RESUMO
Norepinephrine plays an important role in modulating memory through its beta-adrenergic receptors (Adrß: ß1, ß2 and ß3). Here, we hypothesized that multisensory stimulation would reverse memory impairment caused by the inactivation of Adrß3 (Adrß3KO) with consequent inhibition of sustained glial-mediated inflammation. To test this, 21- and 86-day-old Adrß3KO mice were exposed to an 8-week multisensory stimulation (MS) protocol that comprised gustatory and olfactory stimuli of positive and negative valence; intellectual challenges to reach food; the use of hidden objects; and the presentation of food in ways that prompted foraging, which was followed by analysis of GFAP, Iba-1 and EAAT2 protein expression in the hippocampus (HC) and amygdala (AMY). The MS protocol reduced GFAP and Iba-1 expression in the HC of young mice but not in older mice. While this protocol restored memory impairment when applied to Adrß3KO animals immediately after weaning, it had no effect when applied to adult animals. In fact, we observed that aging worsened the memory of Adrß3KO mice. In the AMY of Adrß3KO older mice, we observed an increase in GFAP and EAAT2 expression when compared to wild-type (WT) mice that MS was unable to reduce. These results suggest that a richer and more diverse environment helps to correct memory impairment when applied immediately after weaning in Adrß3KO animals and indicates that the control of neuroinflammation mediates this response.
Assuntos
Transtornos da Memória , Receptores Adrenérgicos beta , Camundongos , Animais , Masculino , Transtornos da Memória/genética , Transtornos da Memória/terapia , Transtornos da Memória/metabolismo , Receptores Adrenérgicos beta/metabolismo , Hipocampo/metabolismo , Norepinefrina/metabolismoRESUMO
Alzheimer disease's (AD) is a neurodegenerative disorder characterized by cognitive and behavioral impairment. The central nervous system is an important target of thyroid hormones (TH). An inverse association between serum triiodothyronine (T3) levels and the risk of AD symptoms and progression has been reported. We investigated the effects of T3 treatment on the depression-like behavior in male transgenic 3xTg-AD mice. Animals were divided into 2 groups treated with daily intraperitoneal injections of 20 ng/g of body weight (b.w.) L-T3 (T3 group) or saline (vehicle, control group). The experimental protocol lasted 21 days, and behavioral tests were conducted on days 18-20. At the end of the experiment, the TH profile and hippocampal gene expression were evaluated. The T3-treated group significantly increased serum T3 and decreased thyroxine (T4) levels. When compared to control hippocampal samples, the T3 group exhibited attenuated glycogen synthase kinase-3 (GSK3), metalloproteinase 10 (ADAM10), amyloid-beta precursor-protein (APP), serotonin transporter (SERT), 5HT1A receptor, monocarboxylate transporter 8 (MCT8) and bone morphogenetic protein 7 (BMP-7) gene expression, whereas augmented superoxide dismutase 2 (SOD2) and Hairless gene expression. T3-treated animals also displayed reduced immobility time in both the tail suspension and forced swim tests, and in the latter presented a higher latency time compared to the control group. Therefore, our findings suggest that in an AD mouse model, T3 supplementation promotes improvements in depression-like behavior, through the modulation of the serotonergic related genes involved in the transmission mediated by 5HT1A receptors and serotonin reuptake, and attenuated disease progression.
