RESUMEN
Hypothalamic Agrp neurons regulate food ingestion in adult mice. Whether these neurons are functional before animals start to ingest food is unknown. Here, we studied the functional ontogeny of Agrp neurons during breastfeeding using postnatal day 10 mice. In contrast to adult mice, we show that isolation from the nursing nest, not milk deprivation or ingestion, activated Agrp neurons. Non-nutritive suckling and warm temperatures blunted this effect. Using in vivo fiber photometry, neonatal Agrp neurons showed a rapid increase in activity upon isolation from the nest, an effect rapidly diminished following reunion with littermates. Neonates unable to release GABA from Agrp neurons expressed blunted emission of isolation-induced ultrasonic vocalizations. Chemogenetic overactivation of these neurons further increased emission of these ultrasonic vocalizations, but not milk ingestion. We uncovered important functional properties of hypothalamic Agrp neurons during mouse development, suggesting these neurons facilitate offspring-to-caregiver bonding.
Asunto(s)
Proteína Relacionada con Agouti/metabolismo , Conducta Alimentaria/fisiología , Hipotálamo/citología , Neuronas/metabolismo , Proteína Relacionada con Agouti/genética , Animales , Animales Recién Nacidos , Ingestión de Alimentos/fisiología , Conducta Materna/fisiología , Ratones , Ratones Noqueados , Leche , Proteínas Proto-Oncogénicas c-fos/metabolismo , Aislamiento Social , Conducta en la Lactancia/fisiología , Temperatura , Vocalización Animal/fisiología , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Hypothalamic Agrp neurons are critical regulators of food intake in adult mice. In addition to food intake, these neurons have been involved in other cognitive processes, such as the manifestation of stereotyped behaviors. Here, we evaluated the extent to which Agrp neurons modulate mouse behavior in spatial memory-related tasks. We found that activation of Agrp neurons did not affect spatial learning but altered behavioral flexibility using a modified version of the Barnes Maze task. Furthermore, using the Y-maze test to probe working memory, we found that chemogenetic activation of Agrp neurons reduced spontaneous alternation behavior mediated by the neuropeptide Y receptor-5 signaling. These findings suggest novel functional properties of Agrp neurons in memory-related cognitive processes.
Asunto(s)
Proteína Relacionada con Agouti/metabolismo , Hipotálamo/fisiología , Memoria , Neuronas/metabolismo , Animales , Cognición , Ingestión de Alimentos , Femenino , Masculino , Aprendizaje por Laberinto , Ratones , Neuropéptido Y/metabolismoRESUMEN
Leptin, a peptide hormone secreted by adipose tissue, exhibits a large range of central and peripheral actions. It has been proposed that the participation of leptin in diseases such as obesity is due to, at least in part, its impaired transport across the blood-brain barrier (BBB). Since, the mechanisms by which brain takes up leptin remain unclear, we set out to study how leptin may cross the BBB. We have used different immunoassays and lentiviral vectors to analyze the role of megalin in the transport of leptin in rodents and humans. We demonstrate that circulating leptin is transported into the brain by binding to megalin at the choroid plexus epithelium. Indeed, the downregulation of megalin expression in physiological and pathological situations such as aging and Alzheimer's disease was correlated with poor entry of leptin into the brain. Moreover, amyloid beta (Abeta) deposits of choroid plexus could be disturbing megalin function. The present data indicate that leptin represents a novel megalin ligand of importance in the levels and therapeutic actions of leptin into the brain.
Asunto(s)
Envejecimiento/metabolismo , Enfermedad de Alzheimer/metabolismo , Barrera Hematoencefálica/metabolismo , Líquido Cefalorraquídeo/metabolismo , Plexo Coroideo/metabolismo , Leptina/metabolismo , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Anciano , Animales , Transporte Biológico Activo/fisiología , Femenino , Humanos , Masculino , Ratas , Ratas Wistar , Transducción de SeñalRESUMEN
It is increasingly recognized that life-style factors, such as physical exercise or diet influence brain health. In the present work we analyzed the effect of a western-style diet ("cafeteria diet") on the entrance to the brain of circulating IGF-1, a neuroprotective agent that has been related to different neurodegenerative diseases. Rats under a cafeteria diet showed reduced passage of systemic IGF-1 across the choroid plexus, a main site of IGF-1 entrance into the brain through the cerebrospinal fluid. Furthermore, the IGF-1 receptor at the choroid plexus of rats fed with a cafeteria diet showed enhanced sensitivity toward IGF-1 while receptor levels remained unchanged. Examination of possible mechanisms underlying reduced entrance of systemic IGF-1 to the brain showed that triglycerides that increased in blood after a cafeteria diet, diminished the passage of IGF-1 across choroid plexus epithelia. This effect of triglycerides was achieved by altering the interaction of IGF-1 with megalin, a choroid plexus transporter involved in transcytosis of IGF-1 from the circulation into the brain. Reduced brain entrance of circulating IGF-1 elicited by a western-style diet suggests that the higher incidence of brain diseases related to inadequate diets is due in part to diminished neurotrophic support.
