Does time heal all wounds? Experimental diffuse traumatic brain injury results in persisting histopathology in the thalamus

HighlightsExperimental diffuse TBI causes thalamic neuron pathology and astrocyte activation that persists up to 1 month.Onset of neuron pathology and glial activation occurs with dynamic changes in neuron morphology.Histopathological changes in the presence of preserved cytoarchitecture support circuit reorganization.Histopathological changes coincide with previously published changes in circuit function and behavior.TBI‐induced persisting histopathology indicates prolonged reparative processes rather than rapid recovery. Background: Thalamic dysfunction has been implicated in overall chronic neurological dysfunction after traumatic brain injury (TBI), however little is known about the underlying histopathology. In experimental diffuse TBI (dTBI), we hypothesize that persisting histopathological changes in the ventral posteromedial (VPM) nucleus of the thalamus is indicative of progressive circuit reorganization. Since circuit reorganization in the VPM impacts the whisker sensory system, the histopathology could explain the development of hypersensitivity to whisker stimulation by 28 days post‐injury; similar to light and sound hypersensitivity in human TBI survivors. Methods: Adult, male Sprague‐Dawley rats underwent craniotomy and midline fluid percussion injury (FPI) (moderate severity; 1.8–2.0 atm) or sham surgery. At 1d, 7d, and 28 days post‐FPI (d FPI) separate experiments confirmed the cytoarchitecture (Giemsa stain) and evaluated neuropathology (silver stain), activated astrocytes (GFAP), neuron morphology (Golgi stain) and microglial morphology (Iba‐1) in the VPM. Results: Cytoarchitecture was unchanged throughout the time course, similar to previously published data; however, neuropathology and astrocyte activation were significantly increased at 7d and 28d and activated microglia were present at all time points. Neuron morphology was dynamic over the time course with decreased dendritic complexity (fewer branch points; decreased length of processes) at 7d FPI and return to sham values by 28d FPI. Conclusions: These data indicate that dTBI results in persisting thalamic histopathology out to a chronic time point. While these changes can be indicative of either adaptive (recovery) or maladaptive (neurological dysfunction) circuit reorganization, they also provide a potential mechanism by which maladaptive circuit reorganization could contribute to the development of chronic neurological dysfunction. Understanding the processes that mediate circuit reorganization is critical to the development of future therapies for TBI patients.

[1]  J. Povlishock,et al.  Axonal response to traumatic brain injury: reactive axonal change, deafferentation, and neuroplasticity. , 1992, Journal of neurotrauma.

[2]  S. Carmichael.  Cellular and molecular mechanisms of neural repair after stroke: Making waves , 2006, Annals of neurology.

[3]  J. Lifshitz,et al.  Comparison of rat sensory behavioral tasks to detect somatosensory morbidity after diffuse brain-injury , 2012, Behavioural Brain Research.

[4]  G. Gerhardt,et al.  Hypersensitive glutamate signaling correlates with the development of late-onset behavioral morbidity in diffuse brain-injured circuitry. , 2012, Journal of neurotrauma.

[5]  M. Nirenberg,et al.  Neuron atrophy during aging: programmed or sporadic? , 1993 .

[6]  Tao Luo,et al.  Spinal Cord Injury Causes Brain Inflammation Associated with Cognitive and Affective Changes: Role of Cell Cycle Pathways , 2014, The Journal of Neuroscience.

[7]  Michael J. Duggan,et al.  Pharmacologic modulation of cerebral metabolic derangement and excitotoxicity in a porcine model of traumatic brain injury and hemorrhagic shock. , 2013, Surgery.

[8]  C. Hulsebosch,et al.  Traumatic brain injury in rats results in increased expression of Gap-43 that correlates with behavioral recovery , 1998, Neuroscience Letters.

[9]  S. Ding,et al.  Reactive astrocytes and therapeutic potential in focal ischemic stroke , 2016, Neurobiology of Disease.

