Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Sci Rep ; 10(1): 2737, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066765

RESUMO

Astronauts on interplanetary missions - such as to Mars - will be exposed to space radiation, a spectrum of highly-charged, fast-moving particles that includes 56Fe and 28Si. Earth-based preclinical studies show space radiation decreases rodent performance in low- and some high-level cognitive tasks. Given astronaut use of touchscreen platforms during training and space flight and given the ability of rodent touchscreen tasks to assess functional integrity of brain circuits and multiple cognitive domains in a non-aversive way, here we exposed 6-month-old C57BL/6J male mice to whole-body space radiation and subsequently assessed them on a touchscreen battery. Relative to Sham treatment, 56Fe irradiation did not overtly change performance on tasks of visual discrimination, reversal learning, rule-based, or object-spatial paired associates learning, suggesting preserved functional integrity of supporting brain circuits. Surprisingly, 56Fe irradiation improved performance on a dentate gyrus-reliant pattern separation task; irradiated mice learned faster and were more accurate than controls. Improved pattern separation performance did not appear to be touchscreen-, radiation particle-, or neurogenesis-dependent, as 56Fe and 28Si irradiation led to faster context discrimination in a non-touchscreen task and 56Fe decreased new dentate gyrus neurons relative to Sham. These data urge revisitation of the broadly-held view that space radiation is detrimental to cognition.


Assuntos
Cognição/efeitos da radiação , Radiação Cósmica , Giro Denteado/efeitos da radiação , Aprendizagem por Associação de Pares/efeitos da radiação , Reconhecimento Visual de Modelos/efeitos da radiação , Reversão de Aprendizagem/efeitos da radiação , Animais , Astronautas , Ciências Biocomportamentais , Cognição/fisiologia , Giro Denteado/fisiologia , Isótopos de Ferro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/citologia , Neurônios/fisiologia , Neurônios/efeitos da radiação , Aprendizagem por Associação de Pares/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Reversão de Aprendizagem/fisiologia , Voo Espacial , Irradiação Corporal Total
2.
Behav Brain Res ; 381: 112448, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-31870778

RESUMO

Opiates - including morphine - are powerful analgesics with high abuse potential. In rodents, chronic opiate exposure or self-administration negatively impacts hippocampal-dependent function, an effect perhaps due in part to the well-documented opiate-induced inhibition of dentate gyrus (DG) precursor proliferation and neurogenesis. Recently, however, intravenous (i.v.) morphine self-administration (MSA) was reported to enhance the survival of new rat DG neurons. To reconcile these disparate results, we used rat i.v. MSA to assess 1) whether a slightly-higher dose MSA paradigm also increases new DG neuron survival; 2) how MSA influences cells in different stages of DG neurogenesis, particularly maturation and survival; and 3) if MSA-induced changes in DG neurogenesis persist through a period of abstinence. To label basal levels of proliferation, rats received the S-phase marker bromodeoxyuridine (BrdU, i.p.) 24 -h prior to 21 days (D) of i.v. MSA or saline self-administration (SSA). Either immediately after SA (0-D) or after 4 weeks in the home cage (28-D withdrawal), stereology was used to quantify DG proliferating precursors (or cells in cell cycle; Ki67+ cells), neuroblast/immature neurons (DCX+ cells), and surviving DG granule cells (BrdU+ cells). Analysis revealed the number of DG cells immunopositive for these neurogenesis-relevant markers was similar between MSA and SSA rats at the 0-D or 28-D timepoints. These negative data highlight the impact experimental parameters, timepoint selection, and quantification approach have on neurogenesis results, and are discussed in the context of the large literature showing the negative impact of opiates on DG neurogenesis.


Assuntos
Analgésicos Opioides/farmacologia , Ciclo Celular/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Morfina/farmacologia , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Analgésicos Opioides/administração & dosagem , Animais , Antígenos Nucleares/metabolismo , Bromodesoxiuridina , Sobrevivência Celular/efeitos dos fármacos , Condicionamento Operante , Giro Denteado/metabolismo , Giro Denteado/patologia , Proteína Duplacortina , Antígeno Ki-67/metabolismo , Masculino , Microscopia Confocal , Morfina/administração & dosagem , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Ratos , Autoadministração
3.
Nat Med ; 24(9): 1482, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29934536

RESUMO

In the version of this article originally published, a URL provided in the Methods section was incorrect. The URL had a solidus at the end but should have appeared as http://www.nature.com/authors/policies/image.html. The error has been corrected in the PDF and HTML versions of this article.

