RESUMEN
Proper establishment of synapses is critical for constructing functional circuits. Interactions between presynaptic neurexins and postsynaptic neuroligins coordinate the formation of synaptic adhesions. An isoform code determines the direct interactions of neurexins and neuroligins across the synapse. However, whether extracellular linker proteins can expand such a code is unknown. Using a combination of in vitro and in vivo approaches, we found that hevin, an astrocyte-secreted synaptogenic protein, assembles glutamatergic synapses by bridging neurexin-1alpha and neuroligin-1B, two isoforms that do not interact with each other. Bridging of neurexin-1alpha and neuroligin-1B via hevin is critical for the formation and plasticity of thalamocortical connections in the developing visual cortex. These results show that astrocytes promote the formation of synapses by modulating neurexin/neuroligin adhesions through hevin secretion. Our findings also provide an important mechanistic insight into how mutations in these genes may lead to circuit dysfunction in diseases such as autism.
Asunto(s)
Astrocitos/metabolismo , Proteínas de Unión al Calcio/metabolismo , Moléculas de Adhesión Celular Neuronal/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Tálamo/metabolismo , Animales , Células COS , Chlorocebus aethiops , Predominio Ocular , Humanos , Ratones , Ratones Noqueados , Enfermedades del Sistema Nervioso/metabolismo , Neuronas/metabolismo , Isoformas de Proteínas/metabolismo , Transducción de Señal , Sinapsis/metabolismoRESUMEN
Tobacco misuse as a comorbidity of schizophrenia is frequently established during adolescence. However, comorbidity markers are still missing. Here, the method of label-free proteomics was used to identify deregulated proteins in the medial prefrontal cortex (prelimbic and infralimbic) of male and female mice modelled to schizophrenia with a history of nicotine exposure during adolescence. Phencyclidine (PCP), used to model schizophrenia (SCHZ), was combined with an established model of nicotine minipump infusions (NIC). The combined insults led to worse outcomes than each insult separately when considering the absolute number of deregulated proteins and that of exclusively deregulated ones. Partially shared Reactome pathways between sexes and between PCP, NIC and PCPNIC groups indicate functional overlaps. Distinctively, proteins differentially expressed exclusively in PCPNIC mice reveal unique effects associated with the comorbidity model. Interactome maps of these proteins identified sex-selective subnetworks, within which some proteins stood out: for females, peptidyl-prolyl cis-trans isomerase (Fkbp1a) and heat shock 70 kDa protein 1B (Hspa1b), both components of the oxidative stress subnetwork, and gamma-enolase (Eno2), a component of the energy metabolism subnetwork; and for males, amphiphysin (Amph), a component of the synaptic transmission subnetwork. These are proposed to be further investigated and validated as markers of the combined insult during adolescence.
Asunto(s)
Fenciclidina , Esquizofrenia , Ratones , Animales , Masculino , Femenino , Fenciclidina/metabolismo , Esquizofrenia/metabolismo , Nicotina/farmacología , Corteza Prefrontal/metabolismo , Transmisión Sináptica , Modelos Animales de EnfermedadRESUMEN
The association between schizophrenia and nicotine addiction becomes evident during adolescence. Here, to investigate interactive events that might underlie the early establishment of this comorbidity, we used phencyclidine-evoked locomotor sensitization, a proxy model of psychotic behavior, and nicotine minipump infusions in adolescent mice. Considering the involvement of dopamine D2 receptors in both schizophrenia and addiction, we further tested their role by exposing mice to raclopride. Adolescent mice that were either exposed to nicotine (24 mg/Kg/day) or not, received single daily raclopride (0.5 mg/kg, s.c.) or saline followed by phencyclidine injections (10 mg/Kg, s.c.) during open field testing for 6 consecutive days (Acquisition phase, ACQ). Phencyclidine and nicotine challenges (Sensitization Test, ST) were carried out after a 5-day withdrawal. Ambulation escalated in response to repeated phencyclidine exposure during ACQ and was increased after phencyclidine challenge, evidencing development and expression of locomotor sensitization. Raclopride prevented phencyclidine-evoked development of sensitization. However, raclopride pre-exposure during ACQ only shortened its expression in phencyclidine-challenged mice. Nicotine failed to interfere with phencyclidine stimulatory effects during ACQ but potentiated raclopride inhibition during the first ACQ days. During ST, nicotine history shortened the expression of phencyclidine-evoked sensitization. Nicotine challenge had no impact on locomotion, which is consistent with a lack of nicotine/phencyclidine cross-sensitization. In conclusion, our results show that nicotine does not worsen, and may even ameliorate phencyclidine-sensitized psychotic-like behavior in adolescent mice. The potentiation of raclopride-mediated inhibition further suggests that nicotine transiently improves the therapeutic efficacy of medication on psychotic symptoms through mechanisms that converge on D2 receptors.
