Early Life Stress Negatively Impacts Spatial Learning Acquisition and Increases Hippocampal CA1 Microglial Activation After a Mild Traumatic Brain Injury in Adult Male Rats.

Early life stress (ELS) affects neurogenesis and spatial learning, and increases neuroinflammation after a pediatric mild traumatic brain injury (mTBI). Previous studies have shown that ELS has minimal effects in juveniles but shows age-dependent effects in adults. Hence, we aimed to evaluate the effects of ELS in adult male rats after an mTBI. Maternal separation for 180 min per day (MS180) during the first 21 post-natal (P) days was used as the ELS model. At P110, the rats were subjected to a mild controlled cortical impact injury (2.6 mm) or sham surgery. Spatial learning was evaluated in the Morris water maze (MWM) 14 days after surgery and both microglial activation and neurogenesis were quantified. The results indicate that MS180 + mTBI, but not control (CONT) + mTBI, rats show deficiencies in the acquisition of spatial learning. mTBI led to comparable increases in microglial activation in both the hilus and cortical regions for both groups. However, MS180 + mTBI rats exhibited a greater increase in microglial activation in the ipsilateral CA1 hippocampus subfield compared with CONT + mTBI. Interestingly, for the contralateral CA1 region, this effect was observed exclusively in MS180 + mTBI. ELS and mTBI independently caused a decrease in hippocampal neurogenesis and this effect was not increased further in MS180 + mTBI rats. The findings demonstrate that ELS and mTBI synergistically affect cognitive performance and neuroinflammation, thus supporting the hypothesis that increased inflammation resulting from the combination of ELS and mTBI could underlie the observed effects on learning.

Experiencias infantiles adversas y síndrome metabólico en adultos de una unidad de medicina familiar en Michoacán, México / Adverse childhood experiences and metabolic syndrome in adults in a family medicine unit Michoacán, Mexico

Introducción: las experiencias infantiles adversas (EIA) aumentan el riesgo de enfermedades metabólicas en la edad adulta; no obstante, esta relación ha sido poco estudiada en la población mexicana Objetivos: determinar la frecuencia de experiencias infantiles adversas (EIA) y su relación con el síndrome metabólico en personas mayores de 19 años de edad en una unidad de medicina familiar urbana en Michoacán, México. Metodología: se realizó un estudio observacional, retrospectivo, transversal y analítico en 127 participantes mayores de 19 años. Se evaluaron sus medidas antropométricas, y cuantificamos los niveles de glucosa en ayuno, triglicéridos y colesterol HDL en sangre. Aplicamos el cuestionario internacional de experiencias infantiles adversas (ACE-IQ). Utilizamos estadística descriptiva y la prueba de Chi cuadrada. Resultados: el 95% de la muestra reportó al menos una EIA, y la más frecuente fue la violencia doméstica. El 45% de los individuos presentaron síndrome metabólico. No se encontró asociación entre el síndrome metabólico ni los componentes con la exposición a las EIA. No obstante, observamos que el divorcio o pérdida de uno de los padres fue más frecuente en los participantes con síndrome metabólico (p = 0.03). Conclusiones: la frecuencia de EIA fue mucho más alta que lo previamente reportado, pero no se observó una asociación con el síndrome metabólico... (AU)

Introduction: Adverse childhood experiences (ACE) increase the risk of metabolic diseases in adulthood; however, this relationship has been scarcely studied in the Mexican population. Objective: To determine the frequency of adverse childhood experiences and their relationship to metabolic syndrome in an urban Primary Care Unit from Michoacán, México. Methods: An observational, retrospective, cross-sectional and analytical study was performed in 127 participants older than 19 years. Their anthropometric measurements were evaluated, and we quantified the blood levels of fasting glucose, triglycerides, and HDL cholesterol. The Adverse Childhood Experiences International Questionnaire (ACE-IQ) was utilized. We used descriptive statistics and the Chi square test. Results: 95% of the sample reported at least one EIA, and the most frequent was domestic violence. 45% of individuals presented metabolic syndrome. No association was found between the metabolic syndrome or its components with the exposure to EIA. However, we observed that divorce or loss of one of the parents was more frequent in the participants with metabolic syndrome (p = 0.03). Conclusions: The frequency of EIA was much higher than previously reported, however, we did not observe an association of ACE with metabolic... (AU)

