Faculty Bibliography

The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented challenge and opportunity for translational investigators to rapidly develop safe and effective therapeutic interventions. Greater risk of severe disease in COVID-19 patients with comorbid diabetes mellitus, obesity, and heart disease may be attributable to synergistic activation of vascular inflammation pathways associated with both COVID-19 and cardiometabolic disease. This mechanistic link provides a scientific framework for translational studies of drugs developed for treatment of cardiometabolic disease as novel therapeutic interventions to mitigate inflammation and improve outcomes in patients with COVID-19.

INTRODUCTION/BACKGROUND:Smoking is a leading cause of death, and genetic variation contributes to smoking behaviors. Identifying genes and sets of genes that contribute to risk for addiction is necessary to prioritize targets for functional characterization and for personalized medicine. METHODS:We performed a gene set-based association and heritable enrichment study of two addiction-related gene sets, those on the Smokescreen Genotyping Array and the nicotinic acetylcholine receptors, using the largest available GWAS summary statistics. We assessed smoking initiation, cigarettes per day, smoking cessation, and age of smoking initiation. RESULTS:Individual genes within each gene set were significantly associated with smoking behaviors. Both sets of genes were significantly associated with cigarettes per day, smoking initiation, and smoking cessation. Age of initiation was only associated with the Smokescreen gene set. While both sets of genes were enriched for trait heritability, each accounts for only a small proportion of the SNP-based heritability (2-12%). CONCLUSIONS:These two gene sets are associated with smoking behaviors, but collectively account for a limited amount of the genetic and phenotypic variation of these complex traits, consistent with high polygenicity. IMPLICATIONS/CONCLUSIONS:We evaluated evidence for association and heritable contribution of expert-curated and bioinformatically identified sets of genes related to smoking. Although they impact smoking behaviors, these specifically targeted genes do not account for much of the heritability in smoking and will be of limited use for predictive purposes. Advanced genome-wide approaches and integration of other 'omics data will be needed to fully account for the genetic variation in smoking phenotypes.

Afferent lesions of the arterial baroreflex occur in familial dysautonomia. This leads to excessive blood pressure variability with falls and frequent surges that damage the organs. These hypertensive surges are the result of excess peripheral catecholamine release and have no adequate treatment. Carbidopa is a selective DOPA-decarboxylase inhibitor that suppresses catecholamines production outside the brain. To learn whether carbidopa can inhibit catecholamine-induced hypertensive surges in patients with severe afferent baroreflex failure, we conducted a double-blind randomized crossover trial in which patients with familial dysautonomia received high dose carbidopa (600 mg/day), low-dose carbidopa (300 mg/day), or matching placebo in 3 4-week treatment periods. Among the 22 patients enrolled (13 females/8 males), the median age was 26 (range, 12-59 years). At enrollment, patients had hypertensive peaks to 164/116 (range, 144/92 to 213/150 mm Hg). Twenty-four hour urinary norepinephrine excretion, a marker of peripheral catecholamine release, was significantly suppressed on both high dose and low dose carbidopa, compared with placebo (P=0.0075). The 2 co-primary end points of the trial were met. The SD of systolic BP variability was reduced at both carbidopa doses (low dose: 17±4; high dose: 18±5 mm Hg) compared with placebo (23±7 mm Hg; P=0.0013), and there was a significant reduction in the systolic BP peaks on active treatment (P=0.0015). High- and low-dose carbidopa were similarly effective and well tolerated. This study provides class Ib evidence that carbidopa can reduce blood pressure variability in patients with congenital afferent baroreflex failure. Similar beneficial effects are observed in patients with acquired baroreflex lesions.

