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Longitudinal physical activity monitoring is a novel and promising objective outcome measure for patients with degenerative spine disorder (DSD) that currently lacks established standards for data collection and interpretation. Here, we monitored 100 patients with DSD with the Apple Watch to establish the optimal duration and pattern of step count monitoring needed to estimate their weekly physical activity before their elective surgery. Participants were predominantly female (65.3%), had an average age of 61.5 years, and showed consistent step counts between preoperative days, as well as across weekends and weekdays. Intraclass correlations (ICC) analysis showed that a step count average over 2 days achieved an ICC of 0.92 when compared to a 7-day average before surgery, while 4 days were required for a similar agreement of 0.93 with a 14-day average. Sequential linear regression demonstrated that incorporating additional preoperative days improved the model’s ability to predict 7- and 14-days step count averages. We conclude that, while daily preoperative step counts remain relatively stable, longer activity monitoring is necessary to account for the variance in step count over an increasing time frame, and the full extent of data fluctuation may only become apparent with long-term trend analysis.

Advances in structure-function analyses and computational biology have enabled a deeper understanding of how excitatory amino acid transporters (EAATs) mediate chloride permeation and substrate transport. However, the mechanism of structural coupling between these functions remains to be established. Using a combination of molecular modeling, substituted cysteine accessibility, electrophysiology and glutamate uptake assays, we identified a chloride-channeling conformer, iChS, transiently accessible as EAAT1 reconfigures from substrate/ion-loaded into a substrate-releasing conformer. Opening of the anion permeation path in this iChS is controlled by the elevator-like movement of the substrate-binding core, along with its wall that simultaneously lines the anion permeation path (global); and repacking of a cluster of hydrophobic residues near the extracellular vestibule (local). Moreover, our results demonstrate that stabilization of iChS by chemical modifications favors anion channeling at the expense of substrate transport, suggesting a mutually exclusive regulation mediated by the movement of the flexible wall lining the two regions.

Previous work has characterized how walking Drosophila coordinate the movements of individual limbs (DeAngelis et al., 2019). To understand the circuit basis of this coordination, one must characterize how sensory feedback from each limb affects walking behavior. However, it has remained difficult to manipulate neural activity in individual limbs of freely moving animals. Here, we demonstrate a simple method for optogenetic stimulation with body side-, body segment-, and limb-specificity that does not require real-time tracking. Instead, we activate at random, precise locations in time and space and use post hoc analysis to determine behavioral responses to specific activations. Using this method, we have characterized limb coordination and walking behavior in response to transient activation of mechanosensitive bristle neurons and sweet-sensing chemoreceptor neurons. Our findings reveal that activating these neurons has opposite effects on turning, and that activations in different limbs and body regions produce distinct behaviors.

Excitatory amino acid transporters (EAATs) are secondary active transporters of L-glutamate and L- or D-aspartate. These carriers also mediate a thermodynamically uncoupled anion conductance that is gated by Na and substrate binding. The activation of the anion channel by binding of Na alone, however, has only been demonstrated for mammalian EAAC1 (EAAT3) and EAAT4. To date, no difference has been observed for the substrate dependence of anion channel gating between the glial, EAAT1 and EAAT2, and the neuronal isoforms EAAT3, EAAT4 and EAAT5. Here we describe a difference in the Na -dependence of anion channel gating between glial and neuronal isoforms. Chloride flux through transporters without glutamate binding has previously been described as substrate-independent or \"leak\" channel activity. Choline or N-methyl-D-glucamine replacement of external Na ions significantly reduced or abolished substrate-independent EAAT channel activity in EAAT3 and EAAT4 yet has no effect on EAAT1 or EAAT2. The interaction of Na with the neuronal carrier isoforms was concentration dependent, consistent with previous data. The presence of substrate and Na -independent open states in the glial EAAT isoforms is a novel finding in the field of EAAT function. Our results reveal an important divergence in anion channel function between glial and neuronal glutamate transporters and highlight new potential roles for the EAAT-associated anion channel activity based on transporter expression and localization in the central nervous system.

Virtually every neuron integrates inputs from excitatory and inhibitory presynaptic cells to produce its output response. Despite this, it remains poorly understood how the dynamics of these inputs influence the neuron’s output. This is in part due to the difficulty of manipulating neural response dynamics with high specificity. Previous studies have used temperature and pharmacology to alter circuit dynamics (Arenz et al., 2017; Long and Fee, 2008; Suver et al., 2012; Tang et al., 2010), but these methods affect entire circuits, making it difficult to investigate how the dynamics of single excitatory and inhibitory input neurons drive computation. In this study, we use the powerful genetic tools in Drosophila to manipulate the dynamics of individual excitatory and inhibitory visual neuron types, in order to examine how these neural dynamics tune downstream computations.Circuits that detect visual motion offer a compelling framework for understanding how excitatory and inhibitory input dynamics contribute to the tuning of downstream neurons. This is because in motion detection, responses to visual signals are highly interpretable in their selectivity for the direction and speed of motion. Specifically, Drosophila’s motion detection circuits are anatomically and functionally well-characterized, making this proposal experimentally feasible. Therefore, to study how upstream input dynamics tune downstream computations, we altered the expression of specific membrane ion channels in five cell types in the fly motion detection circuit. By mis-expressing channels in these upstream neurons, we sped up or slowed down their responses and in so doing, identified channels required for their native dynamics. Then, to test models of motion computation, we asked how those manipulations of neural dynamics influence the tuning of downstream motion signals in the direction-selective neuron T4. To do this, we manipulated membrane ion channel expression in individual neuron types upstream of T4 neurons while measuring the responses of T4 to different speeds of visual motion. This experimental protocol allowed us to record how the different biophysical manipulations changed T4’s sensitivity to motion of different speeds. As a result, we measured changes in T4’s tuning to motion velocity and uncovered an amacrine cell’s role in regulating this tuning. We also showed that perturbation of membrane channel expression in interneurons upstream of motion detectors similarly altered the fly’s behavioral response to motion. Last, we developed a data-driven circuit model that is strongly constrained by the anatomical and functional connectivity of cells in the fly’s visual circuit, as well as by our measurements of dynamics. We compared these models to our experimental data, and found that parallel, redundant excitatory and inhibitory inputs are required to explain our experimental data. We also found that the full filtering properties of the inputs—rather than just their response kinetics—are necessary to reproduce our experimental observations. Together, these results reveal how the dynamics of excitatory and inhibitory inputs jointly tune a canonical circuit computation.

Neurons integrate excitatory and inhibitory signals to produce their outputs, but the role of input timing in this integration remains poorly understood. Motion detection is a paradigmatic example of this integration, since theories of motion detection rely on different delays in visual signals. These delays allow circuits to compare scenes at different times to calculate the direction and speed of motion. It remains untested how response dynamics of individual cell types drive motion detection and velocity sensitivity. Here, we sped up or slowed down specific neuron types in Drosophila’s motion detection circuit by manipulating ion channel expression. Altering the dynamics of individual neurons upstream of motion detectors changed their integrating properties and increased their sensitivity to fast or slow visual motion, exposing distinct roles for dynamics in tuning directional signals. A circuit model constrained by data and anatomy reproduced the observed tuning changes. Together, these results reveal how excitatory and inhibitory dynamics jointly tune a canonical circuit computation.