Asunto(s)
Barrera Hematoencefálica , Peso Corporal , Dieta/etnología , Factor I del Crecimiento Similar a la Insulina/farmacocinética , Restaurantes , Alimentación Animal , Animales , Lípidos/sangre , Masculino , Modelos Animales , RatasRESUMEN
BACKGROUND: Bipolar disorder (BD) has been increasingly associated with abnormalities in neuroplasticity and cellular resilience. Brain Derived Neurotrophic Factor (BDNF) gene has been considered an important candidate marker for the development of bipolar disorder and this neurotrophin seems involved in intracellular pathways modulated by mood stabilizers. Also, previous studies demonstrated a role for BDNF in the pathophysiology and clinical presentation of mood disorders. METHODS: We investigated whether BDNF levels are altered during mania. Sixty subjects (14 M and 46 F) were selected and included in the study. Thirty patients meeting SCID-I criteria for manic episode were age and gender matched with thirty healthy controls. Young Mania Rating Scale (YMRS) evaluated the severity of manic episode and its possible association with the neurotrophin levels. RESULTS: Mean BDNF levels were significantly decreased in drug free/naive (224.8 +/- 76.5 pg/ml) compared to healthy controls (318.5 +/- 114.2), p < .001]. Severity of the manic episode presented a significant negatively correlation to plasma BDNF levels (r= .78; p < .001; Pearson test). CONCLUSIONS: Overall, these results suggest that the decreased plasma BDNF levels may be directly associated with the pathophysiology and severity of manic symptoms in BD. Further studies are necessary to clarify the role of BDNF as a putative biological marker in BD.
Asunto(s)
Trastorno Bipolar/sangre , Factor Neurotrófico Derivado del Encéfalo/sangre , Adulto , Biomarcadores/sangre , Trastorno Bipolar/diagnóstico , Trastorno Bipolar/psicología , Femenino , Humanos , Masculino , Escalas de Valoración Psiquiátrica , Valores de Referencia , Estadística como AsuntoRESUMEN
Physical activity has been proposed as a behavior intervention that promotes mental health and some of the benefits induced by exercise have been related to the glutamatergic system. Indeed, glutamate is the most abundant excitatory neurotransmitter in brain. Thus, we evaluated if voluntary exercise in mice could modulate glutamatergic synapses at level of postsynaptic density (PSD). Through Western blot, we found that exercise during 1 month increased glutamatergic-related protein content in PSD from cortex of mice. Exercise increased the immunocontent of GluR1 (129%), SAP-97 (179%), GRIP-1 (129%), and in less extent, GluR2/3 (118%) and PSD-95 (112%) proteins. The overall content of NMDA subunits R1, R2A and R2B were not altered in mice that had exercised, however, the phosphorylated NMDA subunits, phospho-NMDAR1 (150%), and phospho-NMDAR2B (183%) showed a strong increase. Because exercise increased the content of phosphorylated forms of NMDA receptors, we evaluated the binding of MK-801, a specific ligand that binds to open NMDA channel. Exercise increased the binding of MK-801 in cortical cellular membranes in 51%. Altogether, our results point to a modulation of glutamatergic synapses by exercise with likely implications in the exercise-induced mental health.
