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The modulation of dopamine release from midbrain projections to the striatum has long been demonstrated in reward-based learning, but the synaptic basis of aversive learning is far less characterized. The cerebellum receives axonal projections from the locus coeruleus, and norepinephrine release is implicated in states of arousal and stress, but whether aversive learning relies on plastic changes in norepinephrine release in the cerebellum is unknown. Here we report that in mice, norepinephrine is released in the cerebellum following an unpredicted noxious event (a foot-shock) and that this norepinephrine release is potentiated powerfully with fear acquisition as animals learn that a previously neutral stimulus (tone) predicts the aversive event. Importantly, both chemogenetic and optogenetic inhibition of the locus coeruleus-cerebellum pathway block fear memory without impairing motor function. Thus, norepinephrine release in the cerebellum is modulated by experience and underlies aversive learning.
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Reacción de Prevención , Norepinefrina , Ratones , Animales , Reacción de Prevención/fisiología , Norepinefrina/metabolismo , Locus Coeruleus/fisiología , Cerebelo/metabolismo , Mesencéfalo/metabolismoRESUMEN
Several studies indicate a relationship between maternal gut microbiota alteration and increased risk of autism spectrum disorders (ASD) in offspring. The possibility of compensating for such metabolic dysfunction at a very early stage of disease via maternal treatment has not been enough explored. Here, we examined in BTBR mouse model of ASD the effect of maternal treatment with the gut microbial metabolite butyrate (BUT) on the behavioral and synaptic plasticity deficits in juvenile and adult offspring. We show that BUT treatment of BTBR dams rescues the social and partially the repetitive behavior deficits in the offspring. In addition, maternal BUT implementation prevents the cerebellar cortex hypertrophy as well as the Purkinje cells firing and long-term synaptic plasticity deficits in BTBR mice. Our results demonstrate, for the first time, that maternal BUT treatment can improve ASD-like symptoms in offspring thus providing new directions for the early treatment of neurodevelopmental disorders.
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Trastorno del Espectro Autista , Trastorno Autístico , Ratones , Animales , Trastorno Autístico/tratamiento farmacológico , Ácido Butírico/farmacología , Conducta Social , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/prevención & control , Trastorno del Espectro Autista/metabolismo , Ratones Endogámicos , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Conducta AnimalRESUMEN
The synaptic pathways in the striatum are central to basal ganglia functions including motor control, learning and organization, action selection, acquisition of motor skills, cognitive function, and emotion. Here, we review the role of the striatum and its connections in motor learning and performance. The development of new techniques to record neuronal activity and animal models of motor disorders using neurotoxin, pharmacological, and genetic manipulations are revealing pathways that underlie motor performance and motor learning, as well as how they are altered by pathophysiological mechanisms. We discuss approaches that can be used to analyze complex motor skills, particularly in rodents, and identify specific questions central to understanding how striatal circuits mediate motor learning.
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Ganglios Basales , Cuerpo Estriado , Animales , Ganglios Basales/fisiología , Cuerpo Estriado/fisiologíaRESUMEN
The ability to identify and avoid environmental stimuli that signal danger is essential to survival. Our understanding of how the brain encodes aversive behaviors has been primarily focused on roles for the amygdala, hippocampus (HIPP), prefrontal cortex, ventral midbrain, and ventral striatum. Relatively little attention has been paid to contributions from the dorsal striatum (DS) to aversive learning, despite its well-established role in stimulus-response learning. Here, we review studies exploring the role of DS in aversive learning, including different roles for the dorsomedial and dorsolateral striatum in Pavlovian fear conditioning as well as innate and inhibitory avoidance (IA) behaviors. We outline how future investigation might determine specific contributions from DS subregions, cell types, and connections that contribute to aversive behavior.
