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1.
Cell ; 167(1): 73-86.e12, 2016 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-27662084

RESUMEN

Urine release (micturition) serves an essential physiological function as well as a critical role in social communication in many animals. Here, we show a combined effect of olfaction and social hierarchy on micturition patterns in adult male mice, confirming the existence of a micturition control center that integrates pro- and anti-micturition cues. Furthermore, we demonstrate that a cluster of neurons expressing corticotropin-releasing hormone (Crh) in the pontine micturition center (PMC) is electrophysiologically distinct from their Crh-negative neighbors and sends glutamatergic projections to the spinal cord. The activity of PMC Crh-expressing neurons correlates with and is sufficient to drive bladder contraction, and when silenced impairs micturition behavior. These neurons receive convergent input from widespread higher brain areas that are capable of carrying diverse pro- and anti-micturition signals, and whose activity modulates hierarchy-dependent micturition. Taken together, our results indicate that PMC Crh-expressing neurons are likely the integration center for context-dependent micturition behavior.


Asunto(s)
Hormona Liberadora de Corticotropina/metabolismo , Contracción Muscular/fisiología , Neuronas/fisiología , Puente/fisiología , Vejiga Urinaria/fisiología , Micción/fisiología , Animales , Femenino , Ácido Glutámico/fisiología , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Puente/citología , Olfato , Médula Espinal/citología , Médula Espinal/fisiología , Vejiga Urinaria/inervación
2.
Nat Methods ; 14(4): 388-390, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28218900

RESUMEN

High-resolution optical imaging is critical to understanding brain function. We demonstrate that three-photon microscopy at 1,300-nm excitation enables functional imaging of GCaMP6s-labeled neurons beyond the depth limit of two-photon microscopy. We record spontaneous activity from up to 150 neurons in the hippocampal stratum pyramidale at ∼1-mm depth within an intact mouse brain. Our method creates opportunities for noninvasive recording of neuronal activity with high spatial and temporal resolution deep within scattering brain tissues.


Asunto(s)
Encéfalo/citología , Microscopía de Fluorescencia por Excitación Multifotónica/métodos , Neuronas/fisiología , Animales , Encéfalo/fisiología , Calmodulina/análisis , Calmodulina/metabolismo , Proteínas Fluorescentes Verdes/análisis , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Hipocampo/citología , Hipocampo/fisiología , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas Recombinantes de Fusión/análisis , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes/análisis , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
3.
Neurol Clin ; 41(3): 469-483, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37407100

RESUMEN

Although the fundamental principle behind the Uniform Determination of Death Act (UDDA), the equivalence of death by circulatory-respiratory and neurologic criteria, is accepted throughout the United States and much of the world, some families object to brain death/death by neurologic criteria. Clinicians struggle to address these objections. Some objections have been brought to court, particularly in the United States, leading to inconsistent outcomes and discussion about potential modifications to the UDDA to minimize ethical and legal controversies related to the determination of brain death/death by neurologic criteria.


Asunto(s)
Muerte Encefálica , Humanos , Muerte Encefálica/diagnóstico , Muerte Encefálica/legislación & jurisprudencia , Estados Unidos
4.
Mol Neurodegener ; 17(1): 16, 2022 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-35197079

RESUMEN

BACKGROUND: Epidemiological studies suggest a link between the melanoma-related pigmentation gene melanocortin 1 receptor (MC1R) and risk of Parkinson's disease (PD). We previously showed that MC1R signaling can facilitate nigrostriatal dopaminergic neuron survival. The present study investigates the neuroprotective potential of MC1R against neurotoxicity induced by alpha-synuclein (αSyn), a key player in PD genetics and pathogenesis. METHODS: Nigral dopaminergic neuron toxicity induced by local overexpression of aSyn was assessed in mice that have an inactivating mutation of MC1R, overexpress its wild-type transgene, or were treated with MC1R agonists. The role of nuclear factor erythroid 2-related factor 2 (Nrf2) in MC1R-mediated protection against αSyn was characterized in vitro. Furthermore, MC1R expression was determined in human postmortem midbrain from patients with PD and unaffected subjects. RESULTS: Targeted expression of αSyn in the nigrostriatal pathway induced exacerbated synuclein pathologies in MC1R mutant mice, which were accompanied by neuroinflammation and altered Nrf2 responses, and reversed by the human MC1R transgene. Two MC1R agonists were neuroprotective against αSyn-induced dopaminergic neurotoxicity. In vitro experiments showed that Nrf2 was a necessary mediator of MC1R effects. Lastly, MC1R was present in dopaminergic neurons in the human substantia nigra and appeared to be reduced at the tissue level in PD patients. CONCLUSION: Our study supports an interaction between MC1R and αSyn that can be mediated by neuronal MC1R possibly through Nrf2. It provides evidence for MC1R as a therapeutic target and a rationale for development of MC1R-activating strategies for PD.


