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1.
Mol Neurobiol ; 60(9): 4924-4934, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37198386

RESUMEN

Social isolation is an unpleasant experience associated with an increased risk of mental disorders. Exploring whether these experiences affect behaviors in aged people is particularly important, as the elderly is very likely to suffer from periods of social isolation during their late-life. In this study, we analyzed the depressive-like behaviors, plasma concentrations of homocysteine (Hcy), and brain-derived neurotropic factor (BDNF) levels in aged mice undergoing social isolation. Results showed that depressive-like behavioral performance and decreased BDNF level were correlated with increased Hcy levels that were detected in 2-month isolated mice. Elevated Hcy induced by high methionine diet mimicked the depressive-like behaviors and BDNF downregulation in the same manner as social isolation, while administration of vitamin B complex supplements to reduce Hcy alleviated the depressive-like behaviors and BDNF reduction in socially isolated mice. Altogether, our results indicated that Hcy played a critical role in social isolation-induced depressive-like behaviors and BDNF reduction, suggesting the possibility of Hcy as a potential therapeutic target and vitamin B intake as a potential value in the prevention of stress-induced depression.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Encéfalo , Ratones , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Encéfalo/metabolismo , Conducta Social , Aislamiento Social , Suplementos Dietéticos , Homocisteína
2.
Behav Brain Res ; 397: 112939, 2021 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-32991925

RESUMEN

With the lengthening of the human lifespan, an increasing proportion of the population is subject to age-related cognitive impairments, making it important to investigate ways to confront the effects of aging. Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor that is expressed mainly on the surfaces of microglia. Previous studies have found a significant positive correlation between age and TREM2 levels. An increased concentration of soluble TREM2 in cerebrospinal fluid was also found in Alzheimer's disease (AD) patients. Although TREM2 is more highly expressed in microglia than in astrocytes, little attention has been focused on astrocytic TREM2, and the precise role of astrocytic TREM2 in the aging process remains unknown. In this study, we injected TREM2 shRNA into the hippocampal CA1 region to specifically knock down the expression of this protein in astrocytes. We found that TREM2 shRNA injection can improve learning and memory ability in elderly mice, as demonstrated by improved learning ability and memory performance in the Morris water maze (MWM) test, an increased freezing duration in the contextual fear conditioning test, a higher preference ratio in the novel object recognition (NOR) test and a higher alternation rate in the T-maze test. Knocking down astrocytic TREM2 can also rescue impaired long-term potentiation (LTP) induction in the hippocampal CA1 of elderly mice through a presynaptic mechanism. Our results suggest that decreased astrocytic TREM2 levels have beneficial effects on learning and memory ability in elderly mice, which may provide new insight into the pathological mechanism and potential targets of age-related dementia.


Asunto(s)
Astrocitos/metabolismo , Región CA1 Hipocampal/metabolismo , Hipocampo/fisiología , Aprendizaje/fisiología , Potenciación a Largo Plazo/fisiología , Glicoproteínas de Membrana/metabolismo , Receptores Inmunológicos/metabolismo , Envejecimiento , Animales , Conducta Animal/fisiología , Disfunción Cognitiva , Condicionamiento Clásico/fisiología , Hipocampo/metabolismo , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Transgénicos , ARN Interferente Pequeño , Reconocimiento en Psicología/fisiología
3.
Behav Brain Res ; 379: 112342, 2020 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-31705920

