Biology subjects

Spanagel, R.

Publications and source records attributed to Spanagel, R..

16 recordsLinked to original sources

bioRxiv2026

Impaired Control Symptoms in Alcohol Use Disorder Show Convergent Associations Across Behavioral and Neural Markers of Inhibitory Control and Drinking Behavior

Background: Deficits in inhibitory control are considered a central feature of alcohol use disorder (AUD), yet behavioral and neuroimaging findings have been inconsistent. One potential explanation is the marked heterogeneity of AUD, which encompasses multiple symptom dimensions that may differ in their underlying neurocognitive mechanisms. In this study, we investigated whether behavioral and neural markers of inhibitory control are associated with specific DSM-5 AUD symptom domains. Methods: A total of 589 participants (432 with non-treatment seeking AUD, 157 controls) completed a Stop-Signal Task (SST) during fMRI. Associations between DSM-5 symptom domains (impaired control over alcohol use, risky use, social problems, physical dependence) and SST performance, inhibition-related brain activation, and alcohol consumption were examined. Real-life drinking behavior was additionally assessed over 12 months using ecological momentary assessment (EMA). Results: Greater impaired control symptom severity was associated with poorer performance on go trials and diminished post-error slowing during SST. At the neural level, higher impaired control symptom severity was associated with reduced activation across fronto-insular, parietal, cingulate, supplementary motor, and cerebellar regions. In contrast, other symptom domains showed little to no associations with inhibition-related behavioral or neural measures. Higher impaired control symptom severity was associated with greater alcohol consumption across questionnaire-based and EMA-based assessments. Conclusions: In this large cohort, altered behavioral performance and recruitment of inhibition-related brain regions in the SST was selectively linked to impaired control symptoms. These findings highlight the importance of symptom-based approaches for understanding heterogeneity in addiction and may inform the development of more targeted interventions.

neuroscience↗

bioRxiv2026

Multi-Lab Testing of Early Preclinical Discoveries Identifies Promising Treatments

A fundamental challenge in drug development is the frequent failure of early laboratory research to translate into clinical benefit. One promising solution is to confirm findings from exploratory single-laboratory studies across multiple laboratories before clinical testing. We investigated this approach following the conduct of preclinical multi-laboratory studies across different fields of medicine. For this, we evaluated effect sizes, experimental rigor, and a set of criteria to identify determinants of confirmation success. When tested under increased rigor, only a fraction of multi-laboratory studies confirmed the initial results. The underlying effect size reduction was associated with outcome-relevant experimental differences between exploratory and confirmatory stages. In summary, multi-laboratory studies proved highly informative and served as an effective filter for promising treatments.

scientific communication and education↗

bioRxiv2026

Brain Functional Connectivity Signatures of Craving Across Substance Use Disorders: A Transdiagnostic Approach

Craving is a hallmark feature of substance use disorders (SUDs) and a major risk factor for relapse, yet reliable biomarkers that enable individual-level prediction remain scarce. Here, we applied connectome-based predictive modeling (CPM) to resting-state functional magnetic resonance imaging (fMRI) data in a transdiagnostic sample of individuals with cannabis, opioid, or tobacco use disorder (n = 78). Using CPM, we identified a distributed functional brain network that reliably predicted self-reported craving. Computational lesion analyses revealed key contributions from the right medial orbitofrontal cortex, right dorsal posterior cingulate cortex, and left lateral medial frontal gyrus. Importantly, the craving network generalized across two independent datasets. In alcohol-dependent patients (n = 41), the identified craving network, along with its positive and negative subnetworks, predicted distinct cognitive and motivational components of craving. In a second external dataset of smokers (n = 28), the craving network predicted both nicotine craving after abstinence as well as intra-individual changes in craving between sated and craving states. Together, these findings provide evidence for a robust, transdiagnostic craving signature in SUDs. Future work should assess the networks predictive utility for longitudinal outcomes such as relapse risk and treatment response.

