About

Scott Chandler is a professor in the field of Integrative Biology and Physiology at UCLA. His research primarily focuses on understanding how the central nervous system controls movement, with particular attention to rhythmical movements such as locomotion, mastication, and respiration. He uses animal models to study the production of rhythmical jaw movements, employing electrophysiological, molecular, pharmacological techniques, computational modeling, and bioinformatics to investigate how networks of neurons in the brainstem orchestrate these movements. His work has identified localized groups of neurons within the brainstem that are crucial for the rhythmic component of mastication and has explored the activation of specific ion channels that produce characteristic discharge patterns during these movements. Additionally, his lab has developed transgenic mouse models that exhibit symptoms of Amyotrophic Lateral Sclerosis (ALS), aiming to uncover early molecular changes and potential targets for therapeutic intervention. His research contributes to a better understanding of neurodegenerative processes and the mechanisms underlying motor control.

Research topics

• Biology
• Neuroscience
• Chemistry
• Medicine
• Pathology
• Cell biology
• Anatomy
• Internal medicine
• Immunology
• Genetics
• Endocrinology

Selected publications

• Profiling of the antibody response to viral and bacterial antigens and its correlations with time-to-hospital discharge: Covacta and Mariposa study

  The Journal of Immunology · 2023-05-01

  articleOpen access

  Abstract In this study the role of the humoral response to viral and bacterial antigens in hospitalised patients with severe COVID-19 and its association with clinical endpoint time-to-hospital discharge (TTHD) was investigated. Here, we analysed the antibody (Ab) response to SARS-CoV-2 structural and non structural proteins, other influenza(s) and bacterial proteins using bead-based protein and peptide arrays comprising different viral epitopes. In total, 459 pre-treatment serum samples from hospitalised COVID-19 patients enrolled in the COVACTA and MARIPOSA clinical trials were analysed to identify Ab reactivity to protein antigens and linear epitopes associated with TTHD. Overall we found that most patients had IgG-Abs to SARS-CoV-2 S protein (89%), N protein (90%) and RBD domain (95%). Three major epitopes of the S protein were identified which map to the C-terminus of the RBD, TMPRSS2 cleavage site and fusion peptide 1, and close to the heptad repeat 2 domain. These epitopes could be further researched to understand the immunity to COVID-19 and how it affects outcomes. Abs binding to several peptides mapping to the RBD C-terminus and N-terminal to heptad repeat 2 were associated with longer TTHD. Abs to an epitope mapping to the intracellular domain of S protein and to the RNA-binding domain of the N protein showed the strongest association with longer TTHD. Abs to seasonal corona viruses and influenza A & B, S. aureus, and rhinovirus were associated with shorter TTHD. To conclude, epitope-specific multiplexed Ab profiling of anti-SARS-CoV-2 response may potentially be used to predict clinical outcome. Pre-existing humoral immunity to seasonal corona viruses and influenza may also confer some protective effects against COVID-19

  PublisherOA PDFDOI

• Early deficits in GABA inhibition parallels an increase in L-type Ca2+ currents in the jaw motor neurons of SOD1G93A mouse model for ALS

  Neurobiology of Disease · 2023 · 9 citations

  Senior authorCorresponding
  • Neuroscience
  • Chemistry
  • Anatomy

  currents in the mutant JC MNs around P12. Together these results support that, early modifications in intrinsic properties of vulnerable MNs could be an adaptive response to counter synaptic deficits.

  PublisherDOI

• Diminished GAD67 Terminals and Ambient GABA Inhibition Associated with Reduced Motor Neuron Recruitment Threshold in the SOD1 ^G93A ALS mouse

