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1.
Nat Genet ; 55(9): 1462-1470, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37550530

RESUMO

Binge eating disorder (BED) is the most common eating disorder, yet its genetic architecture remains largely unknown. Studying BED is challenging because it is often comorbid with obesity, a common and highly polygenic trait, and it is underdiagnosed in biobank data sets. To address this limitation, we apply a supervised machine-learning approach (using 822 cases of individuals diagnosed with BED) to estimate the probability of each individual having BED based on electronic medical records from the Million Veteran Program. We perform a genome-wide association study of individuals of African (n = 77,574) and European (n = 285,138) ancestry while controlling for body mass index to identify three independent loci near the HFE, MCHR2 and LRP11 genes and suggest APOE as a risk gene for BED. We identify shared heritability between BED and several neuropsychiatric traits, and implicate iron metabolism in the pathophysiology of BED. Overall, our findings provide insights into the genetics underlying BED and suggest directions for future translational research.


Assuntos
Transtorno da Compulsão Alimentar , Humanos , Transtorno da Compulsão Alimentar/genética , Transtorno da Compulsão Alimentar/psicologia , Estudo de Associação Genômica Ampla , Obesidade/genética , Fenótipo , Ferro
2.
Clin Psychol Rev ; 65: 163-174, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30223161

RESUMO

Mirror exposure therapy is a clinical trial validated treatment component that improves body image and body satisfaction. Mirror exposure therapy has been shown to benefit individuals with high body dissatisfaction and patients with eating disorders (ED) in clinical trials. Mirror exposure is an optional component of cognitive behavioral therapy (CBT), an effective treatment for body dysmorphic disorder (BDD). However, most clinical trials of mirror exposure therapy have been small or uncontrolled and have included few male subjects. Adverse events have been reported during mirror exposure clinical trials. We discuss how individuals respond when looking in a mirror and how mirrors can be used therapeutically, and we critically evaluate the evidence in favor of mirror exposure therapy. We discuss clinical indications and technical considerations for the use of mirror exposure therapy.


Assuntos
Transtornos Dismórficos Corporais/terapia , Imagem Corporal , Transtornos da Alimentação e da Ingestão de Alimentos/terapia , Terapia Implosiva/métodos , Humanos
3.
PLoS One ; 12(9): e0184618, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28910338

RESUMO

Sensory cortical circuits are shaped by experience during sensitive periods in development. In the primary visual cortex (V1) altered visual experience results in changes in visual responsiveness of cortical neurons. The experience-dependent refinement of the circuit in V1 is thought to rely on competitive interactions between feedforward circuits driven by the two eyes. However, recent data have provided evidence for an additional role of cortico-cortical circuits in this process. Indeed, experience-dependent changes in intracortical circuits can be induced rapidly and may result in rapid-onset functional changes. Unilateral occlusion of vision rapidly alters visual responsiveness, synaptic strength and connectivity of local circuits in the binocular region of V1 (V1b), where the inputs from the two eyes converge. In the monocular region of rodent V1 (V1m), where feedforward inputs from the ipsilateral eye are virtually absent, visual deprivation induces rapid plasticity in local circuits; however, functional changes seem to occur only after long periods of deprivation. In V1m there is currently no evidence for functional changes occurring within a time window compatible with that of local circuit plasticity. Here, we probed the visual responsiveness of neurons in rat V1m and assessed the effect of one day unilateral eye lid suture on single neuron visual responses. We report a novel form of plasticity within V1m that occurs on a timescale consistent with the earliest known changes in synaptic strength. Our data provide new insights into how sensory experience can rapidly modulate neuronal responses, even in the absence of direct competition between feedforward thalamocortical inputs.


