Faculty Bibliography

Allylboron reagents are popular in synthesis owing to their versatility and the predictable stereochemical outcomes of their reactions with carbonyl compounds. Herein, we describe the synthesis of (Z,Z)-hexadienyl bis-boronate 1, a configurationally stable, crystalline, and easy to handle compound, which represents a class of bis-allylic boron reagents with heretofore untapped synthetic potential. In combination with a chiral phosphoric acid catalyst, the reagent can be employed for the enantioselective allyl transfer reaction to a variety of one-pot transformations, enabling swift access to functionalized 1,n-diols. The in situ conversion of the reagent into the corresponding bis-borinic ester allows for the direct and diastereoselective two-fold allyl transfer to aldehydes. This affords C₂ - or C_i -symmetric stereotetrads containing a 1,4-diol moiety for natural product synthesis. The usefulness of our method was demonstrated with a short synthesis of the lignan (±)-neo-olivil.

OBJECTIVE:To test whether the plasma levels of norepinephrine (NE) in patients with neurogenic orthostatic hypotension (nOH) predict their pressor response to droxidopa. METHODS:This was an observational study, which included patients with nOH. All patients had standardized autonomic function testing including determination of venous plasma catecholamine levels drawn through an indwelling catheter while resting supine. This was followed by a droxidopa titration with 100 mg increments in successive days until relief of symptoms, side effects, or the maximum dose of 600 mg was reached. No response was defined as an increase of <10 mm Hg in systolic blood pressure (BP) after 3-minute standing 1 hour after droxidopa administration. Nonlinear regression models were used to determine the relationship between BP response and plasma NE levels. RESULTS:= 0.0023). CONCLUSIONS:In patients with nOH, lower supine resting plasma NE levels are associated with a greater pressor effect of droxidopa treatment. This finding should help identify patients with nOH most likely to respond to standard doses of droxidopa. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class I evidence that lower supine plasma NE levels accurately identify patients with nOH more likely to have a greater pressor effect from droxidopa.

Synaptic vesicle fusion occurs at specialized release sites at the active zone. How refilling of release sites with new vesicles is regulated in central synapses remains poorly understood. Using nanoscale-resolution detection of individual release events in rat hippocampal synapses we found that inhibition of myosin V, the predominant vesicle-associated motor, strongly reduced refilling of the release sites during repetitive stimulation. Single-vesicle tracking revealed that recycling vesicles continuously shuttle between a plasma membrane pool and an inner pool. Vesicle retention at the membrane pool was regulated by neural activity in a myosin V dependent manner. Ultrastructural measurements of vesicle occupancy at the plasma membrane together with analyses of single-vesicle trajectories during vesicle shuttling between the pools suggest that myosin V acts as a vesicle tether at the plasma membrane, rather than a motor transporting vesicles to the release sites, or directly regulating vesicle exocytosis.

To understand how neurons assemble to form functional circuits, it is necessary to obtain a detailed knowledge of their diversity and to define the developmental specification programs that give rise to this diversity. Invertebrates and vertebrates appear to share common developmental principles of neuronal specification in which cascades of transcription factors temporally pattern progenitors, while spatial cues modify the outcomes of this temporal patterning. Here, we highlight these conserved mechanisms and describe how they are used in distinct neural structures. We present the questions that remain for a better understanding of neuronal specification. Single-cell RNA profiling approaches will potentially shed light on these questions, allowing not only the characterization of neuronal diversity in adult brains, but also the investigation of the developmental trajectories leading to the generation and maintenance of this diversity.

Many animals guide their movements using optic flow, the displacement of stationary objects across the retina caused by self-motion. How do animals selectively synthesize a global motion pattern from its local motion components? To what extent does this feature selectivity rely on circuit mechanisms versus dendritic processing? Here we used in vivo calcium imaging to identify pre- and postsynaptic mechanisms for processing local motion signals in global motion detection circuits in Drosophila. Lobula plate tangential cells (LPTCs) detect global motion by pooling input from local motion detectors, T4/T5 neurons. We show that T4/T5 neurons suppress responses to adjacent local motion signals whereas LPTC dendrites selectively amplify spatiotemporal sequences of local motion signals consistent with preferred global patterns. We propose that sequential nonlinear suppression and amplification operations allow optic flow circuitry to simultaneously prevent saturating responses to local signals while creating selectivity for global motion patterns critical to behavior.

