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1.
PLoS One ; 19(2): e0297289, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38315685

RESUMO

Alzheimer's disease (AD) is characterized by cognitive and memory impairments and neuropathological abnormalities. AD has no cure, inadequate treatment options, and a limited understanding of possible prevention measures. Previous studies have demonstrated that AD model mice that received a diet high in the essential nutrient choline had reduced amyloidosis, cholinergic deficits, and gliosis, and increased neurogenesis. In this study, we investigated the lifelong effects of perinatal choline supplementation on behavior, cognitive function, and amyloidosis in AppNL-G-F AD model mice. Pregnant and lactating mice were given a diet containing either 1.1 g/kg (control) or 5 g/kg (supplemented) of choline chloride until weaning and subsequently, all offspring received the control diet throughout their life. At 3, 6, 9, and 12 months of age, animals were behaviorally tested in the Open Field Test, Elevated Plus Maze, Barnes Maze, and in a contextual fear conditioning paradigm. Immunohistochemical analysis of Aß42 was also conducted on the brains of these mice. AppNL-G-F mice displayed hippocampal-dependent spatial learning deficits starting at 3-months-old that persisted until 12-months-old. These spatial learning deficits were fully prevented by perinatal choline supplementation at young ages (3 and 6 months) but not in older mice (12 months). AppNL-G-F mice also had impaired fearful learning and memory at 9- and 12-months-old that were diminished by choline supplementation. Perinatal choline supplementation reduced Aß42 deposition in the amygdala, cortex, and hippocampus of AppNL-G-F mice. Together, these results demonstrate that perinatal choline supplementation is capable of preventing cognitive deficits and dampening amyloidosis in AppNL-G-F mice and suggest that ensuring adequate choline consumption during early life may be a valuable method to prevent or reduce AD dementia and neuropathology.


Assuntos
Doença de Alzheimer , Amiloidose , Gravidez , Feminino , Camundongos , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/prevenção & controle , Doença de Alzheimer/patologia , Camundongos Transgênicos , Lactação , Modelos Animais de Doenças , Encéfalo/metabolismo , Amiloidose/patologia , Colina/farmacologia , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/prevenção & controle , Transtornos da Memória/patologia , Aprendizagem em Labirinto , Suplementos Nutricionais , Peptídeos beta-Amiloides/metabolismo
2.
Int J Mol Sci ; 25(3)2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38339117

RESUMO

Sideritis scardica Griseb. and Clinopodium vulgare L., belonging to the Lamiaceae family, are rich in terpenoids and phenolics and exhibit various pharmacological effects, including antioxidant, anti-inflammatory and anti-cancer activities. While the memory-enhancing impacts of S. scardica are well documented, the cognitive benefits of C. vulgare remain unexplored. This study assessed the potential effect of C. vulgare on learning and memory in healthy and scopolamine (Sco)-induced memory-impaired male Wistar rats, comparing it with the effects of S. scardica. Over a 21-day period, rats orally received extracts of cultivated S. scardica (200 mg/kg) and C. vulgare (100 mg/kg), either individually or in combination, with administration starting 10 days before and continuing 11 days simultaneously with Sco injection at a dose of 2 mg/kg intraperitoneally. The results showed that both extracts effectively mitigated Sco-induced memory impairment. Their combination significantly improved recognition memory and maintained monoaminergic function. S. scardica excelled in preserving spatial working memory, while C. vulgare exhibited comparable retention of recognition memory, robust antioxidant activity and acetylcholinesterase inhibitory activity. The extracts alleviated Sco-induced downregulation of p-CREB/BDNF signaling, suggesting neuroprotective mechanisms. The extract combination positively affected most of the Sco-induced impairments, underscoring the potential for further investigation of these extracts for therapeutic development.


Assuntos
Disfunção Cognitiva , Demência , Sideritis , Ratos , Masculino , Animais , Escopolamina/efeitos adversos , Ratos Wistar , Acetilcolinesterase , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Demência/induzido quimicamente , Demência/tratamento farmacológico , Aprendizagem em Labirinto
3.
Int J Mol Sci ; 25(3)2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38339206

