Trent R Anderson

Interests

Research

Migraine, Epilepy, Traumatic Brain Injury, Electrophsyiology, Optogenetics, Imaging, Cancer; Neuro-degenerative, developmental and psychiatric disease; Developmental, cell and molecular biology; Signaling and steroid biology

Teaching

Anatomy, Neuroscience, Neuroanatomy, Neurophysiology, Neuroanatomy

Courses

Scholarly Contributions

Journals/Publications

• Blackman, J. B., Krauss, R., Quiñones, S., Tirja, P., Sommer, M. E., Muñoz-Ballester, C., Noubary, F., Armbruster, M., Robel, S., Anderson, T., & Dulla, C. G. (2025). Evidence for the Transient Presence of Atypical Astrocytes in Mice Following a Single, Closed-Head Mild Traumatic Brain Injury. bioRxiv : the preprint server for biology.
  More info

  Mild traumatic brain injury (mTBI) affects roughly 42 million people each year, causes a variety of physical, behavioral, and cognitive symptoms, and increases the risk for developing neurological disorders, including post-traumatic headache (PTH) and Alzheimer's disease (AD). Multiple molecular and cellular changes occur following mTBI; here we focus on astrocytes - cells that respond to brain injury and are critical to maintaining neuronal and circuit homeostasis. While some astrocytes become reactive after mTBI, others adopt an 'atypical' state characterized by the loss of multiple functional astrocyte proteins, including glutamate transporters (GLT-1, GLAST) and ion channels (Kir4.1), without upregulation of prototypical reactive astrocyte markers (glial fibrillary acidic protein [GFAP]). Previous studies have shown that repeated mTBI causes atypical astrocytes (AtAs) that can persist for months, but we know much less about whether a single mTBI causes similar astrocyte phenotypes. To address this, we employed a closed-head mild traumatic brain injury (chmTBI) model in male and female mice and quantified the abundance of AtAs both acutely (3-days) and chronically (1-month) after a single injury. We found that 3-days after chmTBI, AtAs were present in areas subject to blunt force trauma (BFT), consistent with previous reports, as well as in other brain regions presumably affected by diffuse injury. One month after chmTBI, however, the proportion of AtAs was similar between chmTBI and sham injured mice, thereby suggesting AtAs do not persist long term in this model. Consistent with previous studies, this chmTBI model did not induce significant GFAP-positive reactive astrocytes as assayed using immunohistochemistry, at either timepoint. Overall, we show an increase in AtAs 3-days after a single chmTBI that returns to sham levels when examined 1-month after injury. This suggests that after a single mTBI, AtAs are present but do not persist long term, unlike in repeated mTBI where AtAs persist for months after injury.
• Cui, Y., Ma, X., Wei, J., Chen, C., Shakir, N., Guirram, H., Dai, Z., Anderson, T., Ferguson, D., & Qiu, S. (2025). MET receptor tyrosine kinase promotes the generation of functional synapses in adult cortical circuits. Neural regeneration research, 20(5), 1431-1444.
  More info

  JOURNAL/nrgr/04.03/01300535-202505000-00026/figure1/v/2024-07-28T173839Z/r/image-tiff Loss of synapse and functional connectivity in brain circuits is associated with aging and neurodegeneration, however, few molecular mechanisms are known to intrinsically promote synaptogenesis or enhance synapse function. We have previously shown that MET receptor tyrosine kinase in the developing cortical circuits promotes dendritic growth and dendritic spine morphogenesis. To investigate whether enhancing MET in adult cortex has synapse regenerating potential, we created a knockin mouse line, in which the human MET gene expression and signaling can be turned on in adult (10-12 months) cortical neurons through doxycycline-containing chow. We found that similar to the developing brain, turning on MET signaling in the adult cortex activates small GTPases and increases spine density in prefrontal projection neurons. These findings are further corroborated by increased synaptic activity and transient generation of immature silent synapses. Prolonged MET signaling resulted in an increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-D-aspartate (AMPA/NMDA) receptor current ratio, indicative of enhanced synaptic function and connectivity. Our data reveal that enhancing MET signaling could be an interventional approach to promote synaptogenesis and preserve functional connectivity in the adult brain. These findings may have implications for regenerative therapy in aging and neurodegeneration conditions.
• Ku, D., Mao, L., Nikolova, S., Dumkrieger, G. M., Ross, K. B., Huentelman, M., Anderson, T., Porreca, F., Navratilova, E., Starling, A., Wu, T., Li, J., Chong, C. D., & Schwedt, T. J. (2025). Longitudinal analysis of pain-induced brain activations in post-traumatic headache. Cephalalgia : an international journal of headache, 45(5), 3331024251345160.
  More info

