Brief Oxygen Exposure after Traumatic Brain Injury Hastens Recovery and Promotes Adaptive Chronic Endoplasmic Reticulum Stress Responses.

Traumatic brain injury (TBI) is a major public health concern, particularly in adolescents who have a higher mortality and incidence of visual pathway injury compared to adult patients. Likewise, we have found disparities between adult and adolescent TBI outcomes in rodents. Most interestingly, adolescents suffer a prolonged apneic period immediately post-injury, leading to higher mortality; therefore, we implemented a brief oxygen exposure paradigm to circumvent this increased mortality. Adolescent male mice experienced a closed-head weight-drop TBI and were then exposed to 100% O2 until normal breathing returned or recovered in room air. We followed mice for 7 and 30 days and assessed their optokinetic response; retinal ganglion cell loss; axonal degeneration; glial reactivity; and retinal ER stress protein levels. O2 reduced adolescent mortality by 40%, improved post-injury visual acuity, and reduced axonal degeneration and gliosis in optical projection regions. ER stress protein expression was altered in injured mice, and mice given O2 utilized different ER stress pathways in a time-dependent manner. Finally, O2 exposure may be mediating these ER stress responses through regulation of the redox-sensitive ER folding protein ERO1α, which has been linked to a reduction in the toxic effects of free radicals in other animal models of ER stress.

Connecting endoplasmic reticulum and oxidative stress to retinal degeneration, TBI, and traumatic optic neuropathy.

Traumatic optic neuropathy (TON) is commonly associated with head trauma, and thus is a known comorbidity of traumatic brain injury (TBI). TON has not received much attention in basic research despite being associated with permanent vision loss, color blindness, and loss of visual fields. This mini-review discusses the importance of studying TON in the context of TBI and mechanisms that may be involved in the ongoing optic nerve degeneration of TON. We focus particularly on endoplasmic reticulum (ER) and redox stress processes because of the overlapping presence of these degenerative mechanisms in both TBI and various retinopathies, even though these stress pathways have not yet been used to explain retinal degeneration in a model of TON. We propose that future research is needed to uncover whether ER and redox stress function independently or whether one precedes the other. This understanding is necessary in order to understand the time frames of potential treatment and the prognosis of ongoing secondary effects of TBI including optic nerve injury.

Greater neurodegeneration and behavioral deficits after single closed head traumatic brain injury in adolescent versus adult male mice.

Traumatic brain injury (TBI) is a major public health concern affecting 2.8 million people per year in the United States, of whom about 1 million are children under 19 years old. Animal models of TBI have been developed and used in multiple ages of animals, but direct comparisons of adult and adolescent populations are rare. The current studies were undertaken to directly compare outcomes between adult and adolescent male mice, using a closed head, single-impact model of TBI. Six-week-old adolescent and 9-week-old adult male mice were subjected to mild-moderate TBI. Histological measures for neurodegeneration, gliosis, and microglial neuroinflammation, and behavioral tests of locomotion and memory were performed. Adolescent TBI mice have increased mortality (Χ2  = 20.72, p < 0.001) compared to adults. There is also evidence of hippocampal neurodegeneration in adolescents that is not present in adults. Hippocampal neurodegeneration correlates with histologic activation of microglia, but not with increased astrogliosis. Adults and adolescents have similar locomotion deficits after TBI that recover by 16 days postinjury. Adolescents have memory deficits as evidenced by impaired novel object recognition between 3-4 and 4-16 days postinjury (F1,26  = 5.23, p = 0.031) while adults do not. In conclusion, adults and adolescents within a close age range (6-9 weeks) respond to TBI differently. Adolescents are more severely affected by mortality, neurodegeneration, and inflammation in the hippocampus compared to adults. Adolescents, but not adults, have worse memory performance after TBI that lasts at least 16 days postinjury.

Use of donepezil for neurocognitive recovery after brain injury in adult and pediatric populations: a scoping review.