RESUMO

Methamphetamine (MA) is a highly addictive drug, and MA use disorder is often comorbid with anxiety and cognitive impairment. These comorbid conditions are theorized to reflect glutamate-related neurotoxicity within the frontal cortical regions. However, our prior studies of MA-sensitized mice indicate that subchronic, behaviorally non-contingent MA treatment is sufficient to dysregulate glutamate transmission in mouse brain. Here, we extend this prior work to a mouse model of high-dose oral MA self-administration (0.8, 1.6, or 3.2 g/L; 1 h sessions × 7 days) and show that while female C57BL/6J mice consumed more MA than males, MA-experienced mice of both sexes exhibited some signs of anxiety-like behavior in a behavioral test battery, although not all effects were concentration-dependent. No MA effects were detected for our measures of visually cued spatial navigation, spatial learning, or memory in the Morris water maze; however, females with a history of 3.2 g/L MA exhibited reversal-learning deficits in this task, and mice with a history of 1.6 g/L MA committed more working-memory incorrect errors and relied upon a non-spatial navigation strategy during the radial-arm maze testing. Relative to naïve controls, MA-experienced mice exhibited several changes in the expression of certain glutamate receptor-related proteins and their downstream effectors within the ventral and dorsal areas of the prefrontal cortex, the hippocampus, and the amygdala, many of which were sex-selective. Systemic pretreatment with the mGlu1-negative allosteric modulator JNJ 162596858 reversed the anxiety-like behavior expressed by MA-experienced mice in the marble-burying test, while systemic pretreatment with NMDA or the NMDA antagonist MK-801 bi-directionally affected the MA-induced reversal-learning deficit. Taken together, these data indicate that a relatively brief history of oral MA is sufficient to induce some signs of anxiety-like behavior and cognitive dysfunction during early withdrawal that reflect, at least in part, MA-induced changes in the corticolimbic expression of certain glutamate receptor subtypes of potential relevance to treating symptoms of MA use disorder.


Assuntos
Metanfetamina , Masculino , Camundongos , Animais , Feminino , Metanfetamina/toxicidade , N-Metilaspartato/farmacologia , Camundongos Endogâmicos C57BL , Receptores de Glutamato , Ácido Glutâmico/metabolismo , Cognição , Aprendizagem em Labirinto
4.
Nutrients ; 16(3)2024 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-38337665

RESUMO

Brain physiology and morphology are vulnerable to chronic stress, impacting cognitive performance and behavior. However, functional compounds found in food may alleviate these alterations. White quinoa (Chenopodium quinoa, Wild) seeds contain a high content of n-3 fatty acids, including alpha-linolenic acid. This study aimed to evaluate the potential neuroprotective role of a quinoa-based functional food (QFF) in rats. Prepubertal male Sprague-Dawley rats were fed with rat chow or QFF (50% rat chow + 50% dehydrated quinoa seeds) and exposed or not to restraint stress protocol (2 h/day; 15 days). Four experimental groups were used: Non-stressed (rat chow), Non-stressed + QFF, Stressed (rat chow) and Stressed + QFF. Weight gain, locomotor activity (open field), anxiety (elevated plus maze, light-dark box), spatial memory (Y-maze), and dendritic length in the hippocampus were measured in all animals. QFF intake did not influence anxiety-like behaviors, while the memory of stressed rats fed with QFF improved compared to those fed with rat chow. Additionally, QFF intake mitigated the stress-induced dendritic atrophy in pyramidal neurons located in the CA3 area of the hippocampus. The results suggest that a quinoa-supplemented diet could play a protective role in the memory of chronically stressed rats.


Assuntos
Chenopodium quinoa , Ratos , Animais , Masculino , Ratos Sprague-Dawley , Aprendizagem em Labirinto , Suplementos Nutricionais , Hipocampo/fisiologia , Estresse Psicológico/psicologia
5.
Neurosci Lett ; 824: 137669, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38360145

RESUMO

Maternal nutrition and physical activity during pregnancy and lactation can modify offspring development. Here, we investigated the effects of maternal aerobic exercise (AE) and Western diet (WD) on brain development, cognitive flexibility, and memory of progenies. Sixteen adult female mice were assigned to AE or sedentary groups (SED) and fed a balanced diet (BD) or WD. Offspring were categorized into four groups: WD + AE, WD + SED, BD + AE, and BD + SED. The AE group showed enhanced spontaneous alternation in the T-maze test, suggesting an improvement in working memory and tasks related to cognitive flexibility. The novel object recognition (NOR) test showed that the BD + AE pups improved their absolute discrimination and discrimination index at 24 h, which suggests a delay in memory consolidation without affecting evocation. WD + SED showed poorer discrimination and recognition memory. The pups of AE mothers had better efficiency in short-term memory, whereas WD offspring showed low performance in long-term memory. Interestingly, exercise improved tasks related to cognitive flexibility, regardless of the diet. These findings indicate that maternal diet and physical activity modify offspring development and suggest that maternal AE during pregnancy could be a beneficial intervention to counteract the adverse effects of WD by improving spatial memory and cognitive flexibility in offspring.


