Cerebral hypoperfusion exacerbates traumatic brain injury in male but not female mice.

Mild-moderate traumatic brain injuries (TBIs) are prevalent, and while many individuals recover, there is evidence that a significant number experience long-term health impacts, including increased vulnerability to neurodegenerative diseases. These effects are influenced by other risk factors, such as cardiovascular disease. Our study tested the hypothesis that a pre-injury reduction in cerebral blood flow (CBF), mimicking cardiovascular disease, worsens TBI recovery. We induced bilateral carotid artery stenosis (BCAS) and a mild-moderate closed-head TBI in male and female mice, either alone or in combination, and analyzed CBF, spatial learning, memory, axonal damage, and gene expression. Findings showed that BCAS and TBI independently caused a ~10% decrease in CBF. Mice subjected to both BCAS and TBI experienced more significant CBF reductions, notably affecting spatial learning and memory, particularly in males. Additionally, male mice showed increased axonal damage with both BCAS and TBI compared to either condition alone. Females exhibited spatial memory deficits due to BCAS, but these were not worsened by subsequent TBI. Gene expression analysis in male mice highlighted that TBI and BCAS individually altered neuronal and glial profiles. However, the combination of BCAS and TBI resulted in markedly different transcriptional patterns. Our results suggest that mild cerebrovascular impairments, serving as a stand-in for preexisting cardiovascular conditions, can significantly worsen TBI outcomes in males. This highlights the potential for mild comorbidities to modify TBI outcomes and increase the risk of secondary diseases.

Pericyte dysfunction is a key mediator of the risk of cerebral ischemia.

Pericytes are critical yet understudied cells that are a central component of the neurovascular unit. They are connected to the cerebrovascular endothelium and help control vascular contractility and maintain the blood-brain barrier. Pericyte dysfunction has the potential to mediate many of the deleterious vascular consequences of ischemic stroke. Current therapeutics are designed to be administered after stroke onset and limit damage, but there are few options to target vascular risk factors pre-ischemia which likely contribute to stroke outcomes. Here, we focus on the role of pericytes in health and disease, and discuss how pericyte dysfunction can increase the risk of ischemic injury. Additionally, we note that despite the importance of pericytes in cerebrovascular disease, there are relatively few current therapeutic options that target pericyte function.

Lifelong consequences of brain injuries during development: From risk to resilience.

Traumatic brain injuries in children represent a major public health issue and even relatively mild injuries can have lifelong consequences. However, the outcomes from these injuries are highly heterogeneous, with most individuals recovering fully, but a substantial subset experiencing prolonged or permanent disabilities across a number of domains. Moreover, brain injuries predispose individuals to other kinds of neuropsychiatric and somatic illnesses. Critically, the severity of the injury only partially predicts subsequent outcomes, thus other factors must be involved. In this review, we discuss the psychological, social, neuroendocrine, and autonomic processes that are disrupted following traumatic brain injury during development, and consider the mechanisms the mediate risk or resilience after traumatic brain injury in this vulnerable population.

Dim light at night exacerbates stroke outcome.

Circadian rhythms are endogenous biological cycles that synchronize physiology and behaviour to promote optimal function. These ~24-hr internal rhythms are set to precisely 24 hr daily by exposure to the sun. However, the prevalence of night-time lighting has the potential to dysregulate these biological functions. Hospital patients may be particularly vulnerable to the consequences of light at night because of their compromised physiological state. A mouse model of stroke (middle cerebral artery occlusion; MCAO) was used to test the hypothesis that exposure to dim light at night impairs responses to a major insult. Stroke lesion size was substantially larger among animals housed in dLAN after reperfusion than animals maintained in dark nights. Mice housed in dLAN for three days after the stroke displayed increased post-stroke anxiety-like behaviour. Overall, dLAN amplified pro-inflammatory pathways in the CNS, which may have exacerbated neuronal damage. Our results suggest that exposure to LAN is detrimental to stroke recovery.

Minocycline blocks traumatic brain injury-induced alcohol consumption and nucleus accumbens inflammation in adolescent male mice.

