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Supplemental material, sj-pdf-1-jcb-10.1177_0271678X231172842 for APOE4 expression confers a mild, persistent reduction in neurovascular function in the visual cortex and hippocampus of awake mice by Orla Bonnar, Kira Shaw, Silvia Anderle, Dori M Grijseels, Devin Clarke, Laura Bell, Sarah L King and Catherine N Hall in Journal of Cerebral Blood Flow & Metabolism

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X231172842 for APOE4 expression confers a mild, persistent reduction in neurovascular function in the visual cortex and hippocampus of awake mice by Orla Bonnar, Kira Shaw, Silvia Anderle, Dori M Grijseels, Devin Clarke, Laura Bell, Sarah L King and Catherine N Hall in Journal of Cerebral Blood Flow & Metabolism

Background: The COVID-19 pandemic has driven most clinicians, from those practicing in small independent practices to those in large system, to adopt virtual care. However, individuals and organizations may lack the experience and skills that would be considered fundamental prerequisites to adopting telehealth in less urgent times. What are those skills? Before the pandemic, the Association of American Medical Colleges (AAMC) convened national experts to identify and articulate a consensus set of critical telehealth skills for clinicians. Methods: Through a structured review of the literature, followed by several rounds of review and refinement by committee and community members via a modified Delphi process, the committee came to consensus on a set of skills required by clinicians to provide quality care via telehealth. Conclusion: The consensus set of telehealth skills presented in this paper, developed by the AAMC and national experts, can serve providers and health systems seeking to ensure that clinicians are prepared to meet the demand for care delivered via telehealth now and in the future.

Haplotypes of the Gabra2 gene encoding the α2-subunit of the GABAA receptor (GABAAR) are associated with drug abuse, suggesting that α2-GABAARs may play an important role in the circuitry underlying drug misuse. The genetic association of Gabra2 haplotypes with cocaine addiction appears to be evident primarily in individuals who had experienced childhood trauma. Given this association of childhood trauma, cocaine abuse and the Gabra2 haplotypes, we have explored in a mouse model of early life adversity (ELA) whether such events influence the behavioral effects of cocaine and if, as suggested by the human studies, α2-GABAARs in the nucleus accumbens (NAc) are involved in these perturbed behaviors. In adult mice prior ELA caused a selective decrease of accumbal α2-subunit mRNA, resulting in a selective decrease in the number and size of the α2-subunit (but not the α1-subunit) immunoreactive clusters in NAc core medium spiny neurons (MSNs). Functionally, in adult MSNs ELA decreased the amplitude and frequency of GABAAR-mediated miniature inhibitory postsynaptic currents (mIPSCs), a profile similar to that of α2 “knock-out” (α2−/−) mice. Behaviourally, adult male ELA and α2−/− mice exhibited an enhanced locomotor response to acute cocaine and blunted sensitisation upon repeated cocaine administration, when compared to their appropriate controls. Collectively, these findings reveal a neurobiological mechanism which may relate to the clinical observation that early trauma increases the risk for substance abuse disorder (SAD) in individuals harbouring haplotypic variations in the Gabra2 gene., Highlights • Early-life adversity (ELA) is a risk factor for adult psychopathology and drug abuse. • Gabra2 gene variations coupled with childhood trauma associate with cocaine abuse. • ELA selectively impaired accumbal α2-GABAAR expression and function in adult mice. • ELA and α2−/− mice displayed similar abnormal behavioral responses to cocaine. • The findings complement clinical associations of ELA, Gabra2 gene and drug abuse.

