All Publications


  • Excitatory and inhibitory neural dynamics jointly tune motion detection Current Biology Gonzalez-Suarez, A. D., Zavatone-Veth, J. A., Chen, J., Matulis, C. A., Badwan, B. A., Clark, D. A. 2022: 3659-3675.e8

    Abstract

    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. Different motion detection circuits have different velocity sensitivity, but it remains untested how the response dynamics of individual cell types drive this tuning. 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 neuron types upstream of motion detectors increased their sensitivity to fast or slow visual motion, exposing distinct roles for excitatory and inhibitory dynamics in tuning directional signals, including a role for the amacrine cell CT1. A circuit model constrained by functional data and anatomy qualitatively reproduced the observed tuning changes. Overall, these results reveal how excitatory and inhibitory dynamics together tune a canonical circuit computation.

    View details for DOI 10.1016/j.cub.2022.06.075

    View details for PubMedCentralID PMC9474608

  • RIM-BPs mediate tight coupling of action potentials to Ca2 -triggered neurotransmitter release Neuron Acuna, C., Liu, X., Gonzalez, A., Sudhof, T. C. 2015; 87 (6): 1234-1247
  • Using Machine Learning Models to Identify Factors Associated With 30-Day Readmissions After Posterior Cervical Fusions: A Longitudinal Cohort Study. Neurospine Gonzalez-Suarez, A. D., Rezaii, P. G., Herrick, D., Tigchelaar, S. S., Ratliff, J. K., Rusu, M., Scheinker, D., Jeon, I., Desai, A. M. 2024

    Abstract

    Readmission rates after posterior cervical fusion (PCF) significantly impact patients and healthcare, with complication rates at 15%-5% and up to 12% 90-day readmission rates. In this study, we aim to test whether machine learning (ML) models that capture interfactorial interactions outperform traditional logistic regression (LR) in identifying readmission-associated factors.The Optum Clinformatics Data Mart database was used to identify patients who underwent PCF between 2004-2017. To determine factors associated with 30-day readmissions, 5 ML models were generated and evaluated, including a multivariate LR (MLR) model. Then, the best-performing model, Gradient Boosting Machine (GBM), was compared to the LACE (Length patient stay in the hospital, Acuity of admission of patient in the hospital, Comorbidity, and Emergency visit) index regarding potential cost savings from algorithm implementation.This study included 4,130 patients, 874 of which were readmitted within 30 days. When analyzed and scaled, we found that patient discharge status, comorbidities, and number of procedure codes were factors that influenced MLR, while patient discharge status, billed admission charge, and length of stay influenced the GBM model. The GBM model significantly outperformed MLR in predicting unplanned readmissions (mean area under the receiver operating characteristic curve, 0.846 vs. 0.829; p<0.001), while also projecting an average cost savings of 50% more than the LACE index.Five models (GBM, XGBoost [extreme gradient boosting], RF [random forest], LASSO [least absolute shrinkage and selection operator], and MLR) were evaluated, among which, the GBM model exhibited superior predictive performance, robustness, and accuracy. Factors associated with readmissions impact LR and GBM models differently, suggesting that these models can be used complementarily. When analyzing PCF procedures, the GBM model resulted in greater predictive performance and was associated with higher theoretical cost savings for readmissions associated with PCF complications.

    View details for DOI 10.14245/ns.2347340.670

    View details for PubMedID 38768945

  • Standardizing Continuous Physical Activity Monitoring in Patients with Cervical Spondylosis. Spine Maldaner, N., Gonzalez-Suarez, A. D., Tang, M., Fatemi, P., Leung, C., Desai, A., Tomkins-Lane, C., Zygourakis, C. 2024