Assuntos
Doença de Alzheimer , Tri-Iodotironina , Animais , Camundongos , Masculino , Tri-Iodotironina/farmacologia , Tri-Iodotironina/uso terapêutico , Doença de Alzheimer/metabolismo , Depressão/tratamento farmacológico , Quinase 3 da Glicogênio Sintase , Camundongos Transgênicos , Hormônios Tireóideos/metabolismo , Modelos Animais de DoençasRESUMO
Gestational hypothyroidism can impair development, cognition, and mood. Here, we tested whether multisensory stimulation (MS) improves the phenotype of rats born to surgically thyroidectomized (Tx) dams suboptimally treated with LT4. 8-week-old female Tx Wistar rats were kept on daily LT4 (0.7 µg/100 g body weight) dosed by gavage (serum TSH and T4 levels indicated moderate hypothyroidism) and 3 weeks later placed for breeding. MS of the litter started at age 60 days and lasted for 8 weeks. It consisted of twice per week of physical, cognitive, sensorial, and food stimuli. The offspring were assessed before and after MS for standardized tests of locomotor activity, cognition, and mood. Gestational hypothyroidism resulted in reduced litter size and increased offspring mortality. The pups exhibited delayed physical development, impairment of short- and long-term memory, and anxiety- and depressive-like behaviors. Nonetheless, ambulatory activity, social memory, and social preference were not affected by gestational hypothyroidism. MS restored short-term memory and anxiety while improving depressive like-behaviors. MS did not improve long-term memory. MS also did not modify the performance of control litter born to intact dams. We conclude that cognition and mood impairments caused by moderate gestational hypothyroidism were reversed or minimized in rats through MS. Further studies should define the molecular mechanisms involved.
Assuntos
Hipotireoidismo , Tiroxina , Animais , Cognição , Feminino , Masculino , Parto , Gravidez , Ratos , Ratos WistarRESUMO
The Thr92Ala-Dio2 polymorphism has been associated with reduced cognition in 2-month-old male mice and increased risk for cognitive impairment and Alzheimer's disease in African Americans. This has been attributed to reduced thyroid hormone (TH) signaling and endoplasmic reticulum (ER) stress in the brain. Here we studied the Thr92Ala-Dio2 mouse model and saw that older male mice (7-8-month-old) exhibited a more severe cognition impairment, which extended to different aspects of declarative and working memories. A similar phenotype was observed in 4-5-month-old female mice. There were no structural alterations in the prefrontal cortex (PFC) and hippocampus of the Thr92Ala-Dio2 mouse. Nonetheless, in both male and female PFC, there was an enrichment in genes associated with TH-dependent processes, ER stress, and Golgi apparatus, while in the hippocampus there was additional enrichment in genes associated with inflammation and apoptosis. Reduced TH signaling remains a key mechanism of disease given that short-term treatment with L-T3 rescued the cognitive phenotype observed in males and females. We conclude that in mice, age is an additional risk factor for cognitive impairment associated with the Thr92Ala-Dio2 polymorphism. In addition to reduced TH signaling, ER-stress, and involvement of the Golgi apparatus, hippocampal inflammation and apoptosis were identified as potentially important mechanisms of a disease.
RESUMO
OBJECTIVE: Obesity is characterized by a state of chronic, low-intensity systemic inflammation frequently associated with insulin resistance and dyslipidemia. METHODS: Given that chronic inflammation has been implicated in the pathogenesis of mood disorders, we investigated if chronic obesity that was initiated early in life - lasting through adulthood - could be more harmful to memory impairment and mood fluctuations such as depression. RESULTS: Here we show that pre-pubertal male rats (30 days old) treated with a high-fat diet (40%) for 8-months gained ~50% more weight when compared to controls, exhibited depression and anxiety-like behaviors but no memory impairment. The prefrontal cortex of the obese rats exhibited an increase in the expression of genes related to inflammatory response, such as NFKb, MMP9, CCl2, PPARb, and PPARg. There were no alterations in genes known to be related to depression. CONCLUSION: Long-lasting obesity with onset in prepuberal age led to depression and neuroinflammation but not to memory impairment.
Assuntos
Comportamento Animal , Depressão , Animais , Ansiedade , Depressão/etiologia , Dieta Hiperlipídica/efeitos adversos , Masculino , Obesidade , RatosRESUMO
ABSTRACT Objective: Obesity is characterized by a state of chronic, low-intensity systemic inflammation frequently associated with insulin resistance and dyslipidemia. Materials and methods: Given that chronic inflammation has been implicated in the pathogenesis of mood disorders, we investigated if chronic obesity that was initiated early in life - lasting through adulthood - could be more harmful to memory impairment and mood fluctuations such as depression. Results: Here we show that pre-pubertal male rats (30 days old) treated with a high-fat diet (40%) for 8-months gained ~50% more weight when compared to controls, exhibited depression and anxiety-like behaviors but no memory impairment. The prefrontal cortex of the obese rats exhibited an increase in the expression of genes related to inflammatory response, such as NFKb, MMP9, CCl2, PPARb, and PPARg. There were no alterations in genes known to be related to depression. Conclusion: Long-lasting obesity with onset in prepuberal age led to depression and neuroinflammation but not to memory impairment.