Assuntos
Dieta Ocidental , Memória de Longo Prazo , Gravidez , Humanos , Camundongos , Feminino , Animais , Fenômenos Fisiológicos da Nutrição Materna , Lactação , Aprendizagem em Labirinto
6.
Brain Behav ; 14(1): e3356, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38376046

RESUMO

BACKGROUND AND PURPOSE: Cognitive impairment is a prevalent adverse consequence of traumatic brain injury (TBI). The neuroprotective effects of nicorandil (N-(2-hydroxyethyl)-nicotinamide nitrate) has been previously documented, yet its protective effects against cognitive dysfunction post-TBI remain unclear. Hence, the present study was aimed to evaluate whether nicorandil attenuates cognitive dysfunction in TBI rats and the underlying mechanism behind this process. METHODS: The TBI model was established with a controlled cortical impact (CCI). The effects of nicorandil on cognitive dysfunction of rats with TBI were examined through Novel object recognition (NOR) test, Y-maze test, and Morris water maze (MWM) task. After behavioral tests, hippocampal tissue was collected for Quantitative real-time PCR, Western blot analysis, and Enzyme-linked immunosorbent assay (ELISA) assay. RESULTS: We observed that nicorandil administration effectively ameliorates learning and memory impairment in TBI rats. Alongside, nicorandil treatment attenuated oxidative stress in the hippocampus of TBI rats, characterized by the decreased reactive oxygen species generation, malondialdehyde, and protein carbonyls levels, and concurrent promotion of antioxidant-related factors (including superoxide dismutase, glutathione peroxidase, and catalase) activities. Additionally, nicorandil treatment attenuated the inflammatory response in the hippocampus of TBI rat, as evidenced by the upregulated levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α (TNF-α), as well as the downregulated level of IL-10. Mechanistically, nicorandil treatment significantly enhanced the mRNA and protein levels of neurotrophic factors, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the hippocampus of TBI rats. CONCLUSION: These findings suggest that nicorandil mitigates cognitive impairment after TBI by suppressing oxidative stress and inflammation, potentially through enhancing BDNF and NGF levels.


Assuntos
Lesões Encefálicas Traumáticas , Disfunção Cognitiva , Ratos , Animais , Nicorandil/farmacologia , Nicorandil/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator de Crescimento Neural/metabolismo , Fator de Crescimento Neural/farmacologia , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Estresse Oxidativo , Hipocampo/metabolismo , Aprendizagem em Labirinto , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Modelos Animais de Doenças
7.
Eur Rev Med Pharmacol Sci ; 28(3): 981-994, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38375702

RESUMO

OBJECTIVE: Recent research suggests that butin may also exert neuroprotective effects. However, its influence on cognitive performance and, specifically, its potential to mitigate scopolamine-induced memory impairment remains unexplored. The aim of the study is to investigate the effects of butin on the cognitive and behavioral performance of rats with scopolamine-induced memory impairment. MATERIALS AND METHODS: Scopolamine-injected memory-impediment model in rats was used to determine the efficacy of butin in higher and lower doses (10 and 20 mg/kg) for 14 days. Y-maze, along with Morris water, was used to assess the ability to recall spatial and working information. Biochemistry-related functions such as acetylcholinesterase, choline acetyltransferase, superoxide dismutase, glutathione transferase, malonaldehyde, catalase, nitric oxide, and neurotransmitters levels were estimated as indicators of free radical damage. Furthermore, we evaluated neuro-inflammatory responses by assessing tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1ß), interleukin-6 (IL-6), brain-derived neurotrophic factor (BDNF) and caspase-3 immuno-reactive proteins. RESULTS: When assessed through behavioral paradigms, the butin-treated group enhanced the spatial and working memory of rodents. Scopolamine caused a substantial alteration in biochemical-related parameters, neuronal enzymatic, inflammation responses and apoptosis markers prominently restored by butin. CONCLUSIONS: This study concludes that butin protects scopolamine-injected rats from behavioral impairments and neuronal damage by reducing apoptosis and neuroinflammation.


