Biomedical subjects

Kimberly Nixon

Publications and source records attributed to Kimberly Nixon.

9 recordsLinked to original sources

PubMed2006

Alcohol and adult neurogenesis: roles in neurodegeneration and recovery in chronic alcoholism.

The concept of "structural plasticity" has emerged as a potential mechanism in neurodegenerative and psychiatric diseases such as drug abuse, depression, and dementia. Chronic alcoholism is a progressive neurodegenerative disease while the person continues to abuse alcohol, though clinical and imaging studies show that some recovery may occur with abstinence. The neural plasticity observed in chronic alcoholism coupled with conflicting reports on alcohol-induced hippocampal neuropathology make this disease ripe for reconsideration in terms of the phenomenon of adult neurogenesis. This review describes opposing neurogenic processes that occur with alcohol intoxication and abstinence following alcohol dependence and how these opposing events relate to neurodegeneration and recovery from chronic alcoholism.

Alcohol-Induced Disorders, Nervous System↗

PubMed2006

BHT blocks NF-kappaB activation and ethanol-induced brain damage.

BACKGROUND: Binge ethanol administration causes corticolimbic brain damage that models alcoholic neurodegeneration. The mechanism of binge ethanol-induced degeneration is unknown, but is not simple glutamate-N-methyl-D-aspartate (NMDA) excitotoxicity. To test the hypothesis that oxidative stress and inflammation are mechanisms of binge ethanol-induced brain damage, we administered 4 antioxidants, e.g., butylated hydroxytoluene (BHT), ebselen (Eb), vitamin E (VE), and blueberry (BB) extract, during binge ethanol treatment and assessed various measures of neurodegeneration. METHODS: Adult Sprague-Dawley rats were treated with intragastric ethanol 3 times per day (8-12 g/kg/d) alone or in combination with antioxidants or isocaloric diet for 4 days. Animals were killed, and brains were perfused and extracted for histochemical silver stain determination of brain damage, markers of neurogenesis, or other immunohistochemistry. Some animals were used for determination of nuclear factor kappa B (NF-kappaB)-DNA binding by electrophoretic mobility shift assay (EMSA) or for reverse transcription-polymerase chain reaction (RT-PCR) of cyclooxygenase 2 (COX2). RESULTS: Binge ethanol induced corticolimbic brain damage and reduced neurogenesis. Treatment with BHT reversed binge induced brain damage and blocked ethanol inhibition of neurogenesis in all regions studied. Interestingly, the other antioxidants studied, e.g., Eb, VE, and BB, did not protect against binge-induced brain damage. Binge ethanol treatment also caused microglia activation, increased NF-kappaB-DNA binding and COX2 expression. Butylated hydroxytoluene reduced binge-induced NF-kappaB-DNA binding and COX2 expression. CONCLUSIONS: Binge-induced brain damage and activation of NF-kappaB-DNA binding are blocked by BHT. These studies support a neuroinflammatory mechanism of binge ethanol-induced brain damage.

Animals↗

PubMed2005

Adolescence: booze, brains, and behavior.

This article represents the proceedings of a symposium at the 2004 Research Society on Alcoholism meeting in Vancouver, British Columbia, Canada, organized and chaired by Peter M. Monti and Fulton T. Crews. The presentations and presenters were (1) Introduction, by Peter M. Monti; (2) Adolescent Binge Drinking Causes Life-Long Changes in Brain, by Fulton T. Crews and Kim Nixon; (3) Functional Neuroimaging Studies in Human Adolescent Drinkers, by Susan F. Tapert; (4) Abnormal Emotional Reactivity as a Risk Factor for Alcoholism, by Robert Miranda, Jr.; (5) Alcohol-Induced Memory Impairments, Including Blackouts, and the Changing Adolescent Brain, by Aaron M. White and H. Scott Swartzwelder; and (6) Discussion, by Kenneth Sher.

Adolescent↗

PubMed2005

Chronic alcohol exposure reduces hippocampal neurogenesis and dendritic growth of newborn neurons.