Alcohol use is a well characterized risk factor for traumatic brain injury (TBI); however, emerging clinical and experimental research suggests that TBI may also be an independent risk factor for the development of alcohol use disorders. In particular, TBIs incurred early in life predict the development of problem alcohol use and increase vulnerability to neuroinflammation as a consequence of alcohol use. Critically, the neuroinflammatory response to alcohol, mediated in large part by microglia, may also function as a driver of further alcohol use. Here, we tested the hypothesis that TBI increases alcohol consumption through microglia-mediated neuroinflammation. Mice were injured as juveniles and alcohol consumption and preference were assessed in a free-choice voluntary drinking paradigm in adolescence. TBI increased alcohol consumption; however, treatment with minocycline, an inhibitor of microglial activation, reduced alcohol intake in TBI mice to sham levels. Moreover, a single injection of ethanol (2 g/kg) significantly increased microglial activation in the nucleus accumbens and microglial expression of the proinflammatory cytokine IL-1ß in TBI, but not sham or minocycline-treated, mice. Our data implicate TBI-induced microglial activation as a possible mechanism for the development of alcohol use disorders.

Binge ethanol in adulthood exacerbates negative outcomes following juvenile traumatic brain injury.

Traumatic brain injuries (TBI) are a major public health problem with enormous costs in terms of health care dollars, lost productivity, and reduced quality of life. Alcohol is bidirectionally linked to TBI as many TBI patients are intoxicated at the time of their injury and we recently reported that, in accordance with human epidemiological data, animals injured during juvenile development self-administered significantly more alcohol as adults than did sham injured mice. There are also clinical data that drinking after TBI significantly reduces the efficacy of rehabilitation and leads to poorer long-term outcomes. In order to determine whether juvenile traumatic brain injury also increased the vulnerability of the brain to the toxic effects of high dose alcohol, mice were injured at 21days of age and then seven weeks later treated daily with binge-like levels of alcohol 5g/kg (by oral gavage) for ten days. Binge-like alcohol produced a greater degree of neuronal damage and neuroinflammation in mice that sustained a TBI. Further, mice that sustained a juvenile TBI exhibited mild learning and memory impairments in adulthood following binge alcohol and express a significant increase in hippocampal ectopic localization of newborn neurons. Taken together, these data provide strong evidence that a mild brain injury occurring early in life renders the brain highly vulnerable to the consequences of binge-like alcohol consumption.

Neuroendocrine control of photoperiodic changes in immune function.

Seasonal variation in immune function putatively maximizes survival and reproductive success. Day length (photoperiod) is the most potent signal for time of year. Animals typically organize breeding, growth, and behavior to adapt to spatial and temporal niches. Outside the tropics individuals monitor photoperiod to support adaptations favoring survival and reproductive success. Changes in day length allow anticipation of seasonal changes in temperature and food availability that are critical for reproductive success. Immune function is typically bolstered during winter, whereas reproduction and growth are favored during summer. We provide an overview of how photoperiod influences neuronal function and melatonin secretion, how melatonin acts directly and indirectly to govern seasonal changes in immune function, and the manner by which other neuroendocrine effectors such as glucocorticoids, prolactin, thyroid, and sex steroid hormones modulate seasonal variations in immune function. Potential future research avenues include commensal gut microbiota and light pollution influences on photoperiodic responses.

Traumatic brain injury and obesity induce persistent central insulin resistance.

Traumatic brain injury (TBI)-induced impairments in cerebral energy metabolism impede tissue repair and contribute to delayed functional recovery. Moreover, the transient alteration in brain glucose utilization corresponds to a period of increased vulnerability to the negative effects of a subsequent TBI. In order to better understand the factors contributing to TBI-induced central metabolic dysfunction, we examined the effect of single and repeated TBIs on brain insulin signalling. Here we show that TBI induced acute brain insulin resistance, which resolved within 7 days following a single injury but persisted until 28 days following repeated injuries. Obesity, which causes brain insulin resistance and neuroinflammation, exacerbated the consequences of TBI. Obese mice that underwent a TBI exhibited a prolonged reduction of Akt (also known as protein kinase B) signalling, exacerbated neuroinflammation (microglial activation), learning and memory deficits, and anxiety-like behaviours. Taken together, the transient changes in brain insulin sensitivity following TBI suggest a reduced capacity of the injured brain to respond to the neuroprotective and anti-inflammatory actions of insulin and Akt signalling, and thus may be a contributing factor for the damaging neuroinflammation and long-lasting deficits that occur following TBI.