    Abstract

    STUDY DESIGN/SETTING: Prospective cohort study.OBJECTIVE: To use a commercial wearable device to measure real-life, continuous physical activity in patients with CS and to establish age- and sex-adjusted standardized scores.SUMMARY OF BACKGROUND DATA: Patients with cervical spondylosis (CS) often present with pain or neurologic deficits that results in functional limitations and inactivity. However, little is known regarding the influence of CS on patient's real-life physical activity.METHODS: This study included 100 English-speaking adult patients with cervical degenerative diseases undergoing elective spine surgery at Stanford University who owned iPhones. Patients undergoing surgery for spine infections, trauma, or tumors, or with lumbar degenerative disease were excluded. Activity two weeks before surgery was expressed as raw daily step counts. Standardized z-scores were calculated based on age- and sex-specific values of a control population. Responses to patient-reported outcome measures (PROMs) surveys assessed convergent validity. Functional impairment was categorized based on predetermined z-score cut-off values.RESULTS: 30 CS with mean(±SD) age of 56.0(±13.4) years wore an Apple Watch for ≥8 hours/day in 87.1% of the days. Mean watch wear time was 15.7(±4.2) hours/day, and mean daily step count was 6,400(±3,792). There was no significant difference in activity between 13 patients (43%) with myelopathy and 17 (57%) without myelopathy. Test-Retest reliability between wearable step count measurements was excellent (ICC beta=0.95). Physical activity showed a moderate positive correlation with SF36-PCS, EQ5D VAS, and PROMIS-PF. Activity performance was classified into categories of "no impairment" (step count=9,640(±2,412)), "mild impairment" (6,054(±816)), "moderate impairment" (3,481(±752)), and "severe impairment" (1,619(±240)).CONCLUSION: CS patients' physical activity is significantly lower than the general population, or the frequently stated goals of 7,000-10,000 steps/day. Standardized, continuous wearable physical activity monitoring in CS is a reliable, valid, and normalized outcome tool that may help characterize functional impairment before and after spinal interventions.

    View details for DOI 10.1097/BRS.0000000000004940

    View details for PubMedID 38288595

  • Automated Labeling of Spondylolisthesis Cases through Spinal MRI Radiology Report Interpretation using ChatGPT Moallem, G., Gonzalez, A., Desai, A., Rusu, M., Chen, W., Astley, S. M. SPIE-INT SOC OPTICAL ENGINEERING. 2024

    View details for DOI 10.1117/12.3006999

    View details for Web of Science ID 001208134600098

  • PharmGKB summary: disulfiram pathway. Pharmacogenetics and genomics Gonzalez-Suarez, A. D., Thorn, C. F., Whirl-Carrillo, M., Klein, T. E. 2023

    View details for DOI 10.1097/FPC.0000000000000509

    View details for PubMedID 37728645

  • Manipulating Neural Dynamics to Tune Motion Computation in Drosophila Gonzalez-Suarez, A. D. Yale Graduate School of Arts and Sciences Dissertations. 2022
  • Manipulating neural dynamics to tune motion detection Gonzalez-Suarez, A. D., Zavatone-Veth, J. A., Chen, J., Matulis, C. A., Badwan, B. A., Clark, D. A. Cold Spring Harbor Laboratory. bioRxiv; https://doi.org/10.1101/2021.11.02.466844. 2021
  • Transport rate of EAAT2 is regulated by amino acid located at the interface between the scaffolding and substrate transport domains NEUROCHEMISTRY INTERNATIONAL Duffield, M., Patel, A., Mortensen, O., Schnur, D., Gonzalez-Suarez, A. D., Torres-Salazar, D., Fontana, A. K. 2020; 139: 104792

    Abstract

    Excitatory Amino Acid Transporters (EAATs) are plasma membrane proteins responsible for maintenance of low extracellular concentrations of glutamate in the CNS. Dysfunction in their activity is implicated in various neurological disorders. Glutamate transport by EAATs occurs through the movement of the central transport domain relative to the scaffold domain in the EAAT membrane protein. Previous studies suggested that residues located within the interface of these two domains in EAAT2, the main subtype of glutamate transporter in the brain, are involved in regulating transport rates. We used mutagenesis, structure-function relationship, surface protein expression and electrophysiology studies, in transfected COS-7 cells and oocytes, to examine residue glycine at position 298, which is located within this interface. Mutation G298A results in increased transport rate without changes in surface expression, suggesting a more hydrophobic and larger alanine results in facilitated transport movement. The increased transport rate does not involve changes in sodium affinity. Electrophysiological currents show that G298A increase both transport and anion currents, suggesting faster transitions through the transport cycle. This work identifies a region critically involved in setting the glutamate transport rate.

    View details for DOI 10.1016/j.neuint.2020.104792

    View details for Web of Science ID 000564511800007

    View details for PubMedID 32668264

  • Spatiotemporally precise optogenetic activation of sensory neurons in freely walking Drosophila ELIFE DeAngelis, B. D., Zavatone-Veth, J. A., Gonzalez-Suarez, A. D., Clark, D. A. 2020; 9

    Abstract

    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.