Hippocampal neurogenesis is known as the formation of new neurons from the proliferating neural progenitor cells (NPC) at the dentate gyrus. Cell proliferation, survival, differentiation and maturation are critical stages leading to the generation of healthy neurons. As all of these stages can be influenced by alcohol exposure, we studied the effects of chronic alcohol on each process by immunocytochemistry for stage-specific antigens and prelabelling newborn cells with bromodeoxyuridine (BrdU). Rats were administered alcohol liquid diet or control diet for one, two or four weeks. We found that cell proliferation was inhibited as proliferating cell nuclear antigen (PCNA) expression was reduced by approximately 50% in alcohol-treated animals at all time points. Doublecortin (DCX), a microtubule protein expressed early in differentiating neurons, was progressively decreased over the duration of exposure and significantly reduced after two and four weeks of drinking. Morphological analyses of DCX-positive cells revealed that four weeks of alcohol treatment reduced the size of the dendritic tree including the total length of apical dendrites, number of nodes and endings. Furthermore, BrdU labelling demonstrated a dramatic decrease in cell survival after four weeks of drinking, while cell death was increased by such treatment. Confocal analysis indicated that over 80% of BrdU+ cells colabelled with NeuN suggesting that alcohol reduced neurogenesis. In conclusion, chronic alcohol exposure disrupts neurogenesis by decreasing NPC proliferation, inhibiting cell survival and altering morphological maturation of newborn neurons. These data implicate impaired hippocampal neurogenesis with the cognitive and affective dysfunction associated with chronic alcoholism.

Alcoholism↗

PubMed2004

Temporally specific burst in cell proliferation increases hippocampal neurogenesis in protracted abstinence from alcohol.

Adult neurogenesis is a newly considered form of plasticity that could contribute to brain dysfunction in psychiatric disease. Chronic alcoholism, a disease affecting over 8% of the adult population, produces cognitive impairments and decreased brain volumes, both of which are partially reversed during abstinence. Clinical data and animal models implicate the hippocampus, a region important in learning and memory. In a model of alcohol dependence (chronic binge exposure for 4 d), we show that adult neurogenesis is inhibited during dependence with a pronounced increase in new hippocampal neuron formation after weeks of abstinence. This increase is attributable to a temporally and regionally specific fourfold increase in cell proliferation at day 7 of abstinence, with a majority of those cells surviving and differentiating at percentages similar to controls, effects that doubled the formation of new neurons. Although increases in cell proliferation correlated with alcohol withdrawal severity, proliferation remained increased when diazepam (10 mg/kg) was used to reduce withdrawal severity. Indeed, those animals with little withdrawal activity still show a twofold burst in cell proliferation at day 7 of abstinence. Thus, alcohol dependence and recovery from dependence continues to alter hippocampal plasticity during abstinence. Because neurogenesis may contribute to hippocampal function and/or learning, memory, and mood, compensatory neurogenesis and the return of normal neurogenesis may also have an impact on hippocampal structure and function. For the first time, these data provide a neurobiological mechanism that may underlie the return of human cognitive function and brain volume associated with recovery from addiction.

Alcohol-Induced Disorders, Nervous System↗

PubMed2004

Exercise reverses ethanol inhibition of neural stem cell proliferation.

Neural stem cells in the adult brain may contribute to learning and neural plasticity, to stress-induced neuropathologic changes, to mood and affective disorders, and to other complex brain functions. Learning, an enriched environment, and exercise (as modeled by running) all increase neural stem cell proliferation in the hippocampus and improve performance on learning tests, whereas acute ethanol consumption decreases neural stem cell proliferation in the hippocampus. To explore the interaction of exercise and ethanol consumption (two behaviors important for mental health), C57BL/6 mice were given access to ethanol, a running wheel, or both, and neural stem cell proliferation was investigated in the hippocampal dentate gyrus, corpus callosum, and forebrain subventricular zone of these mice. Mice given access to ethanol consumed large amounts of ethanol, and mice given access to a running wheel ran long distances, with the combined groups' behavior being comparable to that of the ethanol access alone group and of the running wheel access alone group. Neural stem cell proliferation was assessed by treating mice with bromodeoxyuridine (12 days, 300 mg/kg/day, i.p.) and evaluating consequent immunoreactivity. Exercise increased bromodeoxyuridine immunoreactivity in dentate gyrus, but not in other brain regions studied. Self-administration of ethanol decreased bromodeoxyuridine immunoreactivity by approximately 60% (P <.01) in dentate gyrus; 70% (P <.001), in forebrain; and 80% (P <.001), in corpus callosum. Findings for exercise and ethanol consumption combined were remarkably similar to those for exercise alone. The opposing effects of ethanol consumption and exercise on neurogenesis could contribute to the CNS pathology and health benefits, respectively, of these two behaviors.

