Biology subjects

Cheer, J. F.

Publications and source records attributed to Cheer, J. F..

4 recordsLinked to original sources

bioRxiv2022

A multivariate regressor of patterned dopamine release predicts relapse to cocaine

Drug addiction is characterized by a sustained vulnerability to relapse even after long periods of abstinence. A deeper understanding of the brain systems underlying this state could inform therapeutic strategies with novel prognostic biomarkers aimed at preventing renewed drug seeking. Most drugs of abuse, in particular psychostimulants such as cocaine, lead to long-lasting mesolimbic dopamine system adaptations, that ultimately facilitate drug seeking following exposure to drug-paired cues. This "dopaminergic hypothesis" of relapse has been previously addressed, but technical limitations in measuring in vivo dopamine release have precluded the assessment of its sufficiency without introducing pharmacological, electrical, or optogenetic confounds. Using a dopamine receptor-based fluorescent sensor in freely moving mice, we show that long-lasting dopamine recordings in the nucleus accumbens (NAc), throughout the animals entire history of cocaine self-administration, are strong predictors of relapse as well as the time it takes an animal to extinguish its drug seeking behavior. Moreover, we reveal previously unseen sex-specific trajectories of cocaine-related phasic dopamine responses from acquisition to relapse. We show that males exhibit higher-amplitude phasic dopamine responses, a trait accompanied by a greater resistance to extinguish their cocaine seeking, compared to females. Furthermore, we show that a semi-parametric model of the transition to extinction - using only multivariate patterns of dopamine release and sex as covariates - faithfully recapitulates male-specific vulnerability to persistent cocaine seeking. In conclusion, we present a predictive model of reinstatement behavior that uses information exclusively conveyed by NAc phasic dopamine responses, thus confirming, and actuating the sufficiency of the dopaminergic hypothesis of relapse.

neuroscience↗

bioRxiv2022

Decreased ventral tegmental area CB1R signaling reduces sign-tracking and shifts cue-outcome dynamics in rat nucleus accumbens

Sign-tracking rats show enhanced cue sensitivity before drug experience that predicts greater discrete cue-induced drug-seeking compared to goal-tracking or intermediate-rats. Cue-evoked dopamine in the nucleus Accumbens (NAc) is a neurobiological signature of sign-tracking behaviors. Here, we examine a critical regulator of the dopamine system; endocannabinoids, which bind the cannabinoid receptor-1 (CB1R) in the Ventral Tegmental Area (VTA) to control cue-evoked striatal dopamine levels. We use cell-type specific optogenetics, intra-VTA pharmacology and fiber photometry to test the hypothesis that VTA CB1R receptor signaling regulates NAc dopamine levels to control sign-tracking. We trained rats in a Pavlovian lever autoshaping task (PLA) to determine their tracking groups before testing the effect of VTA[->]NAc dopamine inhibition. We found this circuit is critical for mediating the vigor of the ST response. Upstream of this circuit, intra-VTA infusions of rimonabant, a CB1R inverse agonist, during PLA decrease lever and increase foodcup approach in sign-trackers. Using fiber photometry to measure fluorescent signals from dopamine sensor, GRABDA, we tested the effects of intra-VTA rimonabant on NAc dopamine dynamics during autoshaping. We found that intra-VTA rimonabant decreased sign-tracking behaviors, which was associated with increases NAc shell, but not core, dopamine levels during reward delivery (US). We also observed a relationship between cue (CS)-evoked NAc dopamine activity and rigidity of behavior between rimonabant treatment sessions. Our results suggest that CB1R signaling in the VTA influences the balance between the CS- and US-evoked dopamine responses in the NAc and biases behavioral responding to cues in sign-tracking rats. SIGNIFICANCE STATEMENTSubstance Use Disorder is a chronically relapsing neurobiological disorder that affects a subset of individuals that engage in drug use. Recent research suggests that there are individual behavioral and neurobiological differences prior to drug experience that predict addiction and relapse vulnerabilities. Here, we investigate how midbrain endocannabinoids regulate a brain pathway that is exclusively involved in driving cue-motivated behaviors of sign-tracking rats. This work contributes to our mechanistic understanding of individual vulnerabilities to cue-triggered natural reward seeking that have relevance for drug motivated behaviors.

neuroscience↗

bioRxiv2020

Prenatal THC does not affect female mesolimbic dopaminergic system in preadolescent rats

Cannabis use among pregnant women is increasing worldwide along with permissive sociocultural attitudes towards it. Prenatal cannabis exposure (PCE), however, is associated with adverse outcome among offspring ranging from reduced birth weight to child psychopathology. We have previously shown that male rat offspring prenatally exposed to {Delta}9-tetrahydrocannabinol (THC), a rat model of PCE, exhibit extensive molecular, cellular and synaptic changes in dopamine neurons of the ventral tegmental area (VTA), resulting in a susceptible mesolimbic dopamine system associated with a psychotic-like endophenotype. This phenotype only reveals itself upon a single exposure to THC in males but not females. Here, we characterized the impact of PCE on female behaviors and mesolimbic dopamine system function by combining in vivo single-unit extracellular recordings in anesthetized animals and ex vivo patch clamp recordings, along with neurochemical and behavioral analyses. We find that PCE female offspring do not show any spontaneous or THC-induced behavioral disease-relevant phenotypes. The THC-induced increase of dopamine levels in nucleus accumbens was reduced in PCE female offspring, even when VTA dopamine activity in vivo and ex vivo did not differ compared to control. These findings indicate that PCE impacts mesolimbic dopamine function and its related-behavioral domains in a sex-dependent manner and warrant further investigations to decipher the mechanisms determining this sex-related protective effect from intrauterine THC exposure. HighlightsO_LIPCE female offspring do not manifest a disease-relevant phenotype C_LIO_LIPrenatal THC does not affect female dopaminergic neurons C_LIO_LIPCE female mesolimbic dopamine function is less responsive to acute THC C_LI

neuroscience↗

bioRxiv2020

A fast genetically encoded fluorescent sensor for faithful in vivo acetylcholine detection in mice, fish, worms and flies

Here we design and optimize a genetically encoded fluorescent indicator, iAChSnFR, for the ubiquitous neurotransmitter acetylcholine, based on a bacterial periplasmic binding protein. iAChSnFR shows large fluorescence changes, rapid rise and decay kinetics, and insensitivity to most cholinergic drugs. iAChSnFR revealed large transients in a variety of slice and in vivo preparations in mouse, fish, fly and worm. iAChSnFR will be useful for the study of acetylcholine in all animals.

neuroscience↗