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1.
Neuroimage ; 257: 119287, 2022 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-35594811

RESUMO

Normal aging is associated with a variety of neurologic changes including declines in cognition, memory, and motor activity. These declines correlate with neuronal changes in synaptic structure and function. Degradation of brain network activity and connectivity represents a likely mediator of age-related functional deterioration resulting from these neuronal changes. Human studies have demonstrated both general decreases in spontaneous cortical activity and disruption of cortical networks with aging. Current techniques used to study cerebral network activity are hampered either by limited spatial resolution (e.g. electroencephalography, EEG) or limited temporal resolution (e.g., functional magnetic resonance imaging, fMRI). Here we utilize mesoscale imaging of neuronal activity in Thy1-GCaMP6f mice to characterize neuronal network changes in aging with high spatial resolution across a wide frequency range. We show that while evoked activity is unchanged with aging, spontaneous neuronal activity decreases across a wide frequency range (0.01-4 Hz) involving all regions of the cortex. In contrast to this global reduction in cortical power, we found that aging is associated with functional connectivity (FC) deterioration of select networks including somatomotor, cingulate, and retrosplenial nodes. These changes are corroborated by reductions in homotopic FC and node degree within somatomotor and visual cortices. Finally, we found that whole-cortex delta power and delta band node degree correlate with exploratory activity in young but not aged animals. Together these data suggest that aging is associated with global declines in spontaneous cortical activity and focal deterioration of network connectivity, and that these reductions may be associated with age-related behavioral declines.


Assuntos
Envelhecimento , Eletroencefalografia , Idoso , Envelhecimento/fisiologia , Animais , Mapeamento Encefálico , Cognição , Humanos , Imageamento por Ressonância Magnética/métodos , Camundongos
2.
Neurohospitalist ; 8(4): 194-198, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30245771

RESUMO

Here we report the challenging case of a 41-year-old man with HIV complicated by AIDS and a history of prior neurologic injury from progressive multifocal leukoencephalopathy who presented with headache, fevers, lower extremity weakness, hyperreflexic upper extremities, and diminished lower extremity reflexes. We review the clinical decision-making and differential diagnosis for this presentation as the physical examination evolved and diagnostic testing changed over time.

4.
Front Cell Neurosci ; 11: 109, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28469560

RESUMO

Cortical malformations are often associated with pharmaco-resistant epilepsy. Alterations in hyperpolarization-activated, cyclic nucleotide-gated, non-specific cation (HCN) channels have been shown to contribute to malformation associated hyperexcitability. We have recently demonstrated that expression of HCN channels and Ih current amplitudes are reduced in layer (L) 5 pyramidal neurons of rats with freeze lesion induced malformations. These changes were associated with an increased EPSP temporal summation. Here, we examine the effects of HCN channel inhibition on synaptic responses in fast spiking, presumptive basket cells and accommodating, presumptive Martinotti, GABAergic interneurons in slices from freeze lesioned animals. In control animals, fast spiking cells showed small sag responses which were reduced by the HCN channel antagonist ZD7288. Fast spiking cells in lesioned animals showed absent or reduced sag responses. The amplitude of single evoked EPSPs in fast spiking cells in the control group was not affected by HCN channel inhibition with ZD7288. EPSP ratios during short stimulus trains at 25 Hz were not significantly different between control and lesion groups. ZD7288 produced an increase in EPSP ratios in the control but not lesion groups. Under voltage clamp conditions, ZD7288 did not affect EPSC ratios. In the control group, accommodating interneurons showed robust sag responses which were significantly reduced by ZD7288. HCN channel inhibition increased EPSP ratios and area in controls but not the lesioned group. The results indicate that HCN channels differentially modulate EPSPs in different classes of GABAergic interneurons and that this control is reduced in malformed rat neocortex.

