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1.
Cells ; 11(19)2022 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-36231073

RESUMO

Adolescence is a developmental period that encompasses, but is not limited to, puberty and continues into early adulthood. During this period, maturation and refinement are observed across brain regions such as the prefrontal cortex (PFC), which is critical for cognitive function. Adolescence is also a time when excessive alcohol consumption in the form of binge drinking peaks, increasing the risk of long-term cognitive deficits and the risk of developing an alcohol use disorder later in life. Animal models have revealed that adolescent ethanol (EtOH) exposure results in protracted disruption of neuronal function and performance on PFC-dependent tasks that require higher-order decision-making. However, the role of astrocytes in EtOH-induced disruption of prefrontal cortex-dependent function has yet to be elucidated. Astrocytes have complex morphologies with an extensive network of peripheral astrocyte processes (PAPs) that ensheathe pre- and postsynaptic terminals to form the 'tripartite synapse.' At the tripartite synapse, astrocytes play several critical roles, including synaptic maintenance, dendritic spine maturation, and neurotransmitter clearance through proximity-dependent interactions. Here, we investigate the effects of adolescent binge EtOH exposure on astrocyte morphology, PAP-synaptic proximity, synaptic stabilization proteins, and dendritic spine morphology in subregions of the PFC that are important in the emergence of higher cognitive function. We found that adolescent binge EtOH exposure resulted in subregion specific changes in astrocyte morphology and astrocyte-neuronal interactions. While this did not correspond to a loss of astrocytes, synapses, or dendritic spines, there was a corresponding region-specific and EtOH-dependent shift in dendritic spine phenotype. Lastly, we found that changes in astrocyte-neuronal interactions were not a consequence of changes in the expression of key synaptic structural proteins neurexin, neuroligin 1, or neuroligin 3. These data demonstrate that adolescent EtOH exposure results in enduring effects on neuron-glia interactions that persist into adulthood in a subregion-specific PFC manner, suggesting selective vulnerability. Further work is necessary to understand the functional and behavioral implications.


Assuntos
Etanol , Maturidade Sexual , Animais , Etanol/toxicidade , Neurônios/metabolismo , Córtex Pré-Frontal , Sinapses/metabolismo
2.
Front Behav Neurosci ; 16: 830310, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35221947

RESUMO

Adolescence is characterized as a period of increased social behavior, risk taking, and novelty seeking, partly due to ongoing maturation in critical brain areas and the hypothalamic-pituitary-adrenal (HPA) negative-feedback system. During this period there is heightened vulnerability to stress that can drive neuro-immune-endocrine remodeling, resulting in the emergence of maladaptive behaviors that increase susceptibility to alcohol and substance abuse. Here we used a rat model to investigate the impact of chronic adolescent unpredictable stress on a battery of behavioral measures to assess anxiety, novelty seeking, risk taking, depression, and voluntary ethanol consumption while determining whether the PPARγ agonist rosiglitazone can attenuate these effects. Adolescent female rats that experienced stress showed increased risk taking behavior and novelty seeking behavior with no change in ethanol consumption. The administration of rosiglitazone during stress induction attenuated stress-induced cortisol elevation, normalized risk taking behavior in a model anxiety, and attenuated novelty seeking in a task-specific manner. Depressive-like behavior was not impacted by adolescent unpredictable stress or the administration of rosiglitazone. The results from this study demonstrate that exposure to unpredictable stress during adolescence increases the prevalence of maladaptive behaviors that are known to increase susceptibility to alcohol and substance abuse, and that rosiglitazone may be an effective therapeutic to attenuate the emergence of select risk taking and novelty seeking behaviors in females.

3.
Front Neurosci ; 16: 1040049, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36733924

RESUMO

Adolescence is a transitional stage marked by continued brain development. This period is accompanied by physical and neurochemical modifications in the shape and function of the hippocampus, prefrontal cortex, and other limbic system structures. Brain maturation during adolescence, which is typically governed by intrinsic factors, can be dramatically altered by environmental influences such as drugs and alcohol. Unlike many other addictive substances, binge drinking is very common and normative among teenagers and young adults. This repeated pattern of excessive alcohol consumption in adolescents has been shown to cause behavioral changes and neurocognitive impairments that include increased anxiety, risky decision-making, and learning deficits, which could lead to the development of alcohol use disorder (AUD). This manuscript highlights factors that lead to adolescent binge drinking, discusses maturational changes that occur in an adolescent's brain, and then evaluates the effect of adolescent alcohol consumption on brain structure, function, and neurocognitive abilities in both human studies and animal models. The impact of gender/sex and COVID-19 are briefly discussed. Understanding the factors that promote the onset of adolescent binge drinking and its undesirable consequences could serve as a catalyst for developing therapeutic agents that would decrease or eradicate the damaging effects of alcohol on an adolescent brain.

