Faculty Bibliography

Dopamine (DA) is a central monoamine neurotransmitter involved in many physiological and pathological processes. A longstanding yet largely unmet goal is to measure DA changes reliably and specifically with high spatiotemporal precision, particularly in animals executing complex behaviors. Here, we report the development of genetically encoded GPCR-activation-based-DA (GRAB_DA) sensors that enable these measurements. In response to extracellular DA, GRAB_DA sensors exhibit large fluorescence increases (ΔF/F₀ ∼90%) with subcellular resolution, subsecond kinetics, nanomolar to submicromolar affinities, and excellent molecular specificity. GRAB_DA sensors can resolve a single-electrical-stimulus-evoked DA release in mouse brain slices and detect endogenous DA release in living flies, fish, and mice. In freely behaving mice, GRAB_DA sensors readily report optogenetically elicited nigrostriatal DA release and depict dynamic mesoaccumbens DA signaling during Pavlovian conditioning or during sexual behaviors. Thus, GRAB_DA sensors enable spatiotemporally precise measurements of DA dynamics in a variety of model organisms while exhibiting complex behaviors.

The neonatal mammal faces an array of sensory stimuli when diverse neuronal types have yet to form sensory maps. How these inputs interact with intrinsic neuronal activity to facilitate circuit assembly is not well understood. By using longitudinal calcium imaging in unanesthetized mouse pups, we show that layer I (LI) interneurons, delineated by co-expression of the 5HT3a serotonin receptor (5HT3aR) and reelin (Re), display spontaneous calcium transients with the highest degree of synchrony among cell types present in the superficial barrel cortex at postnatal day 6 (P6). 5HT3aR Re interneurons are activated by whisker stimulation during this period, and sensory deprivation induces decorrelation of their activity. Moreover, attenuation of thalamic inputs through knockdown of NMDA receptors (NMDARs) in these interneurons results in expansion of whisker responses, aberrant barrel map formation, and deficits in whisker-dependent behavior. These results indicate that recruitment of specific interneuron types during development is critical for adult somatosensory function. VIDEO ABSTRACT.

The thalamus has long been suspected to have an important role in cognition, yet recent theories have favored a more corticocentric view. According to this view, the thalamus is an excitatory feedforward relay to or between cortical regions, and cognitively relevant computations are exclusively cortical. Here, we review anatomical, physiological, and behavioral studies along evolutionary and theoretical dimensions, arguing for essential and unique thalamic computations in cognition. Considering their architectural features as well as their ability to initiate, sustain, and switch cortical activity, thalamic circuits appear uniquely suited for computing contextual signals that rapidly reconfigure task-relevant cortical representations. We introduce a framework that formalizes this notion, show its consistency with several findings, and discuss its prediction of thalamic roles in perceptual inference and behavioral flexibility. Overall, our framework emphasizes an expanded view of the thalamus in cognitive computations and provides a roadmap to test several of its theoretical and experimental predictions. Expected final online publication date for the Annual Review of Neuroscience Volume 41 is July 8, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Rapid impulse propagation is a defining attribute of the pectinated atrial myocardium and His-Purkinje system (HPS) that safeguards against atrial and ventricular arrhythmias, conduction block, and myocardial dyssynchrony. The complex transcriptional circuitry that dictates rapid conduction remains incompletely understood. Here, we demonstrate that ETV1 (ER81)-dependent gene networks dictate the unique electrophysiological characteristics of atrial and His-Purkinje myocytes. Cardiomyocyte-specific deletion of ETV1 results in cardiac conduction abnormalities, decreased expression of rapid conduction genes (Nkx2-5, Gja5, and Scn5a), HPS hypoplasia, and ventricularization of the unique sodium channel properties that define Purkinje and atrial myocytes in the adult heart. Forced expression of ETV1 in postnatal ventricular myocytes (VMs) reveals that ETV1 promotes a HPS gene signature while diminishing ventricular and nodal gene networks. Remarkably, ETV1 induction in human induced pluripotent stem cell-derived cardiomyocytes increases rapid conduction gene expression and inward sodium currents, converting them towards a HPS phenotype. Our data identify a cardiomyocyte-autonomous, ETV1-dependent pathway that is responsible for specification of rapid conduction zones in the heart and demonstrate that ETV1 is sufficient to promote a HPS transcriptional and functional program upon VMs.

Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for cholinergic systems in overall brain homeostasis and plasticity. As such, the brain's cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. The cholinergic hypothesis of Alzheimer's disease centres on the progressive loss of limbic and neocortical cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain cholinergic neurons, giving rise to a widespread presynaptic cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer's disease dementia, thus validating the cholinergic system as an important therapeutic target in the disease. This review includes an overview of the role of the cholinergic system in cognition and an updated understanding of how cholinergic deficits in Alzheimer's disease interact with other aspects of disease pathophysiology, including plaques composed of amyloid-β proteins. This review also documents the benefits of cholinergic therapies at various stages of Alzheimer's disease and during long-term follow-up as visualized in novel imaging studies. The weight of the evidence supports the continued value of cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer's disease, particularly as we look ahead to future combination therapies that address symptoms as well as disease progression.

Singing behavior in the adult male zebra finch is dependent upon the activity of a cortical region known as HVC (proper name). The vast majority of HVC projection neurons send primary axons to either the downstream premotor nucleus RA (primary motor cortex) or Area X (basal ganglia), which play important roles in song production or song learning, respectively. In addition to these long-range outputs, HVC neurons also send local axon collaterals throughout that nucleus. Despite their implications for a range of circuit models, these local processes have never been completely reconstructed. Here we use in vivo single-neuron Neurobiotin fills to examine 40 projection neurons across 31 birds with somatic positions distributed across HVC. We show that HVC_(RA)and HVC_(X)neurons have categorically distinct dendritic fields. Additionally, these cell classes send axon collaterals that are either restricted to a small portion of HVC ("local neurons") or broadly distributed throughout the entire nucleus ("broadcast neurons"). Overall, these processes within HVC offer a structural basis for significant local processing underlying behaviorally-relevant population activity.

PURPOSE: The aim of this study was to evaluate the effect of integrated high-permittivity materials (HPMs) on excitation homogeneity and global specific absorption rate (SAR) for transmit arrays at 7T. METHODS: A rapid electrodynamic simulation framework was used to calculate L-curves associated with excitation of a uniform 2D profile in a dielectric sphere. We used ultimate intrinsic SAR as an absolute performance reference to compare different transmit arrays in the presence and absence of a layer of HPM. We investigated the optimal permittivity for the HPM as a function of its thickness, the sample size, and the number of array elements. RESULTS: Adding a layer of HPM can improve the performance of a 24-element array to match that of a 48-element array without HPM, whereas a 48-element array with HPM can perform as well as a 64-element array without HPM. Optimal relative permittivity values changed based on sample and coil geometry, but were always within a range obtainable with readily available materials (epsilonr = 100-200). CONCLUSION: Integration of HPMs could be a practical method to improve RF shimming performance, alternative to increasing the number of coils. The proposed simulation framework could be used to explore the design of novel transmit arrays for head imaging at ultra-high field strength. Magn Reson Med, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine.

While neuroscientific research on perceptual awareness has traditionally focused on the spatial and temporal localizations of neural activity underlying conscious processing, recent development suggests that the dynamic characteristics of spatiotemporally distributed neural activity contain important clues about the neural computational mechanisms underlying conscious processing. Here, we summarize recent progress.

The overall goal of this study was to identify an objective physiological correlate of electric-acoustic pitch matching in unilaterally implanted cochlear implant (CI) participants with residual hearing in the non-implanted ear. Electrical and acoustic stimuli were presented in a continuously alternating fashion across ears. The acoustic stimulus and the electrical stimulus were either matched or mismatched in pitch. Auditory evoked potentials were obtained from nine CI users. Results indicated that N1 latency was stimulus-dependent, decreasing when the acoustic frequency of the tone presented to the non-implanted ear was increased. More importantly, there was an additional decrease in N1 latency in the pitch-matched condition. These results indicate the potential utility of N1 latency as an index of pitch matching in CI users.

Although sleep appears to be broadly conserved in animals, the physiological functions of sleep remain unclear. In this study, we sought to identify a physiological defect common to a diverse group of short-sleeping Drosophila mutants, which might provide insight into the function and regulation of sleep. We found that these short-sleeping mutants share a common phenotype of sensitivity to acute oxidative stress, exhibiting shorter survival times than controls. We further showed that increasing sleep in wild-type flies using genetic or pharmacological approaches increases survival after oxidative challenge. Moreover, reducing oxidative stress in the neurons of wild-type flies by overexpression of antioxidant genes reduces the amount of sleep. Together, these results support the hypothesis that a key function of sleep is to defend against oxidative stress and also point to a reciprocal role for reactive oxygen species (ROS) in neurons in the regulation of sleep.