RESUMEN

Post-traumatic stress disorder (PTSD) is a chronic and disabling condition arising after exposure to a severe traumatic event, which affects approximately eight percent of the population. The underlying neurobiology of PTSD, however, has only been partially understood. The exploration of fear memory and its extinction has been the subject to increase our understanding of PTSD. Our previous studies have already found that adolescent mice exhibited impaired fear memory extinction with accompanied depressive-like behaviors. Considering the relationship between ketamine and its rapid antidepressant function, we hypothesis that ketamine can facilitate the fear memory extinction so as to exhibit an antidepressant effects. In this study, to evaluate our hypothesis, we intraperitoneal (i.p.) injection of ketamine in adolescent mice and found that ketamine exhibited a rapid antidepressant effect and facilitated the fear memory extinction. Moreover, ketamine can also reverse the accompanied depressive-like behaviors and restore long-term potentiation (LTP) induction in extinction process, which involved the presynaptic mechanism. Our results suggest that ketamine exhibited an antidepressant effect in FST and facilitated the fear memory extinction via presynaptic-mediated synaptic plasticity, which may provide new strategy for treatment of PTSD.


Asunto(s)
Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Condicionamiento Clásico/efectos de los fármacos , Depresión/tratamiento farmacológico , Extinción Psicológica/efectos de los fármacos , Miedo/efectos de los fármacos , Ketamina/farmacología , Potenciación a Largo Plazo/efectos de los fármacos , Memoria/efectos de los fármacos , Factores de Edad , Animales , Antidepresivos/administración & dosificación , Modelos Animales de Enfermedad , Ketamina/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Trastornos por Estrés Postraumático/tratamiento farmacológico
4.
Neurosci Lett ; 699: 8-15, 2019 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-30684676

RESUMEN

Fear is the emotion that is best understood in terms of brain mechanisms. And the management of fear memories is important when facing mental health disorders such as post-traumatic stress. Adolescence is a transitional stage of physical and psychological human development and the ability to deal with the fear memory in adolescence may be a potent factor for developing mental disorders in adulthood. However, little is known about the direct relationship between the ability to deal with the fear memory and appearance of depressive-like behaviors. To assess this, we used a model of associative learning to induce the fear memories and evaluated the depressive-related behaviors in the fear memory extinction process and its underlying cellular mechanisms from adolescent and adult mice. We found that, compared with adult mice, the adolescent mice exhibited impaired fear memory extinction in contextual fear conditioning extinction process. Meanwhile, impaired fear memory extinction was accompanied by more immobility time in forced swimming test, which was used to assess the depressive-like state. Consistent with this, we observed that long-term potentiation (LTP) induction in the hippocampal CA1 region of adolescent mice persistently larger in extinction process in adolescent mice, which was involved the presynaptic mechanism. Together, our results suggest that adolescent mice exhibited a disability to extinct the fear memory, and that this may lead to the depressive-like behaviors via presynaptic-mediated synaptic plasticity. These findings may give us a new insight in the knowledge of some mental disorders caused by persistent unpleasant memories.


Asunto(s)
Envejecimiento/fisiología , Depresión/fisiopatología , Extinción Psicológica/fisiología , Miedo/psicología , Memoria/fisiología , Animales , Aprendizaje por Asociación/fisiología , Región CA1 Hipocampal/fisiología , Depresión/psicología , Pérdida de Tono Postural/fisiología , Potenciación a Largo Plazo/fisiología , Ratones
5.
Int J Neurosci ; 126(3): 257-68, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26001208

RESUMEN

Recent studies have demonstrated that the molecules secreted from microglias play important roles in the cell fate determination of neural stem cells (NSCs), and nicotinic acetylcholine receptor agonist treatment could reduce neuroinflammation in some neurodegenerative disease models, such as Alzheimer's disease (AD). However, it is not clear how nicotine plays a neuroprotective role in inflammation-mediated central nervous diseases, and its possible mechanisms in the process remain largely elusive. The aim of this study is to improve the survival microenvironment of NSCs co-cultured with microglias in vitro by weakening inflammation that mediated by accumulation of ß-amyloid peptide (Aß). The viability, proliferation, differentiation, apoptosis of NSCs and underlying mechanisms associated with Wnt signaling pathway were investigated. The results showed that Aß could directly damage NSCs. Furthermore, concomitant to elevated levels of TNF-α, IL-1ß derived from microglias, the NSCs had been damaged more severely with the upregulation of Axin 2, p-ß-catenin and the downregulation of ß-catenin, p-GSK-3ß, microtubule-associated protein-2, choline acetyltransferase. However, addition of 10 µmol/L nicotine before microglias treated with Aß was beneficial to protect the NSCs against neurotoxicity of microglial-derived factors induced by Aß, which partially rescued proliferation, differentiation and inhibited apoptosis of NSCs via activation of Wnt/ß-catenin pathway. Taken together, these data imply that low concentration nicotine attenuates NSCs injury induced by microglial-derived factors via Wnt signaling pathway. Thus, treatment with nicotinic acetylcholine receptor agonist provides a promising research field for neural stem cell fate and therapeutic intervention in neuroinflammation diseases.


