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1.
Dev Psychobiol ; 66(1): e22444, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38131238

RESUMO

Exercise is known to promote efficient function of stress circuitry. The developing brain is malleable and thus exercise during adolescence could potentially exert lasting beneficial effects on the stress response that would be detectable in adulthood. The current study determined whether adolescent wheel running was associated with reduced stress response in adulthood, 6 weeks after cessation of exercise. Male and female adolescent rats voluntarily ran for 6 weeks and then were sedentary for 6 weeks prior to 10 days of chronic restraint stress in adulthood. Fecal corticosterone levels were measured during stress, and escape from the restraint tube was assessed on the final day as a proxy for depressive-like behavior. Anxiety-like behavior was measured 24 h later with the elevated plus maze and locomotor behaviors with the open field. Brain and body measurements were taken immediately following behavioral testing. Developmental exercise and adulthood stress both exerted independent effects on physiological and behavioral outcomes in adulthood. Exercise history increased the odds ratio of escape from restraint stress in males, but did not influence other stress-induced behaviors. In summary, exercise early in life exerted lasting effects, but did not substantially alter the adulthood response to restraint stress.


Assuntos
Atividade Motora , Restrição Física , Ratos , Masculino , Feminino , Animais , Atividade Motora/fisiologia , Ansiedade , Corticosterona , Encéfalo , Estresse Psicológico
2.
J Stud Alcohol Drugs ; 84(1): 137-146, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36799684

RESUMO

OBJECTIVE: Evidence indicates a counterintuitive positive relationship between physical activity and alcohol consumption, suggesting that people who engage in more physical activity consume more alcohol. Impulsivity, which has a well-documented role in alcohol use disorders, has been shown to moderate the between-person physical activity-drinking association among emerging adults. However, only a handful of studies have explored within-person associations of physical activity and drinking and potential moderators of this relationship. The current study evaluated the effects of both subjective and behavioral impulsivity on the within- and between-person association between physical activity and alcohol consumption among college students. METHOD: Undergraduate students (N = 250) between ages 18 and 25 years were asked to report their daily physical activity and drinking over 21 days. Physical activity was also recorded objectively through Pacer, a smartphone app. Subjective impulsivity was assessed using the UPPS-P Impulsive Behavior Scale, and behavioral impulsivity was evaluated using the Balloon Analogue Risk Task. RESULTS: Within- and between-subject physical activity-drinking associations were differentially moderated by behavioral impulsivity and self-reported impulsivity. For instance, behavioral impulsivity moderated the within-person association between drinking and self-reported vigorous physical activity, whereas negative urgency moderated the between-person association between drinking and objective physical activity. CONCLUSIONS: Impulsivity, whether measured subjectively or behaviorally, significantly moderates the physical activity-alcohol consumption association. Importantly, this effect operates differently when predicting variation in behavior within individuals as compared with predicting differences in behavior between individuals.


Assuntos
Alcoolismo , Adulto , Humanos , Adolescente , Adulto Jovem , Consumo de Bebidas Alcoólicas/epidemiologia , Comportamento Impulsivo , Autorrelato , Exercício Físico
3.
Psychol Addict Behav ; 37(2): 285-293, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34941330

RESUMO

OBJECTIVE: Recent research has revealed positive associations between alcohol use and physical activity. However, findings from these studies have been inconsistent, and longitudinal designs have been underutilized. Therefore, the present study examined longitudinal associations between physical activity and alcohol use in a sample of young adults. METHOD: This study is a secondary analysis of 383 college students (57% female) who reported their drinking behaviors at 3-month assessments over an approximately 2-year period. Self-reported physical activity was examined for the first 9 months, and drinking was assessed over 21 months. RESULTS: Analyses revealed that increases in the intensity of physical activity over the first 9 months predicted increases in drinking over the same time period; however, predictions over the subsequent year were nonsignificant. Conversely, increases in alcohol use over the first 9 months were associated with concurrent increases in duration of physical activity. CONCLUSIONS: Results extend previous cross-sectional research findings by indicating that positive associations between physical activity and alcohol use also are found longitudinally. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Assuntos
Consumo de Álcool na Faculdade , Consumo de Bebidas Alcoólicas , Humanos , Feminino , Adulto Jovem , Masculino , Consumo de Bebidas Alcoólicas/epidemiologia , Estudos Transversais , Exercício Físico , Autorrelato , Universidades
4.
Neuroscience ; 487: 166-183, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35167938