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Convergent lines of evidence have recently highlighted ß3-adrenoreceptors (ARs) as a potentially critical target in the regulation of nervous and behavioral functions, including memory consolidation, anxiety, and depression. Nevertheless, the role of ß3-ARs in the cerebellum has been never investigated. To address this issue, we first examined the effects of pharmacological manipulation of ß3-ARs on motor learning in mice. We found that blockade of ß3-ARs by SR 59230A impaired the acquisition of the rotarod task with no effect on general locomotion. Since the parallel fiber-Purkinje cell (PF-PC) synapse is considered to be the main cerebellar locus of motor learning, we assessed ß3-AR modulatory action on this synapse as well as its expression in cerebellar slices. We demonstrate, for the first time, a strong expression of ß3-ARs on Purkinje cell soma and dendrites. In addition, whole-cell patch-clamp recordings revealed that bath application of ß3-AR agonist CL316,243 depressed the PF-PC excitatory postsynaptic currents via a postsynaptic mechanism mediated by the PI3K signaling pathway. Application of CL316,243 also interfered with the expression of PF long-term potentiation, whereas SR 59230A prevented the induction of LTD at PF-PC synapse. These results underline the critical role of ß3-AR on cerebellar synaptic transmission and plasticity and provide a new mechanism for adrenergic modulation of motor learning.
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Corteza Cerebelosa/fisiología , Receptores Adrenérgicos beta 3/fisiología , Transmisión Sináptica/fisiología , Animales , Corteza Cerebelosa/metabolismo , Potenciales Postsinápticos Excitadores , Femenino , Potenciación a Largo Plazo , Depresión Sináptica a Largo Plazo , Masculino , Ratones , Plasticidad Neuronal/fisiología , Técnicas de Placa-Clamp , Fosfatidilinositol 3-Quinasas/metabolismo , Células de Purkinje/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Prueba de Desempeño de Rotación con Aceleración Constante , Sinapsis/fisiologíaRESUMEN
G-protein-coupled inwardly rectifying potassium (GIRK) channels contribute to the resting membrane potential of many neurons and play an important role in controlling neuronal excitability. Although previous studies have revealed a high expression of GIRK subunits in the cerebellum, their functional role has never been clearly described. Using patch-clamp recordings in mice cerebellar slices, we examined the properties of the GIRK currents in Purkinje cells (PCs) and investigated the effects of a selective agonist of GIRK1-containing channels, ML297 (ML), on PC firing and synaptic plasticity. We demonstrated that GIRK channel activation decreases the PC excitability by inhibiting both sodium and calcium spikes and, in addition, modulates the complex spike response evoked by climbing fiber stimulation. Our results indicate that GIRK channels have also a marked effect on synaptic plasticity of the parallel fiber-PC synapse, as the application of ML297 increased the expression of LTP while preventing LTD. We, therefore, propose that the recruitment of GIRK channels represents a crucial mechanism by which neuromodulators can control synaptic strength and membrane conductance for proper refinement of the neural network involved in memory storage and higher cognitive functions.
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Potenciales Postsinápticos Excitadores/fisiología , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/fisiología , Plasticidad Neuronal/fisiología , Neurotransmisores/farmacología , Células de Purkinje/fisiología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Animales Recién Nacidos , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Femenino , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/agonistas , Masculino , Ratones , Plasticidad Neuronal/efectos de los fármacos , Compuestos de Fenilurea/farmacología , Células de Purkinje/efectos de los fármacos , Pirazoles/farmacologíaRESUMEN
While protein synthesis in neurons is largely attributed to cell body and dendrites, the capability of synaptic regions to synthesize new proteins independently of the cell body has been widely demonstrated as an advantageous mechanism subserving synaptic plasticity. Thus, the contribution that local protein synthesis at synapses makes to physiology and pathology of brain plasticity may be more prevalent than initially thought. In this study, we tested if local protein synthesis at synapses is deregulated in the brains of TgCRND8 mice, an animal model for Alzheimer's disease (AD) overexpressing mutant human amyloid precursor protein (APP). To this end, we used synaptosomes as a model system to study the functionality of the synaptic regions in mouse brains. Our results showed that, while TgCRND8 mice exhibit early signs of brain inflammation and deficits in learning, the electrophoretic profile of newly synthesized proteins in their synaptosomes was subtly different from that of the control mice. Interestingly, APP itself was, in part, locally synthesized in the synaptosomes, underscoring the potential importance of local translation at synapses. More importantly, after the contextual fear conditioning, de novo synthesis of some individual proteins was significantly enhanced in the synaptosomes of control animals, but the TgCRND8 mice failed to display such synaptic modulation by training. Taken together, our results demonstrate that synaptic synthesis of proteins is impaired in the brain of a mouse model for AD, and raise the possibility that this deregulation may contribute to the early progression of the pathology.