Asunto(s)
Péptidos beta-Amiloides/farmacología , Microglía/efectos de los fármacos , Células-Madre Neurales/efectos de los fármacos , Nicotina/farmacología , Vía de Señalización Wnt/efectos de los fármacos , Animales , Animales Recién Nacidos , Apoptosis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Microglía/metabolismo , Células-Madre Neurales/metabolismo , Ratas , Ratas Sprague-Dawley , Proteínas Wnt/metabolismo , beta Catenina/metabolismo
6.
Mol Neurobiol ; 52(3): 1421-1429, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25860250

RESUMEN

Social isolation during the vulnerable period of adolescence produces emotional dysregulation that often manifests as abnormal behavior in adulthood. The enduring consequence of isolation might be caused by a weakened ability to forget unpleasant memories. However, it remains unclear whether isolation affects unpleasant memories. To address this, we used a model of associative learning to induce the fear memories and evaluated the influence of isolation mice during adolescence on the subsequent retention of fear memories and its underlying cellular mechanisms. Following adolescent social isolation, we found that mice decreased their social interaction time and had an increase in anxiety-related behavior. Interestingly, when we assessed memory retention, we found that isolated mice were unable to forget aversive memories when tested 4 weeks after the original event. Consistent with this, we observed that a single train of high-frequency stimulation (HFS) enabled a late-phase long-term potentiation (L-LTP) in the hippocampal CA1 region of isolated mice, whereas only an early-phase LTP was observed with the same stimulation in the control mice. Social isolation during adolescence also increased brain-derived neurotrophic factor (BDNF) expression in the hippocampus, and application of a tropomyosin-related kinase B (TrkB) receptor inhibitor ameliorated the facilitated L-LTP seen after isolation. Together, our results suggest that adolescent isolation may result in mental disorders during adulthood and that this may stem from an inability to forget the unpleasant memories via BDNF-mediated synaptic plasticity. These findings may give us a new strategy to prevent mental disorders caused by persistent unpleasant memories.


Asunto(s)
Región CA1 Hipocampal/fisiopatología , Miedo/psicología , Potenciación a Largo Plazo/fisiología , Aislamiento Social/psicología , Adolescente , Animales , Ansiedad/fisiopatología , Ansiedad/psicología , Aprendizaje por Asociación/efectos de los fármacos , Aprendizaje por Asociación/fisiología , Factor Neurotrófico Derivado del Encéfalo/fisiología , Región CA1 Hipocampal/efectos de los fármacos , Condicionamiento Clásico , Estimulación Eléctrica , Emetina/farmacología , Potenciales Postsinápticos Excitadores/fisiología , Conducta Exploratoria , Miedo/efectos de los fármacos , Miedo/fisiología , Humanos , Relaciones Interpersonales , Potenciación a Largo Plazo/efectos de los fármacos , Ratones , Modelos Animales , Proteínas del Tejido Nervioso/fisiología , Inhibidores de la Síntesis de la Proteína/farmacología , Psicología del Adolescente , Receptor trkB/antagonistas & inhibidores , Receptor trkB/fisiología , Retención en Psicología/efectos de los fármacos , Retención en Psicología/fisiología
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