Alimentación complementaria en lactantes y su relación con el estado nutricional / Complementary feeding of Mexican infants and its relation to the nutritional status

Background: Apropiate introduction to complementary feeding (CF) decreases the risk of nutritional diseases in infants; however there is a paucity of information about the characteristics of CF in mexican children. Objective: To characterize the complementary feeding of Mexican infants and its relation to the nutritional status. Methodology: Transversal, analytical and retrospective study in dyads that required medical care. We performed a nutritional evaluation of the infants and characterized the type of lactation, type and texture of initial solid foods and the subsequent feeding. Results: Final sample consisted of 141 children in which, 59.6% reported that feeding was provided exclusively with formula and only 40% received breast milk. 14.1% of the infants showed low weight-for-height, 17.7% low weight-for-age, and 24.1% low height-for-age. We observed that 55.3% of the infants did not receive complementary feeding with appropriate texture; 58.9% did not receive the appropriate amount; and 44.7, 62.4% and 11.3% received inappropriate amounts of carbohydrates, proteins and fats respectively. Conclusion: A high proportion of infants do not receive appropriate complementary feeding.

Introducción: La introducción apropiada a la alimentación complementaria (AC) disminuye las enfermedades nutricionales en los niños; sin embargo, actualmente, no contamos con una caracterización apropiada de la AC que reciben los lactantes mexicanos. Objetivo: Caracterizar la alimentación complementaria de los lactantes mexicanos y su relación con el estado nutricional. Métodos: Estudio transversal, analítico, retrospectivo en diadas (madre y lactantes de cinco a 12 meses de edad) que acudieron a la consulta externa en la IMF No 82 y la guardería infantil IMSS 001. Se realizó una valoración nutricional de los niños y se analizó la lactancia, el tipo y textura de los alimentos sólidos de inicio y subsecuentes. Resultados: la muestra consistió en 141 niños. Unicamente el 40% de los lactantes recibían leche materna. 14.1% de los lactantes presentaron bajo peso para la talla, 17.7% bajo peso para la edad y 24.1% baja talla para la edad. Observamos que 55.3% de los niños no recibían alimentación complementaria con textura apropiada; 58.9% no recibían cantidad apropiada; y 44.7%, 62.4% y 11.3% recibían cantidades inapropiadas de carbohidratos, proteínas y grasas respectivamente. Conclusión: nuestros datos indican que una alta proporción de los lactantes no reciben alimentación complementaria apropiada.

Antibiotic-induced microbiota depletion in normally-reared adult rats mimics the neuroendocrine effects of early life stress.

Early life stress induced by maternal separation (MS) causes neuroendocrine, behavioral, and metabolic alterations that are related to gut dysbiosis. MS also increases microglial activation and decreases neurogenesis. Whether these long-term alterations are maintained or worsened in the absence of gut microbiota remains unknown. Hence, this study evaluated the effect of MS symptomatology after antibiotic-induced microbiota depletion (AIMD) in adult rats. Control and maternally separated (3 h per day from postnatal day one to 14, MS180) rats were subjected to AIMD for one month, then assessed for behavioral, metabolic, and neuroendocrine responses. Effects of MS180 and AIMD on gut microbiota were confirmed by qPCR. The data indicate that MS180 caused a passive coping strategy in the forced swimming test and decreased hippocampal neurogenesis. In addition, fasting glucose, cholesterol, and corticosterone levels increased, which correlated with a decrease in Lactobacillus spp counts in the caecum. AIMD also increased immobility in the forced swimming test, decreased hippocampal neurogenesis, and augmented corticosterone levels. However, it had no effects on glucose homeostasis or plasma lipid levels. Furthermore, the MS180-induced long-term effects on behavior and neurogenesis were not affected by microbiota depletion. Meanwhile, the metabolic imbalance was partially reversed in MS180 + AIMD rats. These results show that AIMD mimics the behavioral consequences of MS180 but may prevent metabolic imbalance, suggesting that gut dysbiosis could be part of the mechanisms involved in the maintenance of the long-term consequences of early life stress.

Environmental enrichment improves traumatic brain injury-induced behavioral phenotype and associated neurodegenerative process.

