Neuroanatomical variability associated with early substance use initiation: Results from the ABCD Study.

The extent to which neuroanatomical variability associated with substance involvement reflects pre-existing risk and/or consequences of substance exposure remains poorly understood. In the Adolescent Brain Cognitive DevelopmentSM (ABCD®) Study, we identify associations between global and regional differences in brain structure and early substance use initiation (i.e., occurring <15 years of age; nsanalytic=6,556-9,804), with evidence that associations precede initiation. Neurodevelopmental variability in brain structure may confer risk for substance involvement.

Individual-, peer-, and parent-level substance use-related factors among 9- and 10-year-olds from the ABCD Study: Prevalence rates and sociodemographic differences.

Background: Although a relatively large body of research has identified multiple factors associated with adolescent substance use, less is known about earlier substance-related factors during preadolescence, including curiosity to use substances. The present study examined individual-, peer-, and parent-level domains pertaining to substance use and how these domains vary by sociodemographic subgroups and substance type. Methods: Participants were 11,864 9- and 10-year-olds from the baseline sample of the Adolescent Brain Cognitive Development (ABCD) Study. Youth-reported measures were curiosity to use substances and perceived peer substance use. Parent-reported measures were availability of and rules about substances. Generalized logistic mixed models (GLMM) were used to compare these measures across alcohol, nicotine, and marijuana and across sociodemographic subgroupings (sex, race/ethnicity, household income, and family history of alcohol problems). GLMM was then used to examine predictors of curiosity to use by substance type. Results: The most striking descriptive differences were found between race/ethnicity and income categories (e.g., positive associations between greater income and greater availability of alcohol). In multivariable analyses, greater curiosity to use alcohol was associated with being male, higher household income, perceived peer alcohol use, and easy alcohol availability; greater curiosity to use nicotine was associated with being male, perceived peer cigarette use, easy availability of cigarettes, and no parental rules about cigarette use. Conclusions: This study identified substance use-related individual-, peer-, and parent-level factors among a diverse, national sample. Findings highlight the importance of considering sociodemographic and substance-specific variability and may help identify risk and protective factors preceding adolescent substance use.

Correction: Striatopallidal neurons control avoidance behavior in exploratory tasks.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

Striatopallidal neurons control avoidance behavior in exploratory tasks.

The dorsal striatum has been linked to decision-making under conflict, but the mechanism by which striatal neurons contribute to approach-avoidance conflicts remains unclear. We hypothesized that striatopallidal dopamine D2 receptor (D2R)-expressing neurons promote avoidance, and tested this hypothesis in two exploratory approach-avoidance conflict paradigms in mice: the elevated zero maze and open field. Genetic elimination of D2Rs on striatopallidal neurons (iMSNs), but not other neural populations, increased avoidance of the open areas in both tasks, in a manner that was dissociable from global changes in movement. Population calcium activity of dorsomedial iMSNs was disrupted in mice lacking D2Rs on iMSNs, suggesting that disrupted output of iMSNs contributes to heightened avoidance behavior. Consistently, artificial disruption of iMSN output with optogenetic stimulation heightened avoidance of open areas of these tasks, while inhibition of iMSN output reduced avoidance. We conclude that dorsomedial striatal iMSNs control approach-avoidance conflicts in exploratory tasks, and highlight this neural population as a potential target for reducing avoidance in anxiety disorders.

geneHummus: an R package to define gene families and their expression in legumes and beyond.

BACKGROUND: During the last decade, plant biotechnological laboratories have sparked a monumental revolution with the rapid development of next sequencing technologies at affordable prices. Soon, these sequencing technologies and assembling of whole genomes will extend beyond the plant computational biologists and become commonplace within the plant biology disciplines. The current availability of large-scale genomic resources for non-traditional plant model systems (the so-called 'orphan crops') is enabling the construction of high-density integrated physical and genetic linkage maps with potential applications in plant breeding. The newly available fully sequenced plant genomes represent an incredible opportunity for comparative analyses that may reveal new aspects of genome biology and evolution. The analysis of the expansion and evolution of gene families across species is a common approach to infer biological functions. To date, the extent and role of gene families in plants has only been partially addressed and many gene families remain to be investigated. Manual identification of gene families is highly time-consuming and laborious, requiring an iterative process of manual and computational analysis to identify members of a given family, typically combining numerous BLAST searches and manually cleaning data. Due to the increasing abundance of genome sequences and the agronomical interest in plant gene families, the field needs a clear, automated annotation tool. RESULTS: Here, we present the geneHummus package, an R-based pipeline for the identification and characterization of plant gene families. The impact of this pipeline comes from a reduction in hands-on annotation time combined with high specificity and sensitivity in extracting only proteins from the RefSeq database and providing the conserved domain architectures based on SPARCLE. As a case study we focused on the auxin receptor factors gene (ARF) family in Cicer arietinum (chickpea) and other legumes. CONCLUSION: We anticipate that our pipeline should be suitable for any taxonomic plant family, and likely other gene families, vastly improving the speed and ease of genomic data processing.