  BackgroundHeadache is a common symptom following mild traumatic brain injury (mTBI). Post-traumatic headache (PTH), a secondary headache disorder that develops after mTBI, often persists for months or years. To identify potential recovery mechanisms and prognostic biomarkers, the present study investigated whether longitudinal changes in pain-induced brain activation differ between healthy controls (HC) and PTH participants showing headache improvement and those without improvement.MethodsThirty-three participants who met International Classification of Headache Disorders, 3rd edition, criteria for acute PTH within 59 days post-mTBI and 33 HC participants were included with no significant differences in demographics. All participants underwent functional magnetic resonance imaging scans at baseline, four weeks, and 16 weeks post-enrollment using a thermal stimulation paradigm with noxious and non-painful heat stimuli. 'Painful vs. Non-Painful Heat' contrasts were generated using SPM12. PTH improvement was assessed at three months post-enrollment via electronic headache diaries. Two-sample -tests compared the brain activation between HC and PTH at baseline. Linear mixed-effects models examined longitudinal changes for HC, PTH improvement and non-improvement groups across visits. Generalized linear models compared these groups within visits.ResultsBaseline analysis revealed several regions with significantly higher activation in acute PTH compared to HC, including bilateral postcentral gyrus, right superior temporal gyrus, right middle temporal gyrus, left inferior parietal gyrus, right superior parietal gyrus, left ventral striatum, left olfactory cortex, left gyrus rectus, and left middle occipital gyrus. Over time, the PTH improvement group demonstrated progressive normalization across all identified brain regions, whereas the non-improvement group showed only partial normalization in left ventral striatum, left olfactory cortex, and left gyrus rectus. Sustained elevated activation in specific regions distinguished PTH participants without headache improvement from those with headache improvement, suggesting potential biomarkers for persistent PTH.ConclusionsOur findings demonstrate significantly altered pain-induced brain activations in participants with acute PTH compared to HC. Longitudinal analysis revealed distinct recovery trajectories: progressive normalization in the improvement group versus persistent alterations in the non-improvement group. These neuroimaging patterns may serve as biomarkers for identifying individuals at risk for persistent PTH, with implications for early intervention and personalized treatment approaches.
• Liktor-Busa, E., Levine, A. A., Young, S. J., Bader, C., Palomino, S. M., Polk, F. D., Couture, S. A., Pires, P. W., Anderson, T., & Largent-Milnes, T. M. (2025). Inhibition of diacylglycerol lipase α induced blood-brain barrier breach in female Sprague-Dawley rats. The Journal of physiology.
  More info

  The endocannabinoid system's significance in maintaining blood-brain barrier (BBB) integrity under physiological and pathological conditions is suggested by several reports, but the underlying molecular mechanisms are not well understood. In this paper, we investigated the effects of depletion of 2-arachidonoylglycerol (2-AG), one of the main endocannabinoids in the central nervous system, on BBB integrity using pharmacological tools. Female Sprague-Dawley rats were injected with the diacylglycerol lipase α (DAGLα) inhibitor LEI-106 (40 mg/kg, i.p.), followed by assessment of BBB integrity via in situ brain perfusion. Liquid chromatography-mass spectrometry, western immunoblotting, light transmittance experiments and pressure myography were also used to further examine the results of DAGLα blockade on the BBB and vascular reactivity. We found that DAGLα inhibition caused BBB opening in cortical brain areas, manifesting as increased sucrose transport measured by in situ brain perfusion. This was accompanied by reduced levels of 2-AG and decreased detection of the tight junction protein zonula occludens-1 (ZO-1). The protein level in cortical areas of neuronal PAS domain protein 4 (NPAS4), encoded by an activity-dependent immediate early gene, was increased without the presence of cortical spreading depression after LEI-106 administration. We also observed a significant increase in pressure-induced constriction within the parenchymal microcirculation after inhibition of DAGLα, possibly altering shear stress in the microcirculation. These results support the role of endogenous 2-AG in maintaining normal tight junction function. This improved understanding of the molecular mechanisms of endocannabinoid system function at the neurovascular unit can help to unlock the therapeutic potentials of cannabinoids in central nervous system disorders associated with BBB dysfunction. KEY POINTS: The administration of the diacylglycerol lipase α (DAGLα) inhibitor LEI-106 (40 mg/kg, i.p.) induced blood-brain barrier (BBB) opening of cortical brain areas in female Sprague-Dawley rats. This BBB disruption was accompanied by reduced levels of 2-arachidonoylglycerol (2-AG) and decreased detection of the tight junction protein zonula occludens-1 (ZO-1). The protein level in cortical areas of neuronal PAS domain protein 4 (NPAS4), encoded by an activity-dependent immediate early gene, was increased without the presence of cortical spreading depression after LEI-106 administration. A significant increase in pressure-induced constriction within the parenchymal microcirculation was also observed after inhibition of DAGLα, possibly altering shear stress. These results support the role of endogenous 2-AG in maintaining normal tight junction function.
• Vizin, R. C., Kopruszinski, C. M., Oyarzo, J. N., Dodick, D. W., Broide, R. S., Brideau-Andersen, A. D., Brin, M. F., Anderson, T., Navratilova, E., & Porreca, F. (2025). OnabotulinumtoxinA inhibits dysregulation of descending pain modulation following mild traumatic brain injury in mice. The journal of headache and pain, 26(1), 216.
  More info