There are few pharmacologic options for the treatment of cognitive deficits associated with traumatic brain injury in pediatric patients. Acetylcholinesterase inhibitors such as donepezil have been evaluated in adult patients after traumatic brain injury, but relatively less is known about the effect in pediatric populations. The goal of this review is to identify knowledge gaps in the efficacy and safety of acetylcholinesterase inhibitors as a potential adjuvant treatment for neurocognitive decline in pediatric patients with traumatic brain injury. Investigators queried PubMed to identify literature published from database inception through June 2023 describing the use of donepezil in young adult traumatic brain injury and pediatric patients with predefined conditions. Based on preselected search criteria, 340 unique papers were selected for title and abstract screening. Thirty-two records were reviewed in full after eliminating preclinical studies and papers outside the scope of the project. In adult traumatic brain injury, we review results from 14 papers detailing 227 subjects where evidence suggests donepezil is well tolerated and shows both objective and patient-reported efficacy for reducing cognitive impairment. In children, 3 papers report on 5 children recovering from traumatic brain injury, showing limited efficacy. An additional 15 pediatric studies conducted in populations at risk for cognitive dysfunction provide a broader look at safety and efficacy in 210 patients in the pediatric age group. Given its promise for efficacy in adults with traumatic brain injury and tolerability in pediatric patients, we believe further study of donepezil for children and adolescents with traumatic brain injury is warranted.

Targeting eIF2α in TBI-induced traumatic optic neuropathy: Effects of Salubrinal and the Integrated Stress Response Inhibitor.

Traumatic brain injury (TBI) can induce traumatic axonal injury in the optic nerve, which is referred to as traumatic optic neuropathy (TON). TON occurs in up to 5% of TBI cases and leads to irreversible visual deficits. TON-induced phosphorylation of eIF2α, a downstream ER stress activator in the PERK pathway presents a potential point for therapeutic intervention. For eIF2α phosphorylation can lead to apoptosis or adaptation to stress. We hypothesized that dephosphorylation, rather than phosphorylation, of eIF2α would lead to reduced apoptosis and improved visual performance and retinal cell survival. Adult male mice were injected with Salubrinal (increases p-eIF2α) or ISRIB (decreases p-eIF2α) 60 minutes post-injury. Contrary to literature, both drugs hindered control animal visual function with minimal improvements in injured mice. Additionally, differences in eIF2α phosphorylation, antioxidant responses, and protein folding chaperones were different when examining protein expression between the retina and its axons in the optic nerve. These results reveal important compartmentalized ER stress responses to axon injury and suggest that interventions in the PERK pathway may alter necessary homeostatic regulation of the UPR in the retina.

Pleasurable behaviors reduce stress via brain reward pathways.

Individuals often eat calorically dense, highly palatable "comfort" foods during stress for stress relief. This article demonstrates that palatable food intake (limited intake of sucrose drink) reduces neuroendocrine, cardiovascular, and behavioral responses to stress in rats. Artificially sweetened (saccharin) drink reproduces the stress dampening, whereas oral intragastric gavage of sucrose is without effect. Together, these results suggest that the palatable/rewarding properties of sucrose are necessary and sufficient for stress dampening. In support of this finding, another type of natural reward (sexual activity) similarly reduces stress responses. Ibotenate lesions of the basolateral amygdala (BLA) prevent stress dampening by sucrose, suggesting that neural activity in the BLA is necessary for the effect. Moreover, sucrose intake increases mRNA and protein expression in the BLA for numerous genes linked with functional and/or structural plasticity. Lastly, stress dampening by sucrose is persistent, which is consistent with long-term changes in neural activity after synaptic remodeling. Thus, natural rewards, such as palatable foods, provide a general means of stress reduction, likely via structural and/or functional plasticity in the BLA. These findings provide a clearer understanding of the motivation for consuming palatable foods during times of stress and influence therapeutic strategies for the prevention and/or treatment of obesity and other stress-related disorders.

Brief oxygen exposure after traumatic brain injury speeds recovery and promotes adaptive chronic endoplasmic reticulum stress responses.

