Effects of adolescent intermittent ethanol exposure on cortical perineuronal net and parvalbumin expression in adulthood mediate behavioral inflexibility.

Background: Alcohol is commonly consumed by adolescents in a binge-like pattern, which can lead to long-lasting cognitive deficits, including reduced behavioral flexibility. We and others have determined that adolescent intermittent ethanol (AIE) exposure leads to increased number of perineuronal net (PNN) numbers in brain regions that are important for behavioral flexibility. However, whether altered neurochemistry stemming from AIE exposure plays a significant role in reduced behavioral flexibility is unknown.

Adolescent alcohol exposure persistently alters orbitofrontal cortical encoding of Pavlovian conditional stimulus components in female rats.

Exposure to alcohol during adolescence impacts cortical and limbic brain regions undergoing maturation. In rodent models, long-term effects on behavior and neurophysiology have been described after adolescent intermittent ethanol (AIE), especially in males. We hypothesized that AIE in female rats increases conditional approach to a reward-predictive cue and corresponding neuronal activity in the orbitofrontal cortex (OFC) and nucleus accumbens (NAc).

Altered Cortico-Subcortical Network After Adolescent Alcohol Exposure Mediates Behavioral Deficits in Flexible Decision-Making.

Behavioral flexibility, the ability to modify behavior according to changing conditions, is essential to optimize decision-making. Deficits in behavioral flexibility that persist into adulthood are one consequence of adolescent alcohol exposure, and another is decreased functional connectivity in brain structures involved in decision-making; however, a link between these two outcomes has not been established. We assessed effects of adolescent alcohol and sex on both Pavlovian and instrumental behaviors and resting-state functional connectivity MRI in adult animals to determine associations between behavioral flexibility and resting-state functional connectivity.

The role of sex in the persistent effects of adolescent alcohol exposure on behavior and neurobiology in rodents.

Alcohol drinking is often initiated during adolescence, and this frequently escalates to binge drinking. As adolescence is also a period of dynamic neurodevelopment, preclinical evidence has highlighted that some of the consequences of binge drinking can be long lasting with deficits persisting into adulthood in a variety of cognitive-behavioral tasks. However, while the majority of preclinical work to date has been performed in male rodents, the rapid increase in binge drinking in adolescent female humans has re-emphasized the importance of addressing alcohol effects in the context of sex as a biological variable.

Allopregnanolone Decreases Evoked Dopamine Release Differently in Rats by Sex and Estrous Stage.

Mesolimbic dopamine transmission is dysregulated in multiple psychiatric disorders, including addiction. Previous studies found that the endogenous GABAergic steroid (3α,5α)-3-hydroxy-5-pregnan-20-one (allopregnanolone) modulates dopamine levels in the nucleus accumbens and prefrontal cortex. As allopregnanolone is a potent positive allosteric modulator of GABA receptors, and GABA receptors can regulate dopamine release, we hypothesized that allopregnanolone would reduce phasic fluctuations in mesolimbic dopamine release that are important in learning and reward processing.

Stimuli predicting high-calorie reward increase dopamine release and drive approach to food in the absence of homeostatic need.

Animals and humans are motivated to consume high-fat, high-calorie foods by cues predicting such foods. The neural mechanisms underlying this effect are not well understood. We tested the hypothesis that cues paired with a food reward, as compared to explicitly unpaired cues, increase rats' food-seeking behavior by potentiating dopamine release in the nucleus accumbens, and that this effect would be less evident under satiety.

Characterization of genetically complex Collaborative Cross mouse strains that model divergent locomotor activating and reinforcing properties of cocaine.

Rationale: Few effective treatments exist for cocaine use disorders due to gaps in knowledge about its complex etiology. Genetically defined animal models provide a useful tool for advancing our understanding of the biological and genetic underpinnings of addiction-related behavior and evaluating potential treatments. However, many attempts at developing mouse models of behavioral disorders were based on overly simplified single gene perturbations, often leading to inconsistent and misleading results in pre-clinical pharmacology studies.

Phasic dopamine release identification using convolutional neural network.

Dopamine has a major behavioral impact related to drug dependence, learning and memory functions, as well as pathologies such as schizophrenia and Parkinson's disease. Phasic release of dopamine can be measured in vivo with fast-scan cyclic voltammetry. However, even for a specialist, manual analysis of experiment results is a repetitive and time consuming task.