4.
PLoS One ; 16(12): e0260577, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34898621

RESUMO

Females are more affected by psychiatric illnesses including eating disorders, depression, and post-traumatic stress disorder than males. However, the neural mechanisms mediating these sex differences are poorly understood. Animal models can be useful in exploring such neural mechanisms. Conditioned taste aversion (CTA) is a behavioral task that assesses how animals process the competition between associated reinforcing and aversive stimuli in subsequent task performance, a process critical to healthy behavior in many domains. The purpose of the present study was to identify sex differences in this behavior and associated neural responses. We hypothesized that females would value the rewarding stimulus (Boost®) relative to the aversive stimulus (LiCl) more than males in performing CTA. We evaluated behavior (Boost® intake, LiCl-induced behaviors, ultrasonic vocalizations (USVs), CTA performance) and Fos activation in relevant brain regions after the acute stimuli [acute Boost® (AB), acute LiCl (AL)] and the context-only task control (COT), Boost® only task (BOT) and Boost®-LiCl task (BLT). Acutely, females drank more Boost® than males but showed similar aversive behaviors after LiCl. Females and males performed CTA similarly. Both sexes produced 55 kHz USVs anticipating BOT and inhibited these calls in the BLT. However, more females emitted both 22 kHz and 55 kHz USVs in the BLT than males: the latter correlated with less CTA. Estrous cycle stage also influenced 55 kHz USVs. Fos responses were similar in males and females after AB or AL. Females engaged the gustatory cortex and ventral tegmental area (VTA) more than males during the BOT and males engaged the amygdala more than females in both the BOT and BLT. Network analysis of correlated Fos responses across brain regions identified two unique networks characterizing the BOT and BLT, in both of which the VTA played a central role. In situ hybridization with RNAscope identified a population of D1-receptor expressing cells in the CeA that responded to Boost® and D2 receptor-expressing cells that responded to LiCl. The present study suggests that males and females differentially process the affective valence of a stimulus to produce the same goal-directed behavior.


Assuntos
Condicionamento Psicológico , Proteínas Proto-Oncogênicas c-fos/metabolismo , Estimulação Acústica , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/efeitos da radiação , Feminino , Cloreto de Lítio/farmacologia , Masculino , Ratos , Caracteres Sexuais , Ultrassom
5.
Cells ; 9(2)2020 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-31991879

RESUMO

Astrocytes have critical functions throughout the central nervous system (CNS) and have emerged as regulators of synaptic development and function. With their highly complex morphologies, they are able to interact with thousands of synapses via peripheral astrocytic processes (PAPs), ensheathing neuronal axons and dendrites to form the tripartite synapse. In this way, astrocytes engage in crosstalk with neurons to mediate a variety of CNS processes including the regulation of extracellular matrix protein signaling, formation and maintenance of the blood-brain barrier (BBB), axon growth and guidance, homeostasis of the synaptic microenvironment, synaptogenesis, and the promotion of synaptic diversity. In this review, we discuss several key astrocyte signaling factors (thrombospondins, netrins, apolipoproteins, neuregulins, bone morphogenetic proteins, and neuroligins) in the maintenance and regulation of synapse formation. We also explore how these astrocyte signaling factors are impacted by and contribute to substance abuse, particularly alcohol and cocaine use.


Assuntos
Apolipoproteínas/metabolismo , Astrócitos/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Netrinas/metabolismo , Neurregulinas/metabolismo , Sinapses/metabolismo , Trombospondinas/metabolismo , Transtornos Relacionados ao Uso de Álcool/metabolismo , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Humanos , Receptores Pré-Sinápticos/metabolismo , Transdução de Sinais/fisiologia
6.
Neuroscience ; 400: 98-109, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30599266