Traumatic brain injury (TBI) is a major public health concern particularly in adolescents who have a higher mortality and incidence of visual pathway injury compared to adult patients. Likewise, we have found disparities between adult and adolescent TBI outcomes in rodents. Most interestingly, adolescents suffer a prolonged apneic period immediately post injury leading to higher mortality; so, we implemented a brief oxygen exposure paradigm to circumvent this increased mortality. Adolescent male mice experienced a closed-head weight-drop TBI then were exposed to 100% O 2 until normal breathing returned or recovered in room air. We followed mice for 7- and 30-days and assessed their optokinetic response; retinal ganglion cell loss; axonal degeneration; glial reactivity; and retinal ER stress protein levels. O 2 reduced adolescent mortality by 40%, improved post-injury visual acuity, and reduced axonal degeneration and gliosis in optic projection regions. ER stress protein expression was altered in injured mice, and mice given O 2 utilized different ER-stress pathways in a time dependent manner. Finally, O 2 exposure may be mediating these ER stress responses through regulation of the redox-sensitive ER folding protein ERO1α, which has been linked to a reduction in the toxic effects of free radicals in other animal models of ER stress.

Attitudes and practices of specialty physicians regarding the return to school process after pediatric acquired brain injury.

PURPOSE: More than 50,000 children are hospitalized yearly in the U.S. for acquired brain injury (ABI) with no established standards or protocols for school re-entry and limited resources for hospital-school communication. While ultimately the school has autonomy over curricula and services, specialty physicians were asked about their participation and perception of barriers in the school re-entry process. METHODS: Approximately 545 specialty physicians were sent an electronic survey. RESULTS: 84 responses (43% neurologists and 37% physiatrists) were obtained with a response rate of ∼15%. Thirty-five percent reported that specialty clinicians currently make the plan for school re-entry. The biggest challenge for school re-entry noted by physicians was cognitive difficulties (63%). The biggest gaps perceived by physicians were a lack of hospital-school liaisons to help design and implement a school re-entry plan (27%), schools' inability to implement a school re-entry plan (26%), and an evidence-based cognitive rehab curriculum (26%). Forty-seven percent of physicians reported that they did not have adequate medical personnel to support school re-entry. The most commonly used outcome measure was family satisfaction. Ideal outcome measures included satisfaction (33%) and formal assessment of quality of life (26%). CONCLUSION: These data suggest that specialty physicians identify a lack of school liaisons in the medical setting as an important gap in hospital-school communication. Satisfaction and formal assessment of quality of life are meaningful outcomes for this provider group.

Early Measures of TBI Severity Poorly Predict Later Individual Impairment in a Rat Fluid Percussion Model.

BACKGROUND: Multiple measures of injury severity are suggested as common data elements in preclinical traumatic brain injury (TBI) research. The robustness of these measures in characterizing injury severity is unclear. In particular, it is not known how reliably they predict individual outcomes after experimental TBI. METHODS: We assessed several commonly used measures of initial injury severity for their ability to predict chronic cognitive outcomes in a rat lateral fluid percussion (LFPI) model of TBI. At the time of injury, we assessed reflex righting time, neurologic severity scores, and 24 h weight loss. Sixty days after LFPI, we evaluated working memory using a spontaneous alternation T-maze task. RESULTS: We found that righting time and weight loss had no correlation to chronic T-maze performance, while neurologic severity score correlated weakly. DISCUSSION: Taken together, our results indicate that commonly used early measures of injury severity do not robustly predict longer-term outcomes. This finding parallels the uncertainty in predicting individual outcomes in TBI clinical populations.

Hydration state controls stress responsiveness and social behavior.