[10]  Roland Bammer,et al.  Mild Traumatic Brain Injury: Is Diffusion Imaging Ready for Primetime in Forensic Medicine? , 2010, Topics in magnetic resonance imaging : TMRI.

[11]  R. Switzer.  Application of Silver Degeneration Stains for Neurotoxicity Testing , 2000, Toxicologic pathology.

[12]  Jun Chen,et al.  Animal Models of Acute Neurological Injuries , 2009, Humana Press.

[13]  Xiaoming Jin,et al.  Enhanced Excitatory Synaptic Connectivity in Layer V Pyramidal Neurons of Chronically Injured Epileptogenic Neocortex in Rats , 2006, The Journal of Neuroscience.

[14]  D. Broshek,et al.  A review of post-concussion syndrome and psychological factors associated with concussion , 2015, Brain injury.

[15]  N. J. Allen.  Role of glia in developmental synapse formation , 2013, Current Opinion in Neurobiology.

[16]  Daniel K Sodickson,et al.  Thalamic resting-state functional networks: disruption in patients with mild traumatic brain injury. , 2011, Radiology.

[17]  S. D. Moore,et al.  Adolescent Intermittent Alcohol Exposure: Dysregulation of Thrombospondins and Synapse Formation are Associated with Decreased Neuronal Density in the Adult Hippocampus. , 2015, Alcoholism, clinical and experimental research.

[18]  Xiaoming Jin,et al.  Reorganization of inhibitory synaptic circuits in rodent chronically injured epileptogenic neocortex. , 2011, Cerebral cortex.

[19]  P. Gorelick,et al.  Thalamic integrity underlies executive dysfunction in traumatic brain injury , 2010, Neurology.

[20]  D. Prince,et al.  Gabapentin decreases epileptiform discharges in a chronic model of neocortical trauma , 2012, Neurobiology of Disease.

[21]  J. Povlishock,et al.  Characterization of a prolonged regenerative attempt by diffusely injured axons following traumatic brain injury in adult cat: a light and electron microscopic immunocytochemical study , 1997, Acta Neuropathologica.

[22]  R. Kikinis,et al.  A review of magnetic resonance imaging and diffusion tensor imaging findings in mild traumatic brain injury , 2012, Brain Imaging and Behavior.

[23]  A. Taylor-Weiner,et al.  Gabapentin attenuates hyperexcitability in the freeze-lesion model of developmental cortical malformation , 2014, Neurobiology of Disease.

[24]  D. Katz,et al.  Update of Neuropathology and Neurological Recovery After Traumatic Brain Injury , 2005, The Journal of head trauma rehabilitation.

[25]  Y. Ao,et al.  Heterogeneity of reactive astrocytes , 2014, Neuroscience Letters.

[26]  David H Rowitch,et al.  Astrocytes and disease: a neurodevelopmental perspective. , 2012, Genes & development.

[27]  C. Imms,et al.  Sensory processing abilities of children who have sustained traumatic brain injuries. , 2009, The American journal of occupational therapy : official publication of the American Occupational Therapy Association.

[28]  T. Woolsey,et al.  The structural organization of layer IV in the somatosensory region (S I) of mouse cerebral cortex , 1970 .

[29]  B. Kelley,et al.  Biochemical, Structural, and Biomarker Evidence for Calpain-Mediated Cytoskeletal Change After Diffuse Brain Injury Uncomplicated by Contusion , 2009, Journal of neuropathology and experimental neurology.

[30]  S. Thompson,et al.  Maladaptive Homeostatic Plasticity in a Rodent Model of Central Pain Syndrome: Thalamic Hyperexcitability after Spinothalamic Tract Lesions , 2008, The Journal of Neuroscience.

[31]  H. Killackey,et al.  Thalamic processing of vibrissal information in the rat: II. Morphological and functional properties of medial ventral posterior nucleus and posterior nucleus neurons , 1991, The Journal of comparative neurology.

[32]  J. Lifshitz,et al.  Brain injury forces of moderate magnitude elicit the fencing response. , 2009, Medicine and science in sports and exercise.