Assuntos
Benzopiranos , Fator Neurotrófico Derivado do Encéfalo , Escopolamina , Ratos , Animais , Escopolamina/efeitos adversos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Acetilcolinesterase/metabolismo , Caspase 3/metabolismo , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Colinérgicos/metabolismo , Colinérgicos/farmacologia , Colinérgicos/uso terapêutico , Estresse Oxidativo , Aprendizagem em Labirinto , Hipocampo/metabolismo
8.
Brain Behav ; 14(1): e3351, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38376050

RESUMO

INTRODUCTION: Vascular dementia (VaD) is a common type of dementia. The aim of this study was to investigate the cellular and molecular mechanism of conditioned medium (CM) in VaD. MATERIAL AND METHODS: The rats were divided into four groups of control (n = 9), sham-operation (n = 10), VaD with vehicle (n = 9), and VaD with CM (n = 12) that received CM on days 4, 14, and 24 after 2VO. Before sacrificing the rats, cognitive performance was assessed through the open-field (OP), passive-avoidance, and Morris-water maze. The field-potential recording was used to investigate basal synaptic transmission (BST) and long-term potentiation (LTP). Subsequently, the hippocampus was dissected, and real-time PCR was used to quantify the expression levels of ß1-catenin, insulin-like growth factor-1 (IGF-1), transforming growth factor-beta (TGF-ß), glycogen synthase kinase-3ß (GSK-3ß), postsynaptic density protein 95 (PSD-95), and NR2B genes. RESULTS: The results indicated impaired performance in behavioral tests in 2VO rats, coupled with reductions in BST and LTP induction. The expression levels of ß1-catenin, IGF-1, PSD-95, and TGF-ß genes decreased, whereas NR2B and GSK-3ß expression increased. Treatment with CM restores the expression of PSD-95 and GSK-3ß as well as fear-memory, spatial learning, and grooming number without a positive effect on memory retrieval, time spent on the periphery and center of OP. The BST recovered upon administration of CM but, the LTP induction was still impaired. CONCLUSION: The recovery of BST in VaD rats appears to be the most important outcome of this study which is caused by the improvement of gene expression and leads to the restoration of fear memory.


Assuntos
Demência Vascular , Ratos , Animais , Glicogênio Sintase Quinase 3 beta/metabolismo , Meios de Cultivo Condicionados/metabolismo , Meios de Cultivo Condicionados/farmacologia , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Ratos Sprague-Dawley , Aprendizagem em Labirinto , Proteína 4 Homóloga a Disks-Large , Transmissão Sináptica , Cognição , Células-Tronco/metabolismo , Cateninas/metabolismo , Cateninas/farmacologia , Fator de Crescimento Transformador beta/metabolismo , Hipocampo/metabolismo
9.
Brain Behav ; 14(2): e3444, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38409930

RESUMO

BACKGROUND: Morin is a flavonoid found in many edible fruits. The hippocampus and entorhinal cortex play crucial roles in memory formation and consolidation. This study aimed to characterize the effect of morin on recognition and space memory in healthy C57BL/6 adult mice and explore the underlying molecular mechanism. METHODS: Morin was administered i.p. at 1, 2.5, and 5 mg/kg/24 h for 10 days. The Morris water maze (MWM), novel object recognition, novel context recognition, and tasks were conducted 1 day after the last administration. The mice's brains underwent histological characterization, and their protein expression was examined using immunohistochemistry and Western blot techniques. RESULTS: In the MWM and novel object recognition tests, mice treated with 1 mg/kg of morin exhibited a significant recognition index increase compared to the control group. Besides, they demonstrated faster memory acquisition during MWM training. Additionally, the expression of pro-brain-derived neurotrophic factor (BDNF), BDNF, and postsynaptic density protein 95 proteins in the hippocampus of treated mice showed a significant increase. In the entorhinal cortex, only the pro-BDNF increased. Morin-treated mice exhibited a significant increase in the hippocampus's number and length of dendrites. CONCLUSION: This study shows that morin improves recognition memory and spatial memory in healthy adult mice.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Flavonas , Flavonoides , Camundongos , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Aprendizagem em Labirinto , Camundongos Endogâmicos C57BL , Flavonoides/farmacologia , Flavonoides/metabolismo , Hipocampo/metabolismo , Memória Espacial
10.
Food Funct ; 15(2): 917-929, 2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-38170494