Adolescent intermittent ethanol impairs behavioral flexibility in a rat foraging task in adulthood.

Alcohol exposure is linked to behavioral flexibility deficits in humans, but it is unclear when the critical exposure occurred or if alcohol exposure alone is sufficient to produce behavior deficits. Increasing evidence shows that binge levels of alcohol during adolescence are particularly harmful to the brain, producing physiological and behavioral effects that can persist into adulthood. The present study determined whether adolescent intermittent ethanol (AIE) in rats impaired action selection in a discriminative stimulus task using a foraging response.

Local μ-Opioid Receptor Antagonism Blunts Evoked Phasic Dopamine Release in the Nucleus Accumbens of Rats.

μ-opioid receptors (MORs) in the nucleus accumbens (NAc) can regulate reward-related behaviors that are dependent on mesolimbic dopamine, but the precise mechanism of this MOR regulation is unknown. We hypothesized that MORs within the NAc core regulate dopamine release. Specifically, we infused the MOR antagonist CTAP (d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2) into the NAc core while dopamine release was evoked by electrical stimulation of the ventral tegmental area and measured by fast-scan cyclic voltammetry.

Ethanol Exposure History and Alcoholic Reward Differentially Alter Dopamine Release in the Nucleus Accumbens to a Reward-Predictive Cue.

Background: Conditioned stimuli (CS) that predict reward delivery acquire the ability to induce phasic dopamine release in the nucleus accumbens (NAc). This dopamine release may facilitate conditioned approach behavior, which often manifests as approach to the site of reward delivery (called "goal-tracking") or to the CS itself (called "sign-tracking"). Previous research has linked sign-tracking in particular to impulsivity and drug self-administration, and addictive drugs may promote the expression of sign-tracking.

Partial lesion of dopamine neurons of rat substantia nigra impairs conditioned place aversion but spares conditioned place preference.

Midbrain dopamine neurons play critical roles in reward- and aversion-driven associative learning. However, it is not clear whether they do this by a common mechanism or by separate mechanisms that can be dissociated. In the present study we addressed this question by testing whether a partial lesion of the dopamine neurons of the rat SNc has comparable effects on conditioned place preference (CPP) learning and conditioned place aversion (CPA) learning.

Diazepam Inhibits Electrically Evoked and Tonic Dopamine Release in the Nucleus Accumbens and Reverses the Effect of Amphetamine.

Diazepam is a benzodiazepine receptor agonist with anxiolytic and addictive properties. Although most drugs of abuse increase the level of release of dopamine in the nucleus accumbens, here we show that diazepam not only causes the opposite effect but also prevents amphetamine from enhancing dopamine release. We used 20 min sampling in vivo microdialysis and subsecond fast-scan cyclic voltammetry recordings at carbon-fiber microelectrodes to show that diazepam caused a dose-dependent decrease in the level of tonic and electrically evoked dopamine release in the nucleus accumbens of urethane-anesthetized adult male Swiss mice.

Toward sophisticated basal ganglia neuromodulation: Review on basal ganglia deep brain stimulation.

This review presents state-of-the-art knowledge about the roles of the basal ganglia (BG) in action-selection, cognition, and motivation, and how this knowledge has been used to improve deep brain stimulation (DBS) treatment of neurological and psychiatric disorders. Such pathological conditions include Parkinson's disease, Huntington's disease, Tourette syndrome, depression, and obsessive-compulsive disorder. The first section presents evidence supporting current hypotheses of how the cortico-BG circuitry works to select motor and emotional actions, and how defects in this circuitry can cause symptoms of the BG diseases.

The role of the basal ganglia in motivated behavior.

The present paper reviews foundational and contemporary theories of motivated behaviors and the growing body of evidence that they require specific functional interactions within the basal ganglia. Such evidence suggests that unconditioned responses (UR), conditioned responses (CR), goal-directed actions and stimulus-response (S-R) habits are selected in the basal ganglia. Such selection depends on activation of striatal neurons by cortical and subcortical neurons encoding unconditioned stimuli (US), conditioned stimuli (CS), goals and neutral stimuli (S).