RESUMO

It is well established that astrocytes play pivotal roles in neuronal synapse formation and maturation as well as in the modulation of synaptic transmission. Despite their general importance for brain function, relatively little is known about the maturation of astrocytes during normal postnatal development, especially during adolescence, and how that maturation may influence astroglial-synaptic contact. The medial prefrontal cortex (mPFC) and dorsal hippocampus (dHipp) are critical for executive function, memory, and their effective integration. Further, both regions undergo significant functional changes during adolescence and early adulthood that are believed to mediate these functions. However, it is unclear the extent to which astrocytes change during these late developmental periods, nor is it clear whether their association with functional synapses shifts as adolescent and young adult maturation proceeds. Here we utilize an astrocyte-specific viral labeling approach paired with high-resolution single-cell astrocyte imaging and three-dimensional reconstruction to determine whether mPFC and dHipp astrocytes have temporally distinct maturation trajectories. mPFC astrocytes, in particular, continue to mature well into emerging adulthood (postnatal day 70). Moreover, this ongoing maturation is accompanied by a substantial increase in colocalization of astrocytes with the postsynaptic neuronal marker, PSD-95. Taken together, these data provide novel insight into region-specific astrocyte-synapse interactions in late CNS development and into adulthood, thus raising implications for the mechanism of post-adolescent development of the mPFC.


Assuntos
Astrócitos/citologia , Astrócitos/fisiologia , Hipocampo/citologia , Hipocampo/crescimento & desenvolvimento , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/crescimento & desenvolvimento , Sinapses/fisiologia , Animais , Tamanho Celular , Masculino , Ratos Sprague-Dawley , Análise de Célula Única
7.
Sci Rep ; 7(1): 4680, 2017 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-28680108

RESUMO

Adolescence is a period of development in neural circuits that are critical for adult functioning. There is a relationship between alcohol exposure and risky decision-making, though the enduring effects of adolescent ethanol exposure on risky decision-making in adulthood have not been fully explored. Studies using positive reinforcement have shown that adolescent intermittent ethanol (AIE) exposure results in higher levels of risky decision-making in adulthood, but the effects of AIE on punishment-mediated decision-making have not been explored. Adolescent rats were exposed to AIE or saline vehicle across a 16-day period, and then allowed to mature into adulthood. They were then trained to lever press for food reward and were assessed for risky decision-making by pairing increased levels of food reward with the probability of footshock punishment. AIE did not alter punishment-mediated risky decision-making. However, it did result in a significant increase in the delay to lever pressing. This finding is consistent with previous reports, using other behavioral tasks, which show decreased behavioral efficiency in adulthood after AIE. These findings indicate that AIE increases behavioral inefficiency, but not punishment-mediated risk-taking, in adulthood. Thus they contribute to a more nuanced understanding of the long-term effects of AIE on adult behavior.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Tomada de Decisões/efeitos dos fármacos , Assunção de Riscos , Animais , Escala de Avaliação Comportamental , Modelos Animais de Doenças , Masculino , Punição , Ratos , Recompensa
8.
PLoS One ; 11(5): e0155951, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27213757

RESUMO

Adolescent alcohol use is the strongest predictor for alcohol use disorders. In rodents, adolescents have distinct responses to acute ethanol, and prolonged alcohol exposure during adolescence can maintain these phenotypes into adulthood. One brain region that is particularly sensitive to the effects of both acute and chronic ethanol exposure is the hippocampus. Adolescent intermittent ethanol exposure (AIE) produces long lasting changes in hippocampal synaptic plasticity and dendritic morphology, as well as in the susceptibility to acute ethanol-induced spatial memory impairment. Given the pattern of changes in hippocampal structure and function, one potential target for these effects is the ethanol sensitive GluN2B subunit of the NMDA receptor, which is known to be involved in synaptic plasticity and dendritic morphology. Thus we sought to determine if there were persistent changes in hippocampal GluN2B signaling cascades following AIE. We employed a previously validated GluN2B-targeted proteomic strategy that was used to identify novel signaling mechanisms altered by chronic ethanol exposure in the adult hippocampus. We collected adult hippocampal tissue (P70) from rats that had been given 2 weeks of AIE from P30-45. Tissue extracts were fractionated into synaptic and non-synaptic pools, immuno-precipitated for GluN2B, and then analyzed using proteomic methods. We detected a large number of proteins associated with GluN2B. AIE produced significant changes in the association of many proteins with GluN2B in both synaptic and non-synaptic fractions. Intriguingly the number of proteins changed in the non-synaptic fraction was double that found in the synaptic fraction. Some of these proteins include those involved in glutamate signaling cytoskeleton rearrangement, calcium signaling, and plasticity. Disruptions in these pathways may contribute to the persistent cellular and behavioral changes found in the adult hippocampus following AIE. Further, the robust change in non-synaptic proteins suggests that AIE may prime this signaling pathway for future ethanol exposures in adulthood.