RESUMO

Refreshing beverages, consumed worldwide, commonly take advantage of caffeine's impacts on attention and motor performance. However, excessive long-term caffeine intake might disturb sleep/wake rhythms and exacerbate daily anxiety. Fish-originated collagen peptides (FCP) are of high nutrient value with stimulating, calming or relaxing effects, which could reduce the excitotoxicity of caffeine. This study aims to investigate two facets: (1) the combined effect of caffeine and FCP (namely C&F) on the cognitive function of sleep-deprived mice by different administration strategies with dose dependence (low and high dose) or time dependence (intervention in a day and prevention for a week); (2) the potential "microbiota-gut-brain" mechanism by which C&F improves sleep deprivation (SD)-induced cognitive impairments. Here, C57BL/6 mice were administered caffeine (10 or 20 mg per kg per bw) combined with FCP (100 or 200 mg per kg per bw) and were then subjected to 48 h SD. The open-field and Morris water maze tests were performed to evaluate the cognitive function and spatial learning capacities of mice. Our results indicated that the cognitive impairments of SD mice were significantly relieved to a different degree by treating C&F in a dose- and time-dependent manner. The pathological observation of the hippocampus indicated both intervention (time of a day) and prevention (time of a week) of the C&F protected brain tissue from SD-induced injuries. The accumulated pro-inflammatory neurometabolites and factors were significantly inhibited by C&F via the hypothalamus-hippocampal circuit. Furthermore, 16S rDNA analysis of colonic contents showed that the level of Lactobacillus murinus was significantly upregulated and that of Clostridia_UCG-014 was suppressed in the C&F group. The receiver operating characteristic (ROC) curve of Lactobacillus murinus indicated a certain diagnostic utility to distinguish C&F intervention (AUC = 0.52) or prevention (AUC = 0.68). Pathways of ko04622 (immune system) and ko00472 (metabolism processes) were significantly regulated by C&F in a time-dependent manner. Based on PICRUSt2 algorithm analysis, C&F might potentially regulate gut microbial functions through several metabolic pathways, including the RIG-I-like receptor signaling pathway and limonene and pinene degradation. In conclusion, C&F plays a key role in brain function and behavior, which could synergistically relieve cognitive impairments via the microbiota-gut-brain axis.


Assuntos
Cafeína , Disfunção Cognitiva , Lactobacillus , Camundongos , Animais , Cafeína/farmacologia , Aprendizagem em Labirinto , Camundongos Endogâmicos C57BL , Sono , Privação do Sono/tratamento farmacológico , Cognição , Peptídeos/farmacologia , Peptídeos/uso terapêutico
11.
Molecules ; 29(2)2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38276581

RESUMO

Aging is a well-known factor that accelerates brain deterioration, resulting in impaired learning and memory functions. This current study evaluated the potential of an extract of Alternanthera philoxeroides (AP), an edible flavonoid-rich plant, to ameliorate D-galactose-induced brain aging in male mice. Chronic administration of D-galactose (150 mg/kg/day) in mice mimicked the characteristics of aging by accelerating senescence via downregulation of the following telomere-regulating factors: mouse telomerase reverse transcriptase (mTERT) and mouse telomeric repeat-binding factors 1 (mTRF1) and 2 (mTRF2). D-galactose also decreased the activities of the antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD), while increasing expression of neuroinflammatory cytokines in the frontal cortex and hippocampus. Daily treatment of D-galactose-induced aging mice with AP at 250 and 500 mg/kg/day or vitamin E (100 mg/kg/day) significantly increased the activities of SOD and CAT, as well as expression of mTERT, mTRF1, and mTRF2, which are involved in telomere stabilization, but decreased the levels of proinflammatory cytokines IL-1ß, IL-6, and TNF-α. In the behavioral portion of the study, AP improved aging-related cognitive deficits in short-term memory as shown by the Y-maze task and the novel object recognition test (NORT) and long-term memory as shown by the Morris water maze test (MWMT). The flavones kaempferol-O-glucoside (1), quercetin (2), alternanthin B (3), demethyltorosaflavone D (4), and chrysoeriol-7-O-rhamnoside (5), which could be responsible for the observed effects of AP in the D-galactose-induced aging mice, were identified by HPLC analysis.


Assuntos
Antioxidantes , Galactose , Camundongos , Animais , Antioxidantes/metabolismo , Galactose/metabolismo , Encurtamento do Telômero , Doenças Neuroinflamatórias , Aprendizagem em Labirinto , Envelhecimento , Encéfalo/metabolismo , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Superóxido Dismutase/metabolismo , Citocinas/metabolismo , Estresse Oxidativo
12.
Behav Processes ; 215: 104997, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38278425

RESUMO

Behavioural test is very useful to assess the anxiety activity, screen new anxiolytic drugs, explore the pathogenesis of anxiety disorders. Methods of behavioural testing that reflects different aspects of anxiety emotionality simultaneously have always been a critical issue for academics. In this paper, we reviewed previous methods to use behavioural test to evaluate the anxiety activity. A single test was used to measure only one aspect of anxiety emotionality. A battery of behavioural tests could get a comprehensive information of anxiety profile. In one single trial, open field test, elevated plus maze and light/dark box are integrated to assess different types of emotional behaviours. This new paradigm is useful for evaluating multiple dimensions of behaviours simultaneously, minimizing general concerns about previous test experience and inter-test intervals between tests. It is proposed as a promising alternative to using test battery.


