Genetic Variation and Sex Mediate Differential Responses to ∆-9-tetrahydrocannabinol among Inbred Mice

The plant Cannabis sativa has been used by people for both recreational and medicinal use for thousands of years, but scientific investigation of the plant and its components didn’t begin until the early nineteen hundreds when Cannabis components known as phytocannabinoids were characterized and later isolated. In the 1970’s, ∆9-tetrahydrocannabinol (THC) was isolated and recognized as the major constituent responsible for the psychoactive and intoxicating effects associated with consumption of cannabis. This opened the door for intensive research in the field that lead to the discovery of the endogenous cannabinoid system and its associated receptors, effectors of signaling, and biosynthetic enzymes. The primary cannabinoid receptor, cannabinoid receptor 1, is a G-protein coupled receptor (GPCR) that primarily associates with Gi/o proteins, giving it the properties of having mainly inhibitory actions by decreasing release of neurotransmitters and hormones. Upon receptor activation, the Gi/o protein disassociates with and inhibits adenylyl cyclase, decreasing cAMP production, a major second messenger of the cell. After stimulation by cannabinoids, cannabinoid receptors undergo a desensitization process where they are internalized by β-arrestins. This internalization subjects the receptors to intracellular trafficking during which the majority are degraded. This causes a decrease in surface levels of cannabinoid receptors and makes the cells less sensitive to agonists. Cannabis is among the most widely used psychoactive drugs in the world. In the United States, use and legalization of cannabis continues to grow. The spreading use and legalization of cannabis has the social consequence of a diminished sense of risk to the individual. This can be harmful in and of itself, but cannabis THC concentrations in the U.S. have tripled over the last 20 years, giving rise to a more potent drug, potentially increasing risk of adverse effects associated with use. Effects of acute, short term use include faulty judgment and perception, memory impairment, motor skill dysfunction, alteration of mood, and low levels of attention and alertness. Effects associated with more chronic, long term use include risk of dependence, an increased risk of developing psychotic disorders such as schizophrenia, and long-term cognitive impairment. For cannabis, and other drugs of abuse, initial response and/or tolerance to drug effects can predict later dependence and problematic use. In the work presented here, we identify sex and genetic (strain) differences in initial response and rapid tolerance to THC, the main psychoactive ingredient in cannabis, between highly genetically divergent inbred mouse strains—C57BL/6J (B6) and DBA/2J (D2). To identify variation in THC response we use the cannabinoid-induced tetrad test which quantifies the strength of agonist mediated cannabinoid receptor signaling by measuring the level of motor activity, nociception, and hypothermia elicited by receptor activation. We then extend our study of THC response variation to the BXD genetic reference population derived from B6 and D2 strains. Increasing the number of strains tested by tenfold (N=20) we detect significant strain and sex variation in THC response and use online tools to perform QTL mapping and correlation searches to begin to uncover potential genetic drivers of variation in response to THC

Promoting the Wellness of Physician-Residents: Counselor-Delivered Coaching

Current studies on coaching have largely been process- and outcomes-oriented while lacking a firm theoretical foundation on which to base skills and techniques. Coaching has been utilized in many settings in order to address employee work attitude and well-being. This article explores the effects of counselor-delivered coaching on the wellness of physician-residents. Counselors are trained in many of the skills that organically apply to coaching, and medical education programs can benefit from counselor-facilitated coaching as part of their graduate medical education program. Counselor-delivered coaching also can help residents reduce common stresses, mitigate negative patient outcomes, and avoid burnout. This increase in physician wellness is likely to result in decreased medical errors. For these reasons, the authors explore the use of basic counseling techniques in the context of coaching sessions involving medical school educators and residents, thereby bridging the gap between coaching and counseling. Counselor-delivered coaching may be a valuable resource for reducing physician burnout. Therefore, medical schools and medical practices should consider developing and including counselor-delivered coaching to improve physicians’ quality of life and thus, in turn, patient results. Findings from this study support future data-driven studies of counselor-delivered coaching, training opportunities for counselor education programs, and an evolution of coaching techniques

Catalogue of the Flora of Texas.

130 p

Poisonous Range Plants of Texas.