Assuntos
Potenciais Evocados Visuais , Neurônios/fisiologia , Visão Monocular/fisiologia , Córtex Visual/fisiologia , Potenciais de Ação , Animais , Feminino , Masculino , Plasticidade Neuronal , Estimulação Luminosa , Ratos
4.
Front Cell Neurosci ; 8: 91, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24723851

RESUMO

The mammalian neocortex is composed of a variety of cell types organized in a highly interconnected circuit. GABAergic neurons account for only about 20% of cortical neurons. However, they show widespread connectivity and a high degree of diversity in morphology, location, electrophysiological properties and gene expression. In addition, distinct populations of inhibitory neurons have different sensory response properties, capacities for plasticity and sensitivities to changes in sensory experience. In this review we summarize experimental evidence regarding the properties of GABAergic neurons in primary sensory cortex. We will discuss how distinct GABAergic neurons and different forms of GABAergic inhibitory plasticity may contribute to shaping sensory cortical circuit activity and function.

5.
PLoS Genet ; 9(3): e1003354, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23555279

RESUMO

The Nrf family of transcription factors plays a critical role in mediating adaptive responses to cellular stress and defends against neurodegeneration, aging, and cancer. Here, we report a novel role for the Caenorhabditis elegans Nrf homolog SKN-1 in regulating synaptic transmission at neuromuscular junctions (NMJs). Activation of SKN-1, either by acute pharmacological treatment with the mitochondrial toxin sodium arsenite or by mutations that cause constitutive SKN-1 activation, results in defects in neuromuscular function. Additionally, elimination of the conserved WD40 repeat protein WDR-23, a principal negative regulator of SKN-1, results in impaired locomotion and synaptic vesicle and neuropeptide release from cholinergic motor axons. Mutations that abolish skn-1 activity restore normal neuromuscular function to wdr-23 mutants and animals treated with toxin. We show that negative regulation of SKN-1 by WDR-23 in the intestine, but not at neuromuscular junctions, is necessary and sufficient for proper neuromuscular function. WDR-23 isoforms differentially localize to the outer membranes of mitochondria and to nuclei, and the effects of WDR-23 on neuromuscular function are dependent on its interaction with cullin E3 ubiquitin ligase. Finally, whole-transcriptome RNA sequencing of wdr-23 mutants reveals an increase in the expression of known SKN-1/Nrf2-regulated stress-response genes, as well as neurotransmission genes not previously implicated in SKN-1/Nrf2 responses. Together, our results indicate that SKN-1/Nrf2 activation may be a mechanism through which cellular stress, detected in one tissue, affects cellular function of a distal tissue through endocrine signaling. These results provide insight into how SKN-1/Nrf2 might protect the nervous system from damage in response to oxidative stress.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Proteínas de Ligação a DNA , Sistema Nervoso , Estresse Oxidativo/efeitos dos fármacos , Fatores de Transcrição , Animais , Arsenitos/farmacologia , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Núcleo Celular/genética , Núcleo Celular/metabolismo , Proteínas Culina , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Mutação , Sistema Nervoso/efeitos dos fármacos , Sistema Nervoso/metabolismo , Junção Neuromuscular/genética , Junção Neuromuscular/fisiologia , Compostos de Sódio/farmacologia , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
6.
Front Cell Neurosci ; 6: 65, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23316135

RESUMO

Neural circuits are refined in an experience-dependent manner during early postnatal development. How development modulates the spatio-temporal propagation of activity through cortical circuits is poorly understood. Here we use voltage-sensitive dye imaging (VSD) to show that there are significant changes in the spatio-temporal patterns of intracortical signals in primary visual cortex (V1) from postnatal day 13 (P13), eye opening, to P28, the peak of the critical period for rodent visual cortical plasticity. Upon direct stimulation of layer 4 (L4), activity spreads to L2/3 and to L5 at all ages. However, while from eye opening to the peak of the critical period, the amplitude and persistence of the voltage signal decrease, peak activation is reached more quickly and the interlaminar gain increases with age. The lateral spread of activation within layers remains unchanged throughout the time window under analysis. These developmental changes in spatio-temporal patterns of intracortical circuit activation are mediated by differences in the contributions of excitatory and inhibitory synaptic components. Our results demonstrate that after eye opening the circuit in V1 is refined through a progression of changes that shape the spatio-temporal patterns of circuit activation. Signals become more efficiently propagated across layers through developmentally regulated changes in interlaminar gain.

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