Asunto(s)
Enfermedad de Parkinson , Receptor de Melanocortina Tipo 1 , Animales , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/metabolismo , Humanos , Ratones , Enfermedad de Parkinson/metabolismo , Receptor de Melanocortina Tipo 1/metabolismo , alfa-Sinucleína/metabolismo
5.
Sci Rep ; 9(1): 8964, 2019 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-31221985

RESUMEN

Neuronal activity patterns are disrupted in neurodegenerative disorders, including Alzheimer's disease (AD). One example is disruption of corticothalamic slow oscillations responsible for sleep-dependent memory consolidation. Slow waves are periodic oscillations in neuronal activity occurring at frequencies of <1 Hz. The power, but not the frequency of slow oscillations is altered in a mouse model of AD. Optogenetic rescue of slow oscillations by increasing activity in cortical pyramidal neurons at the frequency of slow waves restores slow wave power, halts deposition of amyloid plaques and prevents neuronal calcium dysregulation. Here we determined whether driving this circuit at an increased rate would exacerbate the amyloid-dependent calcium dyshomeostasis in transgenic mice. Doubling the frequency of slow waves for one month with optogenetics resulted in increased amyloid beta - dependent disruptions in neuronal calcium homeostasis and loss of synaptic spines. Therefore, while restoration of physiological circuit dynamics is sufficient to abrogate the progression of Alzheimer's disease pathology and should be considered an avenue for clinical treatment of AD patients with sleep disorders, pathophysiological stimulation of neuronal circuits leads to activity - dependent acceleration of amyloid production, aggregation and downstream neuronal dysfunction.


Asunto(s)
Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/patología , Susceptibilidad a Enfermedades , Enfermedad de Alzheimer/metabolismo , Amiloide/genética , Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Calcio/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Procesamiento de Imagen Asistido por Computador , Ratones , Ratones Transgénicos , Microscopía de Fluorescencia por Excitación Multifotónica , Imagen Molecular , Neuronas/metabolismo , Neuronas/patología , Neurotransmisores/metabolismo , Placa Amiloide/etiología , Placa Amiloide/metabolismo , Placa Amiloide/patología , Transmisión Sináptica
6.
EBioMedicine ; 29: 13-22, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-29433982

RESUMEN

Alpha-synuclein (αSyn) is encoded by the first causal gene identified in Parkinson's disease (PD) and is the main component of Lewy bodies, a pathological hallmark of PD. aSyn-based animal models have contributed to our understanding of PD pathophysiology and to the development of therapeutics. Overexpression of human wildtype αSyn by viral vectors in rodents recapitulates the loss of dopaminergic neurons from the substantia nigra, another defining pathological feature of the disease. The development of a rat model exhibiting bimolecular fluorescence complementation (BiFC) of αSyn by recombinant adeno-associated virus facilitates detection of the toxic αSyn oligomers species. We report here neurochemical, neuropathological and behavioral characterization of BiFC of αSyn in mice. Overexpression and oligomerization of αSyn through BiFC is detected by conjugated fluorescence. Reduced striatal dopamine and loss of nigral dopaminergic neurons are accompanied neuroinflammation and abnormal motor activities. Our mouse model may provide a valuable tool to study the role of αSyn in PD and to explore therapeutic approaches.