RESUMO

The Munc13 family of proteins is critically involved in synaptic vesicle priming and release in glutamatergic neurons in the brain. Munc13-1 binds to alcohol and, in Drosophila, modulates sedation sensitivity and self-administration. We examined the effect of alcohol consumption on the expression of Munc13-1 and Munc13-2, NMDA receptor subunits GluN1, GluN2A and GluN2B in the hippocampus-derived HT22 cells, hippocampal primary neuron culture, and wild-type and Munc13-1+/- male mouse hippocampus after ethanol consumption (Drinking in the Dark (DID) paradigm). In HT22 cells, Munc13-1 was upregulated following 25 mM ethanol treatment for 24 h. In the primary neuronal culture, however, the expression of both Munc13-1 and Munc13-2 increased after ethanol exposure. While Munc13-1 was upregulated in the hippocampus, Munc13-2 was downregulated following DID. This differential effect was found in the CA1 subfield of the hippocampus. Although Munc13-1+/- mice had approximately 50% Munc13-1 expression compared to wild-type, it was nonetheless significantly increased following DID. Munc13-1 and Munc13-2 were expressed in vesicular glutamate transporter1 (VGLUT1) immunoreactive neurons in the hippocampus, but ethanol did not alter the expression of VGLUT1. The NMDA receptor subunits, GluN1, GluN2A and GluN2B were upregulated in the hippocampal primary culture and in the CA1. Ethanol exerts a differential effect on the expression of Munc13-1 and Munc13-2 in the CA1 in male mice. Our study also found that ethanol's effect on Munc13 expression is dependent on the experimental paradigm, and both Munc13-1 and Munc13-2 could contribute to the ethanol-induced augmentation of glutamatergic neurotransmission.


Assuntos
Consumo de Bebidas Alcoólicas , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas do Tecido Nervoso , Receptores de N-Metil-D-Aspartato , Animais , Drosophila/metabolismo , Etanol/farmacologia , Hipocampo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Masculino , Camundongos , Proteínas do Tecido Nervoso/biossíntese , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica
5.
Brain Sci ; 11(9)2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34573270

RESUMO

Binge alcohol consumption and alcohol use disorders (AUD) are prevalent, and there is comorbidity with depression and anxiety. Potential underlying mechanisms include neurophysiological, genetic, and metabolic changes resulting from alcohol exposure. Mood and anxiety disorders are more common among women, but whether females are more susceptible to binge-induced oxidative stress and co-occurring anxiety and depression-like behaviors remains unknown. Here, we used a repeated, weekly binge alcohol paradigm in male and female rats to investigate sex differences in despair and anxiety-like behaviors and brain oxidative stress parameters. A single binge alcohol exposure significantly elevated glutathione (GSH) levels in prefrontal cortex (PFC) of both male and female animals. This was accompanied by increased lipid peroxidation in PFC of both sexes. Repeated (once weekly) binge exposure induced changes in anxiety- and depression-like behaviors in both males and females and increased GSH level in the PFC without detectable oxidative damage. Our findings suggest that repeated binge alcohol exposure influences affect regardless of sex and in the absence of membrane damage.

6.
Front Behav Neurosci ; 15: 680042, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177480

RESUMO

The recognition of novel objects is a common cognitive test for rodents, but current paradigms have limitations, such as low sensitivity, possible odor confounds and stress due to being performed outside of the homecage. We have developed a paradigm that takes place in the homecage and utilizes four stimuli per trial, to increase sensitivity. Odor confounds are eliminated because stimuli consist of inexpensive, machined wooden beads purchased in bulk, so each experimental animal has its own set of stimuli. This paradigm consists of three steps. In Step 1, the sampling phase, animals freely explore familiar objects (FO). Novel Objects (NO1 and NO2) are soiled with bedding from the homecage, to acquire odor cues identical to those of the FO. Steps 2 and 3 are test phases. Herein we report results of this paradigm from neurologically intact adult rats and mice of both sexes. Identical procedures were used for both species, except that the stimuli used for the mice were smaller. As expected in Step 2 (NO1 test phase), male and female rats and mice explored NO1 significantly more than FO. In Step 3 (NO2 test phase), rats of both sexes demonstrated a preference for NO2, while this was seen only in female mice. These results indicate robust novelty recognition during Steps 2 and 3 in rats. In mice, this was reliably seen only in Step 2, indicating that Step 3 was difficult for them under the given parameters. This paradigm provides flexibility in that length of the sampling phase, and the delay between test and sampling phases can be adjusted, to tailor task difficulty to the model being tested. In sum, this novel object recognition test is simple to perform, requires no expensive supplies or equipment, is conducted in the homecage (reducing stress), eliminates odor confounds, utilizes 4 stimuli to increase sensitivity, can be performed in both rats and mice, and is highly flexible, as sampling phase and the delay between steps can be adjusted to tailor task difficulty. Collectively, these results indicate that this paradigm can be used to quantify novel object recognition across sex and species.