Asunto(s)
Corteza Cerebral/metabolismo , Condicionamiento Físico Animal/fisiología , Receptores de Glutamato/metabolismo , Sinapsis/metabolismo , Animales , Western Blotting , Maleato de Dizocilpina/metabolismo , Electroforesis en Gel de Poliacrilamida , Antagonistas de Aminoácidos Excitadores/metabolismo , Inmunohistoquímica , Masculino , Ratones , Proteínas del Tejido Nervioso/metabolismo , Receptores AMPA/metabolismo , Membranas Sinápticas/metabolismo , Membranas Sinápticas/fisiologíaRESUMEN
The effects of oral exposure to methylmercury chloride (MeHg) on locomotor control and activity in adult mice were investigated in the present study. MeHg was diluted in drinking water (0, 20 and 40mg/L - as methylmercury chloride) and locomotion (spontaneous locomotor activity) and motor impairment tests (beam walking, footprint and clasping) were performed at 7, 14 and 21 days after the beginning of the treatment. MeHg exposure caused a significant decrease in spontaneous locomotor activity and this effect was dose- and time-dependent. Significant dose- and duration-dependent increases in beam walking latency were observed following chronic MeHg exposure. Furthermore, dose- and duration-dependent locomotor deficits on footprint coordination were also observed. Taken together, these results show that MeHg-induced impairment on locomotor activity is not limited to exposures that take place during neural development. We discuss the possible relationship between our findings and the similar clinical signs observed in adult humans exposed to MeHg.
RESUMEN
Protein malnutrition results in a variety of brain dysfunctions, ultimately affecting cognitive functions. The effects of protein malnutrition in brain response to psychostimulants have been less studied in adult animals. We therefore aimed to study the response to psychoactive drugs on the locomotor activity (a behavior paradigm) of adult protein malnourished mice. Two-month-old mice were divided in two groups: (a) low-protein group (LP), which received 6% of protein diet, and (b) a control group that received a 25% of protein diet. After 3 months, they were tested for locomotor activity after an i.p. injection of one of psychoactive drugs: D-amphetamine (5.0 mg/kg), apomorphine (2.0 mg/kg), dizocilpine (0.25 mg/kg), or caffeine (30 mg/kg). Mice submitted to the LP diet presented prolonged induction of hyperlocomotion caused by amphetamine (about 350% between 90 and 180 min post drug injection as compared with well-nourished mice, p<0.01) but presented unaltered response to apomorphine, caffeine, and dizocilpine. These data point to altered catecholamine metabolism induced by protein restriction in adult mice. The results are discussed based on previous works, presenting theoretical hypotheses about the possible mechanisms involved in the present findings.
Asunto(s)
Anfetamina/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Proteínas en la Dieta/farmacología , Actividad Motora/efectos de los fármacos , Desnutrición Proteico-Calórica/psicología , Animales , Apomorfina/farmacología , Cafeína/farmacología , Dieta , Maleato de Dizocilpina/farmacología , Agonistas de Dopamina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Masculino , Ratones , Antagonistas de Receptores Purinérgicos P1 , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
Guanosine has been shown to modulate glutamate system by stimulating astrocytic glutamate uptake. Recent evidence suggest that the locomotor effects of NMDA receptor antagonists, an animal model of schizophrenia, is associated with activation of non-NMDA glutamatergic receptors caused by increased glutamate release. The present work was undertaken to evaluate whether guanosine could have influence on the hyperlocomotion induced in mice by dizocilpine (MK-801), a NMDA antagonist. We also evaluated the effect of guanosine on the hyperlocomotion induced by the indirect dopamine agonist amphetamine, and by the non-selective adenosine receptor antagonist caffeine. Guanosine (7.5 mg/kg) produced an attenuation of about 60% on the hyperlocomotion induced by dizocilpine (0.25 mg/kg), whereas it did not affect the hyperlocomotion induced by amphetamine (5 mg/kg) or caffeine (30 mg/kg). Guanosine pre-treatment did not affect total spontaneous locomotion in all experiments. To test neuronal pathway selectivity, we evaluated MK-801 against guanosine in a working memory paradigm (spontaneous alternation task). Guanosine did not reverted the impairment caused by MK-801 in the spontaneous alternation test, and when administered alone also presented an amnesic effect. The results are discussed based on the current hypothesis of locomotor activation induced by the psychoactive drugs studied. Further studies are necessary to evaluate if guanosine could have clinical utility for the treatment of schizophrenia.
Asunto(s)
Maleato de Dizocilpina/farmacología , Guanosina/farmacología , Actividad Motora/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Anfetamina/farmacología , Animales , Conducta Animal , Cafeína/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Locomoción/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , RatonesRESUMEN
OBJECTIVE: Evaluate anticoagulants influence on blood S100B levels. DESIGN AND METHODS: Blood from 18 healthy adult subjects were collected using: no anticoagulants; EDTA; heparin; and citrate. S100B levels were determined using LIA-mat assay. RESULTS: Heparin and citrate increased S100B levels (p<0.001), whereas EDTA had no effect (p=0.24). Heparin samples were highly (r2=0.97, p<0.001), citrate samples were moderately (r2=0.49, p<0.001), and EDTA samples were not (r2=0.22, p=0.059) correlated with serum samples. CONCLUSION: When anticoagulant is required, heparin should be the primary choice.
