RESUMEN
As yawning is often observed in stressful or emotional situations such as tension and anxiety, this suggests that yawning can be considered to be an emotional behavior. However, the neural mechanisms underlying emotion-induced yawning remain unclear. It is well known that the hypothalamic paraventricular nucleus (PVN) is the most important brain structure for induction of yawning behavior. We previously showed that induction of yawning involves the central nucleus of the amygdala (CeA), as well as the PVN. Therefore, emotion-induced yawning could potentially be induced through activation of the direct/indirect neural pathways from the CeA to the PVN. Our present study used a combination of retrograde tracing (injection of Fluoro-Gold (FG) into the PVN) and c-Fos immunohistochemistry to examine the neural pathways that evoke emotion-induced yawning. We additionally performed lesion experiments on the CeA using ibotenic acid, a neurotoxin, to determine whether the CeA is involved in the induction of emotion-induced yawning. Emotional stress by fear conditioning induced yawning behavior, and induced expression of double-labeled cells for c-Fos and FG in the bed nucleus of the stria terminalis (BNST), but not in the CeA. Furthermore, the CeA lesions caused by ibotenic acid abolished the induction of emotion-induced yawning. These results suggest that a neural pathway from the CeA to the PVN via the BNST may be primarily involved in the induction of emotion-induced yawning behavior.
Asunto(s)
Núcleo Amigdalino Central , Distrés Psicológico , Bostezo , Animales , Núcleo Amigdalino Central/metabolismo , Hipotálamo/metabolismo , Ácido Iboténico/farmacología , Vías Nerviosas/metabolismo , Neurotoxinas/farmacología , Núcleo Hipotalámico Paraventricular/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Estilbamidinas , Bostezo/fisiologíaRESUMEN
Experiments were designed to test the hypothesis that median preoptic (MnPO) neurons are necessary for the full hypertensive response to chronic angiotensin II (AngII) in rats consuming a high salt diet. The MnPO is implicated in many of the physiologic actions of AngII, primarily acting as a downstream nucleus to AngII binding at circumventricular organs such as the organum vasculosum of the lamina terminalis (OVLT). We have previously shown a prominent effect of lesion of the OVLT on the chronic hypertensive effects of AngII in rats consuming high salt. Additionally, we have shown that lesion of the MnPO attenuated the hypertensive response to chronic intravenous infusion of AngII in rats. However, whether MnPO neurons or fibers of passage contribute to this response is not clear. Male Sprague Dawley rats were randomly assigned to either sham (SHAM; n = 8) or ibotenic acid lesion of the MnPO (MnPOx; n = 6). In the MnPOx group, 200 nl of ibotenic acid in phosphate buffer saline (5 µg/µl) was injected into each of 3 predetermined coordinates targeted at the entire MnPO. After a week of recovery, rats were instrumented with radiotelemetric pressure transducers, provided 2.0% NaCl diet and distilled water ad libitum and given another week to recover. After 3 days of baseline measurements, osmotic minipumps were implanted subcutaneously in all rats for administration of AngII at a rate of 150 ng/kg/min. Blood pressure measurements were made for 14 days after minipump implantation. By day 7 of AngII treatment, blood pressure responses appeared to plateau in both groups while the hypertensive response was markedly attenuated in MnPOx rats (MnPOx, 122 ± 6 mmHg; SHAM, 143 ± 8 mmHg). These results support the hypothesis that neurons of the MnPO are involved in the central pathway mediating the chronic hypertensive effects of AngII in rats consuming a high salt diet.
Asunto(s)
Angiotensina II , Hipertensión , Animales , Masculino , Ratas , Angiotensina II/farmacología , Hipertensión/inducido químicamente , Hipertensión/metabolismo , Ácido Iboténico/farmacología , Neuronas/metabolismo , Área Preóptica/metabolismo , Ratas Sprague-Dawley , Cloruro de Sodio Dietético/farmacologíaRESUMEN
Rosemary oil (ROO) is known to have multiple pharmacological effects: it is an antioxidant, anti-inflammatory, and cytoprotective. In the present study, we examined the effects of ROO on Human olfactory bulb neuronal stem cells (hOBNSCs) after their transplantation into rats, with the ibotenic (IBO) acid-induced cognitive deficit model. After 7 weeks, cognitive functions were assessed using the Morris water maze (MWM). After two months blood and hippocampus samples were collected for biochemical, gene expression, and histomorphometric analyses. Learning ability and memory function were significantly enhanced (P < 0.05) after hOBNSCs transplantation and were nearly returned to normal in the treated group. The IBO acid injection was associated with a significant decline (P < 0.05) of total leukocyte count (TLC) and a significant increase (P < 0.05) in total and toxic neutrophils. As well, the level of IL-1ß, TNF-α CRP in serum and levels of MDA and NO in hippocampus tissue were significantly elevated (P < 0.05), while antioxidant markers (CAT, GSH, and SOD) were reduced (P < 0.05) in treated tissue compared to controls. The administration of ROO before or with cell transplantation attenuated all these parameters. In particular, the level of NO nearly returned to normal when rosemary was administrated before cell transplantation. Gene expression analysis revealed the potential protective effect of ROO and hOBNSCs via down-expression of R-ßAmyl and R- CAS 3 and R-GFAP genes. The improvement in the histological organization of the hippocampus was detected after the hOBNSCs transplantation especially in h/ROO/hOBNSCs group.