7.
Alcohol Clin Exp Res ; 45(2): 365-374, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33295022

RESUMO

BACKGROUND: Binge drinking, characterized by brief periods of high intoxication interspersed with periods of abstinence, appears to be particularly damaging to the brain. Binge drinking is increasing among American women, yet few preclinical studies have assessed sex differences in the neurobehavioral effects of binge alcohol. METHODS: Adult Long-Evans rats were administered 4 g/kg ethanol (EtOH; or an isocaloric control dose) via intragastric gavage once-weekly. Brains were collected after 3 or 8 binge doses, and immunohistochemistry for mature neurons (NeuN), microglia (Iba1), neurogenesis (DCX), and reactive astrogliosis (vimentin) performed. Stereology was used to quantify target cell populations in the hippocampus and medial prefrontal cortex (mPFC). In a separate cohort of animals, cognition (spatial navigation and reversal learning), affect (tickling-evoked ultrasonic vocalizations), and task-induced c-fos activation were assessed after 3 or 8 binge doses. RESULTS: Blood EtOH concentration did not differ significantly between females (175 ± 3.6 mg/dl) and males (180 ± 3.7 mg/dl) and did not change significantly over time, indicating that tolerance did not develop. After 3 or 8 binge doses, the number of granule neurons in the hippocampal dentate gyrus of both sexes was significantly reduced in comparison with controls, although there was no binge effect on newly generated neurons. Moreover, 8 (but not 3) binge doses significantly increased the total number of microglia and the number of partially activated microglia in the hippocampus and mPFC in both sexes. There was no detectable reactive astrogliosis (vimentin) in either region at any timepoint. There was no effect of binge alcohol on behavior outcomes in either sex, but binged rats showed increased cellular activation in the mPFC following reversal learning. CONCLUSIONS: Our data indicate that recurrent binge alcohol results in similar neural damage and neuroimmune activation in alcohol-vulnerable corticolimbic brain regions in males and females.


Assuntos
Consumo Excessivo de Bebidas Alcoólicas/imunologia , Etanol/toxicidade , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/imunologia , Animais , Consumo Excessivo de Bebidas Alcoólicas/patologia , Proteína Duplacortina , Feminino , Hipocampo/patologia , Masculino , Córtex Pré-Frontal/patologia , Ratos , Ratos Long-Evans , Caracteres Sexuais , Memória Espacial/efeitos dos fármacos , Memória Espacial/fisiologia
8.
Brain Plast ; 6(1): 5-25, 2020 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-33680843

RESUMO

Historically, most alcohol neurotoxicity studies were conducted in young adult males and focused on chronic intake. There has been a shift towards studying the effects of alcohol on the adolescent brain, due to alcohol consumption during this formative period disrupting the brain's developmental trajectory. Because the most typical pattern of adolescent alcohol intake is heavy episodic (binge) drinking, there has also been a shift towards the study of binge alcohol-induced neurobehavioral toxicity. It has thus become apparent that binge alcohol damages the adolescent brain and there is increasing attention to sex-dependent effects. Significant knowledge gaps remain in our understanding of the effects of binge alcohol on the female brain, however. Moreover, it is unsettling that population-level studies indicate that the prevalence of binge drinking is increasing among American women, particularly those in older age groups. Although study of adolescents has made it apparent that binge alcohol disrupts ongoing brain maturational processes, we know almost nothing about how it impacts the aging brain, as studies of its effects on the aged brain are relatively scarce, and the study of sex-dependent effects is just beginning. Given the rapidly increasing population of older Americans, it is crucial that studies address age-dependent effects of binge alcohol, and given the increase in binge drinking in older women who are at higher risk for cognitive decline relative to men, studies must encompass both sexes. Because adolescence and older age are both characterized by age-typical brain changes, and because binge drinking is the most common pattern of alcohol intake in both age groups, the knowledge that we have amassed on binge alcohol effects on the adolescent brain can inform our study of its effects on the aging brain. In this review, we therefore cover the current state of knowledge of sex and age-dependent effects of binge alcohol, as well as statistical and methodological considerations for studies aimed at addressing them.

