Basolateral Amygdala Modulates Terminal Dopamine Release in the Nucleus Accumbens and Conditioned Responding

Background—Dopamine signaling in the nucleus accumbens (NAc) is essential for goal-directed behaviors and primarily arises from burst firing of ventral tegmental area (VTA) neurons. However, the role of associative neural substrates such as the basolateral amygdala (BLA) in regulating phasic dopamine release in the NAc, particularly during reward-seeking, remains unknown. Methods—Male Sprague-Dawley rats learned to discriminate two cues; a discriminative stimulus (DS) that predicted sucrose reinforcement contingent upon a lever press, and a non-associated stimulus (NS) that predicted a second lever never reinforced with sucrose. Following training, a test session was completed in which NAc dopamine was measured using fast-scan cyclic voltammetry in conjunction with inactivation of the ipsilateral BLA (GABA agonists; baclofen/muscimol) to determine the contribution of BLA activity to dopamine release in the NAc core during the task. Results—Under vehicle conditions, DS and NS presentation elicited dopamine release within the NAc core. The DS evoked significantly more dopamine than the NS. Inactivation of the BLA selectively attenuated the magnitude of DS-evoked dopamine release, concurrent with an attenuation of DS-evoked conditioned approaches. Other behavioral responses (e.g., lever pressing) and dopamine release concomitant with those events were unaltered by BLA inactivation. Furthermore, neither VTA electrically-stimulated dopamine release nor the probability of high concentration dopamine release events was altered following BLA inactivation. Conclusions—These results demonstrate that the BLA terminally modulates dopamine signals within the NAc core under specific, behaviorally-relevant conditions, illustrating a functional mechanism by which the BLA selectively facilitates responding to motivationally salient environmental stimuli

The regenerating skeletal muscle niche drives satellite cell return to quiescence

Skeletal muscle stem cells, or satellite cells (SCs), are essential to regenerate and maintain muscle. Quiescent SCs reside in an asymmetric niche between the basal lamina and myofiber membrane. To repair muscle, SCs activate, proliferate, and differentiate, fusing to repair myofibers or reacquiring quiescence to replenish the SC niche. Little is known about when SCs reacquire quiescence during regeneration or the cellular processes that direct SC fate decisions. We find that most SCs reacquire quiescence 5&ndash;10 days after muscle injury, following differentiation and fusion of most cells to regenerate myofibers. Single-cell sequencing of myogenic cells in regenerating muscle identifies SCs reacquiring quiescence and reveals that noncell autonomous signaling networks influence SC fate decisions during regeneration. SC transplantation experiments confirm that the regenerating environment influences SC fate. We define a window for SC repopulation of the niche, emphasizing the temporal contribution of the regenerative muscle environment on SC fate. &nbsp;</p

A Gene-Based Association Method for Mapping Traits Using Reference Transcriptome Data

Genome-wide association studies (GWAS) have identified thousands of variants robustly associated with complex traits. However, the biological mechanisms underlying these associations are, in general, not well understood. We propose a gene-based association method called PrediXcan that directly tests the molecular mechanisms through which genetic variation affects phenotype. The approach estimates the component of gene expression determined by an individual’s genetic profile and correlates ‘imputed’ gene expression with the phenotype under investigation to identify genes involved in the etiology of the phenotype. Genetically regulated gene expression is estimated using whole-genome tissue-dependent prediction models trained with reference transcriptome data sets. PrediXcan enjoys the benefits of gene-based approaches such as reduced multiple-testing burden and a principled approach to the design of follow-up experiments. Our results demonstrate that PrediXcan can detect known and new genes associated with disease traits and provide insights into the mechanism of these associations

Hydrogen Purification and Recycling for an Integrated Oxygen Recovery System Architecture

No abstract availabl

GALC Deletions Increase the Risk of Primary Open-Angle Glaucoma: The Role of Mendelian Variants in Complex Disease

DNA copy number variants (CNVs) have been reported in many human diseases including autism and schizophrenia. Primary Open Angle Glaucoma (POAG) is a complex adult-onset disorder characterized by progressive optic neuropathy and vision loss. Previous studies have identified rare CNVs in POAG; however, their low frequencies prevented formal association testing. We present here the association between POAG risk and a heterozygous deletion in the galactosylceramidase gene (GALC). This CNV was initially identified in a dataset containing 71 Caucasian POAG cases and 478 ethnically matched controls obtained from dbGAP (study accession phs000126.v1.p1.) (p = 0.017, fisher's exact test). It was validated with array comparative genomic hybridization (arrayCGH) and realtime PCR, and replicated in an independent POAG dataset containing 959 cases and 1852 controls (p = 0.021, OR (odds ratio) = 3.5, 95% CI −1.1–12.0). Evidence for association was strengthened when the discovery and replication datasets were combined (p = 0.002; OR = 5.0, 95% CI 1.6–16.4). Several deletions with different endpoints were identified by array CGH of POAG patients. Homozygous deletions that eliminate GALC enzymatic activity cause Krabbe disease, a recessive Mendelian disorder of childhood displaying bilateral optic neuropathy and vision loss. Our findings suggest that heterozygous deletions that reduce GALC activity are a novel mechanism increasing risk of POAG. This is the first report of a statistically-significant association of a CNV with POAG risk, contributing to a growing body of evidence that CNVs play an important role in complex, inherited disorders. Our findings suggest an attractive biomarker and potential therapeutic target for patients with this form of POAG

Investigation of the Epitaxial Graphene/p-SiC Heterojunction

There has been significant research in the study of in-plane charge-carrier transport in graphene in order to understand and exploit its unique electrical properties; however, the vertical graphene–semiconductor system also presents opportunities for unique devices. In this letter, we investigate the epitaxial graphene/p-type 4H-SiC system to better understand this vertical heterojunction. The I–V behavior does not demonstrate thermionic emission properties that are indicative of a Schottky barrier but rather demonstrates characteristics of a semiconductor heterojunction. This is confirmed by the fitting of the temperature-dependent I–V curves to classical heterojunction equations and the observation of band-edge electroluminescence in SiC

Cocaine Cues Drive Opposing Context-Dependent Shifts in Reward Processing and Emotional State

Prominent neurobiological theories of addiction posit a central role for aberrant mesolimbic dopamine release, but disagree as to whether repeated drug experience blunts or enhances this system. While drug withdrawal diminishes dopamine release, drug sensitization augments mesolimbic function, and both processes have been linked to drug-seeking. One possibility is that the dopamine system can rapidly switch from dampened to enhanced release depending upon the specific drug-predictive environment. To test this, we examined dopamine release when cues signaled delayed cocaine delivery versus imminent cocaine self-administration