5.
J Neurophysiol ; 110(8): 1733-43, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23864381

RESUMO

Hyperpolarization-activated, cyclic nucleotide-gated, nonspecific cation (HCN) channels have a well-characterized role in regulation of cellular excitability and network activity. The role of these channels in control of epileptiform discharges is less thoroughly understood. This is especially pertinent given the altered HCN channel expression in epilepsy. We hypothesized that inhibition of HCN channels would enhance bicuculline-induced epileptiform discharges. Whole cell recordings were obtained from layer (L)2/3 and L5 pyramidal neurons and L1 and L5 GABAergic interneurons. In the presence of bicuculline (10 µM), HCN channel inhibition with ZD 7288 (20 µM) significantly increased the magnitude (defined as area) of evoked epileptiform events in both L2/3 and L5 neurons. We recorded activity associated with epileptiform discharges in L1 and L5 interneurons to test the hypothesis that HCN channels regulate excitatory synaptic inputs differently in interneurons versus pyramidal neurons. HCN channel inhibition increased the magnitude of epileptiform events in both L1 and L5 interneurons. The increased magnitude of epileptiform events in both pyramidal cells and interneurons was due to an increase in network activity, since holding cells at depolarized potentials under voltage-clamp conditions to minimize HCN channel opening did not prevent enhancement in the presence of ZD 7288. In neurons recorded with ZD 7288-containing pipettes, bath application of the noninactivating inward cationic current (Ih) antagonist still produced increases in epileptiform responses. These results show that epileptiform discharges in disinhibited rat neocortex are modulated by HCN channels.


Assuntos
Potenciais de Ação , Canais de Cátion Regulados por Nucleotídeos Cíclicos/fisiologia , Epilepsia/fisiopatologia , Neocórtex/fisiopatologia , Animais , Bicuculina/farmacologia , Convulsivantes/farmacologia , Canais de Cátion Regulados por Nucleotídeos Cíclicos/antagonistas & inibidores , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/fisiologia , Interneurônios/efeitos dos fármacos , Interneurônios/fisiologia , Potenciais da Membrana , Neocórtex/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Pirimidinas/farmacologia , Ratos , Transmissão Sináptica
6.
J Neurophysiol ; 106(5): 2189-200, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21795624

RESUMO

Focal cortical dysplasia is associated with the development of seizures in children and is present in up to 40% of intractable childhood epilepsies. Transcortical freeze lesions in newborn rats reproduce many of the anatomical and physiological characteristics of human cortical dysplasia. Rats with freeze lesions have increased seizure susceptibility and a region of hyperexcitable cortex adjacent to the lesion. Since alterations in hyperpolarization-activated nonspecific cation (HCN) channels are often associated with epilepsy, we used whole cell patch-clamp recording and voltage-sensitive dye imaging to examine alterations in HCN channels and inwardly rectifying hyperpolarization-activated currents (I(h)) in cortical dysplasia. (L5) pyramidal neurons in lesioned animals had hyperpolarized resting membrane potentials, increased input resistances and reduced voltage "sag" associated with I(h) activation. These differences became nonsignificant after application of the I(h) blocker ZD7288. Temporal excitatory postsynaptic potential (EPSP) summation and intrinsic excitability were increased in neurons near the freeze lesion. Using voltage-sensitive dye imaging of neocortical slices, we found that inhibiting I(h) with ZD7288 increased the half-width of dye signals. The anticonvulsant lamotrigine produced a significant decrease in spread of activity. The ability of lamotrigine to decrease network activity was reduced in the hyperexcitable cortex near the freeze lesion. These results suggest that I(h) serves to constrain network activity in addition to its role in regulating cellular excitability. Reduced I(h) may contribute to increased network excitability in cortical dysplasia.


Assuntos
Córtex Cerebral/fisiopatologia , Malformações do Desenvolvimento Cortical/fisiopatologia , Células Piramidais/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Animais Recém-Nascidos , Anticonvulsivantes/farmacologia , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Canais de Cátion Regulados por Nucleotídeos Cíclicos/antagonistas & inibidores , Canais de Cátion Regulados por Nucleotídeos Cíclicos/fisiologia , Epilepsia/tratamento farmacológico , Epilepsia/patologia , Epilepsia/fisiopatologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização , Lamotrigina , Malformações do Desenvolvimento Cortical/tratamento farmacológico , Malformações do Desenvolvimento Cortical/patologia , Técnicas de Cultura de Órgãos , Técnicas de Patch-Clamp , Canais de Potássio/fisiologia , Células Piramidais/efeitos dos fármacos , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Triazinas/farmacologia , Imagens com Corantes Sensíveis à Voltagem/métodos
7.
Menopause ; 16(5): 1030-6, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19512948