9.
Alcohol ; 83: 89-97, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31265903

RESUMO

The role of the munc13-1 presynaptic protein in alcohol-related behaviors has been little-studied, despite being a known site of action for ethanol binding. Munc13-1 is an active zone protein that plays a vital role in vesicle maturation and the release of neurotransmitters in excitatory neurons. Ethanol binds munc13-1, which decreases its functionality. In Drosophila, loss of the homologous protein Dunc13 is associated with an increase in ethanol preference, and is associated with a resistance to sedation following ethanol exposure. The current study assessed the effects of munc13-1 heterozygosity on ethanol sensitivity and consumption in mice, as well as on learning and anxiety-like behaviors, which can influence alcohol intake. Wild-type and mutant mice underwent 6 cycles of drinking-in-the-dark (DID) as well as rotarod testing following ethanol injection, to probe for differences in ethanol consumption and sensitivity, respectively. We did not detect genotype-based differences in our measures of anxiety, spatial learning, ethanol consumption, or ethanol sensitivity. However, heterozygotes showed increased use of a spatial navigation strategy in a dual-solution water maze, as opposed to a stimulus-response strategy. To summarize, although reduction of Dunc13 in flies produces clear effects on ethanol consumption and sensitivity, heterozygosity for munc13-1 does not, potentially due to compensatory adaptation by other munc-13 isoforms.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Etanol/administração & dosagem , Heterozigoto , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Animais , Ansiedade , Cruzamentos Genéticos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Teste do Labirinto Aquático de Morris , Atividade Motora/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos
10.
Int Rev Neurobiol ; 147: 219-267, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31607356

RESUMO

There are vast literatures on the neural effects of alcohol and the neural effects of exercise. Simply put, exercise is associated with brain health, alcohol is not, and the mechanisms by which exercise benefits the brain directly counteract the mechanisms by which alcohol damages it. Although a degree of brain recovery naturally occurs upon cessation of alcohol consumption, effective treatments for alcohol-induced brain damage are badly needed, and exercise is an excellent candidate from a mechanistic standpoint. In this chapter, we cover the small but growing literature on the interactive neural effects of alcohol and exercise, and the capacity of exercise to repair alcohol-induced brain damage. Increasingly, exercise is being used as a component of treatment for alcohol use disorders (AUD), not because it reverses alcohol-induced brain damage, but because it represents a rewarding, alcohol-free activity that could reduce alcohol cravings and improve comorbid conditions such as anxiety and depression. It is important to bear in mind, however, that multiple studies attest to a counterintuitive positive relationship between alcohol intake and exercise. We therefore conclude with cautionary notes regarding the use of exercise to repair the brain after alcohol damage.


Assuntos
Alcoolismo/complicações , Alcoolismo/terapia , Dano Encefálico Crônico/etiologia , Dano Encefálico Crônico/terapia , Encéfalo/efeitos dos fármacos , Etanol/efeitos adversos , Terapia por Exercício/métodos , Humanos
11.
Int J Dev Neurosci ; 78: 147-155, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31229526

RESUMO

Exercise is known to produce a myriad of positive effects on the brain, including increased glia, neurons, blood vessels, white matter and dendritic complexity. Such effects are associated with enhanced cognition and stress resilience in humans and animal models. As such, exercise represents a positive experience with tremendous potential to influence brain development and shape an adult brain capable of responding to life's challenges. Although substantial evidence attests to the benefits of exercise for cognition in children and adolescents, the vast majority of existing studies examine acute effects. Nonetheless, there is emerging evidence indicating that exercise during development has positive cognitive and neural effects that last to adulthood. There is, therefore, a compelling need for studies designed to determine the extent to which plasticity driven by developmental exercise translates into enhanced brain health and function in adulthood and the underlying mechanisms. Such studies are particularly important given that modern Western society is increasingly characterized by sedentary behavior, and we know little about how this impacts the brain's developmental trajectory. This review synthesizes current literature and outlines significant knowledge gaps that must be filled in order to elucidate what exercise (or lack of exercise) during development contributes to the health and function of the adult brain.