Variations in genes encoding several GABAA receptors have been associated with human drug and alcohol abuse. Among these, a number of human studies have suggested an association between GABRB1, the gene encoding GABAA receptor 1 subunits, with alcohol dependence, both on its own and comorbid with other substance dependence and psychiatric illnesses. In the present study, we hypothesised that the GABRB1 genetically-associated increased risk for developing alcoholism may be associated with impaired behavioral control and altered sensitivity to reward, as a consequence of altered brain function. Exploiting the IMAGEN database (Schumann et al, 2010), we explored in a human adolescent population whether possession of the minor (T) variant of the single nucleotide polymorphism rs2044081 is associated with performance of tasks measuring aspects of impulsivity, and reward sensitivity that are implicated in drug and alcohol abuse. Allelic variation did not associate with altered performance in either a stop-signal task (SST), measuring one aspect of impulsivity, or a monetary incentive delay (MID) task assessing reward anticipation. However, increased fMRI BOLD response in the right hemisphere 58 inferior frontal gyrus, left hemisphere caudate/insula, and left hemisphere inferior temporal gyrus during MID performance was higher in the minor (T) allelic group. In contrast, during SST performance, the BOLD response found in the right hemisphere supramarginal gyrus, right hemisphere lingual and left hemisphere inferior parietal gyrus indicated reduced responses in the minor genotype. We suggest that β1-containing GABAA receptors may play a role in excitability of brain regions important in controlling reward-related behavior, which may contribute to susceptibility to addictive behavior.

The presence of the e4 allele of the apolipoprotein E (APOE) gene is the best-known genetic risk factor for Alzheimer's disease. In this study, we investigated the link between functional and behavioural differences and regional brain volume and cortical thickness differences in those who carry the e4 allele (e4+) and those who only carry the e3 allele (e3/e3). We studied these genotype populations in two age groups: a young group (average age, 21 years) and a mid-age group (average age, 50 years). High-resolution T1 -weighted MRI scans were analysed with Freesurfer to measure regional white matter brain volume and cortical thickness differences between genotype groups at each age. These data were correlated with behavioural findings in the same cohort. Resting-state MRI was also conducted to identify differences in underlying brain functional connectivity. We found that there was a positive correlation between the thickness of the parahippocampal cortex in young e4+ individuals and performance on an episodic memory task. Young e4+ individuals also showed a positive correlation between white matter volume in the left anterior cingulate and performance on a covert attention task. At mid-age, e4+ individuals had structural differences relative to e3/e3 individuals in these areas: the parahippocampal cortex was thicker and white matter volume in the left anterior cingulate was greater than in e3/e3 individuals. We discuss the possibility that an over-engagement with these regions by e4+ individuals in youth may have a neurogenic effect that is observable later in life. The cuneus appears to be an important region for APOE-driven differences in the brain, with greater functional connectivity among young e3/e3 individuals and greater white matter volume in young e4+ individuals. Copyright © 2016 John Wiley & Sons, Ltd.

Background: Variations in the GABRA2 gene, encoding α2 subunits of GABAA receptors, have been associated with risk for addiction to several drugs, but the mechanisms by which variations in non-coding regions of GABRA2 increase risk for addictions are not understood. Mice with deletion of GABRA2 show deficits in the ability of psychostimulants to facilitate responding for conditioned reinforcers, offering a potential explanation.\ud \ud Methods: We report human and mouse studies investigating a potential endophenotype underlying this association. Healthy human volunteers carrying either cocaine-addiction “risk” or “protective” GABRA2 single nucleotide polymorphism (SNPs) were tested for their subjective responses to methylphenidate, and methylphenidate’s ability to facilitate conditioned reinforcement (CRf) for visual stimuli (CS+) associated with monetary reward. In parallel, methylphenidate’s ability to facilitate responding for a visual CRf was studied in wildtype and α2 knockout (α2−/−) mice.\ud \ud Results: Methylphenidate increased the number of CS+ presentations obtained by human subjects carrying protective, but not risk SNPs. In mice, methylphenidate increased responding for a CS+ in wildtype, but not α2−/− mice. Human subjects carrying protective SNPs felt stimulated, aroused and restless following methylphenidate, while individuals carrying risk SNPs did not.\ud \ud Conclusion: Human risk SNP carriers were insensitive to methylphenidate’s effects on mood or in facilitating CRf. That mice with the gene deletion were also insensitive to methylphenidate’s ability to increase responding for CRf, suggests a potential mechanism whereby low α2-subunit levels increase risk for addictions. Circuits employing GABAA-α2 subunit-containing receptors may protect against risk for addictions.