Asunto(s)
Nicotina , Fenciclidina , Ratones , Animales , Fenciclidina/toxicidad , Nicotina/toxicidad , Racloprida/farmacología , Locomoción , Actividad Motora , Receptores DopaminérgicosRESUMEN
PURPOSE: Obese individuals have higher production of reactive oxygen species, which leads to oxidative damage. We hypothesize that cranberry extract (CE) can improve this dysfunction in HFD-induced obesity in rats since it has an important antioxidant activity. Here, we evaluated the effects of CE in food intake, adiposity, biochemical and hormonal parameters, lipogenic and adipogenic factors, hepatic morphology and oxidative balance in a HFD model. METHODS: At postnatal day 120 (PN120), male Wistar rats were assigned into two groups: (1) SD (n = 36) fed with a standard diet and (2) HFD (n = 36), fed with a diet containing 44.5% (35.2% from lard) energy from fat. At PN150, 12 animals from SD and HFD groups were killed while the others were subdivided into four groups (n = 12/group): animals that received 200 mg/kg cranberry extract (SD CE, HFD CE) gavage/daily/30 days or water (SD, HFD). At PN180, animals were killed. RESULTS: HFD group showed higher body mass and visceral fat, hypercorticosteronemia, higher liver glucocorticoid sensitivity, cholesterol and triglyceride contents and microsteatosis. Also, HFD group had higher lipid peroxidation (plasma and tissues) and higher protein carbonylation (liver and adipose tissue) compared to SD group. HFD CE group showed lower body mass gain, hypotrygliceridemia, hypocorticosteronemia, and lower hepatic cholesterol and fatty acid synthase contents. HFD CE group displayed lower lipid peroxidation, protein carbonylation (liver and adipose tissue) and accumulation of liver fat compared to HFD group. CONCLUSION: Although adiposity was not completely reversed, cranberry extract improved the metabolic profile and reduced oxidative damage and steatosis in HFD-fed rats, which suggests that it can help manage obesity-related disorders.
Asunto(s)
Dieta Alta en Grasa , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/metabolismo , Obesidad/tratamiento farmacológico , Extractos Vegetales/farmacología , Vaccinium macrocarpon/química , Animales , Brasil , Colesterol/metabolismo , Hígado Graso , Masculino , Ratones , Extractos Vegetales/administración & dosificación , Ratas , Ratas WistarRESUMEN
Fetal alcohol spectrum disorder is the most common cause of mental disabilities in the western world. It has been quite established that acute alcohol exposure can dramatically affect astrocyte function. Because the effects of early alcohol exposure on cell physiology can persist into adulthood, we tested the hypothesis that ethanol exposure in ferrets during a period equivalent to the last months of human gestation leads to persistent changes in astrocyte secretome in vitro. Animals were treated with ethanol (3.5 g/kg) or saline between postnatal day (P)10-30. At P31, astrocyte cultures were made and cells were submitted to stable isotope labeling by amino acids. Twenty-four hour conditioned media of cells obtained from ethanol- or saline-treated animals (ET-CM or SAL-CM) were collected and analyzed by quantitative mass spectrometry in tandem with liquid chromatography. Here, we show that 65 out of 280 quantifiable proteins displayed significant differences comparing ET-CM to SAL-CM. Among the 59 proteins that were found to be reduced in ET-CM we observed components of the extracellular matrix such as laminin subunits α2, α4, ß1, ß2, and γ1 and the proteoglycans biglycan, heparan sulfate proteoglycan 2, and lumican. Proteins with trophic function such as insulin-like growth factor binding protein 4, pigment epithelium-derived factor, and clusterin as well as proteins involved on modulation of proteolysis such as metalloproteinase inhibitor 1 and plasminogen activator inhibitor-1 were also reduced. In contrast, pro-synaptogeneic proteins like thrombospondin-1, hevin as well as the modulator of extracelular matrix expression, angiotensinogen, were found increased in ET-CM. The analysis of interactome maps through ingenuity pathway analysis demonstrated that the amyloid beta A4 protein precursor, which was found reduced in ET-CM, was previously shown to interact with ten other proteins that exhibited significant changes in the ET-CM. Taken together our results strongly suggest that early exposure to teratogens such as alcohol may lead to an enduring change in astrocyte secretome. Despite efforts in prevention, fetal alcohol spectrum disorders are a major cause of mental disabilities. Here, we show that developmental exposure to alcohol lead to a persistent change in the pattern of proteins secreted (secretome) by astrocytes. This study is also the first mass spectrometry-based assessment of the astrocyte secretome in a gyrencephalic animal. Cover Image for this issue: doi: 10.1111/jnc.13320.
