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Agency: Narcis | Branch: Project | Program: Completed | Phase: Physics, Chemistry and Medicine | Award Amount: | Year: 2002

To avoid being overwhelmed by a cacophony of information and sensory input, the brain relies on mechanisms of selective attention that direct our actions toward a small number of tasks at any time. Recent advances in functional imaging studies of human brain have shown that selective attention results from connectivity and synchronization of activity of different cortical and subcortical brain areas. These brain areas consist of vast networks of billions of neurons that are interconnected through synapses. A crucially important disparity in neuroscience is how events that occur at the level of neurons and synaptic contacts relate to processes that govern higher cognitive faculties of the brain, such as selective attention. This project is aimed at significantly narrowing this gap. The central aim of the research proposed is to understand how cellular and synaptic mechanisms give rise to coherent oscillations and synchronization of activity of brain circuits involved in selective attention. A very important brain area in selective attention is the prefrontal cortex (PFC). During normal attention processing the responsiveness of the PFC is modulated by a dopaminergic input from the VTA and a cholinergic input from the basal nucleus of Meynert. In chronic disorders in humans that are associated with severe attention deficits, such as ADHD and schizophrenia, dopaminergic and cholinergic inputs to the PFC are impaired. The main hypothesis of the proposed research is that activation of dopaminergic and cholinergic projections to the PFC alter the cortical network properties in such a way that synchronization of neuronal activity is enhanced. A combination of modern electrophysiological and functional imaging techniques will be used in the PFC in living brain slices of mice. Two-photon laser scanning microscopy and high-speed photodiode array monitoring of living brain slices will be applied, as well as the simultaneous recording from multiple neurons, to address the following questions and hypotheses. Question 1: What is the effect of DA and ACh on neuronal synchronization and oscillations in the PFC? Hypothesis: DA and ACh will increase the extent to which gamma-frequency oscillations in the PFC occur and neuronal activity is synchronized. Question 2: What are the effects of the activation of the DA projection from the VTA on calcium dynamics and activity in dendritic compartments of neurons in the PFC? Hypothesis: DA enhances dendritic and dendritic spine calcium (Ca) oscillations and gamma-frequency membrane potential oscillations by differential effects on ionic channels, receptors and fast synaptic transmission. Question 3: What are the effects of the activation of the cholinergic projections from the basal nucleus of Meynert on neuronal activity and the synaptic connections in the PFC