Acute Post-Traumatic Sleep May Define Vulnerability to a Second Traumatic Brain Injury in Mice

Rowe, Rachel K.; Harrison, Jordan L.; Morrison, Helena W.; Subbian, Vignesh; Murphy, Sean M.; Lifshitz, Jonathan

doi:10.1089/neu.2018.5980

Cited by 24 publications

(29 citation statements)

References 86 publications

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“…Our study does have some limitations, including the use of non-invasive piezoelectric cages, which limit the discrimination of sleep stages. However, measuring sleep following experimental models of TBI and genetic models of AD using piezoelectric sleep cages is well described in the literature and represents an appropriate, validated alternative to EEG recordings (Duncan et al, 2019(Duncan et al, , 2012Rowe, Harrison, Morrison, et al, 2019;Rowe et al, 2014;Saber et al, 2019). Another potential limitation was the use of only female mice, given the mounting evidence for sex-specific differences in sleep and inflammation following experimental TBI (Saber et al, 2019).…”

Section: F I G U R E 11mentioning

confidence: 99%

Experimental diffuse brain injury and a model of Alzheimer's disease exhibit disease‐specific changes in sleep and incongruous peripheral inflammation

Saber

Murphy

Cho

et al. 2020

J of Neuroscience Research

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Elderly populations (≥65 years old) have the highest risk of developing Alzheimer's disease (AD) and/or obtaining a traumatic brain injury (TBI). Using translational mouse models, we investigated sleep disturbances and inflammation associated with normal aging, TBI and aging, and AD. We hypothesized that aging results in marked changes in sleep compared with adult mice, and that TBI and aging would result in sleep and inflammation levels similar to AD mice. We used female 16-month-old wild-type (WT Aged) and 3xTg-AD mice, as well as a 2-month-old reference group (WT Adult), to evaluate sleep changes. WT Aged mice received diffuse TBI by midline fluid percussion, and blood was collected from both WT Aged (pre-and post-TBI) and 3xTg-AD mice to evaluate inflammation. Cognitive behavior was tested, and tissue was collected for histology. Bayesian generalized additive and mixed-effects models were used for analyses. Both normal aging and AD led to increases in sleep compared with adult mice. WT Aged mice with TBI slept substantially more, with fragmented shorter bouts, than they did pre-TBI and compared with AD mice. However, differences between WT Aged and 3xTg-AD mice in immune cell populations and plasma cytokine levels were incongruous, cognitive deficits were similar, and cumulative sleep was not predictive of inflammation or behavior for either group. Our results suggest that in similarly aged individuals, TBI immediately induces more profound sleep alterations than in AD, although both diseases likely include cognitive impairments. Unique pathological sleep pathways may exist in elderly individuals who incur TBI compared with similarly aged individuals who have AD, which may warrant disease-specific treatments in clinical settings.

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Section: F I G U R E 11mentioning

confidence: 99%

Experimental diffuse brain injury and a model of Alzheimer's disease exhibit disease‐specific changes in sleep and incongruous peripheral inflammation

Saber

Murphy

Cho

et al. 2020

J of Neuroscience Research

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“…Injury-induced alterations in sleep are also seen in experimental models of TBI. Midline FPI increases overall sleep during the first 6 h after injury compared to sham controls (150). This increased sleep need defines a period of vulnerability to a second TBI as mice injured again with midline FPI during this period at 3 h post-injury have increased motor deficits, neurological severity scores, anxiety-like behaviors, and neuropathology compared to mice given a second injury at 9 h post-injury.…”

Section: Experimental Stress Models Provide Insight To the Relationshmentioning

confidence: 99%

A Tilted Axis: Maladaptive Inflammation and HPA Axis Dysfunction Contribute to Consequences of TBI