neuroscience↗

bioRxiv2025

Epigenome-wide Association Study of Psilocybin-Induced Methylome Changes in Alcohol Use Disorder

The serotonergic hallucinogen psilocybin has shown potential as a treatment for psychiatric conditions like alcohol use disorder (AUD) and depression in clinical studies. Epigenetic mechanisms, including DNA methylation, are hypothesized to contribute to its lasting therapeutic benefits. In this exploratory study, we present the first methylome-wide analysis of psilocybin-induced changes in a cohort of detoxified patients with AUD. The longitudinal study design included three assessment days in 40 patients with blood sampling and acquisition of psychometrics - at baseline, 24 hours after administration of psilocybin (25 mg) or placebo (mannitol), and one month after treatment. Our epigenome-wide association study (EWAS) identified one CpG site in TLE4 (p = 1.1e-7) associated with psilocybin treatment. Screening for differentially methylated regions, we observed altered methylation in the gene RASGRP4 (pFDR = 3.2e-4). Network analysis revealed co-methylation modules related to psilocybin treatment, as well as modules associated with the reduction of depressive symptoms and drinking behavior. Gene ontology analysis indicated involvement of these modules in neuroplasticity and immune functions, suggesting that they may reflect abstinence-related recovery processes. Investigating candidate genes at nominal significance (p < 0.05) uncovered promoter-associated methylation changes in HTR2A and TNF. Furthermore, at p < 0.05, we found baseline differences between treatment responders (< 1 standard unit alcohol in 4-week follow-up) and non-responders in genes related to synaptic plasticity and different neurotransmitter systems. While these findings are limited by the modest sample size, they align well with previous literature and might provide starting points for further, large-scale investigations or hypothesis-driven experiments.

pharmacology and toxicology↗

bioRxiv2024

Early-life adversity mediates a thalamo-amgydalar circuit dysfunction underlying chronic pain and anxiety

Childhood adversity increases the risk of developing a vicious cycle of chronic pain and comorbid anxious avoidance, yet the underlying biological mechanisms remain unclear. Here, we investigated the role of a brain circuit from the paraventricular thalamus (PVT) to the central amygdala (CeA) in mediating hyperalgesia and comorbid anxiety following early life stress. Using a vulnerability-stress model, we exposed both male and female mice to early social isolation (vulnerability) followed by nerve injury (stress) and showed increased hyperalgesia and anxious avoidance behavior in nerve-injured female mice following early adversity. Chemogenetic, electrophysiological, and optophysiological analyses revealed a causal contribution of a hyperexcitable PVT-CeA circuit dysfunction to chronic hyperalgesia and anxiety in nerve-injured female mice after early life stress. Our findings reveal a neural mechanism linking childhood adversity to chronic pain and anxiety, and suggest that reprogramming this pathway may reverse the impact of childhood adversity.

neuroscience↗

bioRxiv2024

A multi-omics and cell type-specific characterization of the ventral striatum in human cocaine use disorder

Epigenome, transcriptome, and proteome analyses of postmortem brains have revealed initial molecular insights into cocaine use disorder (CUD). However, the inter-relationship between these -omics and the contribution of individual cell types remain largely unknown. We present an in-depth analysis of molecular changes in the ventral striatum in CUD at multi-omics and single-cell resolution. Integrative multi-omics analyses of microRNA-seq, RNA-seq, and proteomics datasets in 41 individuals and single-nuclei RNA-seq in a subset of 16 individuals revealed conserved deregulation of metabolic pathways, oxidative phosphorylation, and glutamatergic signaling. Cell type-specific analyses identified inverse metabolic pathway deregulation patterns in glial and neuronal cells, notably in astrocytes and medium spiny neurons (MSNs). Characterizing astrocyte-neuron crosstalk revealed altered glutamatergic and cell adhesion signaling in CUD. By applying a comprehensive multi-omics analytical framework, our study provides novel insights into CUD-associated molecular changes in the ventral striatum, suggesting astrocytes, MSNs, and their crosstalk as particularly perturbed in CUD.