Assuntos
Etanol/efeitos adversos , Hipocampo/metabolismo , Mapas de Interação de Proteínas/efeitos dos fármacos , Proteoma/metabolismo , Proteômica/métodos , Receptores de N-Metil-D-Aspartato/metabolismo , Adolescente , Animais , Modelos Animais de Doenças , Feminino , Hipocampo/efeitos dos fármacos , Humanos , Masculino , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Consumo de Álcool por Menores
9.
Alcohol Clin Exp Res ; 39(12): 2403-13, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26537975

RESUMO

BACKGROUND: Adolescent intermittent alcohol exposure (AIE) has profound effects on neuronal function. We have previously shown that AIE causes aberrant hippocampal structure and function that persists into adulthood. However, the possible contributions of astrocytes and their signaling factors remain largely unexplored. We investigated the acute and enduring effects of AIE on astrocytic reactivity and signaling on synaptic expression in the hippocampus, including the impact of the thrombospondin (TSP) family of astrocyte-secreted synaptogenic factors and their neuronal receptor, alpha2delta-1 (α2δ-1). Our hypothesis is that some of the influences of AIE on neuronal function may be secondary to direct effects on astrocytes. METHODS: We conducted Western blot analysis on TSPs 1 to 4 and α2δ-1 from whole hippocampal lysates 24 hours after the 4th and 10th doses of AIE, then 24 days after the last dose (in adulthood). We used immunohistochemistry to assess astrocyte reactivity (i.e., morphology) and synaptogenesis (i.e., colocalization of pre- and postsynaptic puncta). RESULTS: Adolescent AIE reduced α2δ-1 expression, and colocalized pre- and postsynaptic puncta after the fourth ethanol (EtOH) dose. By the 10th dose, increased TSP2 levels were accompanied by an increase in colocalized pre- and postsynaptic puncta, while α2δ-1 returned to control levels. Twenty-four days after the last EtOH dose (i.e., adulthood), TSP2, TSP4, and α2δ-1 expression were all elevated. Astrocyte reactivity, indicated by increased astrocytic volume and area, was also observed at that time. CONCLUSIONS: Repeated EtOH exposure during adolescence results in long-term changes in specific astrocyte signaling proteins and their neuronal synaptogenic receptor. Continued signaling by these traditionally developmental factors in adulthood may represent a compensatory mechanism whereby astrocytes reopen the synaptogenic window and repair lost connectivity, and consequently contribute to the enduring maladaptive structural and functional abnormalities previously observed in the hippocampus after AIE.


Assuntos
Etanol/toxicidade , Hipocampo/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismo , Sinapses/metabolismo , Trombospondinas/biossíntese , Fatores Etários , Animais , Etanol/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Masculino , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos , Ratos Sprague-Dawley , Sinapses/efeitos dos fármacos , Sinapses/patologia
10.
PLoS One ; 10(11): e0140042, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26529506

RESUMO

The long-term effects of intermittent ethanol exposure during adolescence (AIE) are of intensive interest and investigation. The effects of AIE on learning and memory and the neural functions that drive them are of particular interest as clinical findings suggest enduring deficits in those cognitive domains in humans after ethanol abuse during adolescence. Although studies of such deficits after AIE hold much promise for identifying mechanisms and therapeutic interventions, the findings are sparse and inconclusive. The present results identify a specific deficit in memory function after AIE and establish a possible neural mechanism of that deficit that may be of translational significance. Male rats (starting at PND-30) received exposure to AIE (5g/kg, i.g.) or vehicle and were allowed to mature into adulthood. At PND-71, one group of animals was assessed using the spatial-temporal object recognition (stOR) test to evaluate memory function. A separate group of animals was used to assess the density of cholinergic neurons in forebrain areas Ch1-4 using immunohistochemistry. AIE exposed animals manifested deficits in the temporal component of the stOR task relative to controls, and a significant decrease in the number of ChAT labeled neurons in forebrain areas Ch1-4. These findings add to the growing literature indicating long-lasting neural and behavioral effects of AIE that persist into adulthood and indicate that memory-related deficits after AIE depend upon the tasks employed, and possibly their degree of complexity. Finally, the parallel finding of diminished cholinergic neuron density suggests a possible mechanism underlying the effects of AIE on memory and hippocampal function as well as possible therapeutic or preventive strategies for AIE.