Asunto(s)
Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Etanol/toxicidad , Proteoma/genética , Proteoma/metabolismo , Animales , Animales Recién Nacidos , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Cultivadas , Etanol/administración & dosificación , Femenino , Hurones , Masculino , EmbarazoRESUMEN
Hypoxic-ischemic (HI) injury is an important cause of death and disabilities. Despite all improvements in neonatal care, the number of children who suffer some kind of injury during birth has remained stable in the last decade. A great number of studies have shown alterations in neural cells and many animal models have been proposed in the last 5 decades. Robinson et al. (2005) proposed an HI model in which the uterine arteries are temporarily clamped on the 18th gestation day. The findings were quite similar to the ones observed in postmortem studies. The white matter is clearly damaged, and a great amount of astrogliosis takes place both in the gray and white matters. Motor changes were also found but no data regarding the cerebellum, an important structure related to motor performance, was presented. Using this model, we have shown an increased level of iNOS at P0 and microgliosis and astrogliosis at P9, and astrogliosis at P23 (up to 4 weeks from the insult). NO is important in migration, maturation, and synaptic plasticity, but in exacerbated levels it may also contribute to cellular and tissue damage. We have also evaluated oligodendroglia development in the cerebellum. At P9 in HI animals, we found a decrease in the number of PDGFRα+ cells and an apparent delay in myelination, suggesting a failure in oligodendroglial progenitors migration/maturation and/or in the myelination process. These results point to an injury in cerebellar development that might help to explain the motor problems in HI.
Asunto(s)
Cerebelo/patología , Gliosis/patología , Hipoxia-Isquemia Encefálica/patología , Neuronas Motoras/patología , Oligodendroglía/patología , Efectos Tardíos de la Exposición Prenatal/patología , Animales , Animales Recién Nacidos , Cerebelo/metabolismo , Femenino , Expresión Génica , Gliosis/genética , Gliosis/metabolismo , Humanos , Hipoxia-Isquemia Encefálica/genética , Hipoxia-Isquemia Encefálica/metabolismo , Ratones , Neuronas Motoras/metabolismo , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Oligodendroglía/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/metabolismo , Ratas , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Sustancia Blanca/metabolismo , Sustancia Blanca/patologíaRESUMEN
The suppression of prolactin production with bromocriptine (BRO) in the last 3 d of lactation reduces milk yield (early weaning) and increases the transfer of leptin through the milk, causing hyperleptinaemia in pups. In adulthood, several changes occur in the offspring as a result of metabolic programming, including overweight, higher visceral fat mass, hypothyroidism, hyperglycaemia, insulin resistance, hyperleptinaemia and central leptin resistance. In the present study, we investigated whether overweight rats programmed by early weaning with maternal BRO treatment have hypothalamic alterations in adulthood. We analysed the expression of neuropeptide Y (NPY), cocaine- and amphetamine-regulated transcript (CART), pro-opiomelanocortin (POMC) and α-melanocyte-stimulating hormone (α-MSH) by immunohistochemistry in the following hypothalamic nuclei: medial and lateral arcuate nucleus (ARC); paraventricular nucleus (PVN); lateral hypothalamus (LH). Additionally, we sought to determine whether these programmed rats exhibited hypothalamic inflammation as indicated by astrogliosis. NPY immunostaining showed a denser NPY-positive fibre network in the ARC and PVN (+82% in both nuclei) of BRO offspring. Regarding the anorexigenic neuropeptides, no difference was found for CART, POMC and α-MSH. The number of astrocytes was higher in all the nuclei of BRO rats. The fibre density of glial fibrillary acidic protein was also increased in both medial and lateral ARC (6·06-fold increase and 9·13-fold increase, respectively), PVN (5·75-fold increase) and LH (2·68-fold increase) of BRO rats. We suggest that early weaning has a long-term effect on the expression of NPY as a consequence of developmental plasticity, and the presence of astrogliosis indicates hypothalamic inflammation that is closely related to overweight and hyperleptinaemia observed in our model.