2019

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Each year approximately 1.7 million people sustain a traumatic brain injury (TBI) in the US alone. Associated with these head injuries is a high prevalence of neuropsychiatric symptoms including irritability, depression, and anxiety. Neuroinflammation, due in part to microglia, can worsen or even cause neuropsychiatric disorders after TBI. For example, mounting evidence demonstrates that microglia become “primed” or hyper-reactive with an exaggerated pro-inflammatory phenotype following multiple immune challenges. Microglial priming occurs after experimental TBI and correlates with the emergence of depressive-like behavior as well as cognitive dysfunction. Critically, immune challenges are various and include illness, aging, and stress. The collective influence of any combination of these immune challenges shapes the neuroimmune environment and the response to TBI. For example, stress reliably induces inflammation and could therefore be a gateway to altered neuropathology and behavioral decline following TBI. Given the increasing incidence of stress-related psychiatric disorders after TBI, the degree in which stress affects outcome is of particular interest. This review aims to highlight the role of the hypothalamic-pituitary-adrenal (HPA) axis as a key mediator of stress-immune pathway communication following TBI. We will first describe maladaptive neuroinflammation after TBI and how stress contributes to inflammation through both anti- and pro-inflammatory mechanisms. Clinical and experimental data describing HPA-axis dysfunction and consequences of altered stress responses after TBI will be discussed. Lastly, we will review common stress models used after TBI that could better elucidate the relationship between HPA axis dysfunction and maladaptive inflammation following TBI. Together, the studies described in this review suggest that HPA axis dysfunction after brain injury is prevalent and contributes to the dynamic nature of the neuroinflammatory response to brain injury. Experimental stressors that directly engage the HPA axis represent important areas for future research to better define the role of stress-immune pathways in mediating outcome following TBI.

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“…The time course of events in the BLA are different in comparison to the VPM, where dendritic loss peaks and 7 DPI and significantly increases by 28 DPI, coinciding with increased neuropathology (silver stain), glial activation, evoked-glutamate release, and the manifestation of hypersensitivity to whisker stimulation (McNamara et al, 2010;Thomas et al, 2012Thomas et al, , 2018. The same archival histology for neuropathology and microglia has also been published for the somatosensory barrel fields of the whisker circuit (Lisembee and Lifshitz, 2008;Cao et al, 2012;Morrison et al, 2017) and replicated in mouse mFPI (Rowe et al, 2019). Together, these data indicate that TBI-induced circuit pathophysiology is dependent on time, region, and likely, circuit connectivity.…”

Section: Discussionmentioning

confidence: 83%

Experimental Traumatic Brain Injury Induces Chronic Glutamatergic Dysfunction in Amygdala Circuitry Known to Regulate Anxiety-Like Behavior

et al. 2020

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Up to 50% of traumatic brain injury (TBI) survivors demonstrate persisting and late-onset anxiety disorders indicative of limbic system dysregulation, yet the pathophysiology underlying the symptoms is unclear. We hypothesize that the development of TBIinduced anxiety-like behavior in an experimental model of TBI is mediated by changes in glutamate neurotransmission within the amygdala. Adult, male Sprague-Dawley rats underwent midline fluid percussion injury or sham surgery. Anxiety-like behavior was assessed at 7 and 28 days post-injury (DPI) followed by assessment of real-time glutamate neurotransmission in the basolateral amygdala (BLA) and central nucleus of the amygdala (CeA) using glutamate-selective microelectrode arrays. The expression of anxiety-like behavior at 28 DPI coincided with decreased evoked glutamate release and slower glutamate clearance in the CeA, not BLA. Numerous factors contribute to the changes in glutamate neurotransmission over time. In two additional animal cohorts, protein levels of glutamatergic transporters (Glt-1 and GLAST) and presynaptic modulators of glutamate release (mGluR2, TrkB, BDNF, and glucocorticoid receptors) were quantified using automated capillary western techniques at 28 DPI. Astrocytosis and microglial activation have been shown to drive maladaptive glutamate signaling and were histologically assessed over 28 DPI. Alterations in glutamate neurotransmission could not be explained by changes in protein levels for glutamate transporters, mGluR2 receptors, astrocytosis, and microglial activation. Presynaptic modulators, BDNF and TrkB, were significantly decreased at 28 DPI in the amygdala. Dysfunction in presynaptic regulation of glutamate neurotransmission may contribute to anxiety-related behavior and serve as a therapeutic target to improve circuit function.

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Acute Post-Traumatic Sleep May Define Vulnerability to a Second Traumatic Brain Injury in Mice

Cited by 24 publications

References 86 publications

Experimental diffuse brain injury and a model of Alzheimer's disease exhibit disease‐specific changes in sleep and incongruous peripheral inflammation

Experimental diffuse brain injury and a model of Alzheimer's disease exhibit disease‐specific changes in sleep and incongruous peripheral inflammation

A Tilted Axis: Maladaptive Inflammation and HPA Axis Dysfunction Contribute to Consequences of TBI

Experimental Traumatic Brain Injury Induces Chronic Glutamatergic Dysfunction in Amygdala Circuitry Known to Regulate Anxiety-Like Behavior

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