Life stress frequently occurs within the context of homeostatic challenge, requiring integration of physiological and psychological need into appropriate hormonal, cardiovascular, and behavioral responses. To test neural mechanisms underlying stress integration within the context of homeostatic adversity, we evaluated the impact of a pronounced physiological (hypernatremia) challenge on hypothalamic-pituitary-adrenal (HPA), cardiovascular, and behavioral responses to an acute psychogenic stress. Relative to normonatremic controls, rats rendered mildly hypernatremic had decreased HPA activation in response to physical restraint, a commonly used rodent model of psychogenic stress. In addition, acute hypernatremia attenuated the cardiovascular response to restraint and promoted faster recovery to prestress levels. Subsequent to restraint, hypernatremic rats had significantly more c-Fos expression in oxytocin- and vasopressin-containing neurons within the supraoptic and paraventricular nuclei of the hypothalamus. Hypernatremia also completely eliminated the increased plasma renin activity that accompanied restraint in controls, but greatly elevated circulating levels of oxytocin. The endocrine and cardiovascular profile of hypernatremic rats was predictive of decreased anxiety-like behavior in the social interaction test. Collectively, the results indicate that acute hypernatremia is a potent inhibitor of the HPA, cardiovascular, and behavioral limbs of the stress response. The implications are that the compensatory responses that promote renal-sodium excretion when faced with hypernatremia also act on the nervous system to decrease reactivity to psychogenic stressors and facilitate social behavior, which may suppress the anxiety associated with approaching a communal water source and support the social interactions that may be encountered when engaging in drinking behavior.

Chronic Histological Outcomes of Indirect Traumatic Optic Neuropathy in Adolescent Mice: Persistent Degeneration and Temporally Regulated Glial Responses.

Injury to the optic nerve, termed, traumatic optic neuropathy (TON) is a known comorbidity of traumatic brain injury (TBI) and is now known to cause chronic and progressive retinal thinning up to 35 years after injury. Although animal models of TBI have described the presence of optic nerve degeneration and research exploring acute mechanisms is underway, few studies in humans or animals have examined chronic TON pathophysiology outside the retina. We used a closed-head weight-drop model of TBI/TON in 6-week-old male C57BL/6 mice. Mice were euthanized 7-, 14-, 30-, 90-, and 150-days post-injury (DPI) to assess histological changes in the visual system of the brain spanning a total of 12 regions. We show chronic elevation of FluoroJade-C, indicative of neurodegeneration, throughout the time course. Intriguingly, FJ-C staining revealed a bimodal distribution of mice indicating the possibility of subpopulations that may be more or less susceptible to injury outcomes. Additionally, we show that microglia and astrocytes react to optic nerve damage in both temporally and regionally different ways. Despite these differences, astrogliosis and microglial changes were alleviated between 14-30 DPI in all regions examined, perhaps indicating a potentially critical period for intervention/recovery that may determine chronic outcomes.

Traumatic Optic Neuropathy Is Associated with Visual Impairment, Neurodegeneration, and Endoplasmic Reticulum Stress in Adolescent Mice.

Traumatic brain injury (TBI) results in a number of impairments, often including visual symptoms. In some cases, visual impairments after head trauma are mediated by traumatic injury to the optic nerve, termed traumatic optic neuropathy (TON), which has few effective options for treatment. Using a murine closed-head weight-drop model of head trauma, we previously reported in adult mice that there is relatively selective injury to the optic tract and thalamic/brainstem projections of the visual system. In the current study, we performed blunt head trauma on adolescent C57BL/6 mice and investigated visual impairment in the primary visual system, now including the retina and using behavioral and histologic methods at new time points. After injury, mice displayed evidence of decreased optomotor responses illustrated by decreased optokinetic nystagmus. There did not appear to be a significant change in circadian locomotor behavior patterns, although there was an overall decrease in locomotor behavior in mice with head injury. There was evidence of axonal degeneration of optic nerve fibers with associated retinal ganglion cell death. There was also evidence of astrogliosis and microgliosis in major central targets of optic nerve projections. Further, there was elevated expression of endoplasmic reticulum (ER) stress markers in retinas of injured mice. Visual impairment, histologic markers of gliosis and neurodegeneration, and elevated ER stress marker expression persisted for at least 30 days after injury. The current results extend our previous findings in adult mice into adolescent mice, provide direct evidence of retinal ganglion cell injury after head trauma and suggest that axonal degeneration is associated with elevated ER stress in this model of TON.

