The Striatal Balancing Act in Drug Addiction: Distinct Roles of Direct and Indirect Pathway Medium Spiny Neurons

The striatum plays a key role in mediating the acute and chronic effects of addictive drugs, with drugs of abuse causing long-lasting molecular and cellular alterations in both dorsal striatum and nucleus accumbens (ventral striatum). Despite the wealth of research on the biological actions of abused drugs in striatum, until recently, the distinct roles of the striatum’s two major subtypes of medium spiny neurons (MSNs) in drug addiction remained elusive. Recent advances in cell-type-specific technologies, including fluorescent reporter mice, transgenic, or knockout mice, and viral-mediated gene transfer, have advanced the field toward a more comprehensive understanding of the two MSN subtypes in the long-term actions of drugs of abuse. Here we review progress in defining the distinct molecular and functional contributions of the two MSN subtypes in mediating addiction

Histone arginine methylation in cocaine action in the nucleus accumbens

Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanisms - such as histone acetylation and methylation on Lys residues - have been linked to these lasting actions of cocaine. In contrast to Lys methylation, the role of histone Arg (R) methylation remains underexplored in addiction models. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine-addicted humans. Such PRMT6 down-regulation occurs selectively in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2-MSNs), with opposite regulation occurring in D1-MSNs, and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we identified Src kinase signaling inhibitor 1 (Srcin1; also referred to as p140Cap) as a key gene target for reduced H3R2me2a binding, and found that consequent Srcin1 induction in the NAc decreases Src signaling, cocaine reward, and the motiv ation to self-administer cocaine. Taken together, these findings suggest that suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a down-regulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of treatments for cocaine addiction. Keywords: histone arginine (R) methylation; drug addiction; medium spiny neurons; ChIP-seq; Sr

Rac1 is essential in cocaine-induced structural plasticity of nucleus accumbens neurons

Repeated cocaine administration increases the dendritic arborization of nucleus accumbens neurons, but the underlying signaling events remain unknown. Here, we show that repeated cocaine negatively regulates the active form of Rac1, a small GTPase that controls actin remodeling in other systems. We show further, using viral-mediated gene transfer, that overexpression of a dominant negative mutant of Rac1, or local knockout of Rac1 from floxed Rac1 mice, is sufficient to increase the density of immature dendritic spines on nucleus accumbens neurons, whereas overexpression of a constitutively active Rac1 mutant, or light activation of a photoactivatible form of Rac1, blocks the ability of repeated cocaine to produce this effect. Downregulation of Rac1 activity in nucleus accumbens likewise promotes behavioral responses to cocaine, with Rac1 activation producing the opposite effect. These findings establish an important role for Rac1 signaling in mediating structural and behavioral plasticity to cocaine

Determinants of cognitive performance and decline in 20 diverse ethno-regional groups: A COSMIC collaboration cohort study.

BACKGROUND: With no effective treatments for cognitive decline or dementia, improving the evidence base for modifiable risk factors is a research priority. This study investigated associations between risk factors and late-life cognitive decline on a global scale, including comparisons between ethno-regional groups. METHODS AND FINDINGS: We harmonized longitudinal data from 20 population-based cohorts from 15 countries over 5 continents, including 48,522 individuals (58.4% women) aged 54-105 (mean = 72.7) years and without dementia at baseline. Studies had 2-15 years of follow-up. The risk factors investigated were age, sex, education, alcohol consumption, anxiety, apolipoprotein E ε4 allele (APOE*4) status, atrial fibrillation, blood pressure and pulse pressure, body mass index, cardiovascular disease, depression, diabetes, self-rated health, high cholesterol, hypertension, peripheral vascular disease, physical activity, smoking, and history of stroke. Associations with risk factors were determined for a global cognitive composite outcome (memory, language, processing speed, and executive functioning tests) and Mini-Mental State Examination score. Individual participant data meta-analyses of multivariable linear mixed model results pooled across cohorts revealed that for at least 1 cognitive outcome, age (B = -0.1, SE = 0.01), APOE*4 carriage (B = -0.31, SE = 0.11), depression (B = -0.11, SE = 0.06), diabetes (B = -0.23, SE = 0.10), current smoking (B = -0.20, SE = 0.08), and history of stroke (B = -0.22, SE = 0.09) were independently associated with poorer cognitive performance (p < 0.05 for all), and higher levels of education (B = 0.12, SE = 0.02) and vigorous physical activity (B = 0.17, SE = 0.06) were associated with better performance (p < 0.01 for both). Age (B = -0.07, SE = 0.01), APOE*4 carriage (B = -0.41, SE = 0.18), and diabetes (B = -0.18, SE = 0.10) were independently associated with faster cognitive decline (p < 0.05 for all). Different effects between Asian people and white people included stronger associations for Asian people between ever smoking and poorer cognition (group by risk factor interaction: B = -0.24, SE = 0.12), and between diabetes and cognitive decline (B = -0.66, SE = 0.27; p < 0.05 for both). Limitations of our study include a loss or distortion of risk factor data with harmonization, and not investigating factors at midlife. CONCLUSIONS: These results suggest that education, smoking, physical activity, diabetes, and stroke are all modifiable factors associated with cognitive decline. If these factors are determined to be causal, controlling them could minimize worldwide levels of cognitive decline. However, any global prevention strategy may need to consider ethno-regional differences