RESUMO

OBJECTIVE: Menopausal hot flashes compromise the quality of life for most women. The physiological mechanisms underlying hot flashes remain poorly understood, and the absence of an animal model to investigate hot flashes hinders investigations in this field. METHODS: We first developed the sheep as a model to study peripheral skin temperature changes using fever-inducing lipopolysaccharide (LPS; 200 microg/kg) administered to ovary-intact ewes. Because a strong correlation between luteinizing hormone pulses and hot flashes has previously been reported, we then determined whether intravenous gonadotropin-releasing hormone (GnRH; 1 mg), a dose sufficient to elevate cerebrospinal fluid-GnRH concentrations, could modulate ear skin temperature in both ovariectomized and low-estrogen-replaced ovariectomized ewes. RESULTS: Some ewes responded to LPS in heart rate and abdominal temperature, but there was no significant effect on either parameter or cheek temperature for the group. In contrast, LPS injection caused a significant (P < 0.001) change in skin temperature at the ear. Ear temperature showed no significant change in response to GnRH relative to control injections in both ovariectomized and low estrogen ewes. CONCLUSIONS: We developed a model animal system in the ewe that can accurately detect small changes in peripheral skin temperature. This system has the potential to be extremely useful in future studies investigating the pathology of hot flashes and holds several advantages over previous model systems developed for this research. GnRH per se does not seem to be involved in thermoregulatory events.


Assuntos
Modelos Animais de Doenças , Hormônio Liberador de Gonadotropina/fisiologia , Hormônio Liberador de Gonadotropina/uso terapêutico , Fogachos , Menopausa , Análise de Variância , Animais , Regulação da Temperatura Corporal/efeitos dos fármacos , Regulação da Temperatura Corporal/fisiologia , Causalidade , Bochecha , Estudos Cross-Over , Avaliação Pré-Clínica de Medicamentos , Orelha , Feminino , Febre/microbiologia , Febre/fisiopatologia , Hormônio Liberador de Gonadotropina/líquido cefalorraquidiano , Frequência Cardíaca , Fogachos/tratamento farmacológico , Fogachos/etiologia , Fogachos/fisiopatologia , Humanos , Injeções Intravenosas , Lipopolissacarídeos/efeitos adversos , Hormônio Luteinizante/efeitos dos fármacos , Hormônio Luteinizante/fisiologia , Menopausa/efeitos dos fármacos , Menopausa/fisiologia , Ovariectomia , Ovinos , Temperatura Cutânea/fisiologia
8.
Neurobiol Dis ; 35(2): 219-33, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19442733

RESUMO

Rett syndrome (RTT) is an X chromosome-linked neurodevelopmental disorder associated with the characteristic neuropathology of dendritic spines common in diseases presenting with mental retardation (MR). Here, we present the first quantitative analyses of dendritic spine density in postmortem brain tissue from female RTT individuals, which revealed that hippocampal CA1 pyramidal neurons have lower spine density than age-matched non-MR female control individuals. The majority of RTT individuals carry mutations in MECP2, the gene coding for a methylated DNA-binding transcriptional regulator. While altered synaptic transmission and plasticity has been demonstrated in Mecp2-deficient mouse models of RTT, observations regarding dendritic spine density and morphology have produced varied results. We investigated the consequences of MeCP2 dysfunction on dendritic spine structure by overexpressing ( approximately twofold) MeCP2-GFP constructs encoding either the wildtype (WT) protein, or missense mutations commonly found in RTT individuals. Pyramidal neurons within hippocampal slice cultures transfected with either WT or mutant MECP2 (either R106W or T158M) showed a significant reduction in total spine density after 48 h of expression. Interestingly, spine density in neurons expressing WT MECP2 for 96 h was comparable to that in control neurons, while neurons expressing mutant MECP2 continued to have lower spine density than controls after 96 h of expression. Knockdown of endogenous Mecp2 with a specific small hairpin interference RNA (shRNA) also reduced dendritic spine density, but only after 96 h of expression. On the other hand, the consequences of manipulating MeCP2 levels for dendritic complexity in CA3 pyramidal neurons were only minor. Together, these results demonstrate reduced dendritic spine density in hippocampal pyramidal neurons from RTT patients, a distinct dendritic phenotype also found in neurons expressing RTT-associated MECP2 mutations or after shRNA-mediated endogenous Mecp2 knockdown, suggesting that this phenotype represent a cell-autonomous consequence of MeCP2 dysfunction.