Traumatic brain injury (TBI) causes persistent cognitive impairment and neurodegeneration. Environmental enrichment (EE) refers to a housing condition that promotes sensory and social stimulation and improves cognition and motor performance but the underlying mechanisms responsible for such beneficial effects are not well defined. In this study, anesthetized adult rats received either a moderate-to-severe controlled cortical impact (CCI) or sham surgery and then were housed in either EE or standard conditions. The results showed a significant increase in protein nitration and oxidation of lipids, impaired cognition and motor performance, and augmented N-methyl-d-aspartate receptor subtype-1 (NMDAR1) levels. However, EE initiated 24 h after CCI resulted in reduced oxidative insult and microglial activation and significant improvement in beam-balance/walk performance and both spatial learning and memory. We hypothesize that following TBI there is an upstream activation of NMDAR that promotes oxidative insult and an inflammatory response, thereby resulting in impaired behavioral functioning but EE may exert a neuroprotective effect via sustained downregulation of NMDAR1.

Chronic early-life stress increases cognitive impulsivity and D2 immunoreactivity in the nucleus accumbens of adult rats.

Chronic early life stress (ECS) induced by limited bedding and nesting (LBN) material in rodents is a naturalistic stress model that mimics many of the behavioral and neural consequences of child abuse and neglect; however, the effect of ECS on adult impulsivity has never been studied. The aim of our work was to determine the effects of ECS on cognitive impulsivity and its relation to D2 immunoreactivity in the nucleus accumbens (NAc) and prefrontal cortex (PFC) of adult male rats. Sprague-Dawley rats were exposed to LBN from postnatal day 2 to 9. We evaluated dams' maternal behavior and offspring corticosterone levels. The rats' impulsive cognitive behavior was evaluated by a delay-discounting task (transitional bridge) on P70, and we evaluated D2 receptors by immunostaining. Our results indicated that ECS affected maternal behavior in the dams and increased pups' corticosterone levels at P9, but not in adults. ECS rats showed lower frequencies of choosing the delayed reinforcer and shorter latencies to cross on the delay-discounting task. In addition, ECS rats showed increased D2 immunoreactivity in the NAc when compared with controls. Our data suggest that ECS can cause impulsive behaviors in adult rats characterized by less convenient choices, likely related to an increase in D2 receptors in the NAc. These findings could contribute to our understanding of the effects of child abuse and neglect on impulsive behavior.

Early life stress induces a transient increase in hippocampal corticotropin-releasing hormone in rat neonates that precedes the effects on hypothalamic neuropeptides.

Early life stress (ELS) programs hypothalamus-pituitary-adrenal (HPA) axis activity and affects synaptic plasticity and cognitive performance in adults; however, the effects of ELS during the temporal window of vulnerability are poorly understood. This study aimed to thoroughly characterize the effects of ELS in the form of periodic maternal separation (MS180) during the time of exposure to stress. Hippocampal corticotropin-releasing hormone (CRH) gene expression and baseline HPA axis activity were analyzed at postnatal (P) days 6, 12, 15, and 21, and in adulthood (P75); these factors were correlated with plasticity markers and adult behavior. Our results indicate that MS180 induces an increase in hippocampal CRH expression at P9, P12, and P15, whereas an increase in hypothalamic CRH expression was observed from P12 to P21. Increased arginine-vasopressin expression and corticosterone levels were observed only at P21. Moreover, MS180 caused transient alterations in hypothalamic synaptophysin expression during early life. As adults, MS180 rats showed a passive coping strategy in the forced swimming test, cognitive impairments in the object location test, increased hypothalamic CRH expression, and decreased oxytocin (OXT) expression. Spearman's analysis indicated that cognitive impairments correlated with CRH and OXT expression. In conclusion, our data indicate that MS180 induces a transient increase in hippocampal CRH expression in neonates that precedes the effects on hypothalamic neuropeptides, confirming the role of increased CRH during the temporal window of vulnerability as a mediator of some of the detrimental effects of ELS on brain development and adult behavior.

Early Life Stress Preceding Mild Pediatric Traumatic Brain Injury Increases Neuroinflammation but Does Not Exacerbate Impairment of Cognitive Flexibility during Adolescence.