Asunto(s)
Gliosis/inducido químicamente , Hipotálamo/patología , Lactancia/efectos de los fármacos , Neuropéptido Y/análisis , Prolactina/antagonistas & inhibidores , Destete , Animales , Núcleo Arqueado del Hipotálamo/química , Femenino , Hipotálamo/química , Hipotálamo/efectos de los fármacos , Leptina/sangre , Leptina/metabolismo , Masculino , Leche/metabolismo , Proteínas del Tejido Nervioso/análisis , Núcleo Hipotalámico Paraventricular/química , Embarazo , Proopiomelanocortina/análisis , Ratas , Ratas Wistar , alfa-MSH/análisisRESUMEN
Habituation is an important tool in the investigation of learning/memory throughout life. Despite that, few studies describe habituation from an ontogenetic perspective. Considering that, as soon as they are born, rodents can twist their bodies when lifted by their tails in an attempt to escape, this behavior should be well suited to study habituation behavior from birth to adulthood. Here, we implement a tail suspension test to study the ontogenetic development of habituation in Swiss mice. Our data indicate that a continuous within-session decrease in trunk movements can be observed from postnatal day (P) 10 onwards and that between-sessions habituation (from one day to another) can be observed from P16 onwards. Furthermore, we show that the adult pattern of within- and between-sessions reductions in activity is already present by the beginning of adolescence, at P28. Our results indicate that between-sessions habituation involves a more complex mechanism of memory and learning than within-session habituation, requiring a longer period of brain maturation before it can be displayed.
Asunto(s)
Conducta Animal/fisiología , Habituación Psicofisiológica/fisiología , Animales , Conducta Exploratoria/fisiología , Suspensión Trasera , Aprendizaje/fisiología , RatonesRESUMEN
Mood disorders and substance use disorder (SUD) are of immense medical and social concern. Although significant progress on neuronal involvement in mood and reward circuitries has been achieved, it is only relatively recently that the role of glia in these disorders has attracted attention. Detailed understanding of the glial functions in these devastating diseases could offer novel interventions. Here, following a brief review of circuitries involved in mood regulation and reward perception, the specific contributions of neurotrophic factors, neuroinflammation, and gut microbiota to these diseases are highlighted. In this context, the role of specific glial cells (e.g., microglia, astroglia, oligodendrocytes, and synantocytes) on phenotypic manifestation of mood disorders or SUD are emphasized. In addition, use of this knowledge in the potential development of novel therapeutics is touched upon.
RESUMEN
INTRODUCTION: Adolescents often associate tobacco smoking and consumption of alcoholic beverages. In spite of that, little is known about the neurobehavioral consequences of the dual exposure in the adolescent brain. In the present work, we assessed the effects of tobacco smoke and/or ethanol exposure during adolescence on memory/learning. METHODS: From postnatal day 30 to 45 (PN30-45), male and female Swiss mice were exposed to tobacco smoke (SMK-generated from research cigarettes type 3R4F, whole body exposure, 8hr/day) and/or ethanol (ETOH-25% solution, 2g/kg intraperitoneally injected every other day) as follows: (a) SMK+ETOH exposure; (b) SMK exposure; (c) ETOH exposure; (d) Control. Memory/learning was evaluated during exposure (PN44-45) and during short- (PN49-50) and long-standing withdrawal (PN74-75). At each timepoint, mice were trained and tested in a step-down passive avoidance task (0.3 mA, 3 s footshock). Two retention tests were carried out in each animal, one at 3hr after training to measure short-term memory and another at 24hr to measure long-term memory. RESULTS: During exposure, the short-term memory was impaired in all groups and the long-term memory was impaired in SMK and SMK+ETOH. During the short-standing withdrawal, a significant impairment was observed only in long-term memory of the male SMK+ETOH mice. At long-standing withdrawal, there were no significant differences between groups. CONCLUSIONS: Tobacco smoke and ethanol exposures during adolescence of mice negatively affect learning/memory performance. Deficits that were still present during SMK+ETOH short-standing withdrawal suggest that the combined exposure elicits a worsened memory/learning outcome and that males are more susceptible.