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Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Neuronas/metabolismo , Sinapsis/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Modelos Animales de Enfermedad , Trastornos de la Memoria/metabolismo , Ratones Transgénicos , Placa Amiloide/patología , Sinaptosomas/metabolismoRESUMEN
BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is a common neurodegenerative disease characterized by a neuroinflammatory state, and to date, there is no cure and its treatment represents a large unmet clinical need. The involvement of Th17 cells in the pathogenesis of AD-related neuroinflammation has been reported in several studies. However, the role of the cytokine, IL-17 has not been well addressed. Herein, we investigate the effects of IL-17 neutralizing antibody (IL-17Ab) injected by i.c.v. or intranasal (IN) routes on amyloid-ß (Aß)-induced neuroinflammation and memory impairment in mice. EXPERIMENTAL APPROACH: Aß1-42 was injected into cerebral ventricles of adult CD1 mice. These mice received IL-17Ab via i.c.v. either at 1 h prior to Aß1-42 injection or IN 5 and 12 days after Aß1-42 injection. After 7 and 14 days of Aß1-42 administration, we evaluated olfactory, spatial and working memory and performed biochemical analyses on whole brain and specific brain areas. KEY RESULTS: Pretreatment with IL-17Ab, given, i.c.v., markedly reduced Aß1-42 -induced neurodegeneration, improved memory function, and prevented the increase of pro-inflammatory mediators in a dose-dependent manner at 7 and 14 days. Similarly, the double IN administration of IL-17Ab after Aß1-42 injection reduced neurodegeneration, memory decline, and the levels of proinflammatory mediators and cytokines. CONCLUSION AND IMPLICATIONS: These findings suggest that the IL-17Ab reduced neuroinflammation and behavioural symptoms induced by Aß. The efficacy of IL-17Ab IN administration in reducing Aß1-42 neurodegeneration points to a possible future therapeutic approach in patients with AD. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.
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Antiinflamatorios/uso terapéutico , Anticuerpos Neutralizantes/uso terapéutico , Interleucina-17/inmunología , Trastornos de la Memoria/tratamiento farmacológico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Péptidos beta-Amiloides , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/metabolismo , Ratones , Enfermedades Neurodegenerativas/metabolismo , Fragmentos de PéptidosRESUMEN
The role of the cerebellum in Alzheimer's disease (AD) has been neglected for a long time. Recent studies carried out using transgenic mouse models have demonstrated that amyloid-ß (Aß) is deposited in the cerebellum and affects synaptic transmission and plasticity, sometimes before plaque formation. A wide variability of motor phenotype has been observed in the different murine models of AD, without a consistent correlation with the extent of cerebellar histopathological changes or with cognitive deficits. The loss of noradrenergic drive may contribute to the impairment of cerebellar synaptic function and motor learning observed in these mice. Furthermore, cerebellar neurons, particularly granule cells, have been used as in vitro model of Aß-induced neuronal damage. An unexpected conclusion is that the cerebellum, for a long time thought to be somehow protected from AD pathology, is actually considered as a region vulnerable to Aß toxic damage, even at the early stage of the disease, with consequences on motor performance.