Early life stress (ELS) followed by pediatric mild traumatic brain injury (mTBI) negatively impacts spatial learning and memory and increases microglial activation in adolescent rats, but whether the same paradigm negatively affects higher order executive function is not known. Hence, we utilized the attentional set-shifting test (AST) to evaluate executive function (cognitive flexibility) and to determine its relationship with neuroinflammation and hypothalamic-pituitary-adrenal (HPA) axis activity after pediatric mTBI in male rats. ELS was induced via maternal separation for 180 min per day (MS180) during the first 21 post-natal (P) days, while controls (CONT) were undisturbed. At P21, fully anesthetized rats received a mild controlled cortical impact (2.2 mm tissue deformation at 4 m/sec) or sham injury. AST was evaluated during adolescence on P35-P40 and cytokine expression and HPA activity were analyzed on P42. The data indicate that pediatric mTBI produced a significant reversal learning deficit on the AST versus sham (p < 0.05), but that the impairment was not exacerbated further by MS180. Additionally, ELS produced an overall elevation in set-loss errors on the AST, and increased hippocampal interleukin (IL)-1ß expression after TBI. A significant correlation was observed in executive dysfunction and IL-1ß expression in the ipsilateral pre-frontal cortex and hippocampus. Although the combination of ELS and pediatric mTBI did not worsen executive function beyond that of mTBI alone (p > 0.05), it did result in increased hippocampal neuroinflammation relative to mTBI (p < 0.05). These findings provide important insight into the susceptibility to incur alterations in cognitive and neuroimmune functioning after stress exposure and TBI during early life.

Early life stress increases vulnerability to the sequelae of pediatric mild traumatic brain injury.

Early life stress (ELS) is a risk factor for many psychopathologies that happen later in life. Although stress can occur in cases of child abuse, studies on non-accidental brain injuries in pediatric populations do not consider the possible increase in vulnerability caused by ELS. Hence, we sought to determine whether ELS increases the effects of pediatric mild traumatic brain injury (mTBI) on cognition, hippocampal inflammation, and plasticity. Male rats were subjected to maternal separation for 180 min per day (MS180) or used as controls (CONT) during the first 21 post-natal (P) days. At P21 the rats were anesthetized with isoflurane and subjected to a mild controlled cortical impact or sham injury. At P32 the rats were injected with the cell proliferation marker bromodeoxyuridine (BrdU, 500 mg/kg), then evaluated for spatial learning and memory in a water maze (P35-40) and sacrificed for quantification of Ki67+, BrdU+ and Iba1+ (P42). Neither MS180 nor mTBI impacted cognitive outcome when provided alone but their combination (MS180 + mTBI) decreased spatial learning and memory relative to Sham controls (p < .01). mTBI increased microglial activation and affected BrdU+ cell survival in the ipsilateral hippocampus without affecting proliferation rates. However, only MS180 + mTBI increased microglial activation in the area adjacent to the injury and the contralateral CA1 hippocampal subfield, and decreased cell proliferation in the ipsilateral neurogenic niche. Overall, the data show that ELS increases the vulnerability to the sequelae of pediatric mTBI and may be mediated by increased neuroinflammation.

Prenatal immobilization stress and postnatal maternal separation cause differential neuroendocrine responses to fasting stress in adult male rats.

Prenatal immobilization stress (PNS) and postnatal maternal separation (MS180) are two widely used rodent models of early-life stress (ELS) that affect the hypothalamus-pituitary-adrenal (HPA) axis, cause behavioral alterations, and affect glucose tolerance in adults. We compared anxiety-like behavior, coping strategies, and HPA axis activity in PNS and MS180 adult (4-month-old) male rats and assessed their glucose tolerance and HPA axis response after mild fasting stress. Both PNS and MS180 induced a passive coping strategy in the forced swimming test, without affecting anxiety-like behavior in the elevated plus-maze. Moreover, both PNS and MS180 increased the hypothalamic corticotropin-releasing hormone expression; however, only MS180 increased the circulating corticosterone levels. Both early life stressors increased fasting glucose levels and this effect was significantly higher in PNS rats. MS180 rats showed impaired glucose tolerance 120 min after intravenous glucose administration, whereas PNS rats displayed an efficient homeostatic response. Moreover, MS180 rats showed higher circulating corticosteroid levels in response to fasting stress (overnight fasting, 12 hr), which were restored after glucose administration. In conclusion, early exposure to postnatal MS180, unlike PNS, increases the HPA axis response to moderate fasting stress, indicating a differential perception of fasting as a stressor in these two ELS models.