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Enfermedad de Alzheimer , Células-Madre Neurales , Síndromes de Neurotoxicidad , Rosmarinus , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Animales , Antioxidantes/uso terapéutico , Suplementos Dietéticos , Humanos , Ácido Iboténico/metabolismo , Ácido Iboténico/farmacología , Ácido Iboténico/uso terapéutico , Aprendizaje por Laberinto , Células-Madre Neurales/metabolismo , Síndromes de Neurotoxicidad/metabolismo , Aceites Volátiles , Bulbo Olfatorio , RatasRESUMEN
Ambient light influences our mood, behavior, and cognition. Phototherapy has been considered as an effective non-pharmacological intervention strategy in the restoration of cognitive functions following central nervous system insults. However, the cellular and molecular underpinnings of phototherapy-mediated functional recovery are yet to be studied. The present study examines the effectiveness of short photoperiod regime (SPR; 6:18-h light:dark cycle) in restoring the cognitive functions in ventral subicular lesioned rats. Bilateral ventral subicular lesion (VSL) resulted in significant impairment of spatial navigational abilities when tested in the Morris water maze (MWM) task. Further, VSL resulted in reduced expression of glucocorticoid receptors (GRs) and activity-regulated cytoskeletal (Arc) protein and suppression of neurogenesis in the hippocampus. VSL also suppressed the magnitude of long-term potentiation (LTP) in the hippocampal Schaffer collateral-CA1 synapses. However, exposure to SPR for 21 days showed significant restoration of spatial performance in the MWM task as the ventral subicular lesioned rats could deploy higher cognitive allocentric navigational strategies to reach the hidden platform. Further, SPR resulted in enhanced expression of hippocampal GR and Arc protein and neurogenesis but not hippocampal LTP suggestive of appropriate need-based SPR intervention. In conclusion, the study demonstrates the effectiveness of SPR in establishing functional recovery as well as the possible molecular and cellular basis of cognitive recovery in a rat model of neurodegeneration. Such studies provide a framework in understanding the efficacy of non-pharmacological strategies in establishing functional recovery in neurodegenerative conditions.
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Hipocampo/metabolismo , Neurogénesis/fisiología , Plasticidad Neuronal/fisiología , Fotoperiodo , Receptores de Glucocorticoides/metabolismo , Aprendizaje Espacial/fisiología , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Hipocampo/efectos de los fármacos , Ácido Iboténico/farmacología , Masculino , Plasticidad Neuronal/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Alterations in dopamine (DA) and serotonin (5-HT) transmission have been implicated in the pathophysiology of attention deficit/hyperactivity disorder (ADHD). We have previously reported that juvenile rats with neonatal habenula lesion (NHL) exhibit an assortment of behavioral alterations resembling ADHD symptoms. In this study, we investigated the impacts of NHL on DA and 5-HT transmission in mesocorticolimbic regions of rats. Male Sprague-Dawley rats with microinjection of ibotenic acid into the habenula at postnatal day (PND) 7 were subjected for a battery of locomotion test, object exploration test and delay discounting test in the juvenile period (PND28-35), followed by DA and 5-HT brain tissue concentration measurements using high-performance liquid chromatography (HPLC). NHL rats exhibited hyperlocomotion, impulsivity, and attention deficits. NHL induced alterations of tissue DA and 5-HT concentrations only in some mesocorticolimbic regions. However, positive correlations, indicating the balance, between DA and 5-HT observed in control (CTR) rats, were more extensively disrupted across mesocorticolimbic regions in NHL rats. Pharmacological manipulations that modulated both DA and 5-HT systems simultaneously with Astragalus membranaceus (AM) and its active compound formononetin (FOR) normalized the NHL-induced DA and 5-HT imbalance in several brain areas, which consequently improved the behavioral alterations. These results suggest that behavioral alterations caused by NHL may be associated with mesocorticolimbic DA/5-HT imbalance. Drug treatments targeting multiple monoamine systems may be useful to improve the NHL-induced changes.