Animals↗

PubMed2004

NMDA receptor subunit expression after combined prenatal and postnatal exposure to ethanol.

BACKGROUND: The N-methyl-D-aspartate receptor (NMDAR), a subtype of glutamate receptor, is essential for normal neurodevelopment. The brain growth spurt, which is both prenatal and postnatal in the rat, is a time when the brain is especially sensitive to the effects of a teratogen, such as alcohol. Changes in NMDAR function after early perinatal exposure to ethanol (EtOH) may be related to alterations in the expression of secondary subunits. Thus, we investigated the expression of the NR1, NR2A, and NR2B subunits after combined prenatal and postnatal exposure to EtOH. METHODS: A binge model was used to administer EtOH (5 g/kg) or isocaloric vehicle to pregnant female rats followed by EtOH (6.2 g/kg) or isocaloric control diet from postnatal days 4 through 9 via an artificial rearing method. Proteins from crude membrane homogenates isolated from cortex and hippocampus at postnatal day 10, 14, or 21 were separated in a standard Western blot procedure. RESULTS: The expression of the NR2A subunit of EtOH-exposed pups showed a significant increase at postnatal day 10 in hippocampus compared with diet controls. No significant changes were seen for any other subunit in either region. CONCLUSIONS: The up-regulation of NR2A during EtOH withdrawal is consistent with compensatory changes to prolonged inhibition of the NMDAR. These results indicate that postnatal exposure to ethanol produces distinct effects on the NMDAR, which may underlie deficits associated with alcohol-related neurodevelopmental disorder.

Animals↗

PubMed2002

NMDA receptor subunit expression following early postnatal exposure to ethanol.

Changes in NMDA receptor function following early postnatal exposure to ethanol may be related to the expression of NMDA receptor subunits. Following early postnatal exposure to ethanol, the expression of NMDA receptor subunits was examined. In cortex from ethanol-exposed rat pups at postnatal day 21, NR2A was significantly increased. There was no change in NR2B, thus suggesting that ethanol exposure during the third-trimester equivalent produces distinct effects on the NMDA receptor.

Alcohol-Induced Disorders, Nervous System↗

PubMed2002

Binge ethanol exposure decreases neurogenesis in adult rat hippocampus.

Alcoholism is associated with cognitive deficits and loss of brain mass. Recent studies have indicated that neural progenitor cells proliferate throughout life forming neurons, astrocytes, and oligodendrocytes. The dentate gyrus is one neurogenic region of the adult brain containing neural progenitor cells. To determine if binge ethanol (EtOH) exposure alters neural progenitor cell proliferation and survival, bromodeoxyuridine was administered to adult male rats following an acute or chronic binge exposure paradigm. For an acute binge, rats were gavaged with a 5 g/kg dose of EtOH or vehicle, administered bromodeoxyuridine, and killed either 5 h or 28 days after EtOH treatment. In a 4-day, chronic-binge paradigm, rats were infused with EtOH three times per day (mean dose 9.3 g/kg/day) or isocaloric control diet. Rats were given bromodeoxyuridine once a day for the 4 days of chronic binge treatment, then perfused either immediately following the last dose of EtOH or 28 days later. In both EtOH treatment groups, binge EtOH decreased neural progenitor cell proliferation. Following the chronic four-day binge, neural progenitor cell survival was decreased. These studies are the first to show EtOH inhibition of neural progenitor cell proliferation and survival in the adult, a possible new mechanism underlying alcoholic cognitive dysfunction.

Alcoholism↗