Asunto(s)
Dopamina/metabolismo , Imagen Molecular , Multimerización de Proteína , alfa-Sinucleína/química , alfa-Sinucleína/metabolismo , Animales , Recuento de Células , Dependovirus/genética , Neuronas Dopaminérgicas/metabolismo , Femenino , Fluorescencia , Técnica del Anticuerpo Fluorescente , Expresión Génica , Orden Génico , Vectores Genéticos/genética , Gliosis/genética , Gliosis/metabolismo , Gliosis/patología , Humanos , Masculino , Ratones , Actividad Motora/genética , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/fisiopatología , Fenotipo , Sustancia Negra/metabolismo , Transducción Genética , alfa-Sinucleína/genética
7.
EBioMedicine ; 37: 259-268, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30415890

RESUMEN

BACKGROUND: Epidemiological, laboratory and clinical studies have established an association between elevated urate and high blood pressure (BP). However, the inference of causality remains controversial. A naturally occurring antioxidant, urate may also be neuroprotective, and urate-elevating treatment with its precursor inosine is currently under clinical development as a potential disease-modifying strategy for Parkinson's disease (PD). METHODS: Our study takes advantage of a recently completed phase II trial evaluating oral inosine in de novo non-disabling early PD with no major cardiovascular and nephrological conditions, and of three lines of genetically engineered mice: urate oxidase (UOx) global knockout (gKO), conditional KO (cKO), and transgenic (Tg) mice with markedly elevated, mildly elevated, and substantially reduced serum urate, respectively, to systematically investigate effects of urate-modifying manipulation on BP. FINDINGS: Among clinical trial participants, change in serum urate but not changes in systolic, diastolic and orthostatic BP differed by treatment group. There was no positive correlation between urate elevations and changes in systolic, diastolic and orthostatic BP ((p = .05 (in inverse direction), 0.30 and 0.63, respectively)). Between UOx gKO, cKO, or Tg mice and their respective wildtype littermates there were no significant differences in systolic or diastolic BP or in their responses to BP-regulating interventions. INTERPRETATION: Our complementary preclinical and human studies of urate modulation in animal models and in generally healthy early PD do not support a hypertensive effect of urate elevation or an association between urate and BP. FUND: U.S. Department of Defense, RJG Foundation, Michael J. Fox Foundation LEAPS program, National Institutes of Health, American Federation for Aging Research, Parkinson's Disease Foundation Advancing Parkinson's Therapies initiative.


Asunto(s)
Presión Sanguínea , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/fisiopatología , Ácido Úrico/sangre , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología
8.
Ann Clin Transl Neurol ; 4(3): 212-216, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28275654

RESUMEN

Several studies have been conducted with mixed results since our initial report of increased Parkinson's disease risk in individuals with red hair and/or red hair-associated p.R151C variant of the MC1R gene, both of which confer high melanoma risk. We performed a meta-analysis of six publications on red hair, MC1R, and Parkinson's disease. We found that red hair (pooled odds ratios = 1.68, 95% confidence intervals: 1.07, 2.64) and p.R151C (pooled odds ratios = 1.10, 95% confidence intervals: 1.00, 1.21), but not p.R160W, were associated with greater risk for Parkinson's disease. Our results support potential roles of pigmentation and its key regulator MC1R in the pathogenesis of Parkinson's disease.

9.
PLoS One ; 12(1): e0170275, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28114405

RESUMEN

Slow oscillations are important for consolidation of memory during sleep, and Alzheimer's disease (AD) patients experience memory disturbances. Thus, we examined slow oscillation activity in an animal model of AD. APP mice exhibit aberrant slow oscillation activity. Aberrant inhibitory activity within the cortical circuit was responsible for slow oscillation dysfunction, since topical application of GABA restored slow oscillations in APP mice. In addition, light activation of channelrhodopsin-2 (ChR2) expressed in excitatory cortical neurons restored slow oscillations by synchronizing neuronal activity. Driving slow oscillation activity with ChR2 halted amyloid plaque deposition and prevented calcium overload associated with this pathology. Thus, targeting slow oscillatory activity in AD patients might prevent neurodegenerative phenotypes and slow disease progression.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Amiloide/metabolismo , Calcio/metabolismo , Modelos Animales de Enfermedad , Homeostasis , Optogenética , Enfermedad de Alzheimer/genética , Animales , Regulación hacia Abajo , Humanos , Ratones , Ratones Transgénicos , Ácido gamma-Aminobutírico/metabolismo
10.
Neuron ; 92(1): 84-92, 2016 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-27710792

RESUMEN

The striatum, the entry nucleus of the basal ganglia, lacks laminar or columnar organization of its principal cells; nevertheless, functional data suggest that it is spatially organized. Here we examine whether the connectivity and synaptic organization of striatal GABAergic interneurons contributes to such spatial organization. Focusing on the two main classes of striatal GABAergic interneurons (fast-spiking interneurons [FSIs] and low-threshold-spiking interneurons [LTSIs]), we apply a combination of optogenetics and viral tracing approaches to dissect striatal microcircuits in mice. Our results reveal fundamental differences between the synaptic organizations of both interneuron types. FSIs target exclusively striatal projection neurons (SPNs) within close proximity and form strong synapses on the proximal somatodendritic region. In contrast, LTSIs target both SPNs and cholinergic interneurons, and synaptic connections onto SPNs are made exclusively over long distances and onto distal dendrites. These results suggest fundamentally different functions of FSIs and LTSIs in shaping striatal output.