Optogenetics is among the most widely employed techniques to manipulate neuronal activity. However, a major drawback is the need for invasive implantation of optical fibers. To develop a minimally invasive optogenetic method that overcomes this challenge, we engineered a new step-function opsin with ultra-high light sensitivity (SOUL). We show that SOUL can activate neurons located in deep mouse brain regions via transcranial optical stimulation and elicit behavioral changes in SOUL knock-in mice. Moreover, SOUL can be used to modulate neuronal spiking and induce oscillations reversibly in macaque cortex via optical stimulation from outside the dura. By enabling external light delivery, our new opsin offers a minimally invasive tool for manipulating neuronal activity in rodent and primate models with fewer limitations on the depth and size of target brain regions and may further facilitate the development of minimally invasive optogenetic tools for the treatment of neurological disorders.

Neural activity and behavior are both notoriously variable, with responses differing widely between repeated presentation of identical stimuli or trials. Recent results in humans and animals reveal that these variations are not random in their nature, but may in fact be due in large part to rapid shifts in neural, cognitive, and behavioral states. Here we review recent advances in the understanding of rapid variations in the waking state, how variations are generated, and how they modulate neural and behavioral responses in both mice and humans. We propose that the brain has an identifiable set of states through which it wanders continuously in a nonrandom fashion, owing to the activity of both ascending modulatory and fast-acting corticocortical and subcortical-cortical neural pathways. These state variations provide the backdrop upon which the brain operates, and understanding them is critical to making progress in revealing the neural mechanisms underlying cognition and behavior. Expected final online publication date for the Annual Review of Neuroscience, Volume 43 is July 8, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Cortical interneurons display striking differences in shape, physiology, and other attributes, challenging us to appropriately classify them. We previously suggested that interneuron types should be defined by their role in cortical processing. Here, we revisit the question of how to codify their diversity based upon their division of labor and function as controllers of cortical information flow. We suggest that developmental trajectories provide a guide for appreciating interneuron diversity and argue that subtype identity is generated using a configurational code of transcription factors that produce attractor states in the underlying gene regulatory network. We present our updated three-stage model for interneuron specification: an initial cardinal step, allocating interneurons into a few major classes, followed by definitive refinement, creating subclasses upon settling within the cortex, and lastly, state determination, reflecting the incorporation of interneurons into functional circuit ensembles. We close by discussing findings indicating that major interneuron classes are both evolutionarily ancient and conserved. We propose that the complexity of cortical circuits is generated by phylogenetically old interneuron types, complemented by an evolutionary increase in principal neuron diversity. This suggests that a natural neurobiological definition of interneuron types might be derived from a match between their developmental origin and computational function. Expected final online publication date for the Annual Review of Neuroscience Volume 43 is July 8, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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

Recently, a novel isolate of the SARS-CoV-2 virus carrying a point mutation in the Spike protein (D614G) has emerged and rapidly surpassed others in prevalence, including the original SARS-CoV-2 isolate from Wuhan, China. This Spike variant is a defining feature of the most prevalent clade (A2a) of SARS-CoV-2 genomes worldwide. Using phylogenomic data, several groups have proposed that the D614G variant may confer increased transmissibility leading to positive selection, while others have claimed that currently available evidence does not support positive selection. Furthermore, in the A2a clade, this mutation is in linkage disequilibrium with a ORF1b protein variant (P314L), making it difficult to discern the functional significance of the Spike D614G mutation from population genetics alone. Here, we perform site-directed mutagenesis on a human codon-optimized spike protein to introduce the D614G variant and produce SARS-CoV-2-pseudotyped lentiviral particles (S-Virus) with this variant and with D614 Spike. We show that in multiple cell lines, including human lung epithelial cells, that S-Virus carrying the D614G mutation is up to 8-fold more effective at transducing cells than wild-type S-Virus. This provides functional evidence that the D614G mutation in the Spike protein increases transduction of human cells. Further we show that the G614 variant is more resistant to cleavage in vitro and in human cells, which may suggest a possible mechanism for the increased transduction. Given that several vaccines in development and in clinical trials are based on the initial (D614) Spike sequence, this result has important implications for the efficacy of these vaccines in protecting against this recent and highly-prevalent SARS-CoV-2 isolate.