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Astragalus propinquus , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Conducta Animal/efectos de los fármacos , Dopamina/metabolismo , Habénula/efectos de los fármacos , Habénula/metabolismo , Isoflavonas/farmacología , Neurotransmisores/farmacología , Serotonina/metabolismo , Factores de Edad , Animales , Animales Recién Nacidos , Trastorno por Déficit de Atención con Hiperactividad/inducido químicamente , Modelos Animales de Enfermedad , Agonistas de Aminoácidos Excitadores/farmacología , Ácido Iboténico/farmacología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
The present study was aimed to investigate the pre-treatment effect of Centella asiatica (CeA) extract on long-term potentiation (LTP) in a rat model of Alzheimer's disease (AD). A total of 32 male Wistar rats weighing 380 ± 30 g were randomly divided into four groups (n = 8). Group 1 (C: Control): the control group. Group 2 (L: Lesion): The nucleus basalis of Meynert (NBM) of rats' brain was bilaterally destroyed by injection of Ibotenic acid. Group 3 (CeA): Animals in this group received the CeA leaf extract for only a period of six weeks. Group 4 (CeA + L): The NBM of rats was destroyed by Ibotenic acid after six weeks of a diet containing the CeA leaf extract. In all groups, LTP was recorded using the electrophysiological technique and fEPSP after high frequency stimulation (HFS). The results showed that the slope and amplitude of PS as well as the sub-curve level significantly increased in the CeA + L group compared with the L and CeA groups. The CeA extract improved and strengthened the slope, amplitude and sub-curve surface of cumulative waves in animals with NBM lesion. The results showed that administration CeA extract for six weeks before induction of NBM lesion and induction of Alzheimer could enhance memory. In other words, the CeA extract had a preventive or protective role. The present study showed that CeA had a protective role for neurons among rats with NBM lesion.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Plantas Medicinales , Enfermedad de Alzheimer/patología , Animales , Núcleo Basal de Meynert/patología , Modelos Animales de Enfermedad , Ácido Iboténico/farmacología , Masculino , Memoria/efectos de los fármacos , Neuronas/patología , Ratas WistarRESUMEN
We investigated the role of autophagy, a controlled lysosomal degradation of cellular macromolecules and organelles, in glutamate excitotoxicity during nutrient deprivation in vitro. The incubation in low-glucose serum/amino acid-free cell culture medium synergized with glutamate in increasing AMP/ATP ratio and causing excitotoxic necrosis in SH-SY5Y human neuroblastoma cells. Glutamate suppressed starvation-triggered autophagy, as confirmed by diminished intracellular acidification, lower LC3 punctuation and LC3-I conversion to autophagosome-associated LC3-II, reduced expression of proautophagic beclin-1 and ATG5, increase of the selective autophagic target NBR1, and decreased number of autophagic vesicles. Similar results were observed in PC12 rat pheochromocytoma cells. Both glutamate-mediated excitotoxicity and autophagy inhibition in starved SH-SY5Y cells were reverted by NMDA antagonist memantine and mimicked by NMDA agonists D-aspartate and ibotenate. Glutamate reduced starvation-triggered phosphorylation of the energy sensor AMP-activated protein kinase (AMPK) without affecting the activity of mammalian target of rapamycin complex 1, a major negative regulator of autophagy. This was associated with reduced mRNA levels of autophagy transcriptional activators (FOXO3, ATF4) and molecules involved in autophagy initiation (ULK1, ATG13, FIP200), autophagosome nucleation/elongation (ATG14, beclin-1, ATG5), and autophagic cargo delivery to autophagosomes (SQSTM1). Glutamate-mediated transcriptional repression of autophagy was alleviated by overexpression of constitutively active AMPK. Genetic or pharmacological AMPK activation by AMPK overexpression or metformin, as well as genetic or pharmacological autophagy induction by TFEB overexpression or lithium chloride, reduced the sensitivity of nutrient-deprived SH-SY5Y cells to glutamate excitotoxicity. These data indicate that transcriptional inhibition of AMPK-dependent cytoprotective autophagy is involved in glutamate-mediated excitotoxicity during nutrient deprivation in vitro.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Autofagia/efectos de los fármacos , Ácido Glutámico/toxicidad , Proteínas Quinasas Activadas por AMP/genética , Autofagosomas/metabolismo , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Beclina-1/metabolismo , Línea Celular Tumoral , Metabolismo Energético/efectos de los fármacos , Proteína Forkhead Box O3/metabolismo , Humanos , Ácido Iboténico/farmacología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Memantina/farmacología , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Necrosis , Neuroblastoma/metabolismo , Neuroblastoma/patología , Nutrientes/deficiencia , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/metabolismo , Proteína Sequestosoma-1/genética , Proteína Sequestosoma-1/metabolismo , Transcripción Genética/efectos de los fármacosRESUMEN