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Purkinje cell (PC) dysfunction or degeneration is the most frequent finding in animal models with ataxic symptoms. Mutations affecting intrinsic membrane properties can lead to ataxia by altering the firing rate of PCs or their firing pattern. However, the relationship between specific firing alterations and motor symptoms is not yet clear, and in some cases PC dysfunction precedes the onset of ataxic signs. Moreover, a great variety of ionic and synaptic mechanisms can affect PC signaling, resulting in different features of motor dysfunction. Mutations affecting Na+ channels (NaV1.1, NaV1.6, NaVß4, Fgf14 or Rer1) reduce the firing rate of PCs, mainly via an impairment of the Na+ resurgent current. Mutations that reduce Kv3 currents limit the firing rate frequency range. Mutations of Kv1 channels act mainly on inhibitory interneurons, generating excessive GABAergic signaling onto PCs, resulting in episodic ataxia. Kv4.3 mutations are responsible for a complex syndrome with several neurologic dysfunctions including ataxia. Mutations of either Cav or BK channels have similar consequences, consisting in a disruption of the firing pattern of PCs, with loss of precision, leading to ataxia. Another category of pathogenic mechanisms of ataxia regards alterations of synaptic signals arriving at the PC. At the parallel fiber (PF)-PC synapse, mutations of glutamate delta-2 (GluD2) or its ligand Crbl1 are responsible for the loss of synaptic contacts, abolishment of long-term depression (LTD) and motor deficits. At the same synapse, a correct function of metabotropic glutamate receptor 1 (mGlu1) receptors is necessary to avoid ataxia. Failure of climbing fiber (CF) maturation and establishment of PC mono-innervation occurs in a great number of mutant mice, including mGlu1 and its transduction pathway, GluD2, semaphorins and their receptors. All these models have in common the alteration of PC output signals, due to a variety of mechanisms affecting incoming synaptic signals or the way they are processed by the repertoire of ionic channels responsible for intrinsic membrane properties. Although the PC is a final common pathway of ataxia, the link between specific firing alterations and neurologic symptoms has not yet been systematically studied and the alterations of the cerebellar contribution to motor signals are still unknown.
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Numerous studies indicate that the cerebellum undergoes structural and functional neurodegenerative changes in Alzheimer's disease. The purpose of this study was to examine the extent of cerebellar alterations at early, preplaque stage of the pathology in TgCRND8 mice through behavioral, electrophysiological, and molecular analysis. Balance beam test and foot-printing analysis revealed significant motor coordination and balance deficits in 2-month-old TgCRND8 mice compared to their littermates. Patch-clamp recordings performed on cerebellar slices of transgenic mice showed synaptic plasticity deficit and loss of noradrenergic modulation at parallel fiber-Purkinje cell synapse suggesting an early dysfunction of the cerebellar circuitry due to amyloid precursor protein overexpression. Finally, western blot analysis revealed an enhanced expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits p47phox and p67phox as well as Ca2+/calmodulin-dependent protein kinase and protein kinase C alpha in the cerebellum of 2-month-old transgenic mice. Therefore, we propose the existence of self-sustaining feedback loop involving the formyl peptide receptor 2-reactive oxygen species-Ca2+/calmodulin-dependent protein kinase II-protein kinase C alpha pathway that may promote reactive oxygen species generation in the early stage of Alzheimer's disease and eventually contribute to the exacerbation of pathological phenotype.
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Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/fisiopatología , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Cerebelo/metabolismo , Cerebelo/fisiopatología , Estudios de Asociación Genética , NADPH Oxidasas/metabolismo , Plasticidad Neuronal , Proteína Quinasa C-alfa/metabolismo , Desempeño Psicomotor , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Técnicas In Vitro , Masculino , Ratones Transgénicos , NADPH Oxidasas/genética , Norepinefrina/fisiología , Estrés Oxidativo , Técnicas de Placa-Clamp , Proteína Quinasa C-alfa/genéticaRESUMEN
Egocentric (self-centered) and allocentric (viewpoint independent) representations of space are essential for spatial navigation and wayfinding. Deficits in spatial memory come with age-related cognitive decline, are marked in mild cognitive impairment (MCI) and Alzheimer's disease (AD), and are associated with cognitive deficits in autism. In most of these disorders, a change in the brain areas engaged in the spatial reference system processing has been documented. However, the spatial memory deficits observed during physiological and pathological aging are quite different. While patients with AD and MCI have a general spatial navigation impairment in both allocentric and egocentric strategies, healthy older adults are particularly limited in the allocentric navigation, but they can still count on egocentric navigation strategy to solve spatial tasks. Therefore, specific navigational tests should be considered for differential diagnosis between healthy and pathological aging conditions. Finally, more research is still needed to better understand the spatial abilities of autistic individuals.