Asunto(s)
Conducta Animal/efectos de los fármacos , Etanol/toxicidad , Aprendizaje/efectos de los fármacos , Memoria a Largo Plazo/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Fumar/efectos adversos , Factores de Edad , Animales , Peso Corporal , Cotinina/sangre , Etanol/sangre , Femenino , Masculino , Ratones , Síndrome de Abstinencia a Sustancias/fisiopatología , Síndrome de Abstinencia a Sustancias/psicologíaRESUMEN
Early nicotine exposure compromises offspring's phenotype at long-term in both sexes. We hypothesize that offspring exposed to nicotine during breastfeeding show deregulated central and peripheral endocannabinoid system (ECS), compromising several aspects of their metabolism. Lactating rats received nicotine (NIC, 6 mg/Kg/day) or saline from postnatal day (PND) 2 to 16 through implanted osmotic minipumps. Offspring were analyzed at PND180. We evaluated protein expression of N-acylphosphatidylethanolamide-phospholipase D (NAPE-PLD), fatty acid amide hydrolase (FAAH), diacylglycerol lipase (DAGL), monoacylglycerol lipase (MAGL) and cannabinoid receptors (CB1 and/or CB2) in lateral hypothalamus, paraventricular nucleus of the hypothalamus, liver, visceral adipose tissue (VAT), adrenal and thyroid. NIC offspring from both sexes did not show differences in hypothalamic ECS markers. Peripheral ECS markers showed no alterations in NIC males. In contrast, NIC females had lower liver DAGL and CB1, higher VAT DAGL, higher adrenal NAPE-PLD and higher thyroid FAAH. Endocannabinoids biosynthesis was affected by nicotine exposure during breastfeeding only in females; alterations in peripheral tissues suggest lower action in liver and higher action in VAT, adrenal and thyroid. Effects of nicotine exposure during lactation on ECS markers are sex- and tissue-dependent. This characterization helps understanding the phenotype of the adult offspring in this model and may contribute to the development of new pharmacological targets for the treatment of several metabolic diseases that originate during development.
Asunto(s)
Endocannabinoides , Nicotina , Animales , Ratas , Masculino , Femenino , Nicotina/efectos adversos , Endocannabinoides/metabolismo , Lactancia , Ratas Wistar , BiomarcadoresRESUMEN
Neonatal undernutrition in rats results in short- and long-term behavioral and hormonal alterations in the offspring. It is not clear, however, whether these effects are present since the original insult or if they develop at some specific age later in life. Here, we assessed the ontogenetic profile of behavioral parameters associated with anxiety, exploration and memory/learning of Wistar rat offspring that were subjected to protein malnutrition during lactation. Dams and respective litters were separated into two groups: (1) protein-restricted (PR), which received a hypoproteic chow (8% protein) from birth to weaning [postnatal day (PN) 21]; (2) control (C), which received normoproteic chow. Offspring's behaviors, corticosterone, catecholamines, T3 and T4 levels were assessed at PN21 (weaning), PN45 (adolescence), PN90 (young adulthood) or PN180 (adulthood). PR offspring showed an age-independent reduction in the levels of anxiety-like behaviors in the Elevated Plus Maze and better memory performance in the Radial Arm Water Maze. PR offspring showed peak exploratory activity in the Open Field earlier in life, at PN45, than C, which showed theirs at PN90. Corticosterone was reduced in PR offspring, particularly at young adulthood, while catecholamines were increased at weaning and adulthood. The current study shows that considerable age-dependent variations in the expression of the observed behaviors and hormonal levels exist from weaning to adulthood in rats, and that protein restriction during lactation has complex variable-dependent effects on the ontogenesis of the assessed parameters.
RESUMEN
Caffeine consumption occurs throughout life, while nicotine use typically begins during adolescence, the period when caffeine-nicotine epidemiological association begins in earnest. Despite that, few studies in animal models parallel the pattern of coexposure that occurs in humans. Therefore, the neurobehavioral consequences of the association between these drugs remain unclear. Here, we exposed Swiss mice to lifetime caffeine. Caffeine solutions of 0.1 g/L (CAF0.1), 0.3 g/L (CAF0.3), or water (CTRL) were used as the sole liquid source, being offered to progenitors until weaning and, after that, directly to the offspring until the last day of adolescent behavioral evaluation. The open field test was used to evaluate acute effects of nicotine, of lifetime caffeine and of their interaction on locomotion and anxiety-like behavior, while the conditioned place preference test was used to assess the impact of caffeine on nicotine (0.5 mg/Kg, i.p.) reward. Frontal cerebral cortex dopamine content, dopamine turnover, and norepinephrine levels, as well as hippocampal serotonin 1A receptor expression were assessed. CAF0.3 mice exhibited an increase in anxiety-like behavior when compared to CAF0.1 and CTRL ones, but nicotine coexposure mitigated the anxiogenic-like caffeine-induced effect. Distinctively, caffeine had no effect on locomotion and failed to interfere with both nicotine-induced hyperactivity and place preference. There were no significant effects on dopaminergic and serotonergic markers. In conclusion, although caffeine did not affect nicotine reward, considering the strong association between anxiety disorders and tobacco consumption, caffeine-induced anxiety-like behavior advises limiting its consumption during development, including adolescence, as caffeine could be a risk factor to nicotine use.