At present, role of the lateral habenula (LHb) calcium-permeable AMPA receptors (CP-AMPARs) in depression is not understood, particularly in Parkinson's disease-related depression. Here we found that lesions of the substantia nigra pars compacta (SNc) in rats induced depressive-like behaviors, and intra-LHb injection of CP-AMPAR antagonist Naspm produced antidepressant-like effects in SNc sham-lesioned and SNc-lesioned rats, however, the doses inducing these effects in SNc-lesioned rats were lower than that of SNc sham-lesioned rats. Blockade of LHb CP-AMPARs decreased the firing rate of the neurons and increased release of dopamine and serotonin in the medial prefrontal cortex (mPFC) in both groups, but the duration of Naspm action on the firing rate and release of the transmitters were prolonged in SNc-lesioned rats. These changes in SNc-lesioned rats were involved in increased expression of ßCaMKII and p-GluR1-S831 in the LHb. Intra-LHb injection of Naspm inhibited dopaminergic neurons in the anterior ventral tegmental area and serotonergic neurons in the dorsal raphe nucleus and excited dopaminergic neurons in the posterior ventral tegmental area (pVTA) and serotonergic neurons in the median raphe nucleus (MRN), and lesioning the GABAergic rostromedial tegmental nucleus (RMTg) decreased the percentages of excited pVTA dopaminergic neurons and MRN serotonergic neurons. Our findings indicate that blockade of LHb CP-AMPARs produces antidepressant-like effects, which attribute to decreased firing activity of LHb neurons and increased levels of dopamine and serotonin in the mPFC, and provide further evidence that LHb CP-AMPARs regulate the firing activity of pVTA dopaminergic neurons and MRN serotonergic neurons indirectly via the RMTg.
Asunto(s)
Antidepresivos/farmacología , Núcleo Dorsal del Rafe/fisiología , Habénula/fisiología , Oxidopamina/farmacología , Porción Compacta de la Sustancia Negra/fisiología , Receptores AMPA/antagonistas & inhibidores , Espermina/análogos & derivados , Potenciales de Acción/fisiología , Animales , Conducta Animal/efectos de los fármacos , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/biosíntesis , Dopamina/metabolismo , Neuronas Dopaminérgicas , Habénula/metabolismo , Ácido Iboténico/farmacología , Masculino , Inhibición Neural/efectos de los fármacos , Porción Compacta de la Sustancia Negra/efectos de los fármacos , Fosforilación/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas , Receptores AMPA/agonistas , Receptores AMPA/metabolismo , Neuronas Serotoninérgicas , Serotonina/metabolismo , Espermina/farmacología , Tegmento Mesencefálico/efectos de los fármacos , Área Tegmental Ventral/fisiologíaRESUMEN
Although the dorsal hippocampus (DH) plays an essential role in the consolidation of contextual fear-conditioned (CxFC) memory, this consolidation may also occur in the absence of DH. It is, however, not known if the development of a compensatory circuit for CxFC memory is time-dependent. The DH-dependent contextual fear memory influences sleep architecture, but whether the compensatory fear memory can influence sleep, is not known. Here, we have studied (a) the temporal progression of compensatory contextual fear memory in the absence of DH and (b) the influence of compensatory contextual fear memory on sleep architecture. Rats were surgically prepared for chronic polysomnographic recordings and drug injections in the DH. They were divided into four groups: DH-non-lesioned and fear-conditioned, DH-non-lesioned and non-fear-conditioned, DH-lesioned and fear-conditioned and DH-lesioned and non-fear-conditioned groups. The DH was lesioned with ibotenic acid. The animals were conditioned to contextual fear twice: 1st training on Day 5 and testing on Day 6; 2nd training on Day 10 and testing on Day 11. The DH-lesioned and fear-conditioned animals did not exhibit freezing response during the first testing but showed a robust freezing response when re-trained after a gap of three days. In addition, wakefulness and NREM sleep amount did not change, but REM sleep significantly decreased in the DH-dependent CxFC memory group. Interestingly, REM sleep did not decrease in the DH-independent CxFC memory group. Our findings suggest that the development of compensatory CxFC memory is a time-dependent process and the compensatory CxFC memory may not influence sleep architecture.