2 p

Identification of a Functional Non-coding Variant in the GABA

GABA type-A (GABA-A) receptors containing the α2 subunit (GABRA2) are expressed in most brain regions and are critical in modulating inhibitory synaptic function. Genetic variation at the GABRA2 locus has been implicated in epilepsy, affective and psychiatric disorders, alcoholism and drug abuse. Gabra2 expression varies as a function of genotype and is modulated by sequence variants in several brain structures and populations, including F2 crosses originating from C57BL/6J (B6J) and the BXD recombinant inbred family derived from B6J and DBA/2J. Here we demonstrate a global reduction of GABRA2 brain protein and mRNA in the B6J strain relative to other inbred strains, and identify and validate the causal mutation in B6J. The mutation is a single base pair deletion located in an intron adjacent to a splice acceptor site that only occurs in the B6J reference genome. The deletion became fixed in B6J between 1976 and 1991 and is now pervasive in many engineered lines, BXD strains generated after 1991, the Collaborative Cross, and the majority of consomic lines. Repair of the deletion using CRISPR-Cas9-mediated gene editing on a B6J genetic background completely restored brain levels of GABRA2 protein and mRNA. Comparison of transcript expression in hippocampus, cortex, and striatum between B6J and repaired genotypes revealed alterations in GABA-A receptor subunit expression, especially in striatum. These results suggest that naturally occurring variation in GABRA2 levels between B6J and other substrains or inbred strains may also explain strain differences in anxiety-like or alcohol and drug response traits related to striatal function. Characterization of the B6J private mutation in the Gabra2 gene is of critical importance to molecular genetic studies in neurobiological research because this strain is widely used to generate genetically engineered mice and murine genetic populations, and is the most widely utilized strain for evaluation of anxiety-like, depression-like, pain, epilepsy, and drug response traits that may be partly modulated by GABRA2 function

Identification of a Functional Non-coding Variant in the GABAA Receptor α2 Subunit of the C57BL/6J Mouse Reference Genome: Major Implications for Neuroscience Research

GABA type-A (GABA-A) receptors containing the α2 subunit (GABRA2) are expressed in most brain regions and are critical in modulating inhibitory synaptic function. Genetic variation at the GABRA2 locus has been implicated in epilepsy, affective and psychiatric disorders, alcoholism and drug abuse. Gabra2 expression varies as a function of genotype and is modulated by sequence variants in several brain structures and populations, including F2 crosses originating from C57BL/6J (B6J) and the BXD recombinant inbred family derived from B6J and DBA/2J. Here we demonstrate a global reduction of GABRA2 brain protein and mRNA in the B6J strain relative to other inbred strains, and identify and validate the causal mutation in B6J. The mutation is a single base pair deletion located in an intron adjacent to a splice acceptor site that only occurs in the B6J reference genome. The deletion became fixed in B6J between 1976 and 1991 and is now pervasive in many engineered lines, BXD strains generated after 1991, the Collaborative Cross, and the majority of consomic lines. Repair of the deletion using CRISPR-Cas9-mediated gene editing on a B6J genetic background completely restored brain levels of GABRA2 protein and mRNA. Comparison of transcript expression in hippocampus, cortex, and striatum between B6J and repaired genotypes revealed alterations in GABA-A receptor subunit expression, especially in striatum. These results suggest that naturally occurring variation in GABRA2 levels between B6J and other substrains or inbred strains may also explain strain differences in anxiety-like or alcohol and drug response traits related to striatal function. Characterization of the B6J private mutation in the Gabra2 gene is of critical importance to molecular genetic studies in neurobiological research because this strain is widely used to generate genetically engineered mice and murine genetic populations, and is the most widely utilized strain for evaluation of anxiety-like, depression-like, pain, epilepsy, and drug response traits that may be partly modulated by GABRA2 function

Variability in organic carbon reactivity across lake residence time and trophic gradients

The transport of dissolved organic carbon from land to ocean is a large dynamic component of the global carbon cycle. Inland waters are hotspots for organic matter turnover, via both biological and photochemical processes, and mediate carbon transfer between land, oceans and atmosphere. However, predicting dissolved organic carbon reactivity remains problematic. Here we present in situ dissolved organic carbon budget data from 82 predominantly European and North American water bodies with varying nutrient concentrations and water residence times ranging from one week to 700 years. We find that trophic status strongly regulates whether water bodies act as net dissolved organic carbon sources or sinks, and that rates of both dissolved organic carbon production and consumption can be predicted from water residence time. Our results suggest a dominant role of rapid light-driven removal in water bodies with a short water residence time, whereas in water bodies with longer residence times, slower biotic production and consumption processes are dominant and counterbalance one another. Eutrophication caused lakes to transition from sinks to sources of dissolved organic carbon. We conclude that rates and locations of dissolved organic carbon processing and associated CO2 emissions in inland waters may be misrepresented in global carbon budgets if temporal and spatial reactivity gradients are not accounted for

Genetic Modulation of Initial Sensitivity to Δ9-Tetrahydrocannabinol (THC) Among the BXD Family of Mice

Cannabinoid receptor 1 activation by the major psychoactive component in cannabis, Δ9-tetrahydrocannabinol (THC), produces motor impairments, hypothermia, and analgesia upon acute exposure. In previous work, we demonstrated significant sex and strain differences in acute responses to THC following administration of a single dose (10 mg/kg