Nocturnal light exposure impairs affective responses in a wavelength-dependent manner.

Life on earth is entrained to a 24 h solar cycle that synchronizes circadian rhythms in physiology and behavior; light is the most potent entraining cue. In mammals, light is detected by (1) rods and cones, which mediate visual function, and (2) intrinsically photosensitive retinal ganglion cells (ipRGCs), which primarily project to the suprachiasmatic nucleus (SCN) in the hypothalamus to regulate circadian rhythms. Recent evidence, however, demonstrates that ipRGCs also project to limbic brain regions, suggesting that, through this pathway, light may have a role in cognition and mood. Therefore, it follows that unnatural exposure to light may have negative consequences for mood or behavior. Modern environmental lighting conditions have led to excessive exposure to light at night (LAN), and particularly to blue wavelength lights. We hypothesized that nocturnal light exposure (i.e., dim LAN) would induce depressive responses and alter neuronal structure in hamsters (Phodopus sungorus). If this effect is mediated by ipRGCs, which have reduced sensitivity to red wavelength light, then we predicted that red LAN would have limited effects on brain and behavior compared with shorter wavelengths. Additionally, red LAN would not induce c-Fos activation in the SCN. Our results demonstrate that exposure to LAN influences behavior and neuronal plasticity and that this effect is likely mediated by ipRGCs. Modern sources of LAN that contain blue wavelengths may be particularly disruptive to the circadian system, potentially contributing to altered mood regulation.

Autonomic dysreflexia causes chronic immune suppression after spinal cord injury.

Autonomic dysreflexia (AD), a potentially dangerous complication of high-level spinal cord injury (SCI) characterized by exaggerated activation of spinal autonomic (sympathetic) reflexes, can cause pulmonary embolism, stroke, and, in severe cases, death. People with high-level SCI also are immune compromised, rendering them more susceptible to infectious morbidity and mortality. The mechanisms underlying postinjury immune suppression are not known. Data presented herein indicate that AD causes immune suppression. Using in vivo telemetry, we show that AD develops spontaneously in SCI mice with the frequency of dysreflexic episodes increasing as a function of time postinjury. As the frequency of AD increases, there is a corresponding increase in splenic leucopenia and immune suppression. Experimental activation of spinal sympathetic reflexes in SCI mice (e.g., via colorectal distension) elicits AD and exacerbates immune suppression via a mechanism that involves aberrant accumulation of norepinephrine and glucocorticoids. Reversal of postinjury immune suppression in SCI mice can be achieved by pharmacological inhibition of receptors for norepinephrine and glucocorticoids during the onset and progression of AD. In a human subject with C5 SCI, stimulating the micturition reflex caused AD with exaggerated catecholamine release and impaired immune function, thus confirming the relevance of the mouse data. These data implicate AD as a cause of secondary immune deficiency after SCI and reveal novel therapeutic targets for overcoming infectious complications that arise due to deficits in immune function.

Injury timing alters metabolic, inflammatory and functional outcomes following repeated mild traumatic brain injury.

Repeated head injuries are a major public health concern both for athletes, and members of the police and armed forces. There is ample experimental and clinical evidence that there is a period of enhanced vulnerability to subsequent injury following head trauma. Injuries that occur close together in time produce greater cognitive, histological, and behavioral impairments than do injuries separated by a longer period. Traumatic brain injuries alter cerebral glucose metabolism and the resolution of altered glucose metabolism may signal the end of the period of greater vulnerability. Here, we injured mice either once or twice separated by three or 20days. Repeated injuries that were separated by three days were associated with greater axonal degeneration, enhanced inflammatory responses, and poorer performance in a spatial learning and memory task. A single injury induced a transient but marked increase in local cerebral glucose utilization in the injured hippocampus and sensorimotor cortex, whereas a second injury, three days after the first, failed to induce an increase in glucose utilization at the same time point. In contrast, when the second injury occurred substantially later (20days after the first injury), an increase in glucose utilization occurred that paralleled the increase observed following a single injury. The increased glucose utilization observed after a single injury appears to be an adaptive component of recovery, while mice with 2 injuries separated by three days were not able to mount this response, thus this second injury may have produced a significant energetic crisis such that energetic demands outstripped the ability of the damaged cells to utilize energy. These data strongly reinforce the idea that too rapid return to activity after a traumatic brain injury can induce permanent damage and disability, and that monitoring cerebral energy utilization may be a tool to determine when it is safe to return to the activity that caused the initial injury.