neuroscience↗

bioRxiv2022

Sex and age specific effects on the development of addiction and compulsive-like drinking in rats

Biological factors are known to influence disease trajectories and treatment effectiveness in alcohol addiction. One important biological factor influencing disease dynamics in alcohol use disorder is sex, as preclinical and clinical evidence suggests that gender influences disease trajectories in subjects with alcohol use disorder. Another critical factor is age at first intoxicating drink, which has been identified as a risk factor for later alcohol binging. Preclinical research allows prospective monitoring of rodents throughout the lifespan, providing very detailed information that cannot be acquired in humans. Lifetime monitoring in rodents can be conducted under highly controlled conditions, during which one can systematically introduce multiple biological and environmental factors that impact behaviors of interest. Here, we used the alcohol deprivation effect (ADE) rat model of alcohol addiction in a computerized drinkometer system to study disease dynamics and transition points of addictive behavior in cohorts of adolescent vs. adult as well as male vs. female rats in direct comparison. Early age of onset of drinking (postnatal day 40) in male rats had surprisingly little impact on the development of drinking behavior and compulsivity (quinine taste adulteration) when compared to rats that started drinking during early adulthood (postnatal day 72). However, female rats showed a stronger resistance to quinine taste adulteration after a history of ADEs, indicative of more pronounced compulsive behavior in females as compared to male rats. Specifically, female rats exhibit during quinine taste adulteration a higher frequency of drinking events and a larger access size, especially from the 20% alcohol solution, resulting in fast intoxication despite taste aversion in a relapse-like situation. Our results suggest that drinking patterns, and specifically solution preference as well as access size, provide a valuable indication into determining compulsive drinking. These findings provide a better understanding of sex and age factors involved in the development of drinking behavior that are important in preclinical development of models of addiction, drug development and exploration options for new treatments.

neuroscience↗

bioRxiv2022

A Systematic Review and Meta-analysis on the Transcriptomic Signatures in Alcohol Use Disorder- a Translational Approach

Alcohol use disorder (AUD) is a complex mental health condition. Currently available clinical treatments exhibit limited efficacy and new druggable targets are required. One promising approach to discover new molecular treatment targets involves the transcriptomic profiling of brain regions within the addiction neurocircuitry, utilizing animal models and post-mortem brain tissue from deceased AUD patients. Unfortunately, such studies suffer from large heterogeneity and small sample sizes. To address these limitations, we conducted a cross-species meta-analysis on transcriptome-wide data obtained from brain tissue of AUD patients and animal models. We integrated 36 cross-species transcriptome-wide RNA-expression datasets with an alcohol-dependent phenotype vs. controls, following the PRISMA guidelines. In total, we meta-analyzed 1,000 samples - 502 samples for the prefrontal cortex (PFC), 318 nucleus accumbens (NAc) samples, and 180 amygdala (AMY) samples. The PFC had the highest number of differentially expressed genes (DEGs) across rodents, monkeys, and humans. Commonly dysregulated DEGs pointed towards enrichment in inflammatory responses and alterations in BBB-regulatory mechanisms in astrocytes, microglia and endothelial cells. Gene set enrichment analysis further showed that MAPK/ERK-signaling plays a critical role in AUD and especially in monkeys Dusp4 as a major inhibitor of the MAPK pathway may be a main driver of these pathway alterations. Our data also suggest that the transcriptomic profile in the NAc is less vulnerable to the maintenance of AUD. Finally, we provide a combination of DEGs that are commonly regulated across different brain tissues as potential biomarker for AUD. In summary, we provide a compendium of genes, signaling pathways, and physiological and cellular processes that are altered in AUD and that require future studies for functional validation.