[33]  B. Kelley,et al.  Traumatic axonal injury in the perisomatic domain triggers ultrarapid secondary axotomy and Wallerian degeneration , 2006, Experimental Neurology.

[34]  E. Bigler,et al.  Lesion volume, injury severity, and thalamic integrity following head injury. , 1996, Journal of neurotrauma.

[35]  J. Lifshitz,et al.  Morphological and genetic activation of microglia after diffuse traumatic brain injury in the rat , 2012, Neuroscience.

[36]  J. Stehberg,et al.  Role of astrocytes in memory and psychiatric disorders , 2014, Journal of Physiology-Paris.

[37]  Toru Nakamura,et al.  Resting Network Plasticity Following Brain Injury , 2009, PloS one.

[38]  J. Lifshitz,et al.  Diffuse traumatic brain injury initially attenuates and later expands activation of the rat somatosensory whisker circuit concomitant with neuroplastic responses , 2010, Brain Research.

[39]  J. Lifshitz,et al.  Rod Microglia: A Morphological Definition , 2014, PloS one.

[40]  T. Mcintosh,et al.  Clinical relevance of midline fluid percussion brain injury: Acute deficits, chronic morbidities and the utility of biomarkers , 2016, Brain injury.

[41]  Milos Pekny,et al.  The dual role of astrocyte activation and reactive gliosis , 2014, Neuroscience Letters.

[42]  B. Barres.  The Mystery and Magic of Glia: A Perspective on Their Roles in Health and Disease , 2008, Neuron.

[43]  P. Adelson,et al.  Plastic reorganization of hippocampal and neocortical circuitry in experimental traumatic brain injury in the immature rat. , 2005, Journal of neurotrauma.

[44]  N. Bohnen,et al.  Neuropsychological deficits in patients with persistent symptoms six months after mild head injury. , 1992, Neurosurgery.

[45]  S. K. Malhotra,et al.  Reactive astrocytes: cellular and molecular cues to biological function , 1997, Trends in Neurosciences.

[46]  Tolerance for light and sound of patients with persistent post-concussional symptoms 6 months after mild head injury , 2004, Journal of Neurology.

[47]  H. Taylor,et al.  Dimensions of postconcussive symptoms in children with mild traumatic brain injuries , 2009, Journal of the International Neuropsychological Society.

[48]  E. Ullian,et al.  Astrocytes and Synaptic Plasticity , 2010, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[49]  J. Dreier.  The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease , 2011, Nature Medicine.

[50]  L. Heimer,et al.  Silver staining as a tool for neurotoxic assessment. , 1993, NIDA research monograph.

[51]  P. Adelson,et al.  Microglia: dismantling and rebuilding circuits after acute neurological injury , 2014, Metabolic Brain Disease.

[52]  Stephen J. Smith,et al.  Gabapentin Receptor α2δ-1 Is a Neuronal Thrombospondin Receptor Responsible for Excitatory CNS Synaptogenesis , 2009, Cell.

[53]  M. Jacquin,et al.  What Makes Subcortical Barrels , 1995 .

[54]  S A Deadwyler,et al.  Neuronal Hypertrophy in the Neocortex of Patients with Temporal Lobe Epilepsy , 2001, The Journal of Neuroscience.

[55]  W. Fellows-Mayle,et al.  Traumatic brain injury alters long-term hippocampal neuron morphology in juvenile, but not immature, rats , 2014, Child's Nervous System.

[56]  B. Kelley,et al.  Perisomatic Thalamic Axotomy After Diffuse Traumatic Brain Injury Is Associated With Atrophy Rather Than Cell Death , 2007, Journal of neuropathology and experimental neurology.

[57]  Frank W Pfrieger,et al.  New roles for astrocytes: Regulation of CNS synaptogenesis , 2003, Trends in Neurosciences.