Asunto(s)
Cafeína , Nicotina , Adolescente , Humanos , Ratones , Animales , Nicotina/efectos adversos , Cafeína/efectos adversos , Dopamina/metabolismo , Dopamina/farmacología , Ansiedad/inducido químicamente , Ansiedad/metabolismo , Recompensa , Conducta AnimalRESUMEN
Sex-biased differences in schizophrenia are evident in several features of the disease, including symptomatology and response to pharmacological treatments. As a neurodevelopmental disorder, these differences might originate early in life and emerge later during adolescence. Considering that the disruption of the glutamatergic system during development is known to contribute to schizophrenia, we hypothesized that the neonatal phencyclidine model could induce sex-dependent behavioral and neurochemical changes associated with this disorder during adolescence. C57BL/6 mice received either saline or phencyclidine (5, 10, or 20 mg/kg) on postnatal days (PN) 7, 9, and 11. Behavioral assessment occurred in late adolescence (PN48-50), when mice were submitted to the open field, social interaction, and prepulse inhibition tests. Either olanzapine or saline was administered before each test. The NMDAR obligatory GluN1 subunit and the postsynaptic density protein 95 (PSD-95) were evaluated in the frontal cortex and hippocampus at early (PN30) and late (PN50) adolescence. Neonatal phencyclidine evoked dose-dependent deficits in all analyzed behaviors and males were more susceptible. Males also had reduced GluN1 expression in the frontal cortex at PN30. There were late-emergent effects at PN50. Cortical GluN1 was increased in both sexes, while phencyclidine increased cortical and decreased hippocampal PSD-95 in females. Olanzapine failed to mitigate most phencyclidine-evoked alterations. In some instances, this antipsychotic aggravated the deficits or potentiated subthreshold effects. These results lend support to the use of neonatal phencyclidine as a sex-biased neurodevelopmental preclinical model of schizophrenia. Olanzapine null effects and deleterious outcomes suggest that its use during adolescence should be further evaluated.
Asunto(s)
Antipsicóticos , Esquizofrenia , Masculino , Femenino , Animales , Ratones , Fenciclidina/farmacología , Esquizofrenia/inducido químicamente , Esquizofrenia/tratamiento farmacológico , Olanzapina/uso terapéutico , Ratones Endogámicos C57BL , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Modelos Animales de EnfermedadRESUMEN
The interruption of lactation for a short period, without the use of pharmacological substances or maternal separation, causes offspring malnutrition and hypoleptinaemia and programmes for metabolic disorders such as higher body weight and adiposity, hyperphagia, hyperleptinaemia and central leptin resistance in adulthood. Here, in order to clarify the mechanisms underlying the phenotype observed in adult early-weaned (EW) rats, we studied the expression of neuropeptide Y (NPY), agouti-related peptide (AgRP), pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) in different hypothalamic nuclei by immunohistochemistry and Western blot. In the EW group, the teats of lactating rats were blocked with a bandage to interrupt lactation during the last 3 d, while control pups had free access to milk throughout the entire lactation period. At age 180 d, EW offspring showed higher NPY staining in the paraventricular nucleus (PVN), as well as NPY protein content (+68 %) in total hypothalamus than control ones. AgRP showed no changes in staining or Western blot. POMC content was not affected; however, its distribution pattern was altered. CART-positive cells of EW offspring had lower immunoreactivity associated with reduced cell number in the PVN and lower protein content ( - 38 %) in total hypothalamus. The present data indicate that precocious weaning can imprint the neuronal circuitry, especially in the PVN, and cause a long-term effect on the expression of specific orexigenic and anorexigenic neuropeptides, such as NPY and CART, that can be caused by leptin resistance and are coherent with the hyperphagia observed in these animals.