Assuntos
Animais , Masculino , Ratos , Comportamento Animal , Depressão/etiologia , Ansiedade , Dieta Hiperlipídica/efeitos adversos , ObesidadeRESUMO
To study thyroid hormone (TH) signaling in the human brain, we analyzed published microarray data sets of the temporal pole (Brodmann area 38) of 19 deceased donors. An index of TH signaling built on the expression of 19 well known TH-responsive genes in mouse brains (T3S+) varied from 0.92 to 1.1. After Factor analysis, T3S+ correlated independently with the expression of TH transporters (MCT8, LAT2), TH receptor (TR) beta and TR coregulators (CARM1, MED1, KAT2B, SRC2, SRC3, NCOR2a). Unexpectedly, no correlation was found between T3S+ vs DIO2, DIO3, SRC1, or TRα. An unbiased systematic analysis of the entire transcriptome identified a set of 1649 genes (set #1) with strong positive correlation with T3S+ (r > 0.75). Factor analysis of set #1 identified 2 sets of genes that correlated independently with T3S+, sets #2 (329 genes) and #3 (191 genes). When processed through the Molecular Signatures Data Base (MSigDB), both sets #2 and #3 were enriched with Gene Ontology (GO)-sets related to synaptic transmission and metabolic processes. Ranking individual human brain donors according to their T3S+ led us to identify 1262 genes (set #4) with >1.3-fold higher expression in the top half. The analysis of the overlapped genes between sets #1 and #4 resulted in 769 genes (set #5), which have a very similar MSigDB signature as sets #2 and #3. In conclusion, gene expression in the human temporal pole can be assessed through T3S+ and fluctuates with subtle variations in local TH signaling.
RESUMO
The ability to understand and to communicate is essential for the adapted social and cultural development of children. Autism spectrum disorders (ASD) are characterized by social interaction deficiencies in the verbal language domain and may incur in repetitive, stereotyped, and restricted gestural behaviors. Regarding animal models in ASD, many studies focus on gene expression, cortical neuronal migration and cell maturation, and neural network deficits. However, very few studies directly link animal oral communication and gene expression in cortical areas of language. The object of our study aimed to review and to correlate genes involved in ASD and those related to ultrasonic communication in animal model studies of language-based social behavior at the PubMed database. The PubMed search yielded 25 selected papers. Some findings showed critical genes, which modulate several aspects of verbal communication. Most of these genes can be markers of communication deficits.
A capacidade de compreender os outros e comunicar-se com eles é fundamental para o desenvolvimento das crianças durante o desenvolvimento típico. Entre os desarranjos sociais, o transtorno do espectro autista (TEA) é caracterizado por deficiências de expressão e interações, em que ocorrem comportamentos repetitivos, estereotipados e com particularidade restrita. Com o objetivo de entender melhor a correlação entre o TEA e estudos de experimentação em comunicação ultrassônica em modelos animais, foi realizada uma revisão teórico-integrativa na base de dados PubMed, sendo selecionados 25 trabalhos. Evidenciou-se, com base nos achados, o papel relevante e promissor de determinados genes que modulam os aspectos de comunicação. Esses genes, em sua grande maioria, podem ser marcadores de déficits de comunicação.