Coordinated Ramping of Dorsal Striatal Pathways preceding Food Approach and Consumption.

The striatum controls food-related actions and consumption and is linked to feeding disorders, including obesity and anorexia nervosa. Two populations of neurons project from the striatum: direct pathway medium spiny neurons and indirect pathway medium spiny neurons. The selective contribution of direct pathway medium spiny neurons and indirect pathway medium spiny neurons to food-related actions and consumption remains unknown. Here, we used in vivo electrophysiology and fiber photometry in mice (of both sexes) to record both spiking activity and pathway-specific calcium activity of dorsal striatal neurons during approach to and consumption of food pellets. While electrophysiology revealed complex task-related dynamics across neurons, population calcium was enhanced during approach and inhibited during consumption in both pathways. We also observed ramping changes in activity that preceded both pellet-directed actions and spontaneous movements. These signals were heterogeneous in the spiking units, with neurons exhibiting either increasing or decreasing ramps. In contrast, the population calcium signals were homogeneous, with both pathways having increasing ramps of activity for several seconds before actions were initiated. An analysis comparing population firing rates to population calcium signals also revealed stronger ramping dynamics in the calcium signals than in the spiking data. In a second experiment, we trained the mice to perform an action sequence to evaluate when the ramping signals terminated. We found that the ramping signals terminated at the beginning of the action sequence, suggesting they may reflect upcoming actions and not preconsumption activity. Plasticity of such mechanisms may underlie disorders that alter action selection, such as drug addiction or obesity.SIGNIFICANCE STATEMENT Alterations in striatal function have been linked to pathological consumption in disorders, such as obesity and drug addiction. We recorded spiking and population calcium activity from the dorsal striatum during ad libitum feeding and an operant task that resulted in mice obtaining food pellets. Dorsal striatal neurons exhibited long ramps in activity that preceded actions by several seconds, and may reflect upcoming actions. Understanding how the striatum controls the preparation and generation of actions may lead to improved therapies for disorders, such as drug addiction or obesity.

Cell-specific pallidal intervention induces long-lasting motor recovery in dopamine-depleted mice.

The identification of distinct cell types in the basal ganglia has been critical to our understanding of basal ganglia function and the treatment of neurological disorders. The external globus pallidus (GPe) is a key contributor to motor suppressing pathways in the basal ganglia, yet its neuronal heterogeneity has remained an untapped resource for therapeutic interventions. Here we demonstrate that optogenetic interventions that dissociate the activity of two neuronal populations in the GPe, elevating the activity of parvalbumin (PV)-expressing GPe neurons over that of Lim homeobox 6 (Lhx6)-expressing GPe neurons, restores movement in dopamine-depleted mice and attenuates pathological activity of basal ganglia output neurons for hours beyond stimulation. These results establish the utility of cell-specific interventions in the GPe to target functionally distinct pathways, with the potential to induce long-lasting recovery of movement despite the continued absence of dopamine.

Cortico-striatal circuits: Novel therapeutic targets for substance use disorders.

It is widely believed that substance use disorder (SUD) results from both pre-alterations (vulnerability) and/or post-alterations (drug effects) on cortico-striatal circuits. These circuits are essential for cognitive control, motivation, reward dependent learning, and emotional processing. As such, dysfunctions in cortico-striatal circuits are thought to relate to the core features of SUD, which include compulsive drug use, loss of the ability to control drug intake, and the emergence of negative emotional states (Koob and Volkow, 2010. Neuropsychopharmacology 35(1), 217-238). While the brain circuits underlying SUD have been studied in human patients largely through imaging studies, experiments in animals have allowed researchers to examine the specific cell-types within these circuits to reveal their role in behavior relevant to SUD. Here, we will review imaging studies on cortico-striatal systems that are altered in SUD, and describe animal experiments that relate SUD to specific neural projections and cell types within this circuitry. We will end with a discussion of novel clinical approaches such as deep brain stimulation (DBS), repeated transcranial magnetic stimulation (rTMS), and pharmacological targeting of G protein-coupled receptor (GPCR) heteromers that may provide promising avenues for modulating these circuits to combat SUD in humans.

Phasic mesolimbic dopamine signaling encodes the facilitation of incentive motivation produced by repeated cocaine exposure.