Assuntos
Encéfalo/fisiologia , Desenvolvimento Infantil/fisiologia , Cognição/fisiologia , Exercício Físico/fisiologia , Neurônios/fisiologia , Criança , Dendritos/fisiologia , Humanos , Atividade Motora/fisiologia , Neuroglia/fisiologia
12.
Neuropharmacology ; 148: 272-283, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30659841

RESUMO

Binge drinking is becoming increasingly common among American women and girls. We have previously shown significant cell loss, downregulation of neurotrophins and microgliosis in female rats after a single 4-day ethanol exposure. To determine whether recurrent binge exposure would produce similar effects, we administered ethanol (5 g/kg) or iso-caloric control diet once-weekly for 11 weeks to adult female rats. As we have previously shown exercise neuroprotection against binge-induced damage, half the rats were given access to exercise wheels. Blood ethanol concentration (BEC) did not differ between sedentary and exercised groups, nor did it change across time. Using stereology, we quantified the number and/or size of neurons in the medial prefrontal cortex (mPFC) and hippocampal dentate gyrus (DG), as well as the number and activation state of microglia. Binged sedentary rats had significant cell loss in the dentate gyrus, but exercise eliminated this effect. Compared to sedentary controls, sedentary binged rats and all exercised rats showed increased neurogenesis in the DG. Number and nuclear volume of neurons in the mPFC were not changed. In the hippocampus and mPFC, the number of microglia with morphology indicative of partial activation was increased by recurrent binge ethanol and decreased by exercise. In summary, we show significant binge-induced loss of DG granule neurons despite increased neurogenesis, suggesting an unsuccessful compensatory response. Although exercise eliminated cell loss, our results indicate that infrequent, but recurrent exposure to clinically relevant BEC is neurotoxic.


Assuntos
Consumo Excessivo de Bebidas Alcoólicas/patologia , Giro Denteado/patologia , Etanol/farmacologia , Neurogênese/efeitos dos fármacos , Neurônios/patologia , Animais , Comportamento Animal/efeitos dos fármacos , Contagem de Células , Etanol/sangue , Feminino , Microglia/efeitos dos fármacos , Atividade Motora , Córtex Pré-Frontal/patologia , Ratos , Comportamento Sedentário
13.
Front Behav Neurosci ; 12: 158, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30116180

RESUMO

Although an effective treatment for pediatric brain tumors, cranial radiation therapy (CRT) damages surrounding healthy tissue, thereby disrupting brain development. Animal models of pediatric CRT have primarily relied on visual tasks to assess cognitive impairment. Moreover, there has been a lack of sex comparisons as most research on the cognitive effects of pediatric CRT does not include females. Therefore, we utilized olfaction, an ethologically relevant sensory modality, to assess cognitive impairment in an animal model of CRT that included both male and female mice. Specifically, we used the novel odor recognition (NOdorR) task with social odors to test recognition memory, a cognitive parameter that has been associated with olfactory neurogenesis, a form of cellular plasticity damaged by CRT. In addition to odor recognition memory, olfactory ability or discrimination of non-social and social odors were assessed both acutely and 3 months after CRT. Magnetic resonance imaging (MRI) and histology were performed after behavioral testing to assess long-term damage by CRT. Long-term but not acute radiation-induced impairment in odor recognition memory was observed, consistent with delayed onset of cognitive impairment in human patients. Males showed greater exploration of social odors than females, but general exploration was not affected by irradiation. However, irradiated males had impaired odor recognition memory in adulthood, compared to non-irradiated males (or simply male controls). Female olfactory recognition memory, in contrast, was dependent on estrus stage. CRT damage was demonstrated by (1) histological evaluation of olfactory neurogenesis, which suggested a reduction in CRT versus control, and (2) imaging analyses which showed that the majority of brain regions were reduced in volume by CRT. Specifically, two regions involved in social odor processing (amygdala and piriform cortex) were damaged by cranial irradiation in males but not females, paralleling olfactory recognition findings.