Beyond Neuronal Activity Markers: Select Immediate Early Genes in Striatal Neuron Subtypes Functionally Mediate Psychostimulant Addiction

Immediate early genes (IEGs) were traditionally used as markers of neuronal activity in striatum in response to stimuli including drugs of abuse such as psychostimulants. Early studies using these neuronal activity markers led to important insights in striatal neuron subtype responsiveness to psychostimulants. Such studies have helped identify striatum as a critical brain center for motivational, reinforcement and habitual behaviors in psychostimulant addiction. While the use of IEGs as neuronal activity markers in response to psychostimulants and other stimuli persists today, the functional role and implications of these IEGs has often been neglected. Nonetheless, there is a subset of research that investigates the functional role of IEGs in molecular, cellular and behavioral alterations by psychostimulants through striatal medium spiny neuron (MSN) subtypes, the two projection neuron subtypes in striatum. This review article will address and highlight the studies that provide a functional mechanism by which IEGs mediate psychostimulant molecular, cellular and behavioral plasticity through MSN subtypes. Insight into the functional role of IEGs in striatal MSN subtypes could provide improved understanding into addiction and neuropsychiatric diseases affecting striatum, such as affective disorders and compulsive disorders characterized by dysfunctional motivation and habitual behavior

Neural circuits underlying emotion and motivation: Insights from optogenetics and pharmacogenetics

Application of optogenetic and pharmacogenetic tools to study the neural circuits underlying emotional valence, feeding, arousal and motivated behaviors has provided crucial insights into brain function. Expression of light sensitive proteins into specific neurons and subsequent stimulation by light (optogenetics) to control neuronal activity or expression of designer receptors exclusively activated by designer drugs (DREADD) in specific neuronal populations with subsequent activation or suppression of neuronal activity by an otherwise inert ligand (pharmacogenetics) provides control over defined elements of neural circuits. These novel tools have provided a more in depth understanding into several questions about brain function. These include: • Regulation of sleep-wake transition by the interaction of hypocretin neurons of lateral hypothalamus and nor adrenergic neurons of the locus coruleaus • Regulation of feeding by AGRP and POMC neurons in arcuate nucleus of the hypothalamus • Place preference and positive reinforcement by activation of DA neuron of VTA • Place aversion by activation of VTA GABA and lateral habenula neurons • Opposing influences on reinforcement by activation of D1 and D2 expressing medium spiny neurons of dorsal striatum and nucleus accumbens The list still grows... From cell type specific manipulations to signaling properties in the cell (Dietz et al 2012) with unprecedented temporal resolution, these tools revolutionize the exploration of pathways/connectivity. Recent years also witnessed the extension of applying these tools from studying emotional valence and motivated behavior to reactivation of memory. c-fos based genetic approaches allowed us to integrate light sensitive opsins or DREADD receptor into specific neurons that are activated by certain learning events (for example fear) (Garner et al 2012; Liu et al 2012). In this Research Topic, we welcome researchers to contribute original research articles, review articles, methods and commentary on topics utilizing optogenetic and pharmacogenetic tools to study the neural circuits underlying emotional valence, motivation, reinforcement and memory. We believe the Research Topic will shine light on various questions we have about brain function by using novel optogenetic and pharmacogenetic tools and will hopefully inspire ongoing research to overcome the hurdles of using these tools to advance clinical applications

Dendritic spine density is increased on nucleus accumbens D2 neurons after chronic social defeat

Abstract Stress alters the structure and function of brain reward circuitry and is an important risk factor for developing depression. In the nucleus accumbens (NAc), structural and physiological plasticity of medium spiny neurons (MSNs) have been linked to increased stress-related and depression-like behaviors. NAc MSNs have opposing roles in driving stress-related behaviors that is dependent on their dopamine receptor expression. After chronic social defeat stress, NAc MSNs exhibit increased dendritic spine density. However, it remains unclear if the dendritic spine plasticity is MSN subtype specific. Here we use viral labeling to characterize dendritic spine morphology specifically in dopamine D2 receptor expressing MSNs (D2-MSNs). After chronic social defeat, D2-MSNs exhibit increased spine density that is correlated with enhanced social avoidance behavior. Together, our data indicate dendritic spine plasticity is MSN subtype specific, improving our understanding of structural plasticity after chronic stress