Asunto(s)
Anticoagulantes/farmacología , Factores de Crecimiento Nervioso/sangre , Proteínas S100/sangre , Adulto , Femenino , Humanos , Masculino , Subunidad beta de la Proteína de Unión al Calcio S100RESUMEN
OBJECTIVE: Evaluate anticoagulants influence on plasma S100B levels. DESIGN AND METHODS: Blood were collected from 18 healthy adult subjects using: no anticoagulants, EDTA, heparin, and citrate. S100B levels were determined using LIA-mat assay. RESULTS: Heparin plasma and citrate increased plasma S100B levels (p < 0.001), whereas EDTA had no effect (p = 0.24). Heparin plasma samples were highly (r2 = 0.97, p < 0.001), citrate samples were moderately (r2 = 0.49, p < 0.001), and EDTA samples were not (r2 = 0.22, p = 0.059) correlated with serum samples. CONCLUSIONS: When anticoagulant is required, heparin plasma should be the primary choice for measurement of S100 B levels.
Asunto(s)
Anticoagulantes/farmacología , Artefactos , Proteínas S100/sangre , Adulto , Ácido Cítrico , Ácido Edético , Femenino , Heparina , Humanos , MasculinoRESUMEN
Methylmercury (MeHg) is a highly neurotoxic compound and the inhibition of glutamate uptake by astrocytes has been pointed as an important mechanism involved in MeHg-induced glutamate excitotoxicity. We examined the effect of oral exposure to MeHg (10 and 40 mg/l in drinking water) on glutamate uptake by brain cortical slices of adult mice. Moreover, the possible protective role of ebselen (20 mg/kg, subcutaneously) against MeHg effect was also examined. In addition, it was measured the glutathione peroxidase and catalase activities in mice brain. Our results demonstrated, for the first time, that in vivo exposure to MeHg causes a dose-dependent decrease in glutamate uptake and that ebselen, which did not affect the uptake per se, reverted this effect. MeHg decreased glutathione peroxidase activity and increased catalase activity, effects which were also prevented by ebselen. These results may indirectly indicate that: (i) the in vivo inhibitory effect of MeHg on glutamate uptake could be probably related to overproduction of H(2)O(2); (ii) the protective effect of ebselen on MeHg-induced inhibition of glutamate uptake could be related to its ability to detoxify H(2)O(2).
Asunto(s)
Antioxidantes/farmacología , Azoles/farmacología , Corteza Cerebral/fisiología , Ácido Glutámico/metabolismo , Ácido Glutámico/farmacocinética , Compuestos de Metilmercurio/toxicidad , Compuestos de Organoselenio/farmacología , Animales , Astrocitos/fisiología , Catalasa/farmacología , Corteza Cerebral/patología , Glutatión Peroxidasa/farmacología , Peróxido de Hidrógeno , Isoindoles , Peroxidación de Lípido , Masculino , RatonesRESUMEN
N-methyl-D aspartate (NMDA) antagonists, such as MK-801, and the dopamine indirect agonist amphetamine are pharmacological models used for the evaluation of putative new treatments for schizophrenia. Since the psychotomimetic effects of NMDA antagonists have recently been linked to their ability to increase glutamate release and since the glutamate release inhibitor riluzole prevented NMDA antagonist neurotoxicity, we evaluated the effect of riluzole on hyperlocomotion induced by MK-801 (0.25 mg/kg) and amphetamine (2.5 mg/kg). Mice pretreated with riluzole (3 mg/kg) did not influence baseline or MK-801-induced behavior, but 10 mg/kg produced moderate hypolocomotion alone and somewhat prolonged MK-801-induced hyperlocomotion. Pretreatment with riluzole 10 mg/kg, but not 3 mg/kg, had a moderately depressant effect both on spontaneous and amphetamine-induced locomotion. Taken together, these results suggest that riluzole would not be particularly effective as a treatment for schizophrenia and the neurotoxic and behavioral effect of NMDA antagonists do not clearly correlate.