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Miedo/fisiología , Memoria/fisiología , Sueño/fisiología , Animales , Condicionamiento Clásico/fisiología , Condicionamiento Psicológico/fisiología , Hipocampo/fisiología , Ácido Iboténico/farmacología , Aprendizaje/fisiología , Masculino , Consolidación de la Memoria/fisiología , Ratas , Ratas Wistar , Sueño REM/fisiología , Vigilia/fisiologíaRESUMEN
Basal ganglia (BG) lesions cause impairments of different mammalian's movement and cognition behaviors. Motor circuit impairment has a dominant role in the movement disorders. An inhibitory factor in BG is GABA neurotransmitter, which is released from striatum. Lesions in GABAergic neurons could trigger movement and cognition disorders. Previous evidence showed that GABAB receptor agonist (Baclofen) administration in human improves movement disorders and exercise can improve neurodegenerative and cognitive decline; however, the effects of both Baclofen and mild forced treadmill exercise on movement disorders are not well known. The main objective of this study is to investigate the combined effects of mild forced treadmill exercise and microinjection of Baclofen in the internal Globus Pallidus on striatum lesion-induced impairments of spatial learning and motor activity. We used Morris water maze and open filed tests for studying spatial learning, and motor activity, respectively. Results showed that mild exercise and Baclofen microinjection could not lonely affect the spatial learning, and motor activity impairments while the combination of them could alleviate spatial learning, and motor activity impairments in striatum-lesion animals. Our results suggest that striatum lesion-induced memory and motor activity impairments can improve with combination interaction of GABAB receptor agonist and exercise training.
Asunto(s)
Baclofeno/farmacología , Cuerpo Estriado/lesiones , Agonistas de Receptores GABA-B/fisiología , Memoria/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Condicionamiento Físico Animal/fisiología , Esfuerzo Físico/fisiología , Aprendizaje Espacial/efectos de los fármacos , Animales , Baclofeno/administración & dosificación , Agonistas de Aminoácidos Excitadores/farmacología , Agonistas de Receptores GABA-B/administración & dosificación , Globo Pálido , Ácido Iboténico/farmacología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Microinyecciones , Ratas , Ratas WistarRESUMEN
Purpose: To investigate the relationship between intraocular pressure (IOP) and GABA receptors within the arcuate nucleus (ARC). Methods: In the chronic high IOP rat model, ibotenic acid (IBO) was injected to induce impairment of the ARC, and IOP was measured at the 0, 1, 2, 3, and 4 week time points with a Tono-Pen. To assess the expression of GABA-A/B receptors within the ARC under persistent high IOP, we performed immunofluorescence (IF) and immunohistochemical (IHC) staining at 2 weeks and 4 weeks. Furthermore, we treated the ARC with GABA-A/B receptor antagonists separately, and IOP was evaluated, as well as retinal ganglion cell apoptosis in the chronic high IOP rat model. In the following induced high IOP animal model, the expression of GABA-A/B receptors within the ARC was evaluated in DBA/2J mice which developed progressive eye abnormalities spontaneously that closely mimic human hereditary glaucoma. Results: Compared with the control group, statistically significant downregulation of IOP was noted due to the IBO injection into the ARC at the 2, 3, and 4 week time points (p<0.05). Persistent high IOP elicited increased expression of the GABA-A/B receptors in the ARC compared with the control group (p<0.01). In addition, treatment with GABA-A/B receptor antagonists separately caused a decrease in the IOP, along with reduced retinal ganglion cell apoptosis (p<0.01). In the DBA/2J mice, the expression of the GABA receptors was statistically significantly increased (p<0.01). Conclusions: GABA-A/B receptors in the ARC may be involved in regulation of IOP, and pathologically high IOP affects the expression of GABA-A/B receptors in the ARC.
Asunto(s)
Núcleo Arqueado del Hipotálamo/metabolismo , Modelos Animales de Enfermedad , Presión Intraocular/fisiología , Hipertensión Ocular/metabolismo , Receptores de GABA-A/metabolismo , Receptores de GABA-B/metabolismo , Animales , Apoptosis , Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Agonistas de Aminoácidos Excitadores/farmacología , Técnica del Anticuerpo Fluorescente Indirecta , Antagonistas de Receptores de GABA-A/farmacología , Antagonistas de Receptores de GABA-B/farmacología , Ácido Iboténico/farmacología , Técnicas para Inmunoenzimas , Etiquetado Corte-Fin in Situ , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratas , Ratas Sprague-Dawley , Células Ganglionares de la Retina/patología , Tonometría Ocular , Factor de Transcripción Brn-3A/metabolismoRESUMEN
Cystic periventricular leukomalacia is commonly diagnosed in premature infants, resulting from severe hypoxic-ischemic white matter injury, and also involving some grey matter damage. Very few is known concerning the cell death pathways involved in these types of premature cerebral lesions. Excitotoxicity is a predominant mechanism of hypoxic-ischemic injury in the developing brain. Concomitantly, it has been recently shown that autophagy could be enhanced in excitotoxic conditions switching this physiological intracellular degradation system to a deleterious process. We here investigated the role of autophagy in a validated rodent model of preterm excitotoxic brain damage mimicking in some aspects cystic periventricular leukomalacia. An excitotoxic lesion affecting periventricular white and grey matter was induced by injecting ibotenate, a glutamate analogue, in the subcortical white matter (subcingulum area) of five-day old rat pups. Ibotenate enhanced autophagy in rat brain dying neurons at 24 h as shown by increased presence of autophagosomes (increased LC3-II and LC3-positive dots) and enhanced autophagic degradation (SQSTM1 reduction and increased number and size of lysosomes (LAMP1- and CATHEPSIN B-positive vesicles)). Co-injection of the pharmacological autophagy inhibitor 3-methyladenine prevented not only autophagy induction but also CASPASE-3 activation and calpain-dependent cleavage of SPECTRIN 24 h after the insult, thus providing a strong reduction of the long term brain injury (16 days after ibotenate injection) including lateral ventricle dilatation, decreases in cerebral tissue volume and in subcortical white matter thickness. The autophagy-dependent neuroprotective effect of 3-methyladenine was confirmed in primary cortical neuronal cultures using not only pharmacological but also genetic autophagy inhibition of the ibotenate-induced autophagy. Strategies inhibiting autophagy could then represent a promising neuroprotective approach in the context of severe preterm brain injuries.