Asunto(s)
Proteína Relacionada con Agouti/análisis , Expresión Génica , Proteínas del Tejido Nervioso/análisis , Neuropéptido Y/análisis , Núcleo Hipotalámico Paraventricular/química , Destete , Factores de Edad , Animales , Western Blotting , Femenino , Hipotálamo/química , Inmunohistoquímica , Lactancia , Masculino , Proopiomelanocortina/análisis , Ratas , Ratas WistarRESUMEN
Evidence exists indicating that cerebral lateralization is a fundamental feature of all vertebrates. In humans, a series of studies demonstrated that the left hemisphere plays a major role in controlling movement. No such asymmetries have been identified in rodents, in spite of the fact that these animals have been frequently used in studies assessing motor behavior. In this regard, here, we used unilateral hemispherectomy to study the relative importance of each hemisphere in controlling movement. Adult Swiss mice were submitted to right unilateral hemispherectomy (RH), left unilateral hemispherectomy (LH) or sham surgery. Fifteen days after surgery, motor performance was assessed in the accelerating rotarod test and in the foot-fault test (in which performance depends on skilled limb use) and in the elevated body swing test (in which performance depends on trunk movements). The surgical removal of the right hemisphere caused a more pronounced impairment in performance than the removal of the left hemisphere both in the rotarod and in the foot-fault tests. In the rotarod, the RH group presented smaller latencies to fall than both LH and sham groups. In the foot-fault test, while both the sham and the LH groups showed no differences between left and right hind limbs, the RH group showed significantly worse performance with the left hind limb than with the right one. The elevated body swing test revealed a similar impairment in the two hemispherectomized groups. Our data suggest a major role of the right hemisphere in controlling skilled limb movements in mice.
Asunto(s)
Cerebro/fisiología , Dominancia Cerebral/fisiología , Lateralidad Funcional/fisiología , Hemisferectomía/efectos adversos , Movimiento/fisiología , Envejecimiento/fisiología , Animales , Cerebro/cirugía , Hemisferectomía/métodos , Masculino , RatonesRESUMEN
(1) Background: Older adults comprise a large proportion of hospitalized patients. Many are frail and require complex care. Geriatrics has developed models of care specific to this inpatient population. Our objective was to demonstrate the effect of a geriatric co-management team on clinical administrative indicators of care in Clinical Teaching Units (CTUs) that have adopted the Age-friendly Hospital (AFH) principles in Brazilian hospitals. (2) Methods: Following 3 months of implementation of the AFH principles in CTUs, two periods of the same 6 months of two consecutive years were compared. (3) Results: The total number of participants in the study was 641 and 743 in 2015 and 2016, respectively. Average length of patient-stay (length of stay: 8.7 ± 2.7 vs. 5.4 ± 1.7 days) and number of monthly complaints (44.2 ± 6.5 vs. 13.5 ± 2.2) were significantly lower with the co-management model. Number of homecare service referrals/month was also significantly higher (2.5 ± 1 vs. 38.3 ± 6.3). The 30-day readmission rates and total hospital costs per patient remained unchanged. (4) Conclusion: The presence of a geriatric co-management team in CTUs is of added benefit to increase the efficiency of the AFH for vulnerable older inpatients with reduced LOS and increased referrals to homecare services without increasing hospital costs.
RESUMEN
Nicotine is the main psychoactive substance present in cigarette smoke that is transferred to the baby by breast milk. In rats, maternal nicotine exposure during breastfeeding induces obesogenesis and hormone dysfunctions in adult male offspring. As glucocorticoid (GC), insulin, and vitamin D change both adipogenesis and lipogenesis processes, we assessed parameters related to metabolism and action of these hormones in visceral and subcutaneous adipose tissues (VAT and SAT) of adult male and female rats in a model of neonatal nicotine exposure. At postnatal (PN) day 2, dams were kept with six pups (three per sex) and divided into nicotine and control groups for implantation of osmotic minipumps that released 6 mg/kg nicotine or saline, respectively. At PN180, fat mass, hormone levels, and protein contents of biomarkers of the GC activation and receptor (11beta-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor alpha), insulin signaling pathway [insulin receptor beta (IRß), phosphorylated insulin receptor substrate 1, insulin receptor substrate 1 (IRS1), phosphorylated serine/threonine kinase (pAKT), serine/threonine kinase, glucose transporter type 4 (GLUT4)], and vitamin D activation and receptor (1α-hydroxylase and vitamin D receptor) were evaluated. While nicotine-exposed males showed increased fat mass, hypercorticosteronemia, hyperinsulinemia, and higher 25-hydroxyvitamin D, these alterations were not observed in nicotine-exposed females. Nicotine-exposed males only showed lower IRS1 in VAT, while the females had hyperglycemia, higher pAKT in VAT, while lower IRß, IRS1, and GLUT4 in SAT. Parameters related to metabolism and action of GC and vitamin D were unaltered in both sexes. We evidence that exposure exclusively to nicotine during breastfeeding affects the hormone status and fat depots of the adult progeny in a sex-dependent manner.