Circadian clock dysfunction is a common symptom of aging and neurodegenerative diseases, though its impact on brain health is poorly understood. Astrocyte activation occurs in response to diverse insults and plays a critical role in brain health and disease. We report that the core circadian clock protein BMAL1 regulates astrogliosis in a synergistic manner via a cell-autonomous mechanism and a lesser non-cell-autonomous signal from neurons. Astrocyte-specific Bmal1 deletion induces astrocyte activation and inflammatory gene expression in vitro and in vivo, mediated in part by suppression of glutathione-S-transferase signaling. Functionally, loss of Bmal1 in astrocytes promotes neuronal death in vitro. Our results demonstrate that the core clock protein BMAL1 regulates astrocyte activation and function in vivo, elucidating a mechanism by which the circadian clock could influence many aspects of brain function and neurological disease.

Brain electric field potentials are dominated by an arrhythmic broadband signal, but the underlying mechanism is poorly understood. Here we propose that broadband power spectra characterize recurrent neural networks of nodes (neurons or clusters of neurons), endowed with an effective balance between excitation and inhibition tuned to keep the network on the edge of dynamical instability. These networks show a fast mode reflecting local dynamics and a slow mode emerging from distributed recurrent connections. Together, the 2 modes produce power spectra similar to those observed in human intracranial EEG (i.e., electrocorticography, ECoG) recordings. Moreover, such networks convert spatial input correlations across nodes into temporal autocorrelation of network activity. Consequently, increased independence between nodes reduces low-frequency power, which may explain changes observed during behavioral tasks. Lastly, varying network coupling causes activity changes that resemble those observed in human ECoG across different arousal states. The model links macroscopic features of empirical ECoG power to a parsimonious underlying network structure, and suggests mechanisms for changes observed across behavioral and arousal states. This work provides a computational framework to generate and test hypotheses about cellular and network mechanisms underlying whole brain electrical dynamics, their variations across states, and potential alterations in brain diseases.

Engineered neural implants have a myriad of potential basic science and clinical neural repair applications. Although there are implants that are currently undergoing their first clinical investigations, optimizing their long-term viability and efficacy remain an open challenge. Functional implants with pre-vascularization of various engineered tissues have proven to enhance post-implantation host integration, and well-known synergistic neural-vascular interplays suggest that this strategy could also be promising for neural tissue engineering. Here, we report the development of a novel bio-engineered neuro-vascular co-culture construct, and demonstrate that it exhibits enhanced neurotrophic factor expression, and more complex neuronal morphology. Crucially, by introducing genetically encoded calcium indicators (GECIs) into the co-culture, we are able to monitor functional activity of the neural network, and demonstrate greater activity levels and complexity as a result of the introduction of endothelial cells in the construct. The presence of this enhanced activity could putatively lead to superior integration outcomes. Indeed, leveraging on the ability to monitor the construct's development post-implantation with GECIs, we observe improved integration phenotypes in the spinal cord of mice relative to non-vascularized controls. Our approach provides a new experimental system with functional neural feedback for studying the interplay between vascular and neural development while advancing the optimization of neural implants towards potential clinical applications.

Neural computations are often compared to instrument-measured distance or duration, and such relationships are interpreted by a human observer. However, neural circuits do not depend on human-made instruments but perform computations relative to an internally defined rate-of-change. While neuronal correlations with external measures, such as distance or duration, can be observed in spike rates or other measures of neuronal activity, what matters for the brain is how such activity patterns are utilized by downstream neural observers. We suggest that hippocampal operations can be described by the sequential activity of neuronal assemblies and their internally defined rate of change without resorting to the concept of space or time.