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Alzheimer's disease (AD) is a common form of dementia mainly characterized by the deposition of neurofibrillary tangles and ß-amyloid (Aß) peptides in the brain. Additionally, increasing evidence demonstrates that a neuro-inflammatory state plays a key role in the development of this disease. Beside synthetic drugs, the use of natural compounds represents an alternative for the development of new potential drugs for the treatment of AD. Among these, the root of Salvia miltiorhiza Bunge (also known as Danshen) used for the treatment of cardiovascular, cerebrovascular disease and CNS functional decline in Chinese traditional medicine is one of the most representative examples. We therefore evaluated the effects of tanshinone IIA (TIIA) and cryptotanshinone (CRY) (the two major lipophilic compounds of Danshen) in a non-genetic mouse model of ß-amyloid (Aß)-induced AD, which is mainly characterized by reactive gliosis and neuro-inflammation in the brain. To this aim, mice were injected intracerebroventricularly (i.c.v.) with Aß1-42 peptide (3µg/3µl) and after with TIIA and CRY (1, 3, or 10mg/kg) intraperitoneally (i.p.) 3 times weekly for 21days following the induction of experimental AD. Spatial working memory was assessed as a measure of short-term memory in mice, whereas the level of GFAP, S100ß, COX-2, iNOS and NF-kBp65 monitored by western blot and ELISA assay, were selected as markers of reactive gliosis and neuro-inflammation. Finally, by docking studies, the modulation of key pro-inflammatory enzymes and pathways involved in the AD-related neuro-inflammation were also investigated. Results indicate that TIIA and CRY alleviate memory decline in Aß1-42-injected mice, in a dose dependent manner. Moreover, the analysis of gliosis-related and neuro-inflammatory markers in the hippocampal tissues reveal a remarkable reduction in the expression of GFAP, S100ß, COX-2, iNOS and NF-kBp65 after CRY (10mg/kg) treatment. These effects were less evident, but still significant, after TIIA (10mg/kg). Finally, in silico analysis also revealed that both compounds were able to interact with the binding sites of NF-kBp65 endorsing the data from biochemical analysis. We conclude that TIIA and CRY display anti-inflammatory and neuroprotective effect in a non-genetic mouse model of AD, thus playing a role in slowing down the course and onset of AD.
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Abietanos/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Antiinflamatorios/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Fenantrenos/uso terapéutico , Péptidos beta-Amiloides , Animales , Modelos Animales de Enfermedad , Masculino , Memoria/efectos de los fármacos , Ratones , Fragmentos de PéptidosRESUMEN
The formation of the complex cerebellar cortical circuits follows different phases, with initial synaptogenesis and subsequent processes of refinement guided by a variety of mechanisms. The regularity of the cellular and synaptic organization of the cerebellar cortex allowed detailed studies of the structural plasticity mechanisms underlying the formation of new synapses and retraction of redundant ones. For the attainment of the monoinnervation of the Purkinje cell by a single climbing fiber, several signals are involved, including electrical activity, contact signals, homosynaptic and heterosynaptic interaction, calcium transients, postsynaptic receptors, and transduction pathways. An important role in this developmental program is played by serotonergic projections that, acting on temporally and spatially regulated postsynaptic receptors, induce and modulate the phases of synaptic formation and maturation. In the adult cerebellar cortex, many developmental mechanisms persist but play different roles, such as supporting synaptic plasticity during learning and formation of cerebellar memory traces. A dysfunction at any stage of this process can lead to disorders of cerebellar origin, which include autism spectrum disorders but are not limited to motor deficits. Recent evidence in animal models links impairment of Purkinje cell function with autism-like symptoms including sociability deficits, stereotyped movements, and interspecific communication by vocalization.