Brachial plexus birth injuries and the association between pre-procedure and post-procedure pediatric outcomes data collection instrument scores and narakas classification.

BACKGROUND: The brachial plexus is a network of nerves exiting the spinal cord through the fifth, sixth, seventh, and eighth cervical nerves (C5-C8) as well as the first thoracic nerve (T1) to conduct signals for motion and sensation throughout the arm. Brachial plexus birth injuries (BPBI) occur in 1.5 per 1,000 live births. The purpose of this study was to determine the perceived change in musculoskeletal health-related quality of life of brachial plexus patients utilizing the Pediatric Outcomes Data Collection Instrument (PODCI). PODCI scores were examined along with the patient's procedure history (surgical or Botulinum Toxin), extent of involvement and demographics. PATIENTS: A total of 81 patients from two to eighteen years of age from nine different states met the inclusion criteria of having a pre-procedure and post-procedure PODCI score along with a Narakas score from 2002-2017. These patients were seen at the Brachial Plexus Center, which is an interdisciplinary clinic at a large academic medical centerMETHODS: This retrospective study utilized PODCI data collected annually during their regular brachial plexus clinic visits. Upper extremity (UE) and global functioning (GFx) scores pre- and post-procedure were stratified by Narakas Classification. Data were analyzed using paired t-test and ANOVA testing. RESULTS: Patients with a Brachial Plexus Birth Injury (BPBI) had lower PODCI scores for UE and GFx when compared with the pediatric normative scores for age-matched healthy children. Scores in both UE and GFx domains were higher after procedure in the groups of Narakas I and IV. There was significant correlation between UE and GFx scores and documented first PODCI score (2 years of age) and age at intervention (5 years of age). CONCLUSION: Procedures increased the perceived quality of life for children with a BPBI and increased their overall PODCI scores for both UE and GFx.

Chronic Dysregulation of Cortical and Subcortical Metabolism After Experimental Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading cause of death and long-term disability worldwide. Although chronic disability is common after TBI, effective treatments remain elusive and chronic TBI pathophysiology is not well understood. Early after TBI, brain metabolism is disrupted due to unregulated ion release, mitochondrial damage, and interruption of molecular trafficking. This metabolic disruption causes at least part of the TBI pathology. However, it is not clear how persistent or pervasive metabolic injury is at later stages of injury. Using untargeted 1H-NMR metabolomics, we examined ex vivo hippocampus, striatum, thalamus, frontal cortex, and brainstem tissue in a rat lateral fluid percussion model of chronic brain injury. We found altered tissue concentrations of metabolites in the hippocampus and thalamus consistent with dysregulation of energy metabolism and excitatory neurotransmission. Furthermore, differential correlation analysis provided additional evidence of metabolic dysregulation, most notably in brainstem and frontal cortex, suggesting that metabolic consequences of injury are persistent and widespread. Interestingly, the patterns of network changes were region-specific. The individual metabolic signatures after injury in different structures of the brain at rest may reflect different compensatory mechanisms engaged to meet variable metabolic demands across brain regions.

Bed nucleus of the stria terminalis subregions differentially regulate hypothalamic-pituitary-adrenal axis activity: implications for the integration of limbic inputs.