neuroscience↗

bioRxiv2022

Generalized habitual tendencies in alcohol dependent rats

Habitual responses and ultimately compulsive behavior are thought to be at the core of addiction including alcohol use disorder (AUD). Little is known whether the habitization concerns exclusively the response towards alcohol or generalizes to other daily activities. Here, we address this question in a well-established animal model of AUD - the postdependent rat model - by testing habitual responses towards a sweet palatable reward in two striatal learning paradigms: spatial navigation and reward conditioning. For the spatial navigation task, alcohol-dependent and control rats were tested on a sequential decision-making test after short and prolonged T-Maze training; for the reward conditioning task, rats were trained under a random interval schedule for a short and prolonged period and tested in a satiety devaluation test at each time point. Another cohort of alcohol-naive rats was trained and tested on both paradigms under DREADD (designer receptors exclusively activated by designer drugs)-mediated inactivation of the dorsomedial striatum (DMS) which controls goal-directed behavior. Our results show that alcohol-dependent rats displayed increased habitual behavior to obtain saccharin reward on both paradigms, with overall more habitual choices after prolonged training on the spatial navigation task, and increased habitual responses already after short training on the reward conditioning task. Finally, DREADD-mediated inactivation of the DMS increased habitual behavior in non-dependent rats on both paradigms. Our results provide evidence that a history of alcohol dependence produces a bias towards habitual responding that generalizes to a natural reward in rats. Similarly, a habitual bias was induced in non-dependent rats after inactivation of the DMS, thus confirming the critical role of this region in maintaining goal-directed behavior and suggesting its diminished control in AUD.

neuroscience↗

bioRxiv2022

Chronic alcohol intake regulates expression of SARS-CoV2 infection-relevant genes in an organ-specific manner

Chronic alcohol consumption and alcohol use disorder (AUD) have a tremendous impact on the patients psychological and physiological health. There is some evidence that chronic alcohol consumption influences SARS-CoV2 infection risk, but the molecular mechanism is unknown. Here, we generated expression data of SARS-CoV2 infection relevant genes (Ace2, Tmprss2 and Mas) in different organs in rat models of chronic alcohol exposure and alcohol dependence. ACE2 and TMPRSS2 represent the virus entry point whereas Mas is activating the anti-inflammatory response once the cells are infected. Across three different chronic alcohol test conditions, we found a consistent upregulation of Ace2 in the lung, which is the most affected organ in Covid-19 patients. Other organs such as liver, ileum, kidney, heart, and the brain showed also up-regulation of Ace2 and Mas but in a less consistent manner across the different animal models, while Tmprss2 was unaffected in all conditions. We suggest that alcohol-induced up-regulation of Ace2 can lead to an elevated stochastic probability of cellular virus entry and may thus confer a molecular risk factor for a SARS-CoV2 infection.

pharmacology and toxicology↗

bioRxiv2021

Long-term sensitization of rat spinal neurons induced by adolescent psychophysical stress is further enhanced by a mild-nociceptive lumbar input

BackgroundNon-specific low back pain (LBP) is one of the most common chronic pain conditions and adverse childhood experiences (ACEs) are known mediators for chronicity of LBP. Sensitization of dorsal horn neurons (DHNs) is a significant element that contributes to chronic LBP. Repeated restraint stress in adult animals is known to cause manifest DHN sensitization when combined with a short-lasting nociceptive input. ObjectiveIn this study, we investigated whether repeated restraint stress in early adolescence leads to a long-term sensitization of DHNs and if an additional mild-nociceptive input by intramuscular nerve growth factor (NGF) leads to further sensitization. MethodsAdolescent Wistar rats were stressed repeatedly in a narrow plastic restrainer, 1 hour per day for 12 consecutive days. Control animals were handled but not restrained. In adulthood, rats were treated with intramuscular injections of saline or NGF (short-lasting mild-nociceptive input) into the lumbar multifidus muscle (L5). Behavioral tests for pain sensitivity were performed before, after stress and inconjunction with intramuscular injections. Rats were transcardially perfused and immunohistochemistry was performed on lumbar (L2) spinal segments. ResultsAdolescent restraint stress significantly lowered the low back pressure pain threshold (PPT) immediately after the stress (p<0.0001) and was maintained throughout adulthood (p<0.05). Additionally, paw withdrawal threshold (PWT) was significantly lowered by stress (p<0.0001) but normalized towards adulthood. An NGF injection in adulthood in previously stressed animals lowered the PPT (Cohens d=0.87) and increased microglia marker (Iba-1) immunoreactive area in the superficial DHN (p<0.01) with a trend in increased ferets diameter of the immunoreactive cell (p=0.05). ConclusionsOur adolescence stress model induced behavioral signs of sensitization and enhanced sensitivity to further sensitization and dorsal horn microglia activation by subsequent mild nociceptive input (NGF injection). These findings help to understand certain aspects of how adolescent stress might predispose to exacerbation of pain with an additional insult.

