Browsing by Author "Higgins, David"

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    Burst-Dependent Bidirectional Plasticity in the Cerebellum Is Driven by Presynaptic NMDA Receptors.
    (Cell reports, 2016-04) Bouvier, Guy; Higgins, David; Spolidoro, Maria; Carrel, Damien; Mathieu, Benjamin; Léna, Clément; Dieudonné, Stéphane; Barbour, Boris; Brunel, Nicolas; Casado, Mariano
    Numerous studies have shown that cerebellar function is related to the plasticity at the synapses between parallel fibers and Purkinje cells. How specific input patterns determine plasticity outcomes, as well as the biophysics underlying plasticity of these synapses, remain unclear. Here, we characterize the patterns of activity that lead to postsynaptically expressed LTP using both in vivo and in vitro experiments. Similar to the requirements of LTD, we find that high-frequency bursts are necessary to trigger LTP and that this burst-dependent plasticity depends on presynaptic NMDA receptors and nitric oxide (NO) signaling. We provide direct evidence for calcium entry through presynaptic NMDA receptors in a subpopulation of parallel fiber varicosities. Finally, we develop and experimentally verify a mechanistic plasticity model based on NO and calcium signaling. The model reproduces plasticity outcomes from data and predicts the effect of arbitrary patterns of synaptic inputs on Purkinje cells, thereby providing a unified description of plasticity.
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    Early propranolol treatment induces lung heme-oxygenase-1, attenuates metabolic dysfunction, and improves survival following experimental sepsis.
    (Crit Care, 2013-09-10) Wilson, Joel; Higgins, David; Hutting, Haley; Serkova, Natalie; Baird, Christine; Khailova, Ludmila; Queensland, Kelly; Vu Tran, Zung; Weitzel, Lindsay; Wischmeyer, Paul E
    INTRODUCTION: Pharmacological agents that block beta-adrenergic receptors have been associated with improved outcome in burn injury. It has been hypothesized that injuries leading to a hypermetabolic state, such as septic shock, may also benefit from beta-blockade; however, outcome data in experimental models have been contradictory. Thus, we investigated the effect of beta-blockade with propranolol on survival, hemodynamics, lung heat shock protein (HSP) expression, metabolism and inflammatory markers in a rat cecal ligation and puncture (CLP) model of sepsis. METHODS: Sprague-Dawley rats receiving either repeated doses (30 minutes pre-CLP and every 8 hours for 24 hours postoperatively) of propranolol or control (normal saline), underwent CLP and were monitored for survival. Additionally, lung and blood samples were collected at 6 and 24 hours for analysis. Animals also underwent monitoring to evaluate global hemodynamics. RESULTS: Seven days following CLP, propranolol improved survival versus control (P < 0.01). Heart rates in the propranolol-treated rats were approximately 23% lower than control rats (P < 0.05) over the first 24 hours, but the mean arterial blood pressure was not different between groups. Metabolic analysis of lung tissue demonstrated an increase in lung ATP/ADP ratio and NAD+ content and a decreased ratio of polyunsaturated fatty acids to monounsaturated fatty acids (PUFA/MUFA). Cytokine analysis of the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) demonstrated decreased expression of TNF-alpha in both lung and plasma at 24 hours post CLP induced sepsis. Finally, propranolol led to a significant increase in lung hemeoxygenase-1 expression, a key cellular protective heat shock protein (HSP) in the lung. Other lung HSP expression was unchanged. CONCLUSIONS: These results suggest that propranolol treatment may decrease mortality during sepsis potentially via a combination of improving metabolism, suppressing aspects of the inflammatory response and enhancing tissue protection.
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    Memory maintenance in synapses with calcium-based plasticity in the presence of background activity.
    (PLoS Comput Biol, 2014-10) Higgins, David; Graupner, Michael; Brunel, Nicolas
    Most models of learning and memory assume that memories are maintained in neuronal circuits by persistent synaptic modifications induced by specific patterns of pre- and postsynaptic activity. For this scenario to be viable, synaptic modifications must survive the ubiquitous ongoing activity present in neural circuits in vivo. In this paper, we investigate the time scales of memory maintenance in a calcium-based synaptic plasticity model that has been shown recently to be able to fit different experimental data-sets from hippocampal and neocortical preparations. We find that in the presence of background activity on the order of 1 Hz parameters that fit pyramidal layer 5 neocortical data lead to a very fast decay of synaptic efficacy, with time scales of minutes. We then identify two ways in which this memory time scale can be extended: (i) the extracellular calcium concentration in the experiments used to fit the model are larger than estimated concentrations in vivo. Lowering extracellular calcium concentration to in vivo levels leads to an increase in memory time scales of several orders of magnitude; (ii) adding a bistability mechanism so that each synapse has two stable states at sufficiently low background activity leads to a further boost in memory time scale, since memory decay is no longer described by an exponential decay from an initial state, but by an escape from a potential well. We argue that both features are expected to be present in synapses in vivo. These results are obtained first in a single synapse connecting two independent Poisson neurons, and then in simulations of a large network of excitatory and inhibitory integrate-and-fire neurons. Our results emphasise the need for studying plasticity at physiological extracellular calcium concentration, and highlight the role of synaptic bi- or multistability in the stability of learned synaptic structures.