4.
Nat Med ; 24(5): 658-666, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29662202

RESUMO

Major depressive disorder (MDD) is considered a 'circuitopathy', and brain stimulation therapies hold promise for ameliorating MDD symptoms, including hippocampal dysfunction. It is unknown whether stimulation of upstream hippocampal circuitry, such as the entorhinal cortex (Ent), is antidepressive, although Ent stimulation improves learning and memory in mice and humans. Here we show that molecular targeting (Ent-specific knockdown of a psychosocial stress-induced protein) and chemogenetic stimulation of Ent neurons induce antidepressive-like effects in mice. Mechanistically, we show that Ent-stimulation-induced antidepressive-like behavior relies on the generation of new hippocampal neurons. Thus, controlled stimulation of Ent hippocampal afferents is antidepressive via increased hippocampal neurogenesis. These findings emphasize the power and potential of Ent glutamatergic afferent stimulation-previously well-known for its ability to influence learning and memory-for MDD treatment.


Assuntos
Antidepressivos/uso terapêutico , Giro Denteado/patologia , Córtex Entorrinal/patologia , Animais , Comportamento Animal , Doença Crônica , Dendritos/patologia , Glutamatos/metabolismo , Células HEK293 , Humanos , Proteínas de Membrana/deficiência , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Rede Nervosa/metabolismo , Rede Nervosa/patologia , Neurogênese , Peroxinas/deficiência , Peroxinas/metabolismo , Estresse Psicológico/complicações
5.
Addict Biol ; 23(2): 665-675, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28626932

RESUMO

Adult dentate gyrus (DG) neurogenesis is important for hippocampal-dependent learning and memory, but the role of new neurons in addiction-relevant learning and memory is unclear. To test the hypothesis that neurogenesis is involved in the vulnerability to morphine addiction, we ablated adult DG neurogenesis and examined morphine self-administration (MSA) and locomotor sensitization. Male Sprague-Dawley rats underwent hippocampal-focused, image-guided X-ray irradiation (IRR) to eliminate new DG neurons or sham treatment (Sham). Six weeks later, rats underwent either MSA (Sham = 16, IRR = 15) or locomotor sensitization (Sham = 12, IRR = 12). Over 21 days of MSA, IRR rats self-administered ~70 percent more morphine than Sham rats. After 28 days of withdrawal, IRR rats pressed the active lever 40 percent more than Sham during extinction. This was not a general enhancement of learning or locomotion, as IRR and Sham groups had similar operant learning and inactive lever presses. For locomotor sensitization, both IRR and Sham rats sensitized, but IRR rats sensitized faster and to a greater extent. Furthermore, dose-response revealed that IRR rats were more sensitive at a lower dose. Importantly, these increases in locomotor activity were not apparent after acute morphine administration and were not a byproduct of irradiation or post-irradiation recovery time. Therefore, these data, along with other previously published data, indicate that reduced hippocampal neurogenesis confers vulnerability for multiple classes of drugs. Thus, therapeutics to specifically increase or stabilize hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse.


Assuntos
Giro Denteado/fisiopatologia , Locomoção/fisiologia , Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Neurogênese/fisiologia , Neurônios/fisiologia , Animais , Comportamento Animal/fisiologia , Irradiação Craniana , Giro Denteado/fisiologia , Proteína Duplacortina , Hipocampo , Aprendizagem , Masculino , Memória , Neurogênese/efeitos da radiação , Transtornos Relacionados ao Uso de Opioides , Ratos , Ratos Sprague-Dawley , Autoadministração
6.
Radiat Res ; 188(5): 532-551, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28945526