Assuntos
Espinhas Dendríticas/patologia , Hipocampo/patologia , Proteína 2 de Ligação a Metil-CpG/metabolismo , Células Piramidais/patologia , Síndrome de Rett/patologia , Adolescente , Adulto , Animais , Criança , Pré-Escolar , Espinhas Dendríticas/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Técnicas de Transferência de Genes , Hipocampo/citologia , Hipocampo/metabolismo , Humanos , Técnicas In Vitro , Proteína 2 de Ligação a Metil-CpG/genética , Mutação , Células Piramidais/citologia , Células Piramidais/metabolismo , Ratos , Ratos Sprague-Dawley , Adulto Jovem
9.
Cerebellum ; 7(3): 379-84, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18592335

RESUMO

Gonadotropin-releasing hormone (GnRH) is a decapeptide hypothalamic hormone that was named according to its first discovered function--at the head of the neuroendocrine reproductive axis. Numerous other organ systems express GnRH and/or its receptor, although a specific physiological role for GnRH outside of the reproductive axis has yet to be established. Several studies in lower vertebrates have reported GnRH and/or its receptor in the cerebellum. Here, we describe the presence of immunoreactive GnRH receptors in the Purkinje cells of the mammalian cerebellum for the first time. This study provides compelling anatomical evidence for a common link between the cerebellum and the hypothalamo-pituitary axis. Dysfunction of this link occurs in the rare genetic ataxia disorders--Gordon Holmes syndrome and Boucher-Neuhauser syndrome.


Assuntos
Ataxia Cerebelar/genética , Cerebelo/fisiologia , Hormônio Liberador de Gonadotropina/genética , Precursores de Proteínas/genética , Células de Purkinje/fisiologia , Animais , Ataxia Cerebelar/patologia , Cerebelo/citologia , Regulação da Expressão Gênica , Hormônio Liberador de Gonadotropina/deficiência , Hormônio Liberador de Gonadotropina/fisiologia , Sistema Hipotálamo-Hipofisário/fisiologia , Masculino , Camundongos , Microscopia Confocal , Hipófise/citologia , Hipófise/patologia , Hipófise/fisiologia , Precursores de Proteínas/deficiência , Precursores de Proteínas/fisiologia , Células de Purkinje/citologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
10.
J Chem Neuroanat ; 35(4): 326-33, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18439800

RESUMO

Gonadotropin Releasing Hormone-I (GnRH) has been implicated in an array of functions outside the neuroendocrine reproductive axis. Previous investigations have reported extensive GnRH binding in numerous sites and this has been supported by in situ hybridization studies reporting GnRH receptor mRNA distribution. The present study on mice and sheep supports and extends these earlier investigations by revealing the distribution of cells immunoreactive for the GnRH receptor. In addition to sites previously shown to express GnRH receptors such as the hippocampus, amygdala and the arcuate nucleus, the improved resolution afforded by immunocytochemistry detected cells in the mitral cell lay of the olfactory bulb as well as the central grey of the mesencephalon. In addition, GnRH receptor immunoreactive neurons in the hippocampus and mesencephalon of the sheep were shown to colocalize with estrogen receptor beta. Although GnRH may act at some of these sites to regulate reproductive processes, evidence is accumulating to support an extra-reproductive role for this hypothalamic decapeptide.


Assuntos
Encéfalo/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Neurônios/metabolismo , Receptores LHRH/metabolismo , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/metabolismo , Animais , Encéfalo/citologia , Mapeamento Encefálico , Células CHO , Bovinos , Cricetinae , Cricetulus , Receptor beta de Estrogênio/metabolismo , Hipocampo/citologia , Hipocampo/metabolismo , Imuno-Histoquímica , Masculino , Camundongos , Neurônios/citologia , Substância Cinzenta Periaquedutal/citologia , Substância Cinzenta Periaquedutal/metabolismo , Ovinos , Especificidade da Espécie
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