    View details for DOI 10.7554/eLife.54183

    View details for Web of Science ID 000531812300001

    View details for PubMedID 32319425

    View details for PubMedCentralID PMC7198233

  • Heterogeneous Temporal Contrast Adaptation in Drosophila Direction-Selective Circuits CURRENT BIOLOGY Matulis, C. A., Chen, J., Gonzalez-Suarez, A. D., Behnia, R., Clark, D. A. 2020; 30 (2): 222-+

    Abstract

    In visual systems, neurons adapt both to the mean light level and to the range of light levels, or the contrast. Contrast adaptation has been studied extensively, but it remains unclear how it is distributed among neurons in connected circuits, and how early adaptation affects subsequent computations. Here, we investigated temporal contrast adaptation in neurons across Drosophila's visual motion circuitry. Several ON-pathway neurons showed strong adaptation to changes in contrast over time. One of these neurons, Mi1, showed almost complete adaptation on fast timescales, and experiments ruled out several potential mechanisms for its adaptive properties. When contrast adaptation reduced the gain in ON-pathway cells, it was accompanied by decreased motion responses in downstream direction-selective cells. Simulations show that contrast adaptation can substantially improve motion estimates in natural scenes. The benefits are larger for ON-pathway adaptation, which helps explain the heterogeneous distribution of contrast adaptation in these circuits.

    View details for DOI 10.1016/j.cub.2019.11.077

    View details for Web of Science ID 000508195800020

    View details for PubMedID 31928874

    View details for PubMedCentralID PMC7003801

  • Peptide-Mediated Neurotransmission Takes Center Stage TRENDS IN NEUROSCIENCES Gonzalez-Suarez, A. D., Nitabach, M. N. 2018; 41 (6): 325-327

    Abstract

    Today, we understand peptide transmitters to be signaling molecules that modulate neural activity. However, in 1982 little was known about neuropeptides and their role in neural communication. The influential 1982 paper by Jan and Jan reported definitive evidence that a presynaptically released neuropeptide evokes postsynaptic responses in an identified cholinergic synapse, thereby fueling a new era in neuroscience.

    View details for DOI 10.1016/j.tins.2018.03.013

    View details for Web of Science ID 000433025300001

    View details for PubMedID 29801523

    View details for PubMedCentralID PMC5975383

  • Substrate transport and anion permeation proceed through distinct pathways in glutamate transporters ELIFE Cheng, M., Torres-Salazar, D., Gonzalez-Suarez, A. D., Amara, S. G., Bahar, I. 2017; 6

    Abstract

    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.

    View details for DOI 10.7554/eLife.25850

    View details for Web of Science ID 000403413600001

    View details for PubMedID 28569666

    View details for PubMedCentralID PMC5472439

  • Glial and Neuronal Glutamate Transporters Differ in the Na+ Requirements for Activation of the Substrate-Independent Anion Conductance FRONTIERS IN MOLECULAR NEUROSCIENCE Divito, C. B., Borowski, J. E., Glasgow, N. G., Gonzalez-Suarez, A. D., Torres-Salazar, D., Johnson, J. W., Amara, S. G. 2017; 10: 150

    Abstract

    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.

    View details for DOI 10.3389/fnmol.2017.00150

    View details for Web of Science ID 000402109400001

    View details for PubMedID 28611584

    View details for PubMedCentralID PMC5447070

  • Insights into the Gating Mechanism of Excitatory Amino Acid Transporters-Associated Anion Channel Torres-Salazar, D., Poblete, H., Gonzalez-Suarez, A., Vergara-Jaque, A., Garcia-Olivares, J., Comer, J., Amara, S. G. CELL PRESS. 2017: 336A
  • Emerging Evidence for a Direct Link between EAAT-Associated Anion Channels and Neurological Disorders JOURNAL OF NEUROSCIENCE Gonzalez-Suarez, A. D., Nash, A. I., Garcia-Olivares, J., Torres-Salazar, D. 2017; 37 (2): 241-243
  • Transport and channel functions in EAATs: the missing link CHANNELS Torres-Salazar, D., Gonzalez-Suarez, A. M., Amara, S. G. 2016; 10 (2): 86-87

    View details for DOI 10.1080/19336950.2015.1119631

    View details for Web of Science ID 000372112100007

    View details for PubMedID 26683197

    View details for PubMedCentralID PMC4961052

  • Elucidating the Anion Channel Gating Mechanism in Excitatory Amino Acid Transporters Salazar, D., Poblete, H., Gonzalez, A., Vergara-Jaque, A., Comer, J., Amara, S. G. CELL PRESS. 2016: 137A