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    The children's brain tumor network (CBTN) - Accelerating research in pediatric central nervous system tumors through collaboration and open science.
    (Neoplasia (New York, N.Y.), 2023-01) Lilly, Jena V; Rokita, Jo Lynne; Mason, Jennifer L; Patton, Tatiana; Stefankiewiz, Stephanie; Higgins, David; Trooskin, Gerri; Larouci, Carina A; Arya, Kamnaa; Appert, Elizabeth; Heath, Allison P; Zhu, Yuankun; Brown, Miguel A; Zhang, Bo; Farrow, Bailey K; Robins, Shannon; Morgan, Allison M; Nguyen, Thinh Q; Frenkel, Elizabeth; Lehmann, Kaitlin; Drake, Emily; Sullivan, Catherine; Plisiewicz, Alexa; Coleman, Noel; Patterson, Luke; Koptyra, Mateusz; Helili, Zeinab; Van Kuren, Nicholas; Young, Nathan; Kim, Meen Chul; Friedman, Christopher; Lubneuski, Alex; Blackden, Christopher; Williams, Marti; Baubet, Valerie; Tauhid, Lamiya; Galanaugh, Jamie; Boucher, Katie; Ijaz, Heba; Cole, Kristina A; Choudhari, Namrata; Santi, Mariarita; Moulder, Robert W; Waller, Jonathan; Rife, Whitney; Diskin, Sharon J; Mateos, Marion; Parsons, Donald W; Pollack, Ian F; Goldman, Stewart; Leary, Sarah; Caporalini, Chiara; Buccoliero, Anna Maria; Scagnet, Mirko; Haussler, David; Hanson, Derek; Firestein, Ron; Cain, Jason; Phillips, Joanna J; Gupta, Nalin; Mueller, Sabine; Grant, Gerald; Monje-Deisseroth, Michelle; Partap, Sonia; Greenfield, Jeffrey P; Hashizume, Rintaro; Smith, Amy; Zhu, Shida; Johnston, James M; Fangusaro, Jason R; Miller, Matthew; Wood, Matthew D; Gardner, Sharon; Carter, Claire L; Prolo, Laura M; Pisapia, Jared; Pehlivan, Katherine; Franson, Andrea; Niazi, Toba; Rubin, Josh; Abdelbaki, Mohamed; Ziegler, David S; Lindsay, Holly B; Stucklin, Ana Guerreiro; Gerber, Nicolas; Vaske, Olena M; Quinsey, Carolyn; Rood, Brian R; Nazarian, Javad; Raabe, Eric; Jackson, Eric M; Stapleton, Stacie; Lober, Robert M; Kram, David E; Koschmann, Carl; Storm, Phillip B; Lulla, Rishi R; Prados, Michael; Resnick, Adam C; Waanders, Angela J
    Pediatric brain tumors are the leading cause of cancer-related death in children in the United States and contribute a disproportionate number of potential years of life lost compared to adult cancers. Moreover, survivors frequently suffer long-term side effects, including secondary cancers. The Children's Brain Tumor Network (CBTN) is a multi-institutional international clinical research consortium created to advance therapeutic development through the collection and rapid distribution of biospecimens and data via open-science research platforms for real-time access and use by the global research community. The CBTN's 32 member institutions utilize a shared regulatory governance architecture at the Children's Hospital of Philadelphia to accelerate and maximize the use of biospecimens and data. As of August 2022, CBTN has enrolled over 4700 subjects, over 1500 parents, and collected over 65,000 biospecimen aliquots for research. Additionally, over 80 preclinical models have been developed from collected tumors. Multi-omic data for over 1000 tumors and germline material are currently available with data generation for > 5000 samples underway. To our knowledge, CBTN provides the largest open-access pediatric brain tumor multi-omic dataset annotated with longitudinal clinical and outcome data, imaging, associated biospecimens, child-parent genomic pedigrees, and in vivo and in vitro preclinical models. Empowered by NIH-supported platforms such as the Kids First Data Resource and the Childhood Cancer Data Initiative, the CBTN continues to expand the resources needed for scientists to accelerate translational impact for improved outcomes and quality of life for children with brain and spinal cord tumors.