  Diminished conditioned pain modulation, a measure of endogenous analgesia, has been reported in patients with persistent post-traumatic headache (PTH), suggesting that inefficient endogenous analgesic mechanisms may contribute to the pain. Injections of onabotulinumtoxinA into the specific regions of the head and neck have shown some benefits in treating post-traumatic headache. We investigated the potential effect of onabotulinumtoxinA on restoring the loss of descending control of nociception (DCN), a preclinical correlate of conditioned pain modulation in humans, induced by mild traumatic brain injury (mTBI) in male and female mice.
• Ziff, N., Dumkrieger, G., Garza, S., Starling, A., Esterov, D., Barrett, K. M., Ross, K., Anderson, T., Porreca, F., Navratilova, E., Nikolova, S., Li, J., Wu, T., Huentelman, M., Chong, C. D., & Schwedt, T. J. (2025). Symptoms of allodynia and pain thresholds amongst those with acute post-traumatic headache attributed to mild traumatic brain injury: a prospective, longitudinal study. The journal of headache and pain, 27(1), 3.
  More info

  Post-traumatic headache (PTH) is a common acute and persistent symptom following mild traumatic brain injury (mTBI). Symptoms of cutaneous allodynia and presence of nociceptive sensitization might be associated with acute PTH and its persistence. The objectives of this study were to compare allodynia symptoms and cutaneous heat pain thresholds amongst males and females with acute PTH to healthy controls (HC) and determine if pain thresholds and allodynia symptoms are associated with PTH outcomes.
• Knowles, S. J., Holter, M. C., Li, G., Bjorklund, G. R., Rees, K. P., Martinez-Fuentes, J. S., Nishimura, K. J., Afshari, A. E., Fry, N., Stafford, A. M., Vogt, D., Mangone, M., Anderson, T., & Newbern, J. M. (2023). Multifunctional requirements for ERK1/2 signaling in the development of ganglionic eminence derived glia and cortical inhibitory neurons. eLife. doi:10.7554/elife.88313
• Rudolph, M., Kopruszinski, C., Wu, C., Navratilova, E., Schwedt, T. J., Dodick, D. W., Porreca, F., & Anderson, T. (2023). Identification of brain areas in mice with peak neural activity across the acute and persistent phases of post-traumatic headache. Cephalalgia : an international journal of headache, 43(11), 3331024231217469.
  More info

  Post-traumatic headache is very common after a mild traumatic brain injury. Post-traumatic headache may persist for months to years after an injury in a substantial proportion of people. The pathophysiology underlying post-traumatic headache remains unknown but is likely distinct from other headache disorders. Identification of brain areas activated in acute and persistent phases of post-traumatic headache can provide insights into the underlying circuits mediating headache pain. We used an animal model of mild traumatic brain injury-induced post-traumatic headache and c-fos immunohistochemistry to identify brain regions with peak activity levels across the acute and persistent phases of post-traumatic headache.
• Bjorklund, G. R., Anderson, T. R., & Stabenfeldt, S. E. (2021). Recent Advances in Stem Cell Therapies to Address Neuroinflammation, Stem Cell Survival, and the Need for Rehabilitative Therapies to Treat Traumatic Brain Injuries. International journal of molecular sciences, 22(4).
  More info

  Traumatic brain injuries (TBIs) are a significant health problem both in the United States and worldwide with over 27 million cases being reported globally every year. TBIs can vary significantly from a mild TBI with short-term symptoms to a moderate or severe TBI that can result in long-term or life-long detrimental effects. In the case of a moderate to severe TBI, the primary injury causes immediate damage to structural tissue and cellular components. This may be followed by secondary injuries that can be the cause of chronic and debilitating neurodegenerative effects. At present, there are no standard treatments that effectively target the primary or secondary TBI injuries themselves. Current treatment strategies often focus on addressing post-injury symptoms, including the trauma itself as well as the development of cognitive, behavioral, and psychiatric impairment. Additional therapies such as pharmacological, stem cell, and rehabilitative have in some cases shown little to no improvement on their own, but when applied in combination have given encouraging results. In this review, we will abridge and discuss some of the most recent research advances in stem cell therapies, advanced engineered biomaterials used to support stem transplantation, and the role of rehabilitative therapies in TBI treatment. These research examples are intended to form a multi-tiered perspective for stem-cell therapies used to treat TBIs; stem cells and stem cell products to mitigate neuroinflammation and provide neuroprotective effects, biomaterials to support the survival, migration, and integration of transplanted stem cells, and finally rehabilitative therapies to support stem cell integration and compensatory and restorative plasticity.
• Kopruszinski, C. M., Turnes, J. M., Swiokla, J., Weinstein, T. J., Schwedt, T. J., Dodick, D. W., Anderson, T., Navratilova, E., & Porreca, F. (2021). CGRP monoclonal antibody prevents the loss of diffuse noxious inhibitory controls (DNIC) in a mouse model of post-traumatic headache. Cephalalgia : an international journal of headache, 333102420981688.
  More info