Limbic and cortical neurocircuits profoundly influence hypothalamic-pituitary-adrenal (HPA) axis responses to stress yet have little or no direct projections to the hypothalamic paraventricular nucleus (PVN). Numerous lines of evidence suggest that the bed nucleus of the stria terminalis (BST) is well positioned to relay limbic information to the PVN. The BST comprises multiple anatomically distinct nuclei, of which some are known to receive direct limbic and/or cortical input and to heavily innervate the PVN. Our studies test the hypothesis that subregions of the BST differentially regulate HPA axis responses to acute stress. Male Sprague Dawley rats received bilateral ibotenate lesions, targeting either the principal nucleus in the posterior BST or the dorsomedial/fusiform nuclei in the anteroventral BST. Posterior BST lesions elevated plasma ACTH and corticosterone in response to acute restraint stress, increased stress-induced PVN c-fos mRNA, and elevated PVN corticotropin-releasing hormone (CRH) and parvocellular arginine vasopressin (AVP) mRNA expression relative to sham-lesion animals. In contrast, anterior BST lesions attenuated the plasma corticosterone response and decreased c-fos mRNA induction in the PVN but did not affect CRH and parvocellular AVP mRNA expression in the PVN. These data suggest that posterior BST nuclei are involved in inhibition of the HPA axis, whereas the anteroventral BST nuclei are involved in HPA axis excitation. The results indicate that the BST contains functional subdomains that play different roles in integrating and processing limbic information in response to stress and further suggest that excitatory as well as inhibitory limbic information is funneled through these important cell groups.

The anteroventral bed nucleus of the stria terminalis differentially regulates hypothalamic-pituitary-adrenocortical axis responses to acute and chronic stress.

The anteroventral region of the bed nucleus of the stria terminalis (BST) stimulates hypothalamic-pituitary-adrenocortical (HPA) axis responses to acute stress. However, the role of the anterior BST nuclei in chronic drive of the HPA axis has yet to be established. Therefore, this study tests the role of the anteroventral BST in physiological responses to chronic drive, using a chronic variable stress (CVS) model. Male Sprague-Dawley rats received either bilateral ibotenate lesions, targeting the anteroventral BST, or vehicle injection into the same region. Half of the lesion and control rats were exposed to a 14-d CVS paradigm consisting of twice-daily exposure to unpredictable, alternating stressors. The remaining rats were nonhandled control animals that remained in home cages. On the morning after the end of CVS exposure, all rats were exposed to a novel restraint stress challenge. CVS induced attenuated body weight gain, adrenal hypertrophy, thymic involution, and enhanced CRH mRNA in hypophysiotrophic neurons of the hypothalamic paraventricular nucleus, none of which were affected by anteroventral BST lesions. In the absence of CVS, lesions attenuated the plasma corticosterone and paraventricular nucleus c-fos mRNA responses to the acute restraint stress. In contrast, lesions of the anteroventral BST elevated plasma ACTH and corticosterone responses to novel restraint in the rats previously exposed to CVS. These data suggest that the anterior BST plays very different roles in integrating acute stimulation and chronic drive of the HPA axis, perhaps mediated by chronic stress-induced recruitment of distinct BST cell groups or functional reorganization of stress-integrative circuits.

The role of the posterior medial bed nucleus of the stria terminalis in modulating hypothalamic-pituitary-adrenocortical axis responsiveness to acute and chronic stress.

The bed nucleus of the stria terminalis (BST) plays a prominent role in brain integration of acute responses to stressful stimuli. This study tests the hypothesis that the BST plays a complementary role in regulation of physiological changes associated with chronic stress exposure. Male Sprague-Dawley rats received bilateral ibotenate lesions or sham lesions of the posterior medial region of the BST (BSTpm), an area known to be involved in inhibition of HPA axis responses to acute stress. Chronic stress was induced by 14-day exposure to twice daily stressors in an unpredictable sequence (chronic variable stress, CVS). In the morning after the end of CVS, stressed and non-stressed controls were exposed to a novel restraint stress challenge. As previously documented, CVS caused adrenal hypertrophy, thymic involution, and attenuated body weight gain. None of these endpoints were affected by BSTpm lesions. Chronic stress exposure facilitated plasma corticosterone responses to the novel restraint stress and elevated CRH mRNA. Lesions of the BSTpm increased novel stressor-induced plasma ACTH and corticosterone secretion and enhanced c-fos mRNA induction in the paraventricular nucleus of the hypothalamus (PVN). In addition, lesion of the BSTpm resulted in an additive increase in CVS-induced facilitation of corticosterone responses and PVN CRH expression. Collectively these data confirm that the BSTpm markedly inhibits HPA responses to acute stress, but do not strongly support an additional role for this region in limiting HPA axis responses to chronic drive. The data further suggest that acute versus chronic stress integration are subserved by different brain circuitry.