Photoperiodic regulation of hippocampal neurogenesis in adult male white-footed mice (Peromyscus leucopus).

Photoperiodic organisms monitor environmental day length to engage in seasonally appropriate adaptions in physiology and behavior. Among these adaptations are changes in brain volume and neurogenesis, which have been well described in multiple species of birds, yet few studies have described such changes in the brains of adult mammals. White-footed mice (Peromyscus leucopus) are an excellent species in which to investigate the effects of day length on adult hippocampal neurogenesis, as males, in addition to having reduced hippocampal volume in short days (SD) with concomitant impairments in hippocampus-mediated behaviors, have photoperiod-dependent changes in olfactory bulb neurogenesis. We performed the current experiment to assess the effects of photoperiod on hippocampal neurogenesis longitudinally, using the thymidine analog bromodeoxyuridine at multiple time points across 10 weeks of SD exposure. Compared with counterparts held in long day (LD) lengths, across the first 8 weeks of SD exposure hippocampal neurogenesis was reduced. However, at 10 weeks in SD lengths neurogenic levels in the hippocampus were elevated above those levels in mice held in LD lengths. The current findings are consistent with the natural photoperiodic cycle of hippocampal function in male white-footed mice, and may help to inform research on photoperiodic plasticity in neurogenesis and provide insight into how the complex interplay among the environment, genes and adaptive responses to changing day lengths affects brain structure, function and behavior at multiple levels.

Dim light at night disrupts the short-day response in Siberian hamsters.

Photoperiodic regulation of physiology, morphology, and behavior is crucial for many animals to survive seasonally variable conditions unfavorable for reproduction and survival. The photoperiodic response in mammals is mediated by nocturnal secretion of melatonin under the control of a circadian clock. However, artificial light at night caused by recent urbanization may disrupt the circadian clock, as well as the photoperiodic response by blunting melatonin secretion. Here we examined the effect of dim light at night (dLAN) (5lux of light during the dark phase) on locomotor activity rhythms and short-day regulation of reproduction, body mass, pelage properties, and immune responses of male Siberian hamsters. Short-day animals reduced gonadal and body mass, decreased spermatid nuclei and sperm numbers, molted to a whiter pelage, and increased pelage density compared to long-day animals. However, animals that experienced short days with dLAN did not show these short-day responses. Moreover, short-day specific immune responses were altered in dLAN conditions. The nocturnal activity pattern was blunted in dLAN hamsters, consistent with the observation that dLAN changed expression of the circadian clock gene, Period1. In addition, we demonstrated that expression levels of genes implicated in the photoperiodic response, Mel-1a melatonin receptor, Eyes absent 3, thyroid stimulating hormone receptor, gonadotropin-releasing hormone, and gonadotropin-inhibitory hormone, were higher in dLAN animals than those in short-day animals. These results suggest that dLAN disturbs the circadian clock function and affects the molecular mechanisms of the photoperiodic response.

Altered temporal patterns of anxiety in aged and amyloid precursor protein (APP) transgenic mice.