  bioRxiv (Cold Spring Harbor Laboratory) · 2021-12-17 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Pre-symptomatic studies in mouse models of the neurodegenerative motor neuron (MN) disease, Amyotrophic Lateral Sclerosis (ALS) highlight early alterations in intrinsic and synaptic excitability and have supported an excitotoxic theory of MN death. However, a role for synaptic inhibition in disease development is not sufficiently explored among other mechanisms. Since inhibition plays a role in both regulating motor output and in neuroprotection, we examined the age-dependent anatomical changes in inhibitory presynaptic terminals on MN cell bodies using fluorescent immunohistochemistry for GAD67 (GABA) and GlyT2 (glycine) presynaptic proteins comparing ALS-vulnerable trigeminal jaw closer (JC) motor pools with the ALS-resistant extraocular (EO) MNs in the SOD1 G93A mouse model for ALS. Our results indicate differential patterns of temporal changes of these terminals in vulnerable versus resilient MNs and relative differences between SOD1 G93A and wild-type (WT) MNs. Notably, we found pre-symptomatic up-regulation in inhibitory terminals in the EO MNs while the vulnerable JC MNs mostly showed a decrease in inhibitory terminals. Specifically, there was a statistically significant decrease in the GAD67 somatic abuttal in the SOD1 G93A JC MNs compared to WT around P12. Using in vitro patch-clamp electrophysiology, we found a parallel decrease in the ambient GABA-dependent tonic inhibition in the SOD1 G93A JC MNs. While it is unclear if the two mechanisms are directly related, pharmacological blockade of specific subtype of GABA A -α5 receptors suggests that tonic inhibition can control MN recruitment threshold. Furthermore, reduction in tonic GABA current as observed here in the mutant, identifies a putative molecular mechanism explaining our observations of hyperexcitable shifts in JC MN recruitment threshold in the SOD1 G93A mouse. Lastly, we showcase non-parametric resampling-based bootstrap statistics for data analyses, and provide the Python code on GitHub for wider reuse.

  PublisherOA PDFDOI

• Single-cell RNA-seq analysis of the brainstem of mutant SOD1 mice reveals perturbed cell types and pathways of amyotrophic lateral sclerosis

  Neurobiology of Disease · 2020 · 89 citations

  Senior authorCorresponding
  • Biology
  • Neuroscience
  • Cell biology

  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons throughout the brain and spinal cord progressively degenerate resulting in muscle atrophy, paralysis and death. Recent studies using animal models of ALS implicate multiple cell-types (e.g., astrocytes and microglia) in ALS pathogenesis in the spinal motor systems. To ascertain cellular vulnerability and cell-type specific mechanisms of ALS in the brainstem that orchestrates oral-motor functions, we conducted parallel single cell RNA sequencing (scRNA-seq) analysis using the high-throughput Drop-seq method. We isolated 1894 and 3199 cells from the brainstem of wildtype and mutant SOD1 symptomatic mice respectively, at postnatal day 100. We recovered major known cell types and neuronal subpopulations, such as interneurons and motor neurons, and trigeminal ganglion (TG) peripheral sensory neurons, as well as, previously uncharacterized interneuron subtypes. We found that the majority of the cell types displayed transcriptomic alterations in ALS mice. Differentially expressed genes (DEGs) of individual cell populations revealed cell-type specific alterations in numerous pathways, including previously known ALS pathways such as inflammation (in microglia), stress response (ependymal and an uncharacterized cell population), neurogenesis (astrocytes, oligodendrocytes, neurons), synapse organization and transmission (microglia, oligodendrocyte precursor cells, and neuronal subtypes), and mitochondrial function (uncharacterized cell populations). Other cell-type specific processes altered in SOD1 mutant brainstem include those from motor neurons (axon regeneration, voltage-gated sodium and potassium channels underlying excitability, potassium ion transport), trigeminal sensory neurons (detection of temperature stimulus involved in sensory perception), and cellular response to toxic substances (uncharacterized cell populations). DEGs consistently altered across cell types (e.g., Malat1), as well as cell-type specific DEGs, were identified. Importantly, DEGs from various cell types overlapped with known ALS genes from the literature and with top hits from an existing human ALS genome-wide association study (GWAS), implicating the potential cell types in which the ALS genes function with ALS pathogenesis. Our molecular investigation at single cell resolution provides comprehensive insights into the cell types, genes and pathways altered in the brainstem in a widely used ALS mouse model.

