Biomedical REAl-Time Health Evaluation (BREATHE): toward an mHealth informatics platform.

OBJECTIVE: To describe a configurable mobile health (mHealth) framework for integration of physiologic and environmental sensors to be used in studies focusing on the domain of pediatric asthma. MATERIALS AND METHODS: The Biomedical REAl-Time Health Evaluation (BREATHE) platform connects different sensors and data streams, contextualizing an individual's symptoms and daily activities over time to understand pediatric asthma's presentation and its management. A smartwatch/smartphone combination serves as a hub for personal/wearable sensing devices collecting data on health (eg, heart rate, spirometry, medications), motion, and personal exposures (eg, particulate matter, ozone); securely transmitting information to BREATHE's servers; and interacting with the user (eg, ecological momentary assessments). Server-side integration of electronic health record data and spatiotemporally correlated information (eg, weather, traffic) elaborates on these observations. An initial panel study involving pediatric asthma patients was conducted to assess BREATHE. RESULTS: Twenty subjects were enrolled, during which BREATHE accrued seven consecutive days of continuous data per individual. The data were used to confirm knowledge about asthma (use of controller inhalers, time-activity behaviors, personal air pollution exposure), and additional analyses provided insights into within-day associations of environmental triggers and asthma exacerbations. Exit surveys focusing on mHealth usability, while positive, noted several translational challenges. DISCUSSION: Based on these promising results, a longitudinal panel study to evaluate individual microenvironments and exposures is ongoing. Lessons learned thus far reflect the need to address various usability aspects, including convenience and ongoing engagement. CONCLUSION: BREATHE enables multi-sensor mHealth studies, capturing new types of information alongside an evolving understanding of personal exposomes.

Behavioral pharmacogenetic analysis on the role of the α4 GABA(A) receptor subunit in the ethanol-mediated impairment of hippocampus-dependent contextual learning.

BACKGROUND: A major effect of low-dose ethanol is impairment of hippocampus-dependent cognitive function. α4/δ -containing GABA(A) Rs are highly expressed within the dentate gyrus region of the hippocampus where they mediate a tonic inhibitory current that is sensitive to the enhancement by low ethanol concentrations. These receptors are also powerful modulators of learning and memory, suggesting that they could play an important role in ethanol's cognitive impairing effects. The goal of this study was to develop a high-throughput cognitive ethanol assay, amenable to use in genetically modified mice that could be used to test this hypothesis. METHODS: We developed a procedure where preexposure to a conditioning chamber is used to rescue the "immediate shock deficit." Using this task, ethanol can be specifically targeted at the hippocampus-dependent process of contextual learning without interfering with pain sensitivity or behavioral performance. RESULTS: Validation of this task in C57BL/6 mice indicated that 1.0 g/kg ethanol and 10 mg/kg allopregnanolone disrupt contextual learning. Ro15-4513 reversed the effects of ethanol but not allopregnanolone, whereas it produced an impairment when given alone. The high-throughput nature of this task allowed for its application in a large cohort of α4 GABA(A) R KO mice. Loss of the α4 GABA(A) R subunit produced an enhanced sensitivity to the cognitive impairing effects of ethanol. This is consistent with the enhanced ethanol sensitivity of synaptic GABA(A) Rs that has been previously observed in the dentate gyrus in these mice, but inconsistent with the reduced ethanol sensitivity of extrasynaptic GABA(A) Rs observed in the same cells. CONCLUSIONS: Overall, these findings are consistent with our hypothesis that ethanol acts directly at GABA(A) receptors to impair hippocampus-dependent cognitive function. Furthermore, validation of this high-throughput assay will allow for future studies to use anatomically and temporally restricted genetic manipulations to probe more deeply into the neural mechanisms of ethanol action on learning and memory circuits.

A role for calcium-permeable AMPA receptors in synaptic plasticity and learning.

A central concept in the field of learning and memory is that NMDARs are essential for synaptic plasticity and memory formation. Surprisingly then, multiple studies have found that behavioral experience can reduce or eliminate the contribution of these receptors to learning. The cellular mechanisms that mediate learning in the absence of NMDAR activation are currently unknown. To address this issue, we examined the contribution of Ca(2+)-permeable AMPARs to learning and plasticity in the hippocampus. Mutant mice were engineered with a conditional genetic deletion of GluR2 in the CA1 region of the hippocampus (GluR2-cKO mice). Electrophysiology experiments in these animals revealed a novel form of long-term potentiation (LTP) that was independent of NMDARs and mediated by GluR2-lacking Ca(2+)-permeable AMPARs. Behavioral analyses found that GluR2-cKO mice were impaired on multiple hippocampus-dependent learning tasks that required NMDAR activation. This suggests that AMPAR-mediated LTP interferes with NMDAR-dependent plasticity. In contrast, NMDAR-independent learning was normal in knockout mice and required the activation of Ca(2+)-permeable AMPARs. These results suggest that GluR2-lacking AMPARs play a functional and previously unidentified role in learning; they appear to mediate changes in synaptic strength that occur after plasticity has been established by NMDARs.