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Animales Recién Nacidos/metabolismo , Autofagia/fisiología , Lesiones Encefálicas/metabolismo , Encéfalo/metabolismo , Animales , Autofagia/efectos de los fármacos , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Ácido Iboténico/farmacología , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Tonic immobility (TI) is an innate defensive response exhibited by prey when physical contact with a predator is prolonged and inescapable. This defensive response is able to activate analgesia mechanisms; this activation has adaptive value because, during an attack by a predator, the manifestation of recuperative behaviors can affect the appropriate behavioral defense strategy. Some studies have suggested that similar structures of the central nervous system can regulate the response of both TI and nociception. Thus, this study evaluated the effect of chemical lesion through the administration of ibotenic acid in restricted brain areas of the periaqueductal gray matter (PAG) in guinea pig on the TI response and nociception evaluated in the hot plate test before and after emission of TI. The data showed that an irreversible chemical lesion in the ventrolateral PAG reduced of the TI response as well as defensive antinociception. However, a lesion in the dorsal PAG blocked the defensive antinociception induced by TI but did not alter TI duration. In summary, one could hypothesize that the neural substrates responsible for defensive behavior and antinociception represent similar systems that are distinct in modulation. Thus, the ventrolateral PAG has been associated with the modulation of TI and the defensive antinociception induced by TI. In contrast, the integrity of the dorsal PAG should be necessary for defensive antinociception to occur but not to elicit TI behavior in guinea pigs.
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Analgesia , Ácido Iboténico/farmacología , Pérdida de Tono Postural/fisiología , Sustancia Gris Periacueductal/fisiopatología , Animales , Cobayas , Ácido Iboténico/administración & dosificación , Masculino , Microinyecciones , Dimensión del Dolor , Sustancia Gris Periacueductal/efectos de los fármacosRESUMEN
The anterior cingulate cortex (ACC) plays a key role in regulating mood in animals, especially anxiety, and is also a brain region that is indispensable to pain perception. Postoperative anxiety is closely related to the experience of pain. Remifentanil is a commonly used surgical analgesic. The mechanism of supraspinal hyperalgesia caused by remifentanil remains unclear. We used animal models to simulate postoperative hyperalgesia and studied the GluR1 AMPA receptor subunit in the ACC using western blots and immunocytochemistry. Behavioral tests were used to estimate anxiety levels. We found no significant change in GluR1 levels before and after hyperalgesia, whereas phosphorylation of GluR1Ser845 was significantly increased after hyperalgesia. Double staining for c-Fos, widely used as a marker of neural activation, and Arc, which facilitates GluR1 endocytosis, revealed that neural activation increased and the expression of Arc decreased after hyperalgesia. Local injection of a protein kinase A inhibitor (H89) in the ACC effectively blocked the phosphorylation of GluR1Ser845 and alleviated the hyperalgesia and anxiety shown in the behavioral tests. Double staining revealed no significant change in c-Fos or Arc levels after the administration of H89. Local injection of ibotenic acid caused damage to the ACC, following which remifentanil did not induce hyperalgesia or anxiety. These results lead us to conclude that the ACC is a critical hub for remifentanil-induced hyperalgesia (RIH) and RIH-related anxiety and that regulating the phosphorylation of GluR1Ser845 may modulate RIH and anxiety. Anxiety may be an influential factor contributing to individual differences in RIH occurrence.