Assuntos
Ansiolíticos , Ansiedade , Animais , Humanos , Ansiedade/psicologia , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Emoções , Transtornos de Ansiedade/tratamento farmacológico , Comportamento Animal , Aprendizagem em Labirinto
13.
J Alzheimers Dis ; 97(3): 1381-1392, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38250768

RESUMO

BACKGROUND: Mitochondrial dysfunction plays a vital role in the progression of vascular dementia (VaD). We hypothesized that transfer of exogenous mitochondria might be a beneficial strategy for VaD treatment. OBJECTIVE: The study was aimed to investigate the role of mitochondrial therapy in cognitive function of VaD. METHODS: The activity and integrity of isolated mitochondria were detected using MitoTracker and Janus Green B staining assays. After VaD mice were intravenously injected with exogenous mitochondria, Morris water maze and passive avoidance tests were used to detect cognitive function of VaD mice. Haematoxylin and eosin, Nissl, TUNEL, and Golgi staining assays were utilized to measure neuronal and synaptic injury in the hippocampus of VaD mice. Detection kits were performed to detect mitochondrial membrane potential (ΔΨ), SOD activity and the levels of ATP, ROS, and MDA in the brains of VaD mice. RESULTS: The results showed that isolated mitochondria were intact and active. Mitochondrial therapy could ameliorate cognitive performance of VaD mice. Additionally, mitochondrial administration could attenuate hippocampal neuronal and synaptic injury, improve mitochondrial ΔΨ, ATP level and SOD activity, and reduce ROS and MDA levels in the brains of VaD mice. CONCLUSIONS: The study reports profitable effect of mitochondrial therapy against cognitive impairment of VaD, making mitochondrial treatment become a promising therapeutic strategy for VaD.


Assuntos
Disfunção Cognitiva , Demência Vascular , Camundongos , Animais , Demência Vascular/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Cognição , Disfunção Cognitiva/metabolismo , Superóxido Dismutase/metabolismo , Mitocôndrias , Trifosfato de Adenosina/metabolismo , Aprendizagem em Labirinto/fisiologia , Hipocampo/metabolismo
14.
ACS Chem Neurosci ; 15(4): 724-734, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38290213

RESUMO

Herbs themselves and various herbal medicines are great resources for discovering therapeutic drugs for various diseases, including Alzheimer's disease (AD), one of the common neurodegenerative diseases. Utilizing mouse primary cortical neurons and DiBAC4(3), a voltage-sensitive indicator, we have set up a drug screening system and identified an herbal extraction compound, paeonol, obtained from Paeonia lactiflora; this compound is able to ameliorate the abnormal depolarization induced by Aß42 oligomers. Our aim was to further find effective paeonol derivatives since paeonol has been previously studied. 6'-Methyl paeonol, one of the six paeonol derivatives surveyed, is able to inhibit the abnormal depolarization induced by Aß oligomers. Furthermore, 6'-methyl paeonol is able to alleviate the NMDA- and AMPA-induced depolarization. When a molecular mechanism was investigated, 6'-methyl paeonol was found to reverse the Aß-induced increase in ERK phosphorylation. At the animal level, mice injected with 6'-methyl paeonol showed little change in their basic physical parameters compared to the control mice. 6'-Methyl paeonol was able to ameliorate the impairment of memory and learning behavior in J20 mice, an AD mouse model, as measured by the Morris water maze. Thus, paeonol derivatives could provide a structural foundation for developing and designing an effective compound with promising clinical benefits.


Assuntos
Doença de Alzheimer , Camundongos , Animais , Doença de Alzheimer/tratamento farmacológico , Neurônios , Acetofenonas/farmacologia , Acetofenonas/uso terapêutico , Modelos Animais de Doenças , Peptídeos beta-Amiloides/toxicidade , Aprendizagem em Labirinto
15.
Exp Neurol ; 374: 114690, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38218585