neuroscience↗

bioRxiv2020

Adverse Social Experiences in Adolescent Rats Results in Persisting Sex-Dependent Effects on Alcohol-Seeking Behavior

BackgroundAccumulating clinical evidence suggests women with prior exposure to adverse childhood experiences are more susceptible to alcohol relapse and other health-related issues. Yet, preclinical studies investigating sex-dependent effects of adolescent adverse social experiences (ASEs) on later alcohol-seeking behavior are lacking. This is mainly due to a lack of valid animal models and a shortage of studies comparing sexes. Therefore, we sought to investigate the sex-dependent effects of ASE on adult alcohol-seeking behavior, locomotion and reward sensitivity in both male and female rats. MethodsWe recently developed a rat model for adolescent peer-rejection which allows us to study the long-term consequences of ASEs. Peer-rejection interferes with adolescent rats ability to engage in adequate and reciprocal play behaviors that result in persistent dysregulation of social and pain-related behavior. Adolescent Wistar rats were reared from postnatal day (pd) 21 to pd 50 either within a group of Fischer 344 rats (ASE) or with Wistar rats (control). Adult male and female rats were tested in the reinstatement paradigm for cue-induced alcohol-seeking behavior, circadian locomotor activity, and sucrose consumption in adulthood long-after the termination of the peer-rejection condition. ResultsPeer-rejection induced persistent sex-dependent changes to cue-induced reinstatement. Females showed an increased reinstatement effect while peer-rejected males demonstrated a decrease. No differences were observed in circadian locomotor activity or reward sensitivity to sucrose. ConclusionsPeer-rejection has lasting sex-dependent consequences on alcohol-seeking behavior without affecting locomotion or sweet reward sensitivity. Our results suggest that peer-rejected female rats represent a vulnerable population to study relapse-like behaviors similar to clinical findings. While males seem to buffer the peer-rejection effect and demonstrate resilience to later-life alcohol-seeking behaviors, measured by the reinstatement effect. Finally, we provide a novel approach to investigate the molecular and neurobiological underpinnings of ASEs on alcohol and other drug-seeking behaviors.

neuroscience↗

bioRxiv2020

Female mice are more prone to develop an addictive-like phenotype for sugar consumption

BackgroundThe concept of "sugar addiction" is gaining increasing attention in both the lay media and scientific literature. However, the concept of sugar addiction is controversial and only a few studies have attempted to determine the "addictive" properties of sugar using rigorous scientific criteria. ObjectiveHere we set out to systematically test the addictive properties of sugar in male and female mice using established paradigms and models from the drug addiction field. MethodsMale and female C57BL/6N (8-10 weeks old) were evaluated in 4 experimental procedures to study the addictive properties of sugar: (i) a drinking in the dark (DID) procedure to model sugar binging; (ii) a long-term free choice home cage drinking procedure measuring the sugar deprivation effect (SDE) following an abstinence phase; (iii) a long-term operant sugar self-administration with persistence, motivation and compulsivity measures and (iv) intracranial self-administration (ICSS). ResultsFemale mice were more vulnerable to the addictive properties of sugar than male mice, showing higher binge and long-term, excessive drinking, a more pronounced relapse-like drinking following deprivation, and higher persistence and motivation for sugar. No sex differences were seen in a compulsivity test or reward sensitivity measured using ICSS following extended sugar consumption. ConclusionThis study demonstrates the occurrence of an addictive-like phenotype for sugar in male and female mice, similar to drugs of abuse, and suggests sex-dependent differences in the development of sugar addiction.