La capacidad de comprender y comunicarse es esencial para el desarrollo social y cultural adaptado de los niños. El trastorno del espectro autista (TEA) se caracterizan por deficiencias de interacción social en el dominio del lenguaje verbal y pueden incurrir en comportamientos gestuales repetitivos, estereotipados y restringidos. Con respecto a los modelos animales en TEA, muchos estudios se centran en la expresión génica, la migración y maduración neuronal cortical y los déficits de la red neuronal, pero muy pocos son los estudios que relacionen directamente la comunicación oral animal y la expresión génica en áreas corticales del lenguaje. El objetivo de nuestro estudio tuvo como objetivo revisar y correlacionar genes involucrados en TEA y aquellos relacionados con la comunicación ultrasónica en estudios con modelos animales de comportamiento social basado en el lenguaje en la base de datos PubMed. La búsqueda en PubMed arrojó 25 artículos seleccionados. Algunos hallazgos mostraron genes críticos, que modulan varios aspectos de la comunicación verbal. Esta evidencia puede ofrecer la oportunidad como biomarcadores genéticos para los déficits de comunicación en los desórdenes en el neurodesarrollo.
Assuntos
Transtornos do Neurodesenvolvimento , Transtorno do Espectro Autista , Desenvolvimento da Linguagem , GenéticaRESUMO
Status epilepticus (SE) is an abnormally prolonged seizure that results from either a failure of mechanisms that terminate seizures or from initiating mechanisms that inherently lead to prolonged seizures. Here we report that mice experiencing a 3 hours of SE caused by pilocarpine exhibit a rapid increase in expression of type 2 iodothyronine deiodinase gene (Dio2) and a decrease in the expression of type 3 iodothyronine deiodinase gene in hippocampus, amygdala and prefrontal cortex. Type 3 iodothyronine deiodinase in hippocampal sections was seen concentrated in the neuronal nuclei, typical of ischemic injury of the brain. An unbiased analysis of the hippocampal transcriptome of mice undergoing 3 hours of SE revealed a number of genes, including those involved with response to oxidative stress, cellular homeostasis, cell signaling, and mitochondrial structure. In contrast, in mice with targeted disruption of Dio2 in astrocytes (Astro D2KO mouse), the highly induced genes in the hippocampus were related to inflammation, apoptosis, and cell death. We propose that Dio2 induction caused by SE accelerates production of T3 in different areas of the central nervous system and modifies the hippocampal gene expression profile, affecting the balance between adaptive and maladaptive mechanisms.
Assuntos
Expressão Gênica , Hipocampo/metabolismo , Iodeto Peroxidase/genética , Estado Epiléptico/genética , Tri-Iodotironina/metabolismo , Tonsila do Cerebelo/metabolismo , Animais , Apoptose/genética , Astrócitos/metabolismo , Morte Celular/genética , Núcleo Celular/metabolismo , Inflamação/genética , Iodeto Peroxidase/metabolismo , Masculino , Camundongos , Camundongos Knockout , Agonistas Muscarínicos/toxicidade , Neurônios/metabolismo , Estresse Oxidativo/genética , Pilocarpina/toxicidade , Córtex Pré-Frontal/metabolismo , Transdução de Sinais , Estado Epiléptico/induzido quimicamente , Iodotironina Desiodinase Tipo IIRESUMO
Liver-specific disruption of the type 2 deiodinase gene (Alb-D2KO) results in resistance to both diet-induced obesity and liver steatosis in mice. Here, we report that this is explained by an â¼60% reduction in liver zinc-finger protein-125 (Zfp125) expression. Zfp125 is a Foxo1-inducible transcriptional repressor that causes lipid accumulation in the AML12 mouse hepatic cell line and liver steatosis in mice by reducing liver secretion of triglycerides and hepatocyte efflux of cholesterol. Zfp125 acts by repressing 18 genes involved in lipoprotein structure, lipid binding, and transport. The ApoE promoter contains a functional Zfp125-binding element that is also present in 17 other lipid-related genes repressed by Zfp125. While liver-specific knockdown of Zfp125 causes an "Alb-D2KO-like" metabolic phenotype, liver-specific normalization of Zfp125 expression in Alb-D2KO mice rescues the phenotype, restoring normal susceptibility to diet-induced obesity, liver steatosis, and hypercholesterolemia.