Assuntos
Etanol/farmacologia , Memória/efeitos dos fármacos , Prosencéfalo/metabolismo , Animais , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/metabolismo , Neurônios Colinérgicos/patologia , Imuno-Histoquímica , Masculino , Modelos Animais , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/patologia , Ratos , Ratos Sprague-Dawley
11.
Alcohol Clin Exp Res ; 39(6): 989-97, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25916839

RESUMO

BACKGROUND: Human adolescence is a crucial stage of neurological development during which ethanol (EtOH) consumption is often at its highest. Alcohol abuse during adolescence may render individuals at heightened risk for subsequent alcohol abuse disorders, cognitive dysfunction, or other neurological impairments by irreversibly altering long-term brain function. To test this possibility, we modeled adolescent alcohol abuse (i.e., intermittent EtOH exposure during adolescence [AIE]) in rats to determine whether adolescent exposure to alcohol leads to long-term structural and functional changes that are manifested in adult neuronal circuitry. METHODS: We specifically focused on hippocampal area CA1, a brain region associated with learning and memory. Using electrophysiological, immunohistochemical, and neuroanatomical approaches, we measured post-AIE changes in synaptic plasticity, dendritic spine morphology, and synaptic structure in adulthood. RESULTS: We found that AIE-pretreated adult rats manifest robust long-term potentiation, induced at stimulus intensities lower than those required in controls, suggesting a state of enhanced synaptic plasticity. Moreover, AIE resulted in an increased number of dendritic spines with characteristics typical of immaturity. Immunohistochemistry-based analysis of synaptic structures indicated a significant decrease in the number of co-localized pre- and postsynaptic puncta. This decrease is driven by an overall decrease in 2 postsynaptic density proteins, PSD-95 and SAP102. CONCLUSIONS: Taken together, these findings reveal that repeated alcohol exposure during adolescence results in enduring structural and functional abnormalities in the hippocampus. These synaptic changes in the hippocampal circuits may help to explain learning-related behavioral changes in adult animals preexposed to AIE.


Assuntos
Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/fisiopatologia , Etanol/efeitos adversos , Envelhecimento/psicologia , Animais , Região CA1 Hipocampal/anormalidades , Região CA1 Hipocampal/patologia , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/patologia , Proteína 4 Homóloga a Disks-Large , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Proteínas de Membrana/metabolismo , Neuropeptídeos/metabolismo , Ratos , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Sinapses/patologia
12.
Alcohol Clin Exp Res ; 38(11): 2800-8, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25421517

RESUMO

BACKGROUND: The long-term consequences of adolescent alcohol abuse that persist into adulthood are poorly understood and have not been widely investigated. We have shown that intermittent exposure to alcohol during adolescence decreased the amplitude of GABAA receptor (GABAA R)-mediated tonic currents in hippocampal dentate granule cells in adulthood. The aim of this study was to investigate the enduring effects of chronic intermittent alcohol exposure during adolescence or adulthood on the expression of hippocampal GABAA Rs. METHODS: We used a previously characterized tissue fractionation method to isolate detergent resistant membranes and soluble fractions, followed by Western blots to measure GABAA R protein expression. We also measured mRNA levels of GABAA R subunits using quantitative real-time polymerase chain reaction. RESULTS: Although the protein levels of α1-, α4-, and δ-GABAA R subunits remained stable between postnatal day (PD) 30 (early adolescence) and PD71 (adulthood), the α5-GABAA R subunit was reduced across that period. In rats that were subjected to adolescent intermittent ethanol (AIE) exposure between PD30 and PD46, there was a significant reduction in the protein levels of the δ-GABAA R, in the absence of any changes in mRNA levels, at 48 hours and 26 days after the last ethanol (EtOH) exposure. Protein levels of the α4-GABAA R subunit were significantly reduced, but mRNA levels were increased, 26 days (but not 48 hours) after the last AIE exposure. Protein levels of α5-GABAA R were not changed by AIE, but mRNA levels were reduced at 48 hours but normalized 26 days after AIE. In contrast to the effects of AIE, chronic intermittent ethanol (CIE) exposure during adulthood had no effect on expression of any of the GABAA R subunits examined. CONCLUSIONS: AIE produced both short- and long-term alterations of GABAA R subunits mRNA and protein expression in the hippocampus, whereas CIE produced no long-lasting effects on those measures. The observed reduction of protein levels of the δ-GABAA R, specifically, is consistent with previously reported altered hippocampal GABAA R-mediated electrophysiological responses after AIE. The absence of effects of CIE underscores the emerging view of adolescence as a time of distinctive vulnerability to the enduring effects of repeated EtOH exposure.