Both normal aging and dementia are associated with dysregulation of the biological clock, which contributes to disrupted circadian organization of physiology and behavior. Diminished circadian organization in conjunction with the loss of cholinergic input to the cortex likely contributes to impaired cognition and behavior. One especially notable and relatively common circadian disturbance among the aged is "sundowning syndrome," which is characterized by exacerbated anxiety, agitation, locomotor activity, and delirium during the hours before bedtime. Sundowning has been reported in both dementia patients and cognitively intact elderly individuals living in institutions; however, little is known about temporal patterns in anxiety and agitation, and the neurobiological basis of these rhythms remains unspecified. In the present study, we explored the diurnal pattern of anxiety-like behavior in aged and amyloid precursor protein (APP) transgenic mice. We then attempted to treat the observed behavioral disturbances in the aged mice using chronic nightly melatonin treatment. Finally, we tested the hypothesis that time-of-day differences in acetylcholinesterase and choline acetyltransferase expression and general neuronal activation (i.e., c-Fos expression) coincide with the behavioral symptoms. Our results show a temporal pattern of anxiety-like behavior that emerges in elderly mice. This behavioral pattern coincides with elevated locomotor activity relative to adult mice near the end of the dark phase, and with time-dependent changes in basal forebrain acetylcholinesterase expression. Transgenic APP mice show a similar behavioral phenomenon that is not observed among age-matched wild-type mice. These results may have useful applications to the study and treatment of age- and dementia-related circadian behavioral disturbances, namely, sundowning syndrome.

Quantitative descriptions of generalized arousal, an elementary function of the vertebrate brain.

We review a concept of the most primitive, fundamental function of the vertebrate CNS, generalized arousal (GA). Three independent lines of evidence indicate the existence of GA: statistical, genetic, and mechanistic. Here we ask, is this concept amenable to quantitative analysis? Answering in the affirmative, four quantitative approaches have proven useful: (i) factor analysis, (ii) information theory, (iii) deterministic chaos, and (iv) application of a Gaussian equation. It strikes us that, to date, not just one but at least four different quantitative approaches seem necessary for describing different aspects of scientific work on GA.

Mild traumatic brain injury induces pericyte detachment independent of stroke vulnerability.

Mild traumatic brain injury (mTBI) is an independent risk factor for ischemic stroke and can result in poorer outcomes- an effect presumed to involve the cerebral vasculature. Here we tested the hypothesis that mTBI-induced pericyte detachment from the cerebrovascular endothelium is responsible for worsened stroke outcomes. We performed a mild closed-head injury and/or treated C57/bl6 mice with imatinib mesylate, a tyrosine kinase inhibitor that induces pericyte detachment. The time course of pericyte detachment was assessed 7, 14, and 28 days post injury (DPI). To test the role of pericytes in TBI-induced exacerbation of ischemic stroke outcomes, we induced mTBI and/or treated mice with imatinib for one week prior to transient middle cerebral artery occlusion. We found that injury promoted pericyte detachment from the vasculature commensurate with the levels of detachment seen in imatinib-only treated animals, and that the detachment persisted for at least 14DPI, but recovered to sham levels by 28DPI. Further, mTBI, but not imatinib-induced pericyte detachment, increased infarct volume. Thus, we conclude that the transient detachment of pericytes caused by mTBI may not be sufficient to exacerbate subsequent ischemic stroke damage. These data have important implications for understanding cerebrovascular dysfunction following mTBI and potential mechanisms of increased risk for future ischemic strokes.

Dim light at night interacts with intermittent hypoxia to alter cognitive and affective responses.

Obstructive sleep apnea (OSA) and dim light at night (dLAN) have both been independently associated with alterations in mood and cognition. We aimed to determine whether dLAN would interact with intermittent hypoxia (IH), a condition characteristic of OSA, to alter the behavioral, cognitive, and affective responses. Adult male mice were housed in either standard lighting conditions (14:10-h light-dark cycle; 150 lux:0 lux) or dLAN (150 lux:5 lux). Mice were then exposed to IH (15 cycles/h, 8 h/day, FiO2 nadir of 5%) for 3 wk, then tested in assays of affective and cognitive responses; brains were collected for dendritic morphology and PCR analysis. Exposure to dLAN and IH increased anxiety-like behaviors, as assessed in the open field, elevated plus maze, and the light/dark box. dLAN and IH increased depressive-like behaviors in the forced swim test. IH impaired learning and memory performance in the passive avoidance task; however, no differences were observed in spatial working memory, as assessed by y-maze or object recognition. IH combined with dLAN decreased cell body area in the CA1 and CA3 regions of the hippocampus. Overall, IH decreased apical spine density in the CA3, whereas dLAN decreased spine density in the CA1 of the hippocampus. TNF-α gene expression was not altered by IH or lighting condition, whereas VEGF expression was increased by dLAN. The combination of IH and dLAN provokes negative effects on hippocampal dendritic morphology, affect, and cognition, suggesting that limiting nighttime exposure to light in combination with other established treatments may be of benefit to patients with OSA.