Drug addiction is marked by pathological drug seeking and intense drug craving, particularly in response to drug-related stimuli. Repeated psychostimulant administration is known to induce long-term alterations in mesolimbic dopamine (DA) signaling that are hypothesized to mediate this heightened sensitivity to environmental stimuli. However, there is little direct evidence that drug-induced alteration in mesolimbic DA function underlies this hypersensitivity to motivational cues. In the current study, we tested this hypothesis using fast-scan cyclic voltammetry to monitor phasic DA signaling in the nucleus accumbens core of cocaine-pretreated (6 once-daily injections of 15 mg/kg, i.p.) and drug-naive rats during a test of cue-evoked incentive motivation for food-the Pavlovian-to-instrumental transfer task. We found that prior cocaine exposure augmented both reward seeking and DA release triggered by the presentation of a reward-paired cue. Furthermore, cue-evoked DA signaling positively correlated with cue-evoked food seeking and was found to be a statistical mediator of this behavioral effect of cocaine. Taken together, these findings provide support for the hypothesis that repeated cocaine exposure enhances cue-evoked incentive motivation through augmented phasic mesolimbic DA signaling. This work sheds new light on a fundamental neurobiological mechanism underlying motivated behavior and its role in the expression of compulsive reward seeking.

Impact of repeated intravenous cocaine administration on incentive motivation depends on mode of drug delivery.

The incentive sensitization theory of addiction posits that repeated exposure to drugs of abuse, like cocaine, can lead to long-term adaptations in the neural circuits that support motivated behavior, providing an account of pathological drug-seeking behavior. Although pre-clinical findings provide strong support for this theory, much remains unknown about the conditions that support incentive sensitization. The current study examined whether the mode of cocaine administration is an important factor governing that drug's long-term impact on behavior. Separate groups of rats were allowed either to self-administer intravenous cocaine or were given an equivalent number and distribution of unsignaled cocaine or saline infusions. During the subsequent test of incentive motivation (Pavlovian-to-instrumental transfer), we found that rats with a history of cocaine self-administration showed strong cue-evoked food seeking, in contrast to rats given unsignaled cocaine or saline. This finding indicates that the manner in which cocaine is administered can determine its lasting behavioral effects, suggesting that subjective experiences during drug use play a critical role in the addiction process. Our findings may therefore have important implications for the study and treatment of compulsive drug seeking.

Repeated cocaine exposure facilitates the expression of incentive motivation and induces habitual control in rats.

There is growing evidence that mere exposure to drugs can induce long-term alterations in the neural systems that mediate reward processing, motivation, and behavioral control, potentially causing the pathological pursuit of drugs that characterizes the addicted state. The incentive sensitization theory proposes that drug exposure potentiates the influence of reward-paired cues on behavior. It has also been suggested that drug exposure biases action selection towards the automatic execution of habits and away from more deliberate goal-directed control. The current study investigated whether rats given repeated exposure to peripherally administered cocaine would show alterations in incentive motivation (assayed using the Pavlovian-to-instrumental transfer (PIT) paradigm) or habit formation (assayed using sensitivity to reward devaluation). After instrumental and Pavlovian training for food pellet rewards, rats were given 6 daily injections of cocaine (15 mg/kg, IP) or saline, followed by a 10-d period of rest. Consistent with the incentive sensitization theory, cocaine-treated rats showed stronger cue-evoked lever pressing than saline-treated rats during the PIT test. The same rats were then trained on a new instrumental action with a new food pellet reward before undergoing a reward devaluation testing. Although saline-treated rats exhibited sensitivity to reward devaluation, indicative of goal-directed performance, cocaine-treated rats were insensitive to this treatment, suggesting a reliance on habitual processes. These findings, when taken together, indicate that repeated exposure to cocaine can cause broad alterations in behavioral control, spanning both motivational and action selection processes, and could therefore help explain aberrations of decision-making that underlie drug addiction.

Pavlovian-to-instrumental transfer in cocaine seeking rats.

Drug-associated cues are believed to be important mediators of addiction and drug relapse. Although such cues may influence drug-seeking behavior through multiple routes, it is their putative incentive motivational properties-their ability to elicit "craving"-that interests many addiction researchers. The Pavlovian-to-instrumental transfer paradigm is commonly used to assay cue-evoked incentive motivation in situations involving natural rewards, but has not been widely applied to the study of drug self-administration. We used this paradigm to determine whether cues paired with intravenous cocaine could promote performance of an independently trained task in which rats self-administered cocaine by completing a chain of two different lever press actions, a procedure used to parse behavior into cocaine seeking (first action) and cocaine taking (second action). Rats showed significant transfer, increasing task performance during cocaine-paired cues. This effect was observed for both seeking and taking actions, although a trend toward greater cocaine taking was observed, a result that is consistent with studies using natural rewards. Our results demonstrate that cocaine-paired cues can provoke the pursuit of cocaine through a Pavlovian motivational process. This phenomenon may provide a useful new tool for modeling drug relapse, particularly as a method for targeting the response-invigorating effects of stimulus-drug learning.