Assuntos
Etanol/toxicidade , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Subunidades Proteicas/biossíntese , Receptores de GABA-A/biossíntese , Fatores Etários , Animais , Etanol/administração & dosagem , Regulação da Expressão Gênica , Hipocampo/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley
13.
Alcohol Clin Exp Res ; 37(12): 2074-85, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23889304

RESUMO

BACKGROUND: Chronic alcohol use, especially exposure to alcohol during adolescence or young adulthood, is closely associated with cognitive deficits that may persist into adulthood. Therefore, it is essential to identify possible neuronal mechanisms underlying the observed deficits in learning and memory. Hippocampal interneurons play a pivotal role in regulating hippocampus-dependent learning and memory by exerting strong inhibition on excitatory pyramidal cells. The function of these interneurons is regulated not only by synaptic inputs from other types of neurons but is also precisely governed by their own intrinsic membrane ionic conductances. The voltage-gated A-type potassium current (IA ) regulates the intrinsic membrane properties of neurons, and disruption of IA is responsible for many neuropathological processes including learning and memory deficits. Thus, it represents a previously unexplored cellular mechanism whereby chronic ethanol (EtOH) may alter hippocampal memory-related functioning. METHODS: Using whole-cell electrophysiological recording methods, we investigated the enduring effects of chronic intermittent ethanol (CIE) exposure during adolescence or adulthood on IA in rat CA1 interneurons. RESULTS: We found that the mean peak amplitude of IA was significantly reduced after CIE in either adolescence or adulthood, but IA density was attenuated after CIE in adolescence but not after CIE in adulthood. In addition, the voltage-dependent steady-state activation and inactivation of IA were altered in interneurons after CIE. CONCLUSIONS: These findings suggest that CIE can cause long-term changes in IA channels in interneurons and thus may alter their inhibitory influences on memory-related local hippocampal circuits, which could be, in turn, responsible for learning and memory impairments observed after chronic EtOH exposure.


Assuntos
Região CA1 Hipocampal/fisiologia , Etanol/administração & dosagem , Interneurônios/fisiologia , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/fisiologia , Fatores Etários , Animais , Condutividade Elétrica , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
14.
PLoS One ; 8(5): e62940, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23675442

RESUMO

BACKGROUND: Adolescence is not only a critical period of late-stage neurological development in humans, but is also a period in which ethanol consumption is often at its highest. Given the prevalence of ethanol use during this vulnerable developmental period we assessed the long-term effects of chronic intermittent ethanol (CIE) exposure during adolescence, compared to adulthood, on performance in the radial-arm maze (RAM) and operant food-reinforced responding in male rats. METHODOLOGY/PRINCIPAL FINDINGS: Male Sprague Dawley rats were exposed to CIE (or saline) and then allowed to recover. Animals were then trained in either the RAM task or an operant task using fixed- and progressive- ratio schedules. After baseline testing was completed all animals received an acute ethanol challenge while blood ethanol levels (BECs) were monitored in a subset of animals. CIE exposure during adolescence, but not adulthood decreased the amount of time that animals spent in the open portions of the RAM arms (reminiscent of deficits in risk-reward integration) and rendered animals more susceptible to the acute effects of an ethanol challenge on working memory tasks. The operant food reinforced task showed that these effects were not due to altered food motivation or to differential sensitivity to the nonspecific performance-disrupting effects of ethanol. However, CIE pre-treated animals had lower BEC levels than controls during the acute ethanol challenges indicating persistent pharmacokinetic tolerance to ethanol after the CIE treatment. There was little evidence of enduring effects of CIE alone on traditional measures of spatial and working memory. CONCLUSIONS/SIGNIFICANCE: These effects indicate that adolescence is a time of selective vulnerability to the long-term effects of repeated ethanol exposure on neurobehavioral function and acute ethanol sensitivity. The positive and negative findings reported here help to further define the nature and extent of the impairments observed after adolescent CIE and provide direction for future research.