14.
eNeuro ; 5(3)2018.
Artigo em Inglês | MEDLINE | ID: mdl-29911175

RESUMO

Ethanol has robust effects on presynaptic activity in many neurons, however, it is not yet clear how this drug acts within this compartment to change neural activity, nor the significance of this change on behavior and physiology in vivo. One possible presynaptic effector for ethanol is the Munc13-1 protein. Herein, we show that ethanol binding to the rat Munc13-1 C1 domain, at concentrations consistent with binge exposure, reduces diacylglycerol (DAG) binding. The inhibition of DAG binding is predicted to reduce the activity of Munc13-1 and presynaptic release. In Drosophila, we show that sedating concentrations of ethanol significantly reduce synaptic vesicle release in olfactory sensory neurons (OSNs), while having no significant impact on membrane depolarization and Ca2+ influx into the presynaptic compartment. These data indicate that ethanol targets the active zone in reducing synaptic vesicle exocytosis. Drosophila, haploinsufficent for the Munc13-1 ortholog Dunc13, are more resistant to the effect of ethanol on presynaptic inhibition. Genetically reducing the activity of Dunc13 through mutation or expression of RNAi transgenes also leads to a significant resistance to the sedative effects of ethanol. The neuronal expression of Munc13-1 in heterozygotes for a Dunc13 loss-of-function mutation can largely rescue the ethanol sedation resistance phenotype, indicating a conservation of function between Munc13-1 and Dunc13 in ethanol sedation. Hence, reducing Dunc13 activity leads to naïve physiological and behavioral resistance to sedating concentrations of ethanol. We propose that reducing Dunc13 activity, genetically or pharmacologically by ethanol binding to the C1 domain of Munc13-1/Dunc13, promotes a homeostatic response that leads to ethanol tolerance.


Assuntos
Proteínas de Drosophila/metabolismo , Etanol/administração & dosagem , Hipnóticos e Sedativos/administração & dosagem , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Animais , Drosophila , Feminino , Masculino , Neurônios/metabolismo , Sinapses/metabolismo , Vesículas Sinápticas/metabolismo
15.
Physiol Behav ; 188: 79-85, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29407478

RESUMO

Excessive alcohol intake is associated with a multitude of health risks, especially for women. Recent studies in animal models indicate that the female brain is more negatively affected by alcohol, compared to the male brain. Among other regions, excessive alcohol consumption damages the frontal cortex, an area important for many functions and decision making of daily life. The objective of the present study was to determine whether the medial prefrontal cortex (mPFC) in female rats is selectively vulnerable to alcohol-induced damage. In humans, loss of prefrontal grey matter resulting from heavy alcohol consumption has been documented, however this volume loss is not necessarily due to a decrease in the number of neurons. We therefore quantified both number and nuclear volume of mPFC neurons following binge alcohol, as well as performance and neuronal activation during a prefrontal-dependent behavioral task. Adult male and female Long-Evans rats were assigned to binge or control groups and exposed to ethanol using a well-established 4-day model of alcohol-induced neurodegeneration. Both males and females had significantly smaller average neuronal nuclei volumes than their respective control groups immediately following alcohol binge, but neither sex showed a decrease in neuron number. Binged rats of both sexes initially showed spatial working memory deficits. Although they eventually achieved control performance, binged rats of both sexes showed increased c-Fos labeling in the mPFC during rewarded alternation, suggesting decreased neural efficiency. Overall, our results substantiate prior evidence indicating that the frontal cortex is vulnerable to alcohol, but also indicate that sex-specific vulnerability to alcohol may be brain region-dependent.


Assuntos
Depressores do Sistema Nervoso Central/administração & dosagem , Etanol/administração & dosagem , Memória de Curto Prazo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Córtex Pré-Frontal/citologia , Caracteres Sexuais , Paladar/efeitos dos fármacos , Consumo de Bebidas Alcoólicas , Animais , Contagem de Células , Depressores do Sistema Nervoso Central/farmacologia , Relação Dose-Resposta a Droga , Feminino , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Memória Espacial , Síndrome de Abstinência a Substâncias/patologia , Síndrome de Abstinência a Substâncias/fisiopatologia
16.
Brain Struct Funct ; 223(1): 195-210, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28752318