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Trastorno Autístico/patología , Corteza Cerebelosa/crecimiento & desarrollo , Red Nerviosa/crecimiento & desarrollo , Serotonina/metabolismo , Animales , Trastorno Autístico/metabolismo , Corteza Cerebelosa/metabolismo , Corteza Cerebelosa/patología , Modelos Animales de Enfermedad , Humanos , Ratones , Red Nerviosa/metabolismo , Red Nerviosa/patología , Plasticidad Neuronal/fisiología , Neuronas/metabolismo , Neuronas/patología , Sinapsis/fisiologíaRESUMEN
The c-Jun N-terminal kinase (JNK) is part of a stress signalling pathway strongly activated by NMDA-stimulation and involved in synaptic plasticity. Many studies have been focused on the post-synaptic mechanism of JNK action, and less is known about JNK presynaptic localization and its physiological role at this site. Here we examined whether JNK is present at the presynaptic site and its activity after presynaptic NMDA receptors stimulation. By using N-SIM Structured Super Resolution Microscopy as well as biochemical approaches, we demonstrated that presynaptic fractions contained significant amount of JNK protein and its activated form. By means of modelling design, we found that JNK, via the JBD domain, acts as a physiological effector on T-SNARE proteins; then using biochemical approaches we demonstrated the interaction between Syntaxin-1-JNK, Syntaxin-2-JNK, and Snap25-JNK. In addition, taking advance of the specific JNK inhibitor peptide, D-JNKI1, we defined JNK action on the SNARE complex formation. Finally, electrophysiological recordings confirmed the role of JNK in the presynaptic modulation of vesicle release. These data suggest that JNK-dependent phosphorylation of T-SNARE proteins may have an important functional role in synaptic plasticity.
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Corteza Cerebral/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Terminales Presinápticos/enzimología , Receptores de N-Metil-D-Aspartato/metabolismo , Proteínas SNARE/metabolismo , Animales , Corteza Cerebral/fisiología , Agonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores , Femenino , Glicina/farmacología , Masculino , Ratones , Proteína Quinasa 10 Activada por Mitógenos/metabolismo , Proteína Quinasa 9 Activada por Mitógenos/metabolismo , N-Metilaspartato/farmacología , Sinaptosomas/metabolismoRESUMEN
Studies in vitro have demonstrated that ß3-adrenergic receptors (ß3-ARs) regulate protein metabolism in skeletal muscle by promoting protein synthesis and inhibiting protein degradation. In this study, we evaluated whether activation of ß3-ARs by the selective agonist CL316,243 modifies the functional and structural properties of skeletal muscles of healthy mice. Daily injections of CL316,243 for 15 days resulted in a significant improvement in muscle force production, assessed by grip strength and weight tests, and an increased myofiber cross-sectional area, indicative of muscle hypertrophy. In addition, atomic force microscopy revealed a significant effect of CL316,243 on the transversal stiffness of isolated muscle fibers. Interestingly, the expression level of mammalian target of rapamycin (mTOR) downstream targets and neuronal nitric oxide synthase (NOS) was also found to be enhanced in tibialis anterior and soleus muscles of CL316,243 treated mice, in accordance with previous data linking ß3-ARs to mTOR and NOS signaling pathways. In conclusion, our data suggest that CL316,243 systemic administration might be a novel therapeutic strategy worthy of further investigations in conditions of muscle wasting and weakness associated with aging and muscular diseases.