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Analgésicos Opioides/farmacología , Ansiedad/metabolismo , Giro del Cíngulo/efectos de los fármacos , Hiperalgesia/metabolismo , Piperidinas/farmacología , Procesamiento Proteico-Postraduccional , Receptores AMPA/metabolismo , Analgésicos Opioides/toxicidad , Animales , Ansiedad/etiología , Ansiedad/fisiopatología , Agonistas de Aminoácidos Excitadores/farmacología , Giro del Cíngulo/metabolismo , Hiperalgesia/etiología , Hiperalgesia/fisiopatología , Ácido Iboténico/farmacología , Masculino , Fosforilación , Piperidinas/toxicidad , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Ratas Sprague-Dawley , RemifentaniloRESUMEN
Advantageous foraging choices benefit from an estimation of two aspects of a resource's value: its current desirability and availability. Both orbitofrontal and ventrolateral prefrontal areas contribute to updating these valuations, but their precise roles remain unclear. To explore their specializations, we trained macaque monkeys on two tasks: one required updating representations of a predicted outcome's desirability, as adjusted by selective satiation, and the other required updating representations of an outcome's availability, as indexed by its probability. We evaluated performance on both tasks in three groups of monkeys: unoperated controls and those with selective, fiber-sparing lesions of either the OFC or VLPFC. Representations that depend on the VLPFC but not the OFC play a necessary role in choices based on outcome availability; in contrast, representations that depend on the OFC but not the VLPFC play a necessary role in choices based on outcome desirability.
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Conducta de Elección/fisiología , Corteza Prefrontal/fisiología , Animales , Condicionamiento Operante/fisiología , Aprendizaje Discriminativo , Discriminación en Psicología/fisiología , Femenino , Ácido Iboténico/farmacología , Macaca mulatta , Masculino , Corteza Prefrontal/efectos de los fármacos , Aprendizaje Inverso/fisiología , RecompensaRESUMEN
The presence of companions renders decreases in cocaine-stimulated dopamine release in the nucleus accumbens and cocaine-induced conditioned place preference (CPP) magnitude. Limbic systems are widely believed to underlie the modulation of accumbal dopamine release and cocaine conditioning. Thus, this study aimed to assess whether intact basolateral nucleus of amygdala (BLA), dorsal hippocampus (DH), and dorsolateral striatum (DLS) is required for the companions-exerted suppressive effect on the cocaine-induced CPP. Three cage mates, serving as companions, were arranged to house with the experimental mice in the cocaine conditioning compartment throughout the cocaine conditioning sessions. Approximately 1week before the conditioning procedure, intracranial ibotenic acid infusions were done in an attempt to cause excitotoxic lesions targeting bilateral BLA, DH and DLS. Albeit their BLA, DH, and DLS lesions, the lesioned mice exhibited comparable cocaine-induced CPP magnitudes compared to the intact and sham lesion controls. Bilateral BLA, but not DH or DLS, lesions abolished the companions-exerted suppressive effect on the cocaine-induced CPP. Intact mice receiving intra-BLA infusion of raclopride, a selective D2 antagonist, 30min prior to the cocaine conditioning did not exhibit the companions-exerted suppressive effect on the cocaine-induced CPP. Intra-BLA infusion of Sch23390, a selective D1 antagonist, did not affect the companions-exerted suppressive effect on the CPP. These results, taken together, prompt us to conclude that the intactness of BLA is required for the companions-exerted suppressive effect on the cocaine-induced CPP. Importantly, activation of D2 receptor in the BLA is required for such suppressive effect on the CPP.
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Aprendizaje por Asociación/efectos de los fármacos , Complejo Nuclear Basolateral/efectos de los fármacos , Cocaína/administración & dosificación , Condicionamiento Operante/efectos de los fármacos , Antagonistas de los Receptores de Dopamina D2/farmacología , Inhibidores de Captación de Dopamina/administración & dosificación , Racloprida/farmacología , Animales , Aprendizaje por Asociación/fisiología , Complejo Nuclear Basolateral/fisiología , Condicionamiento Operante/fisiología , Agonistas de Aminoácidos Excitadores/farmacología , Ácido Iboténico/farmacología , Masculino , RatonesRESUMEN
In three experiments, the nature of the interaction between multiple memory systems in rats solving a variation of a spatial task in the water maze was investigated. Throughout training rats were able to find a submerged platform at a fixed distance and direction from an intramaze landmark by learning a landmark-goal vector. Extramaze cues were also available for standard place learning, or "cognitive mapping," but these cues were valid only within each session, as the position of the platform moved around the pool between sessions together with the intramaze landmark. Animals could therefore learn the position of the platform by taking the consistent vector from the landmark across sessions or by rapidly encoding the new platform position on each session with reference to the extramaze cues. Excitotoxic lesions of the dorsolateral striatum impaired vector-based learning but facilitated cognitive map-based rapid place learning when the extramaze cues were relatively poor (Experiment 1) but not when they were more salient (Experiments 2 and 3). The way the lesion effects interacted with cue availability is consistent with the idea that the memory systems involved in the current navigation task are functionally cooperative yet associatively competitive in nature.
