RESUMEN
Neuronal network dysfunction is a hallmark of Alzheimer's disease (AD). However, the underlying pathomechanisms remain unknown. We analyzed the hippocampal micronetwork in transgenic McGill-R-Thy1-APP rats (APPtg) at the beginning of extracellular amyloid beta (Aß) deposition. We established two-photon Ca2+ -imaging in vivo in the hippocampus of rats and found hyperactivity of CA1 neurons. Patch-clamp recordings in brain slices in vitro revealed increased neuronal input resistance and prolonged action potential width in CA1 pyramidal neurons. We did neither observe changes in synaptic inhibition, nor in excitation. Our data support the view that increased intrinsic excitability of CA1 neurons may precede inhibitory dysfunction at an early stage of Aß-deposition and disease progression.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Modelos Animales de Enfermedad , Potenciales Postsinápticos Excitadores/fisiología , Hipocampo/metabolismo , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Femenino , Hipocampo/patología , Masculino , Técnicas de Cultivo de Órganos , Ratas , Ratas TransgénicasRESUMEN
Behavioral response conflict arises in the color-word Stroop task and triggers the cognitive control network. Midfrontal theta-band oscillations correlate with adaptive control mechanisms during and after conflict resolution. In order to prove causality, in two experiments, we applied transcranial alternating current stimulation (tACS) at 6 Hz to the dorsolateral prefrontal cortex (DLPFC) during Stroop task performance. Sham stimulation served as a control in both experiments; 9.7 Hz tACS served as a nonharmonic alpha band control in the second experiment. We employed generalized linear mixed models for analysis of behavioral data. Accuracy remained unchanged by any type of active stimulation. Over both experiments, the Stroop effect (response time difference between congruent and incongruent trials) was reduced by 6 Hz stimulation as compared to sham, mainly in trials without prior conflict adaptation. Alpha tACS did not modify the Stroop effect. Theta tACS can both reduce the Stroop effect and modulate adaptive mechanisms of the cognitive control network, suggesting midfrontal theta oscillations as causally involved in cognitive control.
Asunto(s)
Conflicto Psicológico , Corteza Prefrontal/fisiología , Test de Stroop , Ritmo Teta/fisiología , Estimulación Transcraneal de Corriente Directa/métodos , Adulto , Método Doble Ciego , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
Dendritic structure critically determines the electrical properties of neurons and, thereby, defines the fundamental process of input-to-output conversion. The diversity of dendritic architectures enables neurons to fulfill their specialized circuit functions during cognitive processes. It is known that this dendritic integrity is impaired in patients with Alzheimer's disease and in relevant mouse models. It is unknown, however, whether this structural degeneration translates into aberrant neuronal function. Here we use in vivo whole-cell patch-clamp recordings, high-resolution STED imaging, and computational modeling of CA1 pyramidal neurons in a mouse model of Alzheimer's disease to show that structural degeneration and neuronal hyperexcitability are crucially linked. Our results demonstrate that a structure-dependent amplification of synaptic input to action potential output conversion might constitute a novel cellular pathomechanism underlying network dysfunction with potential relevance for other neurodegenerative diseases with abnormal changes of dendritic morphology.