RESUMO

Astronauts traveling to Mars will be exposed to chronic low doses of galactic cosmic space radiation, which contains highly charged, high-energy (HZE) particles. 56Fe-HZE-particle exposure decreases hippocampal dentate gyrus (DG) neurogenesis and disrupts hippocampal function in young adult rodents, raising the possibility of impaired astronaut cognition and risk of mission failure. However, far less is known about how exposure to other HZE particles, such as 28Si, influences hippocampal neurogenesis and function. To compare the influence of 28Si exposure on indices of neurogenesis and hippocampal function with previous studies on 56Fe exposure, 9-week-old C57BL/6J and Nestin-GFP mice (NGFP; made and maintained for 10 or more generations on a C57BL/6J background) received whole-body 28Si-particle-radiation exposure (0, 0.2 and 1 Gy, 300 MeV/n, LET 67 KeV/µ, dose rate 1 Gy/min). For neurogenesis assessment, the NGFP mice were injected with the mitotic marker BrdU at 22 h postirradiation and brains were examined for indices of hippocampal proliferation and neurogenesis, including Ki67+, BrdU+, BrdU+NeuN+ and DCX+ cell numbers at short- and long-term time points (24 h and 3 months postirradiation, respectively). In the short-term group, stereology revealed fewer Ki67+, BrdU+ and DCX+ cells in 1-Gy-irradiated group relative to nonirradiated control mice, fewer Ki67+ and DCX+ cells in 0.2 Gy group relative to control group and fewer BrdU+ and DCX+ cells in 1 Gy group relative to 0.2 Gy group. In contrast to the clearly observed radiation-induced, dose-dependent reductions in the short-term group across all markers, only a few neurogenesis indices were changed in the long-term irradiated groups. Notably, there were fewer surviving BrdU+ cells in the 1 Gy group relative to 0- and 0.2-Gy-irradiated mice in the long-term group. When the short- and long-term groups were analyzed by sex, exposure to radiation had a similar effect on neurogenesis indices in male and female mice, although only male mice showed fewer surviving BrdU+ cells in the long-term group. Fluorescent immunolabeling and confocal phenotypic analysis revealed that most surviving BrdU+ cells in the long-term group expressed the neuronal marker NeuN, definitively confirming that exposure to 1 Gy 28Si radiation decreased the number of surviving adult-generated neurons in male mice relative to both 0- and 0.2-Gy-irradiated mice. For hippocampal function assessment, 9-week-old male C57BL/6J mice received whole-body 28Si-particle exposure and were then assessed long-term for performance on contextual and cued fear conditioning. In the context test the animals that received 0.2 Gy froze less relative to control animals, suggesting decreased hippocampal-dependent function. However, in the cued fear conditioning test, animals that received 1 Gy froze more during the pretone portion of the test, relative to controls and 0.2-Gy-irradiated mice, suggesting enhanced anxiety. Compared to previously reported studies, these data suggest that 28Si-radiation exposure damages neurogenesis, but to a lesser extent than 56Fe radiation and that low-dose 28Si exposure induces abnormalities in hippocampal function, disrupting fear memory but also inducing anxiety-like behavior. Furthermore, exposure to 28Si radiation decreased new neuron survival in long-term male groups but not females suggests that sex may be an important factor when performing brain health risk assessment for astronauts traveling in space.


Assuntos
Condicionamento Psicológico/efeitos da radiação , Giro Denteado/citologia , Medo/psicologia , Neurogênese/efeitos da radiação , Neurônios/citologia , Silício , Irradiação Corporal Total/efeitos adversos , Animais , Comportamento Animal/fisiologia , Comportamento Animal/efeitos da radiação , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Radiação Cósmica , Giro Denteado/fisiologia , Giro Denteado/efeitos da radiação , Relação Dose-Resposta à Radiação , Proteína Duplacortina , Medo/efeitos da radiação , Feminino , Memória/fisiologia , Memória/efeitos da radiação , Camundongos , Neurônios/efeitos da radiação , Fatores de Tempo
7.
PLoS One ; 11(1): e0147256, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26795203

