by antidepressant treatment

Major depressive disorder (MDD) is a complex condition with unclear pathophysiology. Molecular disruptions within the periphery and limbic brain regions contribute to depression symptomatology. Here, we utilized a mouse chronic stress model of MDD and performed metabolomic, lipidomic, and proteomic profiling on serum plus several brain regions (ventral hippocampus, nucleus accumbens, and prefrontal cortex) of susceptible, resilient, and unstressed control mice. Proteomic analysis identified three serum proteins reduced in susceptible animals; lipidomic analysis detected differences in lipid species between resilient and susceptible animals in serum and brain; and metabolomic analysis revealed pathway dysfunctions of purine metabolism, beta oxidation, and antioxidants, which were differentially associated with stress susceptibility vs resilience by brain region. Antidepressant treatment ameliorated MDD-like behaviors and affected key metabolites within outlined networks, most dramatically in the ventral hippocampus. This work presents a resource for chronic stress-induced, tissue-specific changes in proteins, lipids, and metabolites and illuminates how molecular dysfunctions contribute to individual differences in stress sensitivity.

neuroscience↗