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Agonistas de Receptores Adrenérgicos beta 3/farmacología , Dioxoles/farmacología , Fuerza Muscular/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Agonistas de Receptores Adrenérgicos beta 3/administración & dosificación , Animales , Dioxoles/administración & dosificación , Regulación de la Expresión Génica , Hipertrofia , Masculino , Ratones Endogámicos C57BL , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/patología , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Óxido Nítrico Sintasa de Tipo I/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
The parallel fiber-Purkinje cell (PF-PC) synapse represents the point of maximal signal divergence in the cerebellar cortex with an estimated number of about 60 billion synaptic contacts in the rat and 100,000 billions in humans. At the same time, the Purkinje cell dendritic tree is a site of remarkable convergence of more than 100,000 parallel fiber synapses. Parallel fiber activity generates fast postsynaptic currents via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and slower signals, mediated by mGlu1 receptors, resulting in Purkinje cell depolarization accompanied by sharp calcium elevation within dendritic regions. Long-term depression (LTD) and long-term potentiation (LTP) have been widely described for the PF-PC synapse and have been proposed as mechanisms for motor learning. The mechanisms of induction for LTP and LTD involve different signaling mechanisms within the presynaptic terminal and/or at the postsynaptic site, promoting enduring modification in the neurotransmitter release and change in responsiveness to the neurotransmitter. The PF-PC synapse is finely modulated by several neurotransmitters, including serotonin, noradrenaline and acetylcholine. The ability of these neuromodulators to gate LTP and LTD at the PF-PC synapse could, at least in part, explain their effect on cerebellar-dependent learning and memory paradigms. Overall, these findings have important implications for understanding the cerebellar involvement in a series of pathological conditions, ranging from ataxia to autism. For example, PF-PC synapse dysfunctions have been identified in several murine models of spino-cerebellar ataxia (SCA) types 1, 3, 5 and 27. In some cases, the defect is specific for the AMPA receptor signaling (SCA27), while in others the mGlu1 pathway is affected (SCA1, 3, 5). Interestingly, the PF-PC synapse has been shown to be hyper-functional in a mutant mouse model of autism spectrum disorder, with a selective deletion of Pten in Purkinje cells. However, the full range of methodological approaches, that allowed the discovery of the physiological principles of PF-PC synapse function, has not yet been completely exploited to investigate the pathophysiological mechanisms of diseases involving the cerebellum. We, therefore, propose to extend the spectrum of experimental investigations to tackle this problem.
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To examine how signals from different sensory modalities are integrated to generate an appropriate goal-oriented behavior, we trained rats in an eight-arm radial maze to visit a cue arm provided with intramaze cues from different sensory modalities, i.e. visual, tactile and auditory, in order to obtain a reward. When the same rats were then examined on test trials in which the cue arm contained one of the stimuli that the animals were trained with (i.e. light, sound or rough sheet), they showed a significant impairment with respect to the performance on the polymodal-cue task. The contribution of the dorsal hippocampus to the acquisition and retention of polymodal-cue guided task was also examined. We found that rats with dorsal hippocampal lesions before training showed a significant deficit in the acquisition of polymodal-cue oriented task that improved with overtraining. The selective lesion of the dorsal hippocampus after training disrupted memory retention, but the animals' performance improved following retraining of the polymodal task. All hippocampal lesioned rats displayed an impaired performance on the unimodal test. These findings suggest that the dorsal hippocampus contributes to the processing of multimodal sensory information for the associative memory formation and consolidation.
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Aprendizaje por Asociación/fisiología , Señales (Psicología) , Hipocampo/fisiología , Memoria/fisiología , Animales , Masculino , Aprendizaje por Laberinto/fisiología , Ratas , Ratas Long-Evans , RecompensaRESUMEN
L-cysteine is currently recognized as a conditionally essential sulphur amino acid. Besides contributing to many biological pathways, cysteine is a key component of the keratin protein by its ability to form disulfide bridges that confer strength and rigidity to the protein. In addition to cysteine, iron represents another critical factor in regulating keratins expression in epidermal tissues, as well as in hair follicle growth and maturation. By focusing on human keratinocytes, the aim of this study was to evaluate the effect of cysteine supplementation as nutraceutical on keratin biosynthesis, as well as to get an insight on the interplay of cysteine availability and cellular iron status in regulating keratins expression in vitro. Herein we demonstrate that cysteine promotes a significant up-regulation of keratins expression as a result of de novo protein synthesis, while the lack of iron impairs keratin expression. Interestingly, cysteine supplementation counteracts the adverse effect of iron deficiency on cellular keratin expression. This effect was likely mediated by the up-regulation of transferrin receptor and ferritin, the main cellular proteins involved in iron homeostasis, at last affecting the labile iron pool. In this manner, cysteine may also enhance the metabolic iron availability for DNA synthesis without creating a detrimental condition of iron overload. To the best of our knowledge, this is one of the first study in an in vitro keratinocyte model providing evidence that cysteine and iron cooperate for keratins expression, indicative of their central role in maintaining healthy epithelia.