RESUMO

Compared to men, women disproportionally experience alcohol-related organ damage, including brain damage, and while men remain more likely to drink and to drink heavily, there is cause for concern because women are beginning to narrow the gender gap in alcohol use disorders. The hippocampus is a brain region that is particularly vulnerable to alcohol damage, due to cell loss and decreased neurogenesis. In the present study, we examined sex differences in hippocampal damage following binge alcohol. Consistent with our prior findings, we found a significant binge-induced decrement in dentate gyrus (DG) granule neurons in the female DG. However, in the present study, we found no significant decrement in granule neurons in the male DG. We show that the decrease in granule neurons in females is associated with both spatial navigation impairments and decreased expression of trophic support molecules. Finally, we show that post-binge exercise is associated with an increase in trophic support and repopulation of the granule neuron layer in the female hippocampus. We conclude that sex differences in alcohol-induced hippocampal damage are due in part to a paucity of trophic support and plasticity-related signaling in females.


Assuntos
Alcoolismo , Transtornos Cognitivos/etiologia , Hipocampo/patologia , Caracteres Sexuais , Alcoolismo/complicações , Alcoolismo/metabolismo , Alcoolismo/patologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação a CREB/metabolismo , Modelos Animais de Doenças , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Etanol/toxicidade , Comportamento Exploratório/fisiologia , Feminino , Fluoresceínas/metabolismo , Marcação In Situ das Extremidades Cortadas , Fator de Crescimento Insulin-Like I/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Aprendizagem em Labirinto/fisiologia , Condicionamento Físico Animal , Ratos , Ratos Long-Evans , Navegação Espacial/fisiologia
17.
Neuro Oncol ; 20(5): 695-704, 2018 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-29121259

RESUMO

Background: While cranial radiation therapy (CRT) is an effective treatment, healthy areas surrounding irradiation sites are negatively affected. Frontal lobe functions involving attention, processing speed, and inhibition control are impaired. These deficits appear months to years after CRT and impair quality of life. Exercise has been shown to rejuvenate the brain and aid in recovery post-injury through its effects on neurogenesis and cognition. Methods: We developed a juvenile rodent CRT model that reproduces neurocognitive deficits. Next, we utilized the model to test whether exercise ameliorates these deficits. Fischer rats (31 days old) were irradiated with a fractionated dose of 4 Gy × 5 days, trained and tested at 6, 9, and 12 months post-CRT using 5-choice serial reaction time task. After testing, fixed rat brains were imaged using diffusion tensor imaging and immunohistochemistry. Results: CRT caused early and lasting impairments in task acquisition, accuracy, and latency to correct response, as well as causing stunting of growth and changes in brain volume and diffusion. Exercising after irradiation improved acquisition, behavioral control, and processing speed, mitigated the stunting of brain size, and increased brain fiber numbers compared with sedentary CRT values. Further, exercise partially restored global connectome organization, including assortativity and characteristic path length, and while it did not improve the specific regional connections that were lowered by CRT, it appeared to remodel these connections by increasing connectivity between alternate regional pairs. Conclusions: Our data strongly suggest that exercise may be useful in combination with interventions aimed at improving cognitive outcome following pediatric CRT.


Assuntos
Encéfalo/patologia , Transtornos Cognitivos/prevenção & controle , Irradiação Craniana/efeitos adversos , Modelos Animais de Doenças , Neurogênese/efeitos da radiação , Condicionamento Físico Animal/métodos , Animais , Animais Recém-Nascidos , Encéfalo/efeitos da radiação , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Imagem de Tensor de Difusão/métodos , Masculino , Ratos , Ratos Endogâmicos F344
18.
Brain Sci ; 7(10)2017 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-29064447

RESUMO

The female brain appears selectively vulnerable to the neurotoxic effects of alcohol, but the reasons for this are unclear. One possibility is an exaggerated neuroimmune response in the female brain, such that alcohol increases microglia number and reactivity to subsequent stimuli, such as exercise. It is important to better characterize the interactive neural effects of alcohol and exercise, as exercise is increasingly being used in the treatment of alcohol use disorders. The present study compared the number of microglia and evidence of their activation in alcohol-vulnerable regions of the brain (medial prefrontal cortex and hippocampus) in male and female rats following binge alcohol and/or exercise. Binge alcohol increased microglia number and morphological characteristics consistent with their activation in the female brain but not the male, regardless of exercise. Binge alcohol followed by exercise did increase the number of MHC II+ (immunocompetent) microglia in females, although the vast majority of microglia did not express MHC II. These results indicate that binge alcohol exerts sex-specific effects on microglia that may result in enhanced reactivity to a subsequent challenge and in part underlie the apparent selective vulnerability of the female brain to alcohol.