Early-life stress increases granule cell density in the cerebellum of male rats.

In rodents, daily maternal separation for 180 min (MS180) during the first weeks of life affects hippocampal granule cell neurogenesis. Development of the cerebellum granule cell layer also occurs during the first weeks of life. However, whether MS180 affects this neurogenic niche remains unknown. To study this, we evaluated the immediate and long term effect of MS180 on granule cell survival within the cerebellum. Pups were injected twice at an 8-hour interval at PND (postnatal day) 5 with bromodeoxyuridine (BrdU, 50 mg/kg) and were sacrificed ten days later (PND15) or allowed to survive into adulthood (PND60). We observed a higher density of BrdU-positive cells in the cerebellar foliae (p < 0.05) of MS180 pups at PND15. This increase was also observed in both, cerebellar foliae and fissures (p < 0.05) at PND60. Triple immunofluorescence staining against BrdU, NeuN (a marker of mature neurons), and GFAP (a marker of mature glia), revealed that BrdU + cells labeled at PND5 co-localized with NeuN but not with GFAP, indicating that they were mature neurons. MS180 did not affect baseline corticosterone levels at PND15 but significantly increased adult corticosterone levels (p < 0.05). In conclusion, MS180 increased cell survival in the granular layer of cerebellar foliae and fissures and resulted in further integration of the cells into adult circuits. These effects occurred without early alterations of basal corticosterone by MS180. Our results indicate that early-life stress induces a permanent increase in cerebellar neurogenesis.

Delayed and Abbreviated Environmental Enrichment after Brain Trauma Promotes Motor and Cognitive Recovery That Is Not Contingent on Increased Neurogenesis.

Environmental enrichment (EE) confers motor and cognitive recovery in pre-clinical models of traumatic brain injury (TBI), and neurogenesis has been attributed to mediating the benefits. Whether that ascription is correct has not been fully investigated. Hence, the goal of the current study is to further clarify the possible role of learning-induced hippocampal neurogenesis on functional recovery after cortical impact or sham injury by utilizing two EE paradigms (i.e., early + continuous, initiated immediately after TBI and presented 24 h/day; and delayed + abbreviated, initiated 4 days after TBI for 6 h/day) and comparing them to one another as well as to standard (STD) housed controls. Motor and cognitive performance was assessed on post-operative Days 1-5 and 14-19, respectively, for the STD and early + continuous EE groups and on Days 4-8 and 17-22, for the delayed + abbreviated EE groups. Rats were injected with bromodeoxyuridine (BrdU, 500 mg/ kg; intraperitoneally) for 3 days (12 h apart) before cognitive training and sacrificed 1 week later for quantification of BrdU+ and doublecortin (DCX+) labeled cells. Both early + continuous and delayed + abbreviated EE promoted motor and cognitive recovery after TBI, relative to STD (p < 0.05), and did not differ from one another (p > 0.05). However, only early + continuous EE increased DCX+ cells beyond the level of STD-housed controls (p < 0.05). No effect of EE on non-injured controls was observed. Based on these data, two novel conclusions emerged. First, EE does not need to be provided early and continuously after TBI to confer benefits, which lends credence to the delayed + abbreviated EE paradigm as a relevant pre-clinical model of neurorehabilitation. Second, the functional recovery observed after TBI in the delayed + abbreviated EE paradigm is not contingent on increased hippocampal neurogenesis. Future studies will elucidate alternate viable mechanisms mediating the benefits induced by EE.

Early life stress accelerates age-induced effects on neurogenesis, depression, and metabolic risk.

