Investigating the Role of the Hypothalamus in Outcomes to Repetitive Mild Traumatic Brain Injury: Neonatal Monosodium Glutamate Does Not Exacerbate Deficits

Yamakawa, Glenn R.; Weerawardhena, Himanthri; Eyolfson, Eric; Griep, Yannick; Antle, Michael C.; Mychasiuk, Richelle

doi:10.1016/j.neuroscience.2019.06.022

Cited by 11 publications

(4 citation statements)

References 83 publications

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“…Most animal studies examining RmTBI use 2–7 mTBIs spaced over days or weeks (e.g. Ojo et al 2013 ; McAteer et al 2016 ; Mychasiuk et al 2016a , 2016b ; Gao et al 2017 ; Salberg et al 2018 ; Yamakawa et al 2019 ). This innovative study examined 30 mTBIs over 15 weeks (~4 months), covering all of adolescence and early adulthood.…”

Section: Discussionmentioning

confidence: 99%

Examining the Progressive Behavior and Neuropathological Outcomes Associated with Chronic Repetitive Mild Traumatic Brain Injury in Rats

Eyolfson

Yamakawa

Griep

et al. 2020

Cerebral Cortex Communications

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While the physical and behavioral symptomologies associated with a single mild traumatic brain injury (mTBI) are typically transient, repetitive mTBIs (RmTBI) have been associated with persisting neurological deficits. Therefore, this study examined the progressive changes in behavior and the neuropathological outcomes associated with chronic RmTBI through adolescence and adulthood in male and female Sprague Dawley rats. Rats experienced 2 mTBIs/week for 15 weeks and were periodically tested for changes in motor behavior, cognitive function, emotional disturbances, and aggression. Brain tissue was examined for neuropathological changes in ventricle size and presentation of Iba1 and GFAP. We did not see progressively worse behavioral impairments with the accumulation of injuries or time, but did find evidence for neurological and functional change (motor disturbance, reduced exploration, reduced aggression, alteration in depressive-like behavior, deficits in short-term working memory). Neuropathological assessment of RmTBI animals identified an increase in ventricle size, prolonged changes in GFAP, and sex differences in Iba1, in the corpus callosum, thalamus, and medial prefrontal cortex. Telomere length reduced exponentially as the injury load increased. Overall, chronic RmTBI did not result in accumulating behavioral impairment, and there is a need to further investigate progressive behavioral changes associated with repeated injuries in adolescence and young adulthood.

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Section: Discussionmentioning

confidence: 99%

Examining the Progressive Behavior and Neuropathological Outcomes Associated with Chronic Repetitive Mild Traumatic Brain Injury in Rats

Eyolfson

Yamakawa

Griep

et al. 2020

Cerebral Cortex Communications

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“…Given the important role of the orexins in sleep, and the known bi-directional relationship between sleep and pain/headache [ 82 , 83 ], this study would have been improved if sleep duration/quality was analyzed. Importantly however, our laboratory has previously examined circadian rhythms (i.e., heart rate, body temperature, and sleep) following RmTBI with this model and found that they were largely unaffected, and only detectable when all light cues were removed and the rats were housed in total darkness [ 84 ]. Finally, it would be important to include females in future experiments, as sex could influence both the behavioural and structural outcomes.…”

Section: Discussionmentioning

confidence: 99%

Repeat mild traumatic brain injuries (RmTBI) modify nociception and disrupt orexinergic connectivity within the descending pain pathway

