Faculty Bibliography
Searched for:
school:SOM
Department/Unit:Neuroscience Institute
Total Results:
13409
Comparison of Selective Versus Empiric Pharmacologic Preventative Therapy With Kidney Stone Recurrence
OBJECTIVE:To assess the effectiveness of an empiric approach to metabolic stone prevention. METHODS:Using medical claims from a cohort of working age adults with kidney stone diagnoses (2008-2017), we identified the subset who were prescribed thiazides, alkali therapy, or allopurinol-collectively known as preventive pharmacologic therapy (PPT). We distinguished between those who had 24-hour urine testing prior to initiating PPT (selective therapy) from those without it (empiric therapy). We conducted a survival analysis for time to first recurrence for stone-related events, including ED visits, hospitalizations, and surgery, up to 2 years after initiating PPT. RESULTS:Of 10,125 patients identified, 2744 (27%) and 7381 (73%) received selective and empiric therapy, respectively. The overall frequency of any stone-related event was 11%, and this did not differ between the 2 groups on bivariate analysis (P = .29). After adjusting for sociodemographic factors, comorbidities, medication class, and adherence, there was no difference in the hazard of a stone-related event between the selective and empiric therapy groups (hazard ratio, 0.97; 95% confidence interval, 0.84-1.12). When considered individually, the frequency of ED visits, hospitalizations, and surgeries did not differ between groups. Greater adherence to PPT and older age were associated with a lower hazard of a stone-related event (both P < .05). CONCLUSION/CONCLUSIONS:Compared to empiric therapy, PPT guided by 24-hour urine testing, on average, is not associated with a lower hazard of a stone-related event. These results suggest a need to identify kidney stone patients who benefit from 24-hour urine testing.
PMID: 33352163
ISSN: 1527-9995
CID: 4751242
The serotonin 2B receptor is required in neonatal microglia to limit neuroinflammation and sickness behavior in adulthood
Severe peripheral infections induce an adaptive sickness behavior and an innate immune reaction in various organs including the brain. On the long term, persistent alteration of microglia, the brain innate immune cells, is associated with an increased risk of psychiatric disorders. It is thus critical to identify genes and mechanisms controlling the intensity and duration of the neuroinflammation induced by peripheral immune challenges. We tested the hypothesis that the 5-HT2B receptor, the main serotonin receptor expressed by microglia, might represent a valuable candidate. First, we observed that Htr2b-/- mice, knock-out for the 5-HT2B receptor gene, developed, when exposed to a peripheral lipopolysaccharide (LPS) challenge, a stronger weight loss compared to wild-type mice; in addition, comparison of inflammatory markers in brain, 4 and 24 hr after LPS injection, showed that Htr2b deficiency leads to a prolonged neuroinflammation. Second, to assess the specific contribution of the microglial 5-HT2B receptor, we investigated the response to LPS of conditional knock-out mice invalidated for Htr2b in microglia only. We found that deletion of Htr2b in microglia since birth is sufficient to cause enhanced weight loss and increased neuroinflammatory response upon LPS injection at adult stage. In contrast, mice deleted for microglial Htr2b in adulthood responded normally to LPS, revealing a neonatal developmental effect. These results highlight the role of microglia in the response to a peripheral immune challenge and suggest the existence of a developmental, neonatal period, during which instruction of microglia through 5-HT2B receptors is necessary to prevent microglia overreactivity in adulthood.
PMID: 33095507
ISSN: 1098-1136
CID: 4642612
How alcohol affects motor control: not your usual suspects
PMID: 33758418
ISSN: 2522-5812
CID: 4822692
Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture
The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
PMCID:7946812
PMID: 33589841
ISSN: 1546-1718
CID: 4808032
IEEE transactions on ultrasonics, ferroelectrics, & frequency control. 2021:68(3):538-548.DOI: 10.1109/TUFFC.2020.3014844
Characterization of vortex flow in a mouse model of ventricular dyssynchrony by plane-wave ultrasound using hexplex processing
The rodent heart is frequently used to study human cardiovascular disease (CVD). Although advanced cardiovascular ultrasound imaging methods are available for human clinical practice, application of these techniques to small animals remains limited due to the temporal and spatial-resolution demands. Here, an ultrasound vector-flow workflow is demonstrated that enables visualization and quantification of the complex hemodynamics within the mouse heart. Wild type (WT) and fibroblast growth factor homologous factor 2 (FHF2)-deficient mice (Fhf2KO/Y), which present with hyperthermia-induced ECG abnormalities highly reminiscent of Brugada syndrome, were used as a mouse model of human CVD. An 18-MHz linear array was used to acquire high-speed (30 kHz), plane-wave data of the left ventricle (LV) while increasing core body temperature up to 41.5°C. Hexplex (i.e., six output) processing of the raw data sets produced the output of vector-flow estimates (magnitude and phase); B-mode and color-Doppler images; Doppler spectrograms; and local time histories of vorticity and pericardium motion. Fhf2WT/Y mice had repeatable beat-to-beat cardiac function, including vortex formation during diastole, at all temperatures. In contrast, Fhf2KO/Y mice displayed dyssynchronous contractile motion that disrupted normal inflow vortex formation and impaired LV filling as temperature rose. The hexplex processing approach demonstrates the ability to visualize and quantify the interplay between hemodynamic and mechanical function in a mouse model of human CVD.