Early life stress (ELS) affects hippocampal neurogenesis, increases depressive-like behavior, and causes mild metabolic imbalance in early adulthood (2 months). However, whether these effects worsen in mid life remains unclear. To test whether age-dependent effects of ELS on hippocampal neurogenesis are related to deficient hypothalamic-pituitary-adrenal (HPA) axis feedback that causes increased comorbidity of depression and metabolic risk, we evaluated the effects of periodic maternal separation (MS180) in young (4-months-old) and middle-aged (10-months-old) adult rats. MS180 caused more severe depressive-like behavior in middle-aged adults than in young animals. There were no behavioral phenotypic differences between young MS180 and control middle-aged groups. MS180 similarly affected glucose tolerance, increased fasting corticosterone, insulin, and the quantitative insulin sensitivity check index (QUICKI) at both ages. However, middle-aged adult MS180 rats showed more severe age-induced obesity (>40% BW) than controls (>22% BW). MS180 differentially affected dorsal and ventral neurogenesis. In young adults, MS180 animals only showed a decrease in dorsal hippocampal neurogenesis as compared to their age-matched counterparts. In contrast, at 10 months of age, MS180 caused a similar decrease in both dorsal and ventral hippocampal neurogenesis as compared to age-matched controls, and a more severe decrease as compared to young animals. Taken together, our data indicate that MS180 animals show an early onset of age-induced alterations on depression and metabolic risk, and these effects relate to alterations in hippocampal neurogenesis.

Preclinical Models of Traumatic Brain Injury: Emerging Role of Glutamate in the Pathophysiology of Depression.

More than 10 million people worldwide incur a traumatic brain injury (TBI) each year, with two million cases occurring in the United States. TBI survivors exhibit long-lasting cognitive and affective sequelae that are associated with reduced quality of life and work productivity, as well as mental and emotional disturbances. While TBI-related disabilities often manifest physically and conspicuously, TBI has been linked with a "silent epidemic" of psychological disorders, including major depressive disorder (MDD). The prevalence of MDD post-insult is approximately 50% within the 1st year. Furthermore, given they are often under-reported when mild, TBIs could be a significant overall cause of MDD in the United States. The emergence of MDD post-TBI may be rooted in widespread disturbances in the modulatory role of glutamate, such that glutamatergic signaling becomes excessive and deleterious to neuronal integrity, as reported in both clinical and preclinical studies. Following this acute glutamatergic storm, regulators of glutamatergic function undergo various manipulations, which include, but are not limited to, alterations in glutamatergic subunit composition, release, and reuptake. This review will characterize the glutamatergic functional and signaling changes that emerge and persist following experimental TBI, utilizing evidence from clinical, molecular, and rodent behavioral investigations. Special care will be taken to speculate on how these manipulations may correlate with the development of MDD following injury in the clinic, as well as pharmacotherapies to date. Indisputably, TBI is a significant healthcare issue that warrants discovery and subsequent refinement of therapeutic strategies to improve neurobehavioral recovery and mental health.

Albeit nocturnal, rats subjected to traumatic brain injury do not differ in neurobehavioral performance whether tested during the day or night.

Behavioral assessments in rats are overwhelmingly conducted during the day, albeit that is when they are least active. This incongruity may preclude optimal performance. Hence, the goal of this study was to determine if differences in neurobehavior exist in traumatic brain injured (TBI) rats when assessed during the day vs. night. The hypothesis was that the night group would perform better than the day group on all behavioral tasks. Anesthetized adult male rats received either a cortical impact or sham injury and then were randomly assigned to either Day (1:00-3:00p.m.) or Night (7:30-9:30p.m.) testing. Motor function (beam-balance/walk) was conducted on post-operative days 1-5 and cognitive performance (spatial learning) was assessed on days 14-18. Corticosterone (CORT) levels were quantified at 24h and 21days after TBI. No significant differences were revealed between the TBI rats tested during the Day vs. Night for motor or cognition (p's<0.05). CORT levels were higher in the Night-tested TBI and sham groups at 24h (p<0.05), but returned to baseline and were no longer different by day 21 (p>0.05), suggesting an initial, but transient, stress response that did not affect neurobehavioral outcome. These data suggest that the time rats are tested has no noticeable impact on their performance, which does not support the hypothesis. The finding validates the interpretations from numerous studies conducted when rats were tested during the day vs. their natural active period.

Comparable impediment of cognitive function in female and male rats subsequent to daily administration of haloperidol after traumatic brain injury.