Asunto(s)
Cuerpo Estriado/citología , Neuronas GABAérgicas/fisiología , Interneuronas/fisiología , Sinapsis/fisiología , Animales , Ratones , Ratones Noqueados , Ratones Transgénicos , Vías Nerviosas/citología , Vías Nerviosas/fisiología , Técnicas de Trazados de Vías Neuroanatómicas , Receptor de Adenosina A2A/genética , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/genética
11.
Transl Neurodegener ; 4: 20, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26504519

RESUMEN

Epidemiological studies support a general inverse association between the risk of cancer development and Parkinson's disease (PD). In recent years however, increasing amount of eclectic evidence points to a positive association between PD and cancers through different temporal analyses and ethnic groups. This positive association has been supported by several common genetic mutations in SNCA, PARK2, PARK8, ATM, p53, PTEN, and MC1R resulting in cellular changes such as mitochondrial dysfunction, aberrant protein aggregation, and cell cycle dysregulation. Here, we review the epidemiological and biological advances of the past decade in the association between PD and cancers to offer insight on the recent and sometimes contradictory findings.

12.
PLoS One ; 9(11): e112802, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25426709

RESUMEN

Recombinant subunit vaccine engineering increasingly focuses on the development of more effective delivery platforms. However, current recombinant vaccines fail to sufficiently stimulate protective adaptive immunity against a wide range of pathogens while remaining a cost effective solution to global health challenges. Taking an unorthodox approach to this fundamental immunological challenge, we isolated the TLR-targeting capability of the probiotic E. coli Nissle 1917 bacteria (EcN) by engineering bionanoparticlate antigen carriers derived from EcN outer membrane vesicles (OMVs). Exogenous model antigens expressed by these modified bacteria as protein fusions with the bacterial enterotoxin ClyA resulted in their display on the surface of the carrier OMVs. Vaccination with the engineered EcN OMVs in a BALB/c mouse model, and subsequent mechanism of action analysis, established the EcN OMV's ability to induce self-adjuvanted robust and protective humoral and T(H)1-biased cellular immunity to model antigens. This finding appears to be strain-dependent, as OMV antigen carriers similarly engineered from a standard K12 E. coli strain derivative failed to generate a comparably robust antigen-specific TH1 bias. The results demonstrate that unlike traditional subunit vaccines, these biomolecularly engineered "pathogen-like particles" derived from traditionally overlooked, naturally potent immunomodulators have the potential to effectively couple recombinant antigens with meaningful immunity in a broadly applicable fashion.


Asunto(s)
Anticuerpos Antibacterianos/biosíntesis , Antígenos Bacterianos/inmunología , Proteínas de la Membrana Bacteriana Externa/inmunología , Vacunas Bacterianas/inmunología , Escherichia coli/inmunología , Células TH1/inmunología , Animales , Antígenos Bacterianos/administración & dosificación , Antígenos Bacterianos/genética , Proteínas de la Membrana Bacteriana Externa/administración & dosificación , Proteínas de la Membrana Bacteriana Externa/genética , Vacunas Bacterianas/administración & dosificación , Vacunas Bacterianas/genética , Membrana Celular/química , Membrana Celular/inmunología , Escherichia coli/química , Proteínas de Escherichia coli/administración & dosificación , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/inmunología , Femenino , Expresión Génica , Proteínas Hemolisinas/administración & dosificación , Proteínas Hemolisinas/genética , Proteínas Hemolisinas/inmunología , Inmunidad Celular/efectos de los fármacos , Inmunidad Humoral/efectos de los fármacos , Inmunización , Ratones , Ratones Endogámicos BALB C , Probióticos/química , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Especificidad de la Especie , Células TH1/citología , Vacunas de Subunidad , Vacunas Sintéticas
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