Asunto(s)
Insulina , Nicotina , Animales , Femenino , Glucocorticoides , Humanos , Insulina/metabolismo , Proteínas Sustrato del Receptor de Insulina/metabolismo , Masculino , Nicotina/efectos adversos , Proteínas Serina-Treonina Quinasas , Ratas , Ratas Wistar , Serina , Vitamina DRESUMEN
The first symptoms of schizophrenia (SCHZ) are usually observed during adolescence, a developmental period during which first exposure to psychoactive drugs also occurs. These epidemiological findings point to adolescence as critical for nicotine addiction and SCHZ comorbidity, however it is not clear whether exposure to nicotine during this period has a detrimental impact on the development of SCHZ symptoms since there is a lack of studies that investigate the interactions between these conditions during this period of development. To elucidate the impact of a short course of nicotine exposure across the spectrum of SCHZ-like symptoms, we used a phencyclidine-induced adolescent mice model of SCHZ (2.5mg/Kg, s.c., daily, postnatal day (PN) 38-PN52; 10mg/Kg on PN53), combined with an established model of nicotine minipump infusions (24mg/Kg/day, PN37-44). Behavioral assessment began 4 days after the end of nicotine exposure (PN48) using the following tests: open field to assess the hyperlocomotion phenotype; novel object recognition, a declarative memory task; three-chamber sociability, to verify social interaction and prepulse inhibition, a measure of sensorimotor gating. Phencyclidine exposure evoked deficits in all analyzed behaviors. Nicotine history reduced the magnitude of phencyclidine-evoked hyperlocomotion and impeded the development of locomotor sensitization. It also mitigated the deficient sociability elicited by phencyclidine. In contrast, memory and sensorimotor gating deficits evoked by phencyclidine were neither improved nor worsened by nicotine history. In conclusion, our results show for the first time that nicotine history, restricted to a short period during adolescence, does not worsen SCHZ-like symptoms evoked by a phencyclidine-induced mice model.
Asunto(s)
Conducta Animal/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Nicotina/farmacología , Reconocimiento en Psicología/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Filtrado Sensorial/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Femenino , Locomoción/efectos de los fármacos , Masculino , Ratones , Nicotina/uso terapéutico , Fenciclidina , Esquizofrenia/inducido químicamenteRESUMEN
Either tobacco smoking or alcohol consumption during pregnancy sex-selectively increases susceptibility to drugs of abuse later in life. Considering that pregnant smoking women are frequently intermittent consumers of alcoholic beverages, here, we investigated whether a short-term ethanol exposure restricted to the brain growth spurt period when combined with chronic developmental exposure to tobacco smoke aggravates susceptibility to nicotine in adolescent and adult mice. Swiss male and female mice were exposed to tobacco smoke (SMK; research cigarettes 3R4F, whole-body exposure, 8 h/daily) or ambient air during the gestational period and until the tenth postnatal day (PN). Ethanol (ETOH, 2 g/Kg, 25%, i.p.) or saline was injected in the pups every other day from PN2 to PN10. There were no significant differences in cotinine (nicotine metabolite) and ethanol serum levels among SMK, ETOH and SMK + ETOH groups. During adolescence (PN30) and adulthood (PN90), nicotine (NIC, 0.5 mg/Kg) susceptibility was evaluated in the conditioned place preference and open field tests. NIC impact was more evident in females: SMK, ETOH and SMK + ETOH adolescent females were equally more susceptible to nicotine-induced place preference than control animals. At adulthood, SMK and SMK + ETOH adult females exhibited a nicotine-evoked hyperlocomotor profile in the open field, with a stronger effect in the SMK + ETOH group. Our results indicate that ethanol exposure during the brain growth spurt, when combined to developmental exposure to tobacco smoke, increases nicotine susceptibility with stronger effects in adult females. This result represents a worsened outcome from the early developmental dual exposure and may predispose nicotine use/abuse later in life.