Trent R Anderson
- Associate Professor, Basic Medical Sciences
The brain is a fascinating lesson in duality – constantly balancing between the needs for diametrically opposed extremes. At its core it is an elegantly simplistic processing and computation center and yet its function results in the complicated behaviour, perception and reality we all experience. Built from simple single neurons the brain forms emergent networks that drive and govern our basic behaviour and how we perceive and interpret the world around us. Specifically, as a scientist I am intrigued by the duality of the balance the brain strikes between excitation and inhibition – tempering the need for excitatory activity to convey sensory and motor information with inhibitory activity that prevents run away excitation. Understanding the regulatory mechanisms that control this balance as well as the way disease states alter this balance has been the focus of my research career.
Did you know the brain consumes over 25% of the energy the body produces? This rate of consumption is 10 times greater than that of any other tissue. What is intriguing is given this extraordinary demand for energy the brain functions “inefficiently” – its excitatory activity is constantly being suppressed by an over-riding inhibitory activity. It is as if the brain is applying pressure to both the gas pedal and brake at the same time. The necessity for this inhibitory action is clearly evident as its loss or reduction has profound implication on the development and propagation of numerous disease states including epilepsy, Parkinson’s disease, stroke and migraine. In the cerebral cortex, the higher order processing center of the brain, inhibitory interneurons are responsible for this “brake”. These interneurons are a distinct and yet diverse group of specialized neurons with varying anatomical, pharmacologic and physiological properties that make them ideally situated to understand and manipulate this balance.
My research program combines aspects of cellular, synaptic and network neuroscience by using advanced tools in cellular physiology, neuropharmacology, imaging and molecular biology to elucidate mechanisms regulating excitability. Ongoing research points to neurosteroids as a prime candidate in regulating the balance between excitation and inhibition. Cortical neurons possess unique properties and sensitivities to neurosteroids that may be exploited to increase our understanding of the way the brain functions and as potential sources of therapeutic action. Steroids such as progesterone, pregnenonlone and dehydropiandrosterone are normally associated with their peripheral origin and action but have recently been shown to be de-novo synthesized in the brain itself. Specifically, several reports have indicated the ability of neurosteroids to alter both inhibitory (GABA) and excitatory (NMDA) function. Determining selective and novel pathways to up or down regulate the excitability of the brain may reveal significant sources of new therapeutic potential.
- Ph.D. Anatomy and Cell Biology
- Queen's University
- B.Sc.H Life Sciences
- Queens University, Kingston, Ontario
- Stanford University (2005 - 2008)
- University of Calgary - Hotchkiss Brain Institute (2002 - 2005)
Migraine, Epilepy, Traumatic Brain Injury, Electrophsyiology, Optogenetics, Imaging, Cancer; Neuro-degenerative, developmental and psychiatric disease; Developmental, cell and molecular biology; Signaling and steroid biology
Anatomy, Neuroscience, Neuroanatomy, Neurophysiology, Neuroanatomy
Cellular Molecular& Neural BioCTS 555 (Fall 2020)
Cellular Molecular& Neural BioCTS 555 (Fall 2019)
- Chen, K., Ma, X., Nehme, A., Wei, J., Cui, Y., Cui, Y., Yao, D., Wu, J., Anderson, T., Ferguson, D., Levitt, P., & Qiu, S. (2020). Time-delimited signaling of MET receptor tyrosine kinase regulates cortical circuit development and critical period plasticity. Molecular psychiatry.More infoNormal development of cortical circuits, including experience-dependent cortical maturation and plasticity, requires precise temporal regulation of gene expression and molecular signaling. Such regulation, and the concomitant impact on plasticity and critical periods, is hypothesized to be disrupted in neurodevelopmental disorders. A protein that may serve such a function is the MET receptor tyrosine kinase, which is tightly regulated developmentally in rodents and primates, and exhibits reduced cortical expression in autism spectrum disorder and Rett Syndrome. We found that the peak of MET expression in developing mouse cortex coincides with the heightened period of synaptogenesis, but is precipitously downregulated prior to extensive synapse pruning and certain peak periods of cortical plasticity. These results reflect a potential on-off regulatory synaptic mechanism for specific glutamatergic cortical circuits in which MET is enriched. In order to address the functional significance of the 'off' component of the proposed mechanism, we created a controllable transgenic mouse line that sustains cortical MET signaling. Continued MET expression in cortical excitatory neurons disrupted synaptic protein profiles, altered neuronal morphology, and impaired visual cortex circuit maturation and connectivity. Remarkably, sustained MET signaling eliminates monocular deprivation-induced ocular dominance plasticity during the normal cortical critical period; while ablating MET signaling leads to early closure of critical period plasticity. The results demonstrate a novel mechanism in which temporal regulation of a pleiotropic signaling protein underlies cortical circuit maturation and timing of cortical critical period, features that may be disrupted in neurodevelopmental disorders.
- Ashina, H., Porreca, F., Anderson, T., Amin, F. M., Ashina, M., Schytz, H. W., & Dodick, D. W. (2019). Post-traumatic headache: epidemiology and pathophysiological insights. Nature reviews. Neurology, 15(10), 607-617.More infoPost-traumatic headache (PTH) is a highly disabling secondary headache disorder and one of the most common sequelae of mild traumatic brain injury, also known as concussion. Considerable overlap exists between PTH and common primary headache disorders. The most common PTH phenotypes are migraine-like headache and tension-type-like headache. A better understanding of the pathophysiological similarities and differences between primary headache disorders and PTH could uncover unique treatment targets for PTH. Although possible underlying mechanisms of PTH have been elucidated, a substantial void remains in our understanding, and further research is needed. In this Review, we describe the evidence from animal and human studies that indicates involvement of several potential mechanisms in the development and persistence of PTH. These mechanisms include impaired descending modulation, neurometabolic changes, neuroinflammation and activation of the trigeminal sensory system. Furthermore, we outline future research directions to establish biomarkers involved in progression from acute to persistent PTH, and we identify potential drug targets to prevent and treat persistent PTH.
- Navratilova, E., Rau, J., Oyarzo, J., Tien, J., Mackenzie, K., Stratton, J., Remeniuk, B., Schwedt, T., Anderson, T., Dodick, D., & Porreca, F. (2019). CGRP-dependent and independent mechanisms of acute and persistent post-traumatic headache following mild traumatic brain injury in mice. Cephalalgia : an international journal of headache, 39(14), 1762-1775.More infoAcute and persistent post-traumatic headache are often debilitating consequences of traumatic brain injury. Underlying physiological mechanisms of post-traumatic headache and its persistence remain unknown, and there are currently no approved therapies for these conditions. Post-traumatic headache often presents with a migraine-like phenotype. As calcitonin-gene related peptide promotes migraine headache, we explored the efficacy and timing of intervention with an anti- calcitonin-gene related peptide monoclonal antibody in novel preclinical models of acute post-traumatic headache and persistent post-traumatic headache following a mild traumatic brain injury event in mice.
- Nichols, J., Perez, R., Wu, C., Adelson, P. D., & Anderson, T. (2015). Traumatic brain injury induces rapid enhancement of cortical excitability in juvenile rats. CNS neuroscience & therapeutics, 21(2), 193-203.More infoFollowing a traumatic brain injury (TBI), 5-50% of patients will develop posttraumatic epilepsy (PTE) with children being particularly susceptible. Currently, PTE cannot be prevented and there is limited understanding of the underlying epileptogenic mechanisms. We hypothesize that early after TBI the brain undergoes distinct cellular and synaptic reorganization that facilitates cortical excitability and promotes the development of epilepsy.