RESUMO

RNA binding motif 5 (RBM5) is a tumor suppressor in cancer but its role in the brain is unclear. We used conditional gene knockout (KO) mice to test if RBM5 inhibition in the brain affects chronic cortical brain tissue survival or function after a controlled cortical impact (CCI) traumatic brain injury (TBI). RBM5 KO decreased baseline contralateral hemispheric volume (p < 0.0001) and exacerbated ipsilateral tissue loss at 21 d after CCI in male mice vs. wild type (WT) (p = 0.0019). CCI injury, but not RBM5 KO, impaired beam balance performance (0-5d post-injury) and swim speed on the Morris Water Maze (MWM) (19-20d) (p < 0.0001). RBM5 KO was associated with mild learning impairment in female mice (p = 0.0426), reflected as a modest increase in escape latency early in training (14-18d post-injury). However, KO did not affect spatial memory at 19d post-injury in male or in female mice but it was impaired by CCI in females (p = 0.0061). RBM5 KO was associated with impaired visual function in male mice on the visible platform test at 20d post-injury (p = 0.0256). To explore signaling disturbances in KOs related to behavior, we first cross-referenced known brain-specific RBM5-regulated gene targets with genes in the curated RetNet database that impact vision. We then performed a secondary literature search on RBM5-regulated genes with a putative role in hippocampal function. Regulating synaptic membrane exocytosis 2 (RIMS) 2 was identified as a gene of interest because it regulates both vision and hippocampal function. Immunoprecipitation and western blot confirmed protein expression of a novel ~170 kDa RIMS2 variant in the cerebellum, and in the hippocampus, it was significantly increased in KO vs WT (p < 0.0001), and in a sex-dependent manner (p = 0.0390). Furthermore, male KOs had decreased total canonical RIMS2 levels in the cerebellum (p = 0.0027) and hippocampus (p < 0.0001), whereas female KOs had increased total RIMS1 levels in the cerebellum (p = 0.0389). In summary, RBM5 modulates brain function in mammals. Future work is needed to test if RBM5 dependent regulation of RIMS2 splicing effects vision and cognition, and to verify potential sex differences on behavior in a larger cohort of mice.


Assuntos
Lesões Encefálicas Traumáticas , Lesões Encefálicas , Doenças do Sistema Nervoso , Proteínas Supressoras de Tumor , Animais , Feminino , Masculino , Camundongos , Encéfalo/metabolismo , Lesões Encefálicas/patologia , Lesões Encefálicas Traumáticas/patologia , Proteínas de Ciclo Celular/metabolismo , Cerebelo/patologia , Proteínas de Ligação a DNA/metabolismo , Técnicas de Inativação de Genes , Hipocampo/metabolismo , Aprendizagem em Labirinto/fisiologia , Camundongos Knockout , Doenças do Sistema Nervoso/patologia , Proteostase , Proteínas de Ligação a RNA/metabolismo
16.
Neural Netw ; 172: 106050, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38232429

RESUMO

Navigation is a complex skill with a long history of research in animals and humans. In this work, we simulate the Morris Water Maze in 2D to train deep reinforcement learning agents. We perform automatic classification of navigation strategies, analyze the distribution of strategies used by artificial agents, and compare them with experimental data to show similar learning dynamics as those seen in humans and rodents. We develop environment-specific auxiliary tasks and examine factors affecting their usefulness. We suggest that the most beneficial tasks are potentially more biologically feasible for real agents to use. Lastly, we explore the development of internal representations in the activations of artificial agent neural networks. These representations resemble place cells and head-direction cells found in mouse brains, and their presence has correlation to the navigation strategies that artificial agents employ.


Assuntos
Teste do Labirinto Aquático de Morris , Navegação Espacial , Camundongos , Animais , Humanos , Reforço Psicológico , Aprendizagem , Redes Neurais de Computação , Aprendizagem em Labirinto
17.
Neurosci Lett ; 818: 137550, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37926292

RESUMO

Mild traumatic brain injury (TBI) can lead to various disorders, encompassing cognitive and psychiatric complications. While pre-clinical studies have long investigated behavioral alterations, the fluid percussion injury (FPI) model still lacks a comprehensive behavioral battery that includes psychiatric-like disorders. To address this gap, we conducted multiple behavioral tasks over two months in adult male Wistar rats, focusing on mild FPI. Statistical analyses revealed that both naive and sham animals exhibited an increase in sweet liquid consumption over time. In contrast, the TBI group did not show any temporal changes, although mild FPI did induce a statistically significant decrease in sucrose consumption compared to control groups during the chronic phase. Additionally, social interaction tasks indicated reduced contact time in TBI animals. The elevated plus maze task demonstrated an increase in open-arm exploration following fluid percussion. Nonetheless, no significant differences were observed in the acute and chronic phases for the forced swim and light-dark box tasks. Evaluation of three distinct memory tasks in the chronic phase revealed that mild FPI led to long-term memory deficits, as assessed by the object recognition task, while the surgical procedure itself resulted in short-term spatial memory deficits, as evaluated by the Y-maze task. Conversely, working memory remained unaffected in the water maze task. Collectively, these findings provide a nuanced characterization of behavioral deficits induced by mild FPI.