Assuntos
Consumo de Bebidas Alcoólicas/psicologia , Condicionamento Operante/efeitos dos fármacos , Etanol/administração & dosagem , Aprendizagem em Labirinto/efeitos dos fármacos , Adolescente , Adulto , Fatores Etários , Consumo de Bebidas Alcoólicas/sangue , Animais , Alimentos , Humanos , Masculino , Memória/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Reforço Psicológico , Recompensa , Tempo
15.
Alcohol Clin Exp Res ; 37(7): 1154-60, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23413887

RESUMO

BACKGROUND: In recent years, it has become clear that acute ethanol (EtOH) affects various neurobiological and behavioral functions differently in adolescent animals than in adults. However, less is known about the long-term neural consequences of chronic EtOH exposure during adolescence, and most importantly whether adolescence represents a developmental period of enhanced vulnerability to such effects. METHODS: We made whole-cell recordings of GABAA receptor-mediated tonic inhibitory currents from dentate gyrus granule cells (DGGCs) in hippocampal slices from adult rats that had been treated with chronic intermittent ethanol (CIE) or saline during adolescence, young adulthood, or adulthood. RESULTS: CIE reduced baseline tonic current amplitude in DGGCs from animals pretreated with EtOH during adolescence, but not in GCs from those pretreated with EtOH during young adulthood or adulthood. Similarly, the enhancement of tonic currents by acute EtOH exposure ex vivo was increased in GCs from animals pretreated with EtOH during adolescence, but not in those from animals pretreated during either of the other 2 developmental periods. CONCLUSIONS: These findings underscore our recent report that CIE during adolescence results in enduring alterations in tonic current and its acute EtOH sensitivity and establish that adolescence is a developmental period during which the hippocampal formation is distinctively vulnerable to long-term alteration by chronic EtOH exposure.


Assuntos
Consumo Excessivo de Bebidas Alcoólicas/fisiopatologia , Giro Denteado/fisiologia , Etanol/toxicidade , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Receptores de GABA-A/fisiologia , Fatores Etários , Animais , Giro Denteado/efeitos dos fármacos , Etanol/administração & dosagem , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/fisiologia , Masculino , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley
16.
J Pharmacol Exp Ther ; 339(2): 341-9, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21799050

RESUMO

Organophosphate (OP)-based pesticides have been used extensively for decades, and as a result, they have become almost ubiquitous in our environment. There is clinical and animal evidence to suggest that chronic exposures to OPs can lead to cognitive dysfunction and other neurological abnormalities, although the mechanism for these effects is unknown. We previously reported that repeated, subthreshold exposures (defined as doses not associated with signs of acute toxicity) to the commonly used OP chlorpyrifos (CPF) resulted in protracted impairments in the performance of attention and memory-related tasks in rodents as well as deficits in axonal transport ex vivo (in the sciatic nerve). Here, we investigated the effects of CPF and its active metabolite CPF oxon (CPO) on the dynamics and movement of mitochondria in rat primary cortical neurons using time-lapse imaging techniques. Exposure to CPF (1.0-20.0 µM) or CPO (5.0 nM-20.0 µM) for 1 or 24 h resulted in a concentration-dependent increase in mitochondrial length, a decrease in mitochondrial number (indicative of increased fusion events), and a decrease in their movement in axons. The changes occurred at concentrations of CPF and CPO that did not inhibit acetylcholinesterase activity (the commonly cited mechanism of acute OP toxicity), and they were not blocked by cholinergic receptor antagonists. Furthermore, the changes did not seem to be associated with direct (OP-related) effects on mitochondrial viability or function (i.e., mitochondrial membrane potential or ATP production). The results suggest that an underlying mechanism of organophosphate-based deficits in cognitive function might involve alterations in mitochondrial dynamics and/or their transport in axons.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Clorpirifos/toxicidade , Inibidores da Colinesterase/toxicidade , Inseticidas/toxicidade , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Receptores Colinérgicos/metabolismo , Acetilcolinesterase , Trifosfato de Adenosina/biossíntese , Trifosfato de Adenosina/metabolismo , Animais , Transporte Axonal/efeitos dos fármacos , Axônios/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Córtex Cerebral/citologia , Córtex Cerebral/fisiologia , Clorpirifos/análogos & derivados , Relação Dose-Resposta a Droga , Proteínas Ligadas por GPI/antagonistas & inibidores , Inseticidas/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/fisiologia , Antagonistas Nicotínicos/farmacologia , Ratos , Ratos Sprague-Dawley , Superóxidos/metabolismo
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