RESUMO

Depression and anxiety involve hippocampal dysfunction, but the specific relationship between these mood disorders and adult hippocampal dentate gyrus neurogenesis remains unclear. In both humans with MDD and rodent models of depression, administration of antidepressants increases DG progenitor and granule cell number, yet rodents with induced ablation of DG neurogenesis typically do not demonstrate depressive- or anxiety-like behaviors. The conflicting data may be explained by the varied duration and degree to which adult neurogenesis is reduced in different rodent neurogenesis ablation models. In order to test this hypothesis we examined how a transient-rather than permanent-inducible reduction in neurogenesis would alter depressive- and anxiety-like behaviors. Transgenic Nestin-CreERT2/floxed diphtheria toxin fragment A (DTA) mice (Cre+DTA+) and littermates (Cre+DTA-; control) were given tamoxifen (TAM) to induce recombination and decrease nestin-expressing stem cells and their progeny. The decreased neurogenesis was transient: 12 days post-TAM Cre+DTA+ mice had fewer DG proliferating Ki67+ cells and fewer DCX+ neuroblasts/immature neurons relative to control, but 30 days post-TAM Cre+DTA+ mice had the same DCX+ cell number as control. This ability of DG neurogenesis to recover after partial ablation also correlated with changes in behavior. Relative to control, Cre+DTA+ mice tested between 12-30 days post-TAM displayed indices of a stress-induced anxiety phenotype-longer latency to consume highly palatable food in the unfamiliar cage in the novelty-induced hypophagia test, and a depression phenotype-longer time of immobility in the tail suspension test, but Cre+DTA+ mice tested after 30 days post-TAM did not. These findings suggest a functional association between adult neurogenesis and stress induced anxiety- and depressive-like behaviors, where induced reduction in DCX+ cells at the time of behavioral testing is coupled with stress-induced anxiety and a depressive phenotype, and recovery of DCX+ cell number corresponds to normalization of these behaviors.


Assuntos
Transtornos de Ansiedade/etiologia , Depressão/etiologia , Toxina Diftérica/genética , Hipocampo/patologia , Nestina/fisiologia , Neurogênese , Neurônios/patologia , Fragmentos de Peptídeos/genética , Estresse Fisiológico , Animais , Comportamento Animal , Proteína Duplacortina , Feminino , Hipocampo/metabolismo , Integrases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/metabolismo , Fenótipo
8.
Neurosci Lett ; 516(1): 99-104, 2012 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-22487733

RESUMO

Methadone is a synthetic opiate that is useful in a variety of clinical settings, including in maintenance therapy of heroin dependence and as an analgesic. However, methadone can have negative effects on cognition in humans and in rodents. The mechanisms underlying methadone-induced disruption in cognition are unknown. One possibility is that methadone disrupts adult hippocampal neurogenesis, a form of hippocampal plasticity involved in cognition that is disrupted by other opiates, like morphine. The goal of this study was to determine if methadone alters key parameters of hippocampal neurogenesis in the adult rat. Four groups of male rats were injected with saline (Saline, n=11) or methadone (Escalating, Short Term, Acute, n=10-11/group) over the course of three weeks. Weight gain, locomotor activity, and neurogenesis data were collected. Consistent with prior results, Escalating rats had slower weight gain (-4% vs. Saline). Also consistent with prior results, methadone did not alter locomotor activity over the course of a 90 min test. However, closer analysis revealed that methadone - irrespective of the dose or duration - led to a decrease in locomotor activity (-11 to -20% vs. saline) when examined during the first 5 min of the locomotor test. Surprisingly, methadone did not alter any of three quantified parameters relevant to adult hippocampal neurogenesis (number of Ki67-, doublecortin-, or BrdU-immunoreactive cells [BrdU given prior to saline/methadone exposure]). These results suggest that - unlike other opiates such as morphine - experimenter-delivered methadone does not alter hippocampal plasticity by decreasing the number of adult-generated neurons.


Assuntos
Hipocampo/fisiologia , Locomoção/fisiologia , Metadona/farmacologia , Neurogênese/fisiologia , Plasticidade Neuronal/fisiologia , Analgésicos Opioides/farmacologia , Animais , Relação Dose-Resposta a Droga , Proteína Duplacortina , Heroína/farmacologia , Hipocampo/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Neurogênese/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Ratos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...