Asunto(s)
Anfetamina/efectos adversos , Maleato de Dizocilpina/efectos adversos , Hipercinesia/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Riluzol/uso terapéutico , Animales , Estimulantes del Sistema Nervioso Central/efectos adversos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación/veterinaria , Interacciones Farmacológicas , Hipercinesia/inducido químicamente , Locomoción/efectos de los fármacos , Masculino , Ratones , Fármacos Neuroprotectores/efectos adversos , Fármacos Neuroprotectores/farmacología , Distribución Aleatoria , Riluzol/farmacologíaRESUMEN
RATIONALE: Administration of N-methyl- d-aspartate (NMDA) receptor antagonists produce hyperlocomotion and cognitive deficits in rodents. Activation of NMDA receptors promotes adenosine release, and adenosine agonists prevent central effects of NMDA receptor antagonists. We hypothesized that if NMDA receptor antagonists require adenosine to produce behavioral effects, mice tolerant to the adenosine receptor antagonist caffeine would have a diminished response to NMDA receptor antagonists. OBJECTIVES: To evaluate MK-801-induced hyperlocomotion and cognitive deficits after chronic caffeine treatment in mice. METHODS: Locomotor activity was analyzed in a computerized system, spontaneous alternation was assessed in the Y-maze and long-term memory was assessed with the inhibitory avoidance task in mice. RESULTS: Mice chronically treated with caffeine in drinking solution (1 mg/ml for 7 days) presented normal habituation and substantial tolerance to acute caffeine (30 mg/kg, i.p.) locomotor effects. MK-801 (0.25 mg/kg, i.p.) produced pronounced hyperlocomotion in water-treated mice, but this effect was abolished in caffeine-drinking mice. Chronic caffeine treatment had no influence on either normal or MK-801-induced deficits in spontaneous alternation and inhibitory avoidance tasks. CONCLUSION: Hyperlocomotion induced by MK-801 may be mediated by reduced adenosinergic activity. These results also suggest that locomotor and cognitive effects of MK-801 can be dissociated and are distinctly modulated. Finally, these findings agree with the adenosine hypofunction model of schizophrenia, since NMDA receptor antagonists are a pharmacological model for this disorder.
Asunto(s)
Cafeína/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Cognición/efectos de los fármacos , Maleato de Dizocilpina/antagonistas & inhibidores , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Actividad Motora/efectos de los fármacos , Adenosina/farmacología , Animales , Reacción de Prevención/efectos de los fármacos , Cafeína/administración & dosificación , Estimulantes del Sistema Nervioso Central/administración & dosificación , Relación Dosis-Respuesta a Droga , Tolerancia a Medicamentos , Inyecciones Intraperitoneales , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Ratones , Equilibrio Postural/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
Physical activity has been shown to be a beneficial stimulus to the central and peripheral nervous systems. The S100B is a cytokine physiologically produced and released predominantly by astrocytes on the central nervous system (CNS). In order to study the possible influence of a nonimpact exercise on S100B serum levels, we measured this protein serum level after a 7,600-meter swimming race. We observed an increase in S100B levels in athletes post-race compared with their baseline values, pointing to a potential acute influence of physical exercise on serum S100B levels not related with CNS injury. We discuss this result and emphasize the possible central and peripheral origins of S100B serum levels.
Asunto(s)
Autoantígenos/sangre , Factores de Crecimiento Nervioso/sangre , Proteínas S100/sangre , Natación/fisiología , Adolescente , Adulto , Humanos , Masculino , Subunidad beta de la Proteína de Unión al Calcio S100RESUMEN
The cellular prion protein (PrP(C)) has been involved in several neurodegenerative disorders however it has been proposed that it is also be implicated in psychotic disorders. We investigated the effect of three psychotropic drugs in locomotor activity of PrP(C) knockout (Prnp(O/O)) and wild-type mice. The NMDA receptor channel blocker MK-801 (0.25 mg/kg), the indirect dopamine agonist amphetamine (1 mg/kg) and the adenosine receptor antagonist caffeine (10 mg/kg) were administered i.p. after 60 min of habituation and locomotion was monitored for 3 h. Prnp(O/O) mice presented a diminished hyperlocomotor response to MK-801 treatment but normal response to amphetamine and caffeine compared to wild type mice. These results suggest that lack of PrP(C) leads to a functional alteration in the glutamatergic system, whereas the regulation of both dopaminergic and adenosinergic systems are preserved. Finally, lack of PrP(C) seems not to exacerbate the response to these psychotropic drugs, which modulate neurotransmitter systems possibly involved in schizophrenia and psychotic disorders.