[58]  J. Povlishock,et al.  Neurobiology of Disease Identification and Characterization of Heterogeneous Neuronal Injury and Death in Regions of Diffuse Brain Injury: Evidence for Multiple Independent , 2022 .

[59]  K A Dunn,et al.  Traumatic brain injury in the United States: A public health perspective. , 1999, The Journal of head trauma rehabilitation.

[60]  B. Volk,et al.  AIDS does not alter the total number of neurons in the hippocampal formation but induces cell atrophy: a stereological study , 2000, Acta Neuropathologica.

[61]  J. Lifshitz,et al.  The whisker nuisance task identifies a late-onset, persistent sensory sensitivity in diffuse brain-injured rats. , 2010, Journal of neurotrauma.

[62]  Martini,et al.  Role of , 1995, Physical review. B, Condensed matter.

[63]  A. Zonderman,et al.  Neuronal Hypertrophy in Asymptomatic Alzheimer Disease , 2008, Journal of neuropathology and experimental neurology.

[64]  S. Buffer,et al.  Barreloids in adult rat thalamus: Three‐dimensional architecture and relationship to somatosensory cortical barrels , 1995, The Journal of comparative neurology.

[65]  Andrew J. Saykin,et al.  Differential Working Memory Load Effects after Mild Traumatic Brain Injury , 2001, NeuroImage.

[66]  J. Lifshitz,et al.  Rod microglia: elongation, alignment, and coupling to form trains across the somatosensory cortex after experimental diffuse brain injury , 2012, Journal of Neuroinflammation.

[67]  Pooja M. Talauliker,et al.  Neuropathology in sensory, but not motor, brainstem nuclei of the rat whisker circuit after diffuse brain injury , 2014, Somatosensory & motor research.

[68]  P. Adelson,et al.  Diffuse traumatic brain injury affects chronic corticosterone function in the rat , 2016, Endocrine connections.

[69]  B. Barres,et al.  Role for glia in synaptogenesis , 2004, Glia.

[70]  M. Ortiz,et al.  Biomechanics of traumatic brain injury , 2008 .

[71]  D. Loane,et al.  Role of microglia in neurotrauma , 2010, Neurotherapeutics.

[72]  M. Sofroniew.  Molecular dissection of reactive astrogliosis and glial scar formation , 2009, Trends in Neurosciences.

[73]  W. Alves,et al.  Postconcussive symptoms after uncomplicated mild head injury , 1993 .

[74]  Maiken Nedergaard,et al.  Astroglial cradle in the life of the synapse , 2014, Philosophical Transactions of the Royal Society B: Biological Sciences.

[75]  Orsolya Farkas,et al.  Cellular and subcellular change evoked by diffuse traumatic brain injury: a complex web of change extending far beyond focal damage. , 2007, Progress in brain research.

[76]  Neurodegeneration in the somatosensory cortex after experimental diffuse brain injury , 2011, Brain Structure and Function.

[77]  Li-Shan Chou,et al.  An assessment of gait and balance deficits after traumatic brain injury. , 2003, Archives of physical medicine and rehabilitation.

[78]  G. Gerhardt,et al.  Substantia nigra vulnerability after a single moderate diffuse brain injury in the rat , 2012, Experimental Neurology.

[79]  D. Türck,et al.  Disposition of gabapentin (neurontin) in mice, rats, dogs, and monkeys. , 1995, Drug metabolism and disposition: the biological fate of chemicals.

[80]  Martin G Pomper,et al.  Isolated spinal cord contusion in rats induces chronic brain neuroinflammation, neurodegeneration, and cognitive impairment , 2014, Cell cycle.

[81]  J. Langlois,et al.  The Epidemiology and Impact of Traumatic Brain Injury: A Brief Overview , 2006, The Journal of head trauma rehabilitation.

[82]  Yulin Ge,et al.  Thalamus and cognitive impairment in mild traumatic brain injury: a diffusional kurtosis imaging study. , 2012, Journal of neurotrauma.