  Determine the role of calcitonin-gene related peptide in promoting post-traumatic headache and dysregulation of central pain modulation induced by mild traumatic brain injury in mice.
• Bharadwaj, V. N., Copeland, C., Mathew, E., Newbern, J., Anderson, T. R., Lifshitz, J., Kodibagkar, V. D., & Stabenfeldt, S. E. (2020). Sex-Dependent Macromolecule and Nanoparticle Delivery in Experimental Brain Injury. Tissue engineering. Part A, 26(13-14), 688-701.
  More info

  The development of effective therapeutics for brain disorders is challenging, in particular, the blood-brain barrier (BBB) severely limits access of the therapeutics into the brain parenchyma. Traumatic brain injury (TBI) may lead to transient BBB permeability that affords a unique opportunity for therapeutic delivery via intravenous administration ranging from macromolecules to nanoparticles (NPs) for developing precision therapeutics. In this regard, we address critical gaps in understanding the range/size of therapeutics, delivery window(s), and moreover, the potential impact of biological factors for optimal delivery parameters. Here we show, for the first time, to the best of our knowledge, that 24-h postfocal TBI female mice exhibit a heightened macromolecular tracer and NP accumulation compared with male mice, indicating sex-dependent differences in BBB permeability. Furthermore, we report for the first time the potential to deliver NP-based therapeutics within 3 days after focal injury in both female and male mice. The delineation of injury-induced BBB permeability with respect to sex and temporal profile is essential to more accurately tailor time-dependent precision and personalized nanotherapeutics. Impact statement In this study, we identified a sex-dependent temporal profile of blood/brain barrier disruption in a preclinical mouse model of traumatic brain injury (TBI) that contributes to starkly different macromolecule and nanoparticle delivery profiles post-TBI. The implications and potential impact of this work are profound and far reaching as it indicates that a demand of true personalized medicine for TBI is necessary to deliver the right therapeutic at the right time for the right patient.
• 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 info

  Normal 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.
• Holter, M. C., Hewitt, L. T., Nishimura, K. J., Knowles, S. J., Bjorklund, G. R., Shah, S., Fry, N. R., Rees, K. P., Gupta, T. A., Daniels, C. W., Li, G., Marsh, S., Treiman, D. M., Olive, M. F., Anderson, T. R., Sanabria, F., Snider, W. D., & Newbern, J. M. (2021). Hyperactive MEK1 Signaling in Cortical GABAergic Neurons Promotes Embryonic Parvalbumin Neuron Loss and Defects in Behavioral Inhibition. Cerebral cortex (New York, N.Y. : 1991).
  More info

  Many developmental syndromes have been linked to genetic mutations that cause abnormal ERK/MAPK activity; however, the neuropathological effects of hyperactive signaling are not fully understood. Here, we examined whether hyperactivation of MEK1 modifies the development of GABAergic cortical interneurons (CINs), a heterogeneous population of inhibitory neurons necessary for cortical function. We show that GABAergic-neuron specific MEK1 hyperactivation in vivo leads to increased cleaved caspase-3 labeling in a subpopulation of immature neurons in the embryonic subpallial mantle zone. Adult mutants displayed a significant loss of parvalbumin (PV), but not somatostatin, expressing CINs and a reduction in perisomatic inhibitory synapses on excitatory neurons. Surviving mutant PV-CINs maintained a typical fast-spiking phenotype but showed signs of decreased intrinsic excitability that coincided with an increased risk of seizure-like phenotypes. In contrast to other mouse models of PV-CIN loss, we discovered a robust increase in the accumulation of perineuronal nets, an extracellular structure thought to restrict plasticity. Indeed, we found that mutants exhibited a significant impairment in the acquisition of behavioral response inhibition capacity. Overall, our data suggest PV-CIN development is particularly sensitive to hyperactive MEK1 signaling, which may underlie certain neurological deficits frequently observed in ERK/MAPK-linked syndromes.
• 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 info

  Post-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 info

  Acute 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 info

  Following 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.