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• Neuropeptide Y modulates membrane excitability in neonatal rat mesencephalic V neurons

  Journal of Neuroscience Research · 2020 · 8 citations

  • Neuroscience
  • Internal medicine
  • Endocrinology

  Neuropeptide Y (NPY) is one of a number of neuropeptides with powerful orexigenic effects. Intracerebroventricular administration of NPY induces increases in food intake and alters feeding rate. Besides it role in feeding behavior, NPY also has significant effects on neuronal systems related to other spontaneous behaviors such as rearing and grooming. In the present study, we examined the direct effects of NPY on mesencephalic V neurons (Mes V), which are important sensory neurons involved in oral motor reflexes and rhythmical jaw movements, as well as masticatory proprioception. Coronal brain slices were prepared from neonatal Sprague-Dawley rats (P3-17) and whole-cell patch clamp recordings were obtained from Mes V neurons. Bath application of NPY depolarized the membrane potential and induced inward current in most neurons. Application of NPY shortened the duration of the afterhyperpolarization following an action potential, and increased the mean spike frequency during repetitive discharge. In those neurons which exhibited rhythmical burst discharge in response to maintained current injection, the bursting frequency was also increased. These effects were mediated predominately by both Y1 and Y5 receptors.

  PublisherDOI

• Circuit-Specific Early Impairment of Proprioceptive Sensory Neurons in the SOD1 ^G93A Mouse Model for ALS

  bioRxiv (Cold Spring Harbor Laboratory) · 2019-06-13

  preprintOpen accessCorresponding

  Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease in which motor neurons degenerate resulting in muscle atrophy, paralysis and fatality. Studies using mouse models of ALS indicate a protracted period of disease development with progressive motor neuron pathology, evident as early as embryonic and postnatal stages. Key missing information includes concomitant alterations in the sensorimotor circuit essential for normal development and function of the neuromuscular system. Leveraging unique brainstem circuitry, we show in vitro evidence for reflex circuit-specific postnatal abnormalities in the jaw proprioceptive sensory neurons in the well-studied SOD1 G93A mouse. These include impaired and arrhythmic action potential burst discharge associated with a deficit in Nav1.6 Na + channels. However, the mechanoreceptive and nociceptive trigeminal ganglion neurons and the visual sensory retinal ganglion neurons were resistant to excitability changes in age matched SOD1 G93A mice. Computational modeling of the observed disruption in sensory patterns predicted asynchronous self-sustained motor neuron discharge suggestive of imminent reflexive defects such as muscle fasciculations in ALS. These results demonstrate a novel reflex circuit-specific proprioceptive sensory abnormality in ALS. Significance Statement Neurodegenerative diseases have prolonged periods of disease development and progression. Identifying early markers of vulnerability can therefore help devise better diagnostic and treatment strategies. In this study, we examined postnatal abnormalities in the electrical excitability of muscle spindle afferent proprioceptive neurons in the well-studied SOD1 G93A mouse model for neurodegenerative motor neuron disease, ALS. Our findings suggest that these proprioceptive sensory neurons are exclusively afflicted early in the disease process relative to sensory neurons of other modalities. Moreover, they presented Nav1.6 Na + channel deficiency which contributed to arrhythmic burst discharge. Such sensory arrhythmia could initiate reflexive defects such as muscle fasciculations in ALS as suggested by our computational model.

  PublisherOA PDFDOI

• Reflections on my longtime friendship with Mike Levine

  Journal of Neuroscience Research · 2019-10-15

  article1st authorCorresponding
  PublisherDOI

• Resurgent Na+ Current Offers Noise Modulation in Bursting Neurons

  PLoS Computational Biology · 2019-06-21 · 15 citations

  articleOpen accessSenior author

  Neurons utilize bursts of action potentials as an efficient and reliable way to encode information. It is likely that the intrinsic membrane properties of neurons involved in burst generation may also participate in preserving its temporal features. Here we examined the contribution of the persistent and resurgent components of voltage-gated Na+ currents in modulating the burst discharge in sensory neurons. Using mathematical modeling, theory and dynamic-clamp electrophysiology, we show that, distinct from the persistent Na+ component which is important for membrane resonance and burst generation, the resurgent Na+ can help stabilize burst timing features including the duration and intervals. Moreover, such a physiological role for the resurgent Na+ offered noise tolerance and preserved the regularity of burst patterns. Model analysis further predicted a negative feedback loop between the persistent and resurgent gating variables which mediate such gain in burst stability. These results highlight a novel role for the voltage-gated resurgent Na+ component in moderating the entropy of burst-encoded neural information.