Optic tract injury after closed head traumatic brain injury in mice: A model of indirect traumatic optic neuropathy.

Adult male C57BL/6J mice have previously been reported to have motor and memory deficits after experimental closed head traumatic brain injury (TBI), without associated gross pathologic damage or neuroimaging changes detectable by magnetic resonance imaging or diffusion tensor imaging protocols. The presence of neurologic deficits, however, suggests neural damage or dysfunction in these animals. Accordingly, we undertook a histologic analysis of mice after TBI. Gross pathology and histologic analysis using Nissl stain and NeuN immunohistochemistry demonstrated no obvious tissue damage or neuron loss. However, Luxol Fast Blue stain revealed myelin injury in the optic tract, while Fluoro Jade B and silver degeneration staining revealed evidence of axonal neurodegeneration in the optic tract as well as the lateral geniculate nucleus of the thalamus and superior colliculus (detectable at 7 days, but not 24 hours, after injury). Fluoro Jade B staining was not detectable in other white matter tracts, brain regions or in cell somata. In addition, there was increased GFAP staining in these optic tract, lateral geniculate, and superior colliculus 7 days post-injury, and morphologic changes in optic tract microglia that were detectable 24 hours after injury but were more prominent 7 days post-injury. Interestingly, there were no findings of degeneration or gliosis in the suprachiasmatic nucleus, which is also heavily innervated by the optic tract. Using micro-computed tomography imaging, we also found that the optic canal appears to decrease in diameter with a dorsal-ventral load on the skull, which suggests that the optic canal may be the site of injury. These results suggest that there is axonal degeneration in the optic tract and a subset of directly innervated areas, with associated neuroinflammation and astrocytosis, which develop within 7 days of injury, and also suggest that this weight drop injury may be a model for studying indirect traumatic optic neuropathy.

A Narrative Review of Pharmacologic and Non-pharmacologic Interventions for Disorders of Consciousness Following Brain Injury in the Pediatric Population.

Traumatic brain injury (TBI) is the most common cause of long-term disability in the United States. A significant proportion of children who experience a TBI will have moderate or severe injuries, which includes a period of decreased responsiveness. Both pharmacological and non-pharmacological modalities are used for treating disorders of consciousness after TBI in children. However, the evidence supporting the use of potential therapies is relatively scant, even in adults, and overall, there is a paucity of study in pediatrics. The goal of this review is to describe the state of the science for use of pharmacologic and non-pharmacologic interventions for disorders of consciousness in the pediatric population.

Stability of neuroendocrine and behavioral responsiveness in aging Fischer 344/Brown-Norway hybrid rats.

Aging in rodents and primates is accompanied by changes in hypothalamic-pituitary-adrenal (HPA) activity. We examined behavioral and neuroendocrine responses in 3, 15-, and 30-month-old F344/Brown-Norway rats. Basal corticosterone and ACTH levels did not differ with age, although ACTH responses, but not corticosterone responses to restraint stress, were significantly lower in the 30-month-old group relative to 3- and 15-month-old rats. Induction of c-fos mRNA in the paraventricular nucleus from restraint was not affected by age. Furthermore, there was an enhanced sensitivity to dexamethasone suppression in aged animals as evidenced by lesser ACTH and corticosterone release after dexamethasone administration. Evaluation of emotional behaviors in the forced swim test revealed no differences between the age groups. With fear conditioning, aged rats had decreased freeze times relative to middle-aged or young rats. Regression analysis revealed no significant correlations between the behavioral and HPA axis data in any group. Overall, the data suggest that an apparent decrease in pituitary drive is compensated for at the level of the adrenal, resulting in stable patterns of glucocorticoid secretion. The lack of a correlation between HPA axis measures and emotional as well as fear conditioning-related behaviors indicates that corticosteroid dysfunction may not predict age-related behavioral deficits in this aging model.