Antipsychotic drugs, such as haloperidol (HAL), are prescribed in the clinic to manage traumatic brain injury (TBI)-induced agitation. While preclinical studies have consistently shown that once-daily administration of HAL hinders functional recovery after TBI in male rats, its effects in females are unknown. Hence, the objective of this study was to directly compare neurobehavioral and histological outcomes in both sexes to determine whether the reported deleterious effects of HAL extend to females. Anesthetized adult female and male rats received either a controlled cortical impact (CCI) or sham injury and then were randomly assigned to a dosing regimen of HAL (0.5mg/kg, i.p.) or vehicle (VEH; 1mL/kg, i.p.) that was initiated 24h after injury and continued once daily for 19 consecutive days. Motor function was tested using established beam-balance/walk protocols on post-operative days 1-5 and acquisition of spatial learning was assessed with a well-validated Morris water maze task on days 14-19. Cortical lesion volume was quantified at 21days. No statistical differences were revealed between the HAL and VEH-treated sham groups and thus they were pooled for each sex. HAL only impaired motor recovery in males (p<0.05), but significantly diminished spatial learning in both sexes (p<0.05). Females, regardless of treatment, exhibited smaller cortical lesions vs VEH-treated males (p<0.05). Taken together, the data show that daily HAL does not prohibit motor recovery in females, but does negatively impact cognition. These task-dependent differential effects of HAL in female vs male rats may have clinical significance as they can direct therapy.

Refining environmental enrichment to advance rehabilitation based research after experimental traumatic brain injury.

The typical environmental enrichment (EE) paradigm, which consists of continuous exposure after experimental traumatic brain injury (TBI), promotes behavioral and histological benefits. However, rehabilitation is often abbreviated in the clinic and administered in multiple daily sessions. While recent studies have demonstrated that a once daily 6-hr bout of EE confers benefits comparable to continuous EE, breaking the therapy into two shorter sessions may increase novelty and ultimately enhance recovery. Hence, the aim of the study was to test the hypothesis that functional and histological outcomes will be significantly improved by daily preclinical neurorehabilitation consisting of two 3-hr periods of EE vs. a single 6-hr session. Anesthetized adult male rats received a controlled cortical impact of moderate-to-severe injury (2.8mm tissue deformation at 4m/s) or sham surgery and were then randomly assigned to groups receiving standard (STD) housing, a single 6-hr session of EE, or two 3-hr sessions of EE daily for 3weeks. Motor function (beam-balance/traversal) and acquisition of spatial learning/memory retention (Morris water maze) were assessed on post-operative days 1-5 and 14-19, respectively. Cortical lesion volume was quantified on day 21. Both EE conditions improved motor function and acquisition of spatial learning, and reduced cortical lesion volume relative to STD housing (p<0.05), but did not differ from one another in any endpoint (p>0.05). The findings replicate previous work showing that 6-hr of EE daily is sufficient to confer behavioral and histological benefits after TBI and extend the findings by demonstrating that the benefits are comparable regardless of how the 6-hrs of EE are accrued. The relevance of the finding is that it can be extrapolated to the clinic and may benefit patients who cannot endure a single extended period of neurorehabilitation.

Galantamine and Environmental Enrichment Enhance Cognitive Recovery after Experimental Traumatic Brain Injury But Do Not Confer Additional Benefits When Combined.

Environmental enrichment (EE) enhances cognition after traumatic brain injury (TBI). Galantamine (GAL) is an acetylcholinesterase inhibitor that also may promote benefits. Hence, the aims of this study were to assess the efficacy of GAL alone (standard [STD] housing) and in combination with EE in adult male rats after TBI. The hypothesis was that both therapies would confer motor, cognitive, and histological benefits when provided singly, but that their combination would be more efficacious. Anesthetized rats received a controlled cortical impact or sham injury, then were randomly assigned to receive GAL (1, 2, or 3 mg/kg; intraperitoneally [i.p.]) or saline vehicle (VEH; 1 mL/kg; i.p.) beginning 24 h after surgery and once daily for 21 days (experiment 1). Motor (beam-balance/walk) and cognitive (Morris water maze [MWM]) assessments were conducted on post-operative Days 1-5 and 14-19, respectively. Cortical lesion volumes were quantified on Day 21. Sham controls were better versus all TBI groups. No differences in motor function or lesion volumes were observed among the TBI groups (p > 0.05). In contrast, GAL (2 mg/kg) enhanced MWM performance versus VEH and GAL (1 and 3 mg/kg; p < 0.05). In experiment 2, GAL (2 mg/kg) or VEH was combined with EE and the data were compared with the STD-housed groups from experiment 1. EE alone enhanced motor performance over the VEH-treated and GAL-treated (2 mg/kg) STD-housed groups (p < 0.05). Moreover, both EE groups (VEH or GAL) facilitated spatial learning and reduced lesion size versus STD + VEH controls (p < 0.05). No additional benefits were observed with the combination paradigm, which does not support the hypothesis. Overall, the data demonstrate that EE and once daily GAL (2 mg/kg) promote cognitive recovery after TBI. Importantly, the combined therapies did not negatively affect outcome and thus this therapeutic protocol may have clinical utility.