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Cognición/fisiología , Señales (Psicología) , Objetivos , Neostriado/fisiología , Aprendizaje Espacial/fisiología , Navegación Espacial/fisiología , Animales , Cognición/efectos de los fármacos , Ácido Iboténico/farmacología , Masculino , Neostriado/efectos de los fármacos , Ratas , Aprendizaje Espacial/efectos de los fármacos , Navegación Espacial/efectos de los fármacosRESUMEN
In this study, we aim to demonstrate the fate of allogenic adult human olfactory bulb neural stem/progenitor cells (OBNSC/NPCs) transplanted into the rat hippocampus treated with ibotenic acid (IBO), a neurotoxicant specific to hippocampal cholinergic neurons that are lost in Alzheimer's disease. We assessed their possible ability to survive, integrate, proliferate, and differentiate into different neuronal and glial elements: we also evaluate their possible therapeutic potential, and the mechanism(s) relevant to neuroprotection following their engraftment into the CNS milieu. OBNSC/NPCs were isolated from adult human olfactory bulb patients, genetically engineered to express GFP and human nerve growth factor (hNGF) by lentivirus-mediated infection, and stereotaxically transplanted into the hippocampus of IBO-treated animals and controls. Stereological analysis of engrafted OBNSCs eight weeks post transplantation revealed a 1.89 fold increase with respect to the initial cell population, indicating a marked ability for survival and proliferation. In addition, 54.71 ± 11.38%, 30.18 ± 6.00%, and 15.09 ± 5.38% of engrafted OBNSCs were identified by morphological criteria suggestive of mature neurons, oligodendrocytes and astrocytes respectively. Taken together, this work demonstrated that human OBNSCs expressing NGF ameliorate the cognitive deficiencies associated with IBO-induced lesions in AD model rats, and the improvement can probably be attributed primarily to neuronal and glial cell replacement as well as the trophic influence exerted by the secreted NGF.
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Enfermedad de Alzheimer/terapia , Tratamiento Basado en Trasplante de Células y Tejidos , Factor de Crecimiento Nervioso/biosíntesis , Células-Madre Neurales/trasplante , Bulbo Olfatorio/citología , Animales , Astrocitos/metabolismo , Diferenciación Celular , Línea Celular , Proliferación Celular , Neuronas Colinérgicas/efectos de los fármacos , Trastornos del Conocimiento/terapia , Modelos Animales de Enfermedad , Proteínas Fluorescentes Verdes/biosíntesis , Proteínas Fluorescentes Verdes/genética , Células HEK293 , Hipocampo/citología , Humanos , Ácido Iboténico/farmacología , Masculino , Aprendizaje por Laberinto , Neovascularización Fisiológica , Factor de Crecimiento Nervioso/genética , Células-Madre Neurales/metabolismo , Oligodendroglía/metabolismo , Ratas , Ratas WistarRESUMEN
Disabilities caused by neurodegeneration have become one of the main causes of mortality in elderly population, with drug distribution to the brain remaining one of the most difficult challenges in the treatment of the central nervous system (CNS) diseases due to the existence of blood-brain barrier. Lectins modified polyethylene glycol-polylactide-polyglycolide (PEG-PLGA) nanoparticles could enhance the drug delivery to the brain following intranasal administration. In this study, basic fibroblast growth factor (bFGF) was entrapped in nanoparticles conjugated with Solanum tuberosum lectin (STL), which selectively binds to N-acetylglucosamine on the nasal epithelial membrane for its brain delivery. The resulting nanoparticles had uniform particle size and negative zeta potential. The brain distribution of the formulations following intranasal administration was assessed using radioisotopic tracing method. The areas under the concentration-time curve of (125)I-bFGF in the olfactory bulb, cerebrum, and cerebellum of rats following nasal application of STL modified nanoparticles (STL-bFGF-NP) were 1.79-5.17 folds of that of rats with intravenous administration, and 0.61-2.21 and 0.19-1.07 folds higher compared with intranasal solution and unmodified nanoparticles, respectively. Neuroprotective effect was evaluated using Mirror water maze task in rats with intracerebroventricular injection of ß-amyloid25-35 and ibotenic acid. The spatial learning and memory of Alzheimer's disease (AD) rats in STL-bFGF-NP group were significantly improved compared with AD model group, and were also better than other preparations. The results were consistent with the value of choline acetyltransferase activity of rat hippocampus as well as the histological observations of rat hippocampal region. The histopathology assays also confirmed the in vivo safety of STL-bFGF-NP. These results clearly indicated that STL-NP was a promising drug delivery system for peptide and protein drugs such as bFGF to enter the CNS and play the therapeutic role.