neuroscience↗

bioRxiv2020

Single-dose ethanol intoxication causes acute and lasting neuronal changes in the brain

Alcohol intoxication at early ages is a risk factor for development of addictive behavior. To uncover neuronal molecular correlates of acute ethanol intoxication, we used stable-isotope labeled mice combined with quantitative mass spectrometry to screen over 2000 hippocampal proteins of which 72 changed synaptic abundance up to two-fold after ethanol exposure. Among those were mitochondrial proteins and proteins important for neuronal morphology, including MAP6 and Ankyrin-G. Based on these candidate proteins, we found acute and lasting molecular, cellular, and behavioral changes following a single intoxication in alcohol-naive mice. Immunofluorescence analysis revealed a shortening of axon initial segments. Longitudinal two-photon in vivo imaging showed increased synaptic dynamics and mitochondrial trafficking in axons. Knockdown of mitochondrial trafficking in dopaminergic neurons abolished conditioned alcohol preference in Drosophila. This introduces mitochondrial trafficking as a process implicated in reward learning, and highlights the potential of high-resolution proteomics to identify cellular mechanisms relevant for addictive behavior.

neuroscience↗

bioRxiv2020

A common molecular mechanism for cognitive deficits and craving in alcoholism

Alcohol-dependent patients commonly show impairments in executive functions that facilitate craving and can lead to relapse. The medial prefrontal cortex, a key brain region for executive control, is prone to alcohol-induced neuroadaptations. However, the molecular mechanisms leading to executive dysfunction in alcoholism are poorly understood. Here using a bi-directional neuromodulation approach we demonstrate a causal link for reduced prefrontal mGluR2 function and both impaired executive control and alcohol craving. By neuron-specific prefrontal knockdown of mGluR2 in rats, we generated a phenotype of reduced cognitive flexibility and excessive alcohol-seeking. Conversely, restoring prefrontal mGluR2 levels in alcohol-dependent rats rescued these pathological behaviors. Also targeting mGluR2 pharmacologically reduced relapse behavior. Finally, we developed a FDG-PET biomarker to identify those individuals that respond to mGluR2-based interventions. In conclusion, we identified a common molecular pathological mechanism for both executive dysfunction and alcohol craving, and provide a personalized mGluR2-mechanism-based intervention strategy for medication development of alcoholism.

neuroscience↗

bioRxiv2020

Coordinated prefrontal state transition leads extinction of reward-seeking behaviors

Extinction learning suppresses conditioned reward responses and is thus fundamental to adapt to changing environmental demands and to control excessive reward seeking. The medial prefrontal cortex (mPFC) monitors and controls conditioned reward responses. Using in vivo multiple single-unit recordings of mPFC we studied the relationship between single-unit and population dynamics during different phases of an operant conditioning task. To examine the fine temporal relation between neural activity and behavior, we developed a model-based statistical analysis that captured behavioral idiosyncrasies. We found that single-unit responses to conditioned stimuli changed throughout the course of a session even under stable experimental conditions and consistent behavior. However, when behavioral responses to task contingencies had to be updated during the extinction phase, unit-specific modulations became coordinated across the whole population, pushing the network into a new stable attractor state. These results show that extinction learning is not associated with suppressed mPFC responses to conditioned stimuli, but is driven by single-unit coordination into population-wide transitions of the animals internal state.

neuroscience↗