Abbreviated environmental enrichment confers neurobehavioral, cognitive, and histological benefits in brain-injured female rats.

Environmental enrichment (EE) promotes behavioral recovery after experimental traumatic brain injury (TBI). However, the chronic rehabilitation provided in the laboratory is not analogous to the clinic where physiotherapy is typically limited. Moreover, females make up approximately 40% of the clinical TBI population, yet they are seldom studied in brain trauma. Hence, the goal of this study was to test the hypothesis that abbreviated EE would confer neurobehavioral, cognitive, and histological benefits in brain injured female rats. Anesthetized rats received a cortical impact of moderate-to-severe injury (2.8mm tissue deformation at 4m/s) or sham surgery and then were randomly assigned to groups receiving standard (STD) housing or 4h, 6h, or 24h of EE daily. Motor function (beam-balance/walk and rotarod) was assessed on post-operative days 1-5 and every other day from 1 to 19, respectively. Spatial learning/memory (Morris water maze) was evaluated on days 14-19, and cortical lesion volume was quantified on day 21. No statistical differences were appreciated among the sham controls in any assessment and thus the data were pooled. All EE conditions improved motor function and memory retention, but only 6h and 24h enhanced spatial learning relative to STD (p<0.05). Moreover, EE, regardless of duration reduced cortical lesion volume (p<0.05). These data confirm that abbreviated EE confers robust neurobehavioral, cognitive, and histological benefits in TBI female rats, which supports the hypothesis and strengthens the utility of EE as a pre-clinical model of neurorehabilitation.

Early Life Stress Increases Metabolic Risk, HPA Axis Reactivity, and Depressive-Like Behavior When Combined with Postweaning Social Isolation in Rats.

Early-life stress is associated with depression and metabolic abnormalities that increase the risk of cardiovascular disease and diabetes. Such associations could be due to increased glucocorticoid levels. Periodic maternal separation in the neonate and rearing in social isolation are potent stressors that increase hypothalamus-pituitary-adrenal axis activity. Moreover, social isolation promotes feed intake and body weight gain in rats subjected to periodic maternal separation; however, its effects on metabolic risks have not been described. In the present study, we evaluated whether periodic maternal separation, social isolation rearing, and a combination of these two stressors (periodic maternal separation + social isolation rearing) impair glucose homeostasis and its relation to the hypothalamus-pituitary-adrenal axis and depressive-like behavior. Periodic maternal separation increased basal corticosterone levels, induced a passive coping strategy in the forced swimming test, and was associated with a mild (24%) increase in fasting glucose, insulin resistance, and dyslipidemia. Rearing in social isolation increased stress reactivity in comparison to both controls and in combination with periodic maternal separation, without affecting the coping strategy associated with the forced swimming test. However, social isolation also increased body weight gain, fasting glucose (120%), and insulin levels in rats subjected to periodic maternal separation. Correlation analyses showed that stress-induced effects on coping strategy on the forced swimming test (but not on metabolic risk markers) are associated with basal corticosterone levels. These findings suggest that maternal separation and postweaning social isolation affect stress and metabolic vulnerability differentially and that early-life stress-related effects on metabolism are not directly dependent on glucocorticoid levels. In conclusion, our study supports the cumulative stress hypothesis, which suggests that metabolic risk markers arise when vulnerable individuals are exposed to social challenges later in life.