RESUMO
It is critical for survival to assign positive or negative valence to salient stimuli in a correct manner. Accordingly, harmful stimuli and internal states characterized by perturbed homeostasis are accompanied by discomfort, unease, and aversion. Aversive signaling causes extensive suffering during chronic diseases, including inflammatory conditions, cancer, and depression. Here, we investigated the role of melanocortin 4 receptors (MC4Rs) in aversive processing using genetically modified mice and a behavioral test in which mice avoid an environment that they have learned to associate with aversive stimuli. In normal mice, robust aversions were induced by systemic inflammation, nausea, pain, and κ opioid receptor-induced dysphoria. In sharp contrast, mice lacking MC4Rs displayed preference or indifference toward the aversive stimuli. The unusual flip from aversion to reward in mice lacking MC4Rs was dopamine dependent and associated with a change from decreased to increased activity of the dopamine system. The responses to aversive stimuli were normalized when MC4Rs were reexpressed on dopamine D1 receptor-expressing cells or in the striatum of mice otherwise lacking MC4Rs. Furthermore, activation of arcuate nucleus proopiomelanocortin neurons projecting to the ventral striatum increased the activity of striatal neurons in an MC4R-dependent manner and elicited aversion. Our findings demonstrate that melanocortin signaling through striatal MC4Rs is critical for assigning negative motivational valence to harmful stimuli.
Assuntos
Corpo Estriado/fisiologia , Motivação/fisiologia , Receptor Tipo 4 de Melanocortina/fisiologia , Animais , Aprendizagem da Esquiva/fisiologia , Comportamento Animal/fisiologia , Benzazepinas/administração & dosagem , Corpo Estriado/efeitos dos fármacos , Dopamina/fisiologia , Antagonistas de Dopamina/administração & dosagem , Feminino , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Pró-Opiomelanocortina/fisiologia , Receptor Tipo 4 de Melanocortina/deficiência , Receptor Tipo 4 de Melanocortina/genética , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/fisiologia , RecompensaRESUMO
Alzheimer's disease (AD) is the major cause of dementia. During the development of AD, neurofibrillary tangles progress in a fixed pattern, starting in the transentorhinal cortex followed by the hippocampus and cortical areas. In contrast, the deposition of ß-amyloid (Aß) plaques, which are the other histological hallmark of AD, does not follow the same strict spatiotemporal pattern, and it correlates poorly with cognitive decline. Instead, soluble Aß oligomers have received increasing attention as probable inducers of pathogenesis. In this study, we use microinjections into electrophysiologically defined primary hippocampal rat neurons to demonstrate the direct neuron-to-neuron transfer of soluble oligomeric Aß. Additional studies conducted in a human donor-acceptor cell model show that this Aß transfer depends on direct cellular connections. As the transferred oligomers accumulate, acceptor cells gradually show beading of tubulin, a sign of neurite damage, and gradual endosomal leakage, a sign of cytotoxicity. These observations support that intracellular Aß oligomers play a role in neurodegeneration, and they explain the manner in which Aß can drive disease progression, even if the extracellular plaque load is poorly correlated with the degree of cognitive decline. Understanding this phenomenon sheds light on the pathophysiological mechanism of AD progression. Additional elucidation will help uncover the detailed mechanisms responsible for the manner in which AD progresses via anatomical connections and will facilitate the development of new strategies for stopping the progression of this incapacitating disease.