PMID: 32763851
ISSN: 1525-8955
CID: 4555602
Excitatory-inhibitory tone shapes decision strategies in a hierarchical neural network model of multi-attribute choice
We are constantly faced with decisions between alternatives defined by multiple attributes, necessitating an evaluation and integration of different information sources. Time-varying signals in multiple brain areas are implicated in decision-making; but we lack a rigorous biophysical description of how basic circuit properties, such as excitatory-inhibitory (E/I) tone and cascading nonlinearities, shape attribute processing and choice behavior. Furthermore, how such properties govern choice performance under varying levels of environmental uncertainty is unknown. We investigated two-attribute, two-alternative decision-making in a dynamical, cascading nonlinear neural network with three layers: an input layer encoding choice alternative attribute values; an intermediate layer of modules processing separate attributes; and a final layer producing the decision. Depending on intermediate layer E/I tone, the network displays distinct regimes characterized by linear (I), convex (II) or concave (III) choice indifference curves. In regimes I and II, each option's attribute information is additively integrated. In regime III, time-varying nonlinear operations amplify the separation between offer distributions by selectively attending to the attribute with the larger differences in input values. At low environmental uncertainty, a linear combination most consistently selects higher valued alternatives. However, at high environmental uncertainty, regime III is more likely than a linear operation to select alternatives with higher value. Furthermore, there are conditions where readout from the intermediate layer could be experimentally indistinguishable from the final layer. Finally, these principles are used to examine multi-attribute decisions in systems with reduced inhibitory tone, leading to predictions of different choice patterns and overall performance between those with restrictions on inhibitory tone and neurotypicals.
PMCID:7987200
PMID: 33705386
ISSN: 1553-7358
CID: 4851972
Sleep down state-active ID2/Nkx2.1 interneurons in the neocortex
Pyramidal cells and GABAergic interneurons fire together in balanced cortical networks. In contrast to this general rule, we describe a distinct neuron type in mice and rats whose spiking activity is anti-correlated with all principal cells and interneurons in all brain states but, most prevalently, during the down state of non-REM (NREM) sleep. We identify these down state-active (DSA) neurons as deep-layer neocortical neurogliaform cells that express ID2 and Nkx2.1 and are weakly immunoreactive to neuronal nitric oxide synthase. DSA neurons are weakly excited by deep-layer pyramidal cells and strongly inhibited by several other GABAergic cell types. Spiking of DSA neurons modified the sequential firing order of other neurons at down-up transitions. Optogenetic activation of ID2+Nkx2.1+ interneurons in the posterior parietal cortex during NREM sleep, but not during waking, interfered with consolidation of cue discrimination memory. Despite their sparsity, DSA neurons perform critical physiological functions.
PMID: 33619404
ISSN: 1546-1726
CID: 4794392
In Memoriam: Kathryn V. Anderson (1952-2020)
PMID: 33618188
ISSN: 1095-564x
CID: 4794302
Body language signals for rodent social communication
Integration of social cues to initiate adaptive emotional and behavioral responses is a fundamental aspect of animal and human behavior. In humans, social communication includes prominent nonverbal components, such as social touch, gestures and facial expressions. Comparative studies investigating the neural basis of social communication in rodents has historically been centered on olfactory signals and vocalizations, with relatively less focus on non-verbal social cues. Here, we outline two exciting research directions: First, we will review recent observations pointing to a role of social facial expressions in rodents. Second, we will review observations that point to a role of 'non-canonical' rodent body language: body posture signals beyond stereotyped displays in aggressive and sexual behavior. In both sections, we will outline how social neuroscience can build on recent advances in machine learning, robotics and micro-engineering to push these research directions forward towards a holistic systems neurobiology of rodent body language.
PMID: 33582455
ISSN: 1873-6882
CID: 4799842
The Spike D614G mutation increases SARS-CoV-2 infection of multiple human cell types
A novel variant of the SARS-CoV-2 virus carrying a point mutation in the Spike protein (D614G) has recently emerged and rapidly surpassed others in prevalence. This mutation is in linkage disequilibrium with an 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 wild-type human codon optimized Spike to introduce the D614G variant. Using multiple human cell lines, including human lung epithelial cells, we found that the lentiviral particles pseudotyped with Spike D614G are more effective at transducing cells than ones pseudotyped with wild-type Spike. The increased transduction with Spike D614G ranged from 1.3 to 2.4-fold in Caco-2 and Calu-3 cells expressing endogenous ACE2, and 1.5 to 7.7-fold in A549ACE2 and Huh7.5ACE2 overexpressing ACE2. Furthermore, trans-complementation of SARS-CoV-2 virus with Spike D614G showed an increased infectivity of human cells. Although there is minimal difference in ACE2 receptor binding between the D614 and G614 Spike variants, we show that the G614 variant is more resistant to proteolytic cleavage in human cells, suggesting a possible mechanism for the increased transduction.
PMID: 33570490
ISSN: 2050-084x
CID: 4779902