  PublisherOA PDFDOI

• Circuit-Specific Early Impairment of Proprioceptive Sensory Neurons in the SOD1 ^G93A Mouse Model for ALS

  Journal of Neuroscience · 2019-09-17 · 36 citations

  articleOpen access

  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons degenerate, resulting in muscle atrophy, paralysis, and fatality. Studies using mouse models of ALS indicate a protracted period of disease development with progressive motor neuron pathology, evident as early as embryonic and postnatal stages. Key missing information includes concomitant alterations in the sensorimotor circuit essential for normal development and function of the neuromuscular system. Leveraging unique brainstem circuitry, we show in vitro evidence for reflex circuit-specific postnatal abnormalities in the jaw proprioceptive sensory neurons in the well-studied SOD1 G93A mouse. These include impaired and arrhythmic action potential burst discharge associated with a deficit in Nav1.6 Na + channels. However, the mechanoreceptive and nociceptive trigeminal ganglion neurons and the visual sensory retinal ganglion neurons were resistant to excitability changes in age-matched SOD1 G93A mice. Computational modeling of the observed disruption in sensory patterns predicted asynchronous self-sustained motor neuron discharge suggestive of imminent reflexive defects, such as muscle fasciculations in ALS. These results demonstrate a novel reflex circuit-specific proprioceptive sensory abnormality in ALS. SIGNIFICANCE STATEMENT Neurodegenerative diseases have prolonged periods of disease development and progression. Identifying early markers of vulnerability can therefore help devise better diagnostic and treatment strategies. In this study, we examined postnatal abnormalities in the electrical excitability of muscle spindle afferent proprioceptive neurons in the well-studied SOD1 G93A mouse model for neurodegenerative motor neuron disease, amyotrophic lateral sclerosis. Our findings suggest that these proprioceptive sensory neurons are exclusively afflicted early in the disease process relative to sensory neurons of other modalities. Moreover, they presented Nav1.6 Na + channel deficiency, which contributed to arrhythmic burst discharge. Such sensory arrhythmia could initiate reflexive defects, such as muscle fasciculations in amyotrophic lateral sclerosis, as suggested by our computational model.

  PublisherOA PDFDOI

• A Mechanism of Real-Time Noise Modulation in Neurons

  bioRxiv (Cold Spring Harbor Laboratory) · 2018-12-09 · 1 citations

  preprintOpen accessSenior author

  Uncertainties pose an ongoing challenge for information processing in the nervous system. It is not entirely clear how neurons maintain dynamic stability of information, encoded in the temporal features of spike trains, notwithstanding stochastic influences. Here we examined the contribution of subclasses of membrane sodium currents in real-time noise modulation in sensory neurons. Fast sodium (Na + ) currents are essential for spike generation, and a persistent Na+ current can entrain preferred input frequencies via membrane resonance. Using mathematical modeling, theory and experiments, we show that a resurgent Na + current can stabilize the temporal features of burst discharge and confer noise tolerance. These novel insights reckon the role of biophysical properties of Na + currents beyond mere spike generation. Instead, these mechanisms might be how neurons perform real-time signal processing to maintain order and entropy in neural discharge. Our model analysis further predicts a negative feedback loop in the molecular machinery of an underlying Nav1.6-type Na + channel gating considered in this study.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01DE006193

  NIH · $4.6M · 2010

• NIH Grant R21NS071348

  NIH · $424k · 2014

• NIH Grant R01DE004166

  NIH · $695k · 1995

Frequent coauthors

• Louis J. Goldberg

  Cornell University

  17 shared

• Martina Wiedau‐Pazos

  University of California, Los Angeles

  12 shared

• Sharmila Venugopal

  University of California, Los Angeles

  12 shared

• Chie‐Fang Hsiao

  12 shared

• Jack E. Turman

  Indiana University – Purdue University Indianapolis

  11 shared

• Michael S. Levine

  University of California, Los Angeles

  8 shared

• Susumu Tanaka

  Osaka Metropolitan University

  8 shared

• Riccardo Olcese

  University of California, Los Angeles

  8 shared

Labs

• Scott Chandler LabPI

Education

• Ph.D., Integrative Biology and Physiology

  University of California, Los Angeles

  2005

• M.S., Integrative Biology and Physiology

  University of California, Los Angeles

  2001

• B.S., Biology

  University of California, Los Angeles

  1999