Mice exposed to dim light at night exaggerate inflammatory responses to lipopolysaccharide.

The mammalian circadian system regulates many physiological functions including inflammatory responses. Appropriately timed light information is essential for maintaining circadian organization. Over the past ∼120 years, urbanization and the widespread adoption of electric lights have dramatically altered lighting environments. Exposure to light at night (LAN) is pervasive in modern society and disrupts core circadian clock mechanisms. Because microglia are the resident macrophages in the brain and macrophages contain intrinsic circadian clocks, we hypothesized that chronic exposure to LAN would alter microglia cytokine expression and sickness behavior following LPS administration. Exposure to 4 weeks of dim LAN elevated inflammatory responses in mice. Mice exposed to dimly lit, as compared to dark, nights exaggerated changes in body temperature and elevated microglia pro-inflammatory cytokine expression following LPS administration. Furthermore, dLAN mice had a prolonged sickness response following the LPS challenge. Mice exposed to dark or dimly lit nights had comparable sickness behavior directly following the LPS injection; however, dLAN mice showed greater reductions in locomotor activity, increased anorectic behavior, and increased weight loss than mice maintained in dark nights 24h post-LPS injection. Overall, these data suggest that chronic exposure to even very low levels of light pollution may alter inflammatory responses. These results may have important implications for humans and other urban dwelling species that commonly experience nighttime light exposure.

Artificial light at night alters delayed-type hypersensitivity reaction in response to acute stress in Siberian hamsters.

Several physiological and behavioral processes rely on precisely timed light information derived from the natural solar cycle. Using this information, traits have adapted to allow individuals within specific niches to optimize survival and reproduction, but urbanization by humans has significantly altered natural habitats. Nighttime light exposure alters immune function in several species, which could lead to decreased fitness or survival, particularly in the face of an environmental challenge. We exposed male Siberian hamsters (Phodopus sungorus) to five lux of light at night for four weeks, and then administered six hours of acute restraint stress. Delayed-type hypersensitivity (DTH) response was assessed immediately following stress. Acute restraint increased the DTH reaction in dark nights, but exposure to nighttime light prevented this response. Exposure to light at night prolonged the DTH response in non-stressed control hamsters. These results suggest that light pollution may significantly alter physiological responses in Siberian hamsters, particularly in response to a salient environmental challenge such as stress.

Sexual experience and testosterone during adolescence alter adult neuronal morphology and behavior.

Steroid hormones released immediately before and after birth provoke sexual differentiation of neural circuits. Further, steroid hormones secreted during adolescence also exert long lasting effects on the nervous system. Hormones secreted during development may act through two distinct pathways: (1) hormones can directly affect neuron and synapse elimination and (2) endocrine changes in the nervous system may occur secondary to changes in social behaviors. Therefore, a critical period for organization of the nervous system by steroid hormones during adolescence may also be a sensitive period for the effects of social experience. The overall goal of this experiment was to determine whether the opportunity to mate with a sexually receptive female during this adolescent critical period would have enduring effects on behavior and neuronal morphology into adulthood. A second question was to determine the extent to which testosterone mediated the effects of these social interactions on adult outcomes. Compared to sexually inexperienced hamsters and those that experienced sex for the first time in adulthood, hamsters that experienced adolescent sexual experience displayed increased anxiety- and depressive-like behavioral responses. Adolescent sexual experiences decreased the complexity and length of dendrites on prefrontal cortical neurons and increased the expression of the pro-inflammatory cytokine interleukin 1ß (IL-1ß) in the PFC. In a second experiment, administration of testosterone during the adolescent period largely recapitulated the effects of adolescent sexual experience. These data support the overall hypothesis that a sensitive period extends into adolescence and that salient social stimuli during this time can significantly and persistently alter adult phenotype.