19.
Neuroscience ; 343: 165-173, 2017 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-27932309

RESUMO

Exercise is increasingly being used as a treatment for alcohol use disorders (AUD), but the interactive effects of alcohol and exercise on the brain remain largely unexplored. Alcohol damages the brain, in part by altering glial functioning. In contrast, exercise promotes glial health and plasticity. In the present study, we investigated whether binge alcohol would attenuate the effects of subsequent exercise on glia. We focused on the medial prefrontal cortex (mPFC), an alcohol-vulnerable region that also undergoes neuroplastic changes in response to exercise. Adult female Long-Evans rats were gavaged with ethanol (25% w/v) every 8h for 4days. Control animals received an isocaloric, non-alcohol diet. After 7days of abstinence, rats remained sedentary or exercised for 4weeks. Immunofluorescence was then used to label microglia, astrocytes, and neurons in serial tissue sections through the mPFC. Confocal microscope images were processed using FARSIGHT, a computational image analysis toolkit capable of automated analysis of cell number and morphology. We found that exercise increased the number of microglia in the mPFC in control animals. Binged animals that exercised, however, had significantly fewer microglia. Furthermore, computational arbor analytics revealed that the binged animals (regardless of exercise) had microglia with thicker, shorter arbors and significantly less branching, suggestive of partial activation. We found no changes in the number or morphology of mPFC astrocytes. We conclude that binge alcohol exerts a prolonged effect on morphology of mPFC microglia and limits the capacity of exercise to increase their numbers.


Assuntos
Consumo Excessivo de Bebidas Alcoólicas/fisiopatologia , Microglia/fisiologia , Atividade Motora/fisiologia , Plasticidade Neuronal/fisiologia , Córtex Pré-Frontal/fisiopatologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Astrócitos/fisiologia , Automação Laboratorial , Consumo Excessivo de Bebidas Alcoólicas/patologia , Consumo Excessivo de Bebidas Alcoólicas/terapia , Contagem de Células , Depressores do Sistema Nervoso Central/toxicidade , Modelos Animais de Doenças , Etanol/toxicidade , Terapia por Exercício , Feminino , Imunofluorescência , Processamento de Imagem Assistida por Computador , Microglia/efeitos dos fármacos , Microglia/patologia , Microscopia Confocal , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/patologia , Distribuição Aleatória , Ratos Long-Evans , Comportamento Sedentário
20.
Neural Plast ; 2016: 3259621, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27242931

RESUMO

Cranial radiotherapy (CRT) increases survival in pediatric brain-tumor patients but can cause deleterious effects. This study evaluates the acute and long-term impact of CRT delivered during childhood/adolescence on the brain and body using a rodent model. Rats received CRT, either 4 Gy fractions × 5 d (fractionated) or a cumulative dose of 20 Gy (single dose) at 28 d of age. Animals were euthanized 1 d, 5 d, or 3.5 mo after CRT. The 3.5 mo group was imaged prior to euthanasia. At 3.5 mo, we observed significant growth retardation in irradiated animals, versus controls, and the effects of single dose on brain and body weights were more severe than fractionated. Acutely single dose significantly reduced body weight but increased brain weight, whereas fractionation significantly reduced brain but not body weights, versus controls. CRT suppressed cell proliferation in the hippocampal subgranular zone acutely. Fractional anisotropy (FA) in the fimbria was significantly lower in the single dose versus controls. Hippocampal metabolite levels were significantly altered in the single dose animals, reflecting a heightened state of inflammation that was absent in the fractionated. Our findings indicate that despite the differences in severity between the doses they both demonstrated an effect on cell proliferation and growth retardation, important factors in pediatric CRT.


Assuntos
Peso Corporal/efeitos da radiação , Proliferação de Células/efeitos da radiação , Irradiação Craniana/efeitos adversos , Transtornos do Crescimento/etiologia , Hipocampo/efeitos da radiação , Animais , Transtornos do Crescimento/metabolismo , Hipocampo/metabolismo , Masculino , Ratos , Ratos Wistar
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