Assuntos
Concussão Encefálica , Lesões Encefálicas Traumáticas , Ratos , Animais , Masculino , Lesões Encefálicas Traumáticas/complicações , Percussão/efeitos adversos , Ratos Wistar , Memória de Curto Prazo , Modelos Animais de Doenças , Aprendizagem em Labirinto
18.
Behav Brain Res ; 458: 114730, 2024 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-37898351

RESUMO

The Barnes maze is a task used to assess spatial learning and memory in rodents. It requires animals to learn the position of a hole that can be used as an escape from a bright and open arena. The often-used parameters of latency and path length to measure learning and memory do not reflect the different navigation strategies chosen by the animals. Here, we propose an 11-point scoring scheme to classify the search strategies developed by the animals during the initial training as well as after the change of the escape target to a new position. Strategy scores add an important dimension to time and path length to assess the behavior in this popular maze.


Assuntos
Aprendizagem Espacial , Memória Espacial , Camundongos , Animais , Aprendizagem em Labirinto
19.
Curr Biol ; 34(1): 79-91.e4, 2024 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-38101403

RESUMO

Navigation tasks involve the gradual selection and deployment of increasingly effective searching procedures to reach targets. The brain mechanisms underlying such complex behavior are poorly understood, but their elucidation might provide insights into the systems linking exploration and decision making in complex learning. Here, we developed a trial-by-trial goal-related search strategy analysis as mice learned to navigate identical water mazes encompassing distinct goal-related rules and monitored the strategy deployment process throughout learning. We found that navigation learning involved the following three distinct phases: an early phase during which maze-specific search strategies are deployed in a minority of trials, a second phase of preferential increasing deployment of one search strategy, and a final phase of increasing commitment to this strategy only. The three maze learning phases were affected differently by inhibition of retrosplenial cortex (RSC), dorsomedial striatum (DMS), or dorsolateral striatum (DLS). Through brain region-specific inactivation experiments and gain-of-function experiments involving activation of learning-related cFos+ ensembles, we unraveled how goal-related strategy selection relates to deployment throughout these sequential processes. We found that RSC is critically important for search strategy selection, DMS mediates strategy deployment, and DLS ensures searching consistency throughout maze learning. Notably, activation of specific learning-related ensembles was sufficient to direct strategy selection (RSC) or strategy deployment (DMS) in a different maze. Our results establish a goal-related search strategy deployment approach to dissect unsupervised navigation learning processes and suggest that effective searching in navigation involves evidence-based goal-related strategy direction by RSC, reinforcement-modulated strategy deployment through DMS, and online guidance through DLS.


Assuntos
Neostriado , Navegação Espacial , Camundongos , Animais , Neostriado/fisiologia , Corpo Estriado/fisiologia , Aprendizagem em Labirinto/fisiologia , Motivação , Giro do Cíngulo , Navegação Espacial/fisiologia
20.
Neuroimmunomodulation ; 31(1): 12-24, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38151008

RESUMO

INTRODUCTION: Both sleep deprivation (SD) and inflammation can negatively affect cognitive function. This study aimed to investigate how SD impacts the brain's inflammatory response to lipopolysaccharide (LPS) and its subsequent effects on cognitive functions. METHODS: To this end, male rats were tested through a Morris water maze (MWM) to assess their spatial learning and memory. Also, in vivo field potential recordings (to evaluate synaptic plasticity) were done in the Saline, SD, LPS1 (1 mg/kg/7 days), and LPS1+SD groups. Cytokine levels were measured using an enzyme-linked immunosorbent assay (ELISA). RESULTS: Based on the results, the LPS1+SD group showed increased total distance and escape latency compared to the other groups in the MWM test. Besides, the LPS1+SD group exhibited a significant decrease in long-term potentiation (LTP) induction and maintenance in the CA1 area of the brain. Finally, the inflammatory cytokine interleukin-1ß (IL-1ß) levels were significantly higher in the LPS1+SD group than in the Saline group. CONCLUSION: These findings suggest that the combined effects of SD and brain inflammatory response can have more harmful effects on cognitive function, LTP, and inflammatory factors than either SD or LPS1 alone.


Assuntos
Potenciação de Longa Duração , Aprendizagem Espacial , Ratos , Masculino , Animais , Potenciação de Longa Duração/fisiologia , Aprendizagem Espacial/fisiologia , Privação do Sono/psicologia , Lipopolissacarídeos/toxicidade , Aprendizagem em Labirinto , Encéfalo , Citocinas , Hipocampo
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