Christensen,

MacPherson,

et al. 2023

J Headache Pain

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Repeat mild traumatic brain injuries (RmTBI) result in substantial burden to the public health system given their association with chronic post-injury pathologies, such as chronic pain and post-traumatic headache. Although this may relate to dysfunctional descending pain modulation (DPM), it is uncertain what mechanisms drive changes within this pathway. One possibility is altered orexinergic system functioning, as orexin is a potent anti-nociceptive neuromodulator. Orexin is exclusively produced by the lateral hypothalamus (LH) and receives excitatory innervation from the lateral parabrachial nucleus (lPBN). Therefore, we used neuronal tract-tracing to investigate the relationship between RmTBI and connectivity between lPBN and the LH, as well as orexinergic projections to a key site within the DPM, the periaqueductal gray (PAG). Prior to injury induction, retrograde and anterograde tract-tracing surgery was performed on 70 young-adult male Sprague Dawley rats, targeting the lPBN and PAG. Rodents were then randomly assigned to receive RmTBIs or sham injuries before undergoing testing for anxiety-like behaviour and nociceptive sensitivity. Immunohistochemical analysis identified distinct and co-localized orexin and tract-tracing cell bodies and projections within the LH. The RmTBI group exhibited altered nociception and reduced anxiety as well as a loss of orexin cell bodies and a reduction of hypothalamic projections to the ventrolateral nucleus of the PAG. However, there was no significant effect of injury on neuronal connectivity between the lPBN and orexinergic cell bodies within the LH. Our identification of structural losses and the resulting physiological changes in the orexinergic system following RmTBI begins to clarify acute post-injury mechanistic changes that drive may drive the development of post-traumatic headache and the chronification of pain.

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“…The expression of both Dnmt3a and Iba1 increased following RmTBI. While an increase in Iba1 expression following TBI is common 64,92 as it is associated with microglia activation, Dnmt3a has shown both increases 67,93 and no change 94 in expression. Given that Dnmt3a is a key epigenetic regulator involved in brain plasticity, 95 the increase in expression and subsequent gene silencing, suggests that the RmTBIs reduced the plastic capabilities of the developing brain.…”

Section: Discussionmentioning

confidence: 99%

Paternal exposure to exercise and/or caffeine and alcohol modify offspring behavioral and pathophysiological recovery from repetitive mild traumatic brain injury in adolescence

Eyolfson

Bhatt

Wang

et al. 2021

Genes Brain and Behavior

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Only recently has the scope of parental research expanded to include the paternal sphere with epidemiological studies implicating stress, nutrition and alcohol consumption in the neurobiological and behavioral characteristics of offspring. This study was designed to determine if paternal exposure to caffeine, alcohol and exercise prior to conception would improve or exacerbate offspring recovery from adolescent repetitive mild traumatic brain injury (RmTBI). Sires received 7 weeks of standard drinking water, or caffeine and ethanol and were housed in regular cages or cages with running wheels, prior to being mated to control females. At postnatal day 40, offspring were administered RmTBI or sham injuries and were assessed for post concussive symptomology. Post‐mortem quantitative real‐time polymerase chain reaction (qRT‐PCR) was used to assess gene expression in the prefrontal cortex (PFC), nucleus accumbens (NAc) and changes in telomere length. Additionally, enzyme‐linked immunosorbent assay (ELISA's) were run on serum to detect levels of cytokines, chemokines and sex hormones. Paternal experience did not improve or exacerbate RmTBI behavioral outcomes. However, female and male offspring displayed unique responses to RmTBI and paternal experience, resulting in changes in physical, behavioral and molecular outcomes. Injury and paternal exercise modified changes in female offspring, whereas male offspring were affected by paternal exercise, caffeine and alcohol treatment. Additionally, paternal experience and RmTBI modified expression of many genes in the PFC, NAc, telomere length and levels of sex hormones. Although further exploration is required to understand the heterogeneity that exists in disease risk and resiliency, this study provides corroborating evidence that paternal experiences prior to conception influences offspring development.

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Investigating the Role of the Hypothalamus in Outcomes to Repetitive Mild Traumatic Brain Injury: Neonatal Monosodium Glutamate Does Not Exacerbate Deficits

Cited by 11 publications

References 83 publications

Examining the Progressive Behavior and Neuropathological Outcomes Associated with Chronic Repetitive Mild Traumatic Brain Injury in Rats

Examining the Progressive Behavior and Neuropathological Outcomes Associated with Chronic Repetitive Mild Traumatic Brain Injury in Rats

Repeat mild traumatic brain injuries (RmTBI) modify nociception and disrupt orexinergic connectivity within the descending pain pathway

Paternal exposure to exercise and/or caffeine and alcohol modify offspring behavioral and pathophysiological recovery from repetitive mild traumatic brain injury in adolescence

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