[83]  J. de Olmos,et al.  Use of an amino-cupric-silver technique for the detection of early and semiacute neuronal degeneration caused by neurotoxicants, hypoxia, and physical trauma. , 1994, Neurotoxicology and teratology.

[84]  Per-Olof Bergemalm,et al.  Appearances are deceptive? long-term cognitive and central auditory sequelae from closed head injury ¿Las apariencias engañan? Secuelas cognitivas y auditivas centrales a largo plazo después de un traumatismo cráneo-encefálico cerrado , 2005, International journal of audiology.

[85]  Kevin W Eliceiri,et al.  NIH Image to ImageJ: 25 years of image analysis , 2012, Nature Methods.

[86]  Giuseppe Biagini,et al.  The pilocarpine model of temporal lobe epilepsy , 2008, Journal of Neuroscience Methods.

[87]  D C Good,et al.  Changes in resting connectivity during recovery from severe traumatic brain injury. , 2011, International journal of psychophysiology : official journal of the International Organization of Psychophysiology.

[88]  A. Hoffman,et al.  Early and Persistent Dendritic Hypertrophy in the Basolateral Amygdala following Experimental Diffuse Traumatic Brain Injury. , 2017, Journal of neurotrauma.

[89]  E. Liemburg,et al.  Post-concussive complaints after mild traumatic brain injury associated with altered brain networks during working memory performance , 2015, Brain Imaging and Behavior.

[90]  M. Shenton,et al.  Use of Anisotropy, 3D Segmented Atlas, and Computational Analysis to Identify Gray Matter Subcortical Lesions Common to Concussive Injury from Different Sites on the Cortex , 2015, PloS one.

[91]  K. Ragnarsson.  Results of the NIH consensus conference on "rehabilitation of persons with traumatic brain injury". , 2002, Restorative neurology and neuroscience.

[92]  K. Ciuffreda,et al.  Critical flicker frequency and related symptoms in mild traumatic brain injury , 2007, Brain injury.

[93]  Recovery from visual and acoustic hyperaesthesia after mild head injury in relation to patterns of behavioural dysfunction. , 1992, Journal of neurology, neurosurgery, and psychiatry.

[94]  B M Bly,et al.  Functional magnetic resonance imaging of working memory impairment after traumatic brain injury , 2001, Journal of neurology, neurosurgery, and psychiatry.

[95]  M. Nilsson,et al.  Astrocyte activation and reactive gliosis , 2005, Glia.

[96]  S. Wisniewski,et al.  Increased adrenomedullin in cerebrospinal fluid after traumatic brain injury in infants and children. , 2001, Journal of neurotrauma.

[97]  A. Faden,et al.  Cell cycle inhibition limits development and maintenance of neuropathic pain following spinal cord injury , 2016, Pain.

[98]  T. Woolsey,et al.  The structural organization of layer IV in the somatosensory region (SI) of mouse cerebral cortex. The description of a cortical field composed of discrete cytoarchitectonic units. , 1970, Brain research.

[99]  Cell Cycle Activation Contributes to Increased Neuronal Activity in the Posterior Thalamic Nucleus and Associated Chronic Hyperesthesia after Rat Spinal Cord Contusion , 2013, Neurotherapeutics.

[100]  Heidi K. Blume,et al.  Subacute concussion-related symptoms and postconcussion syndrome in pediatrics , 2012, Current opinion in pediatrics.

[101]  A R McIntosh,et al.  Functional reorganisation of memory after traumatic brain injury: a study with H2150 positron emission tomography , 2002, Journal of neurology, neurosurgery, and psychiatry.

[102]  S. Naddaf,et al.  SPECT brain perfusion abnormalities in mild or moderate traumatic brain injury. , 1998, Clinical nuclear medicine.

[103]  M. Mattson,et al.  Glutamate and Neurotrophic Factors in Neuronal Plasticity and Disease , 2008, Annals of the New York Academy of Sciences.

[104]  J. Thomson.  Epidemiology of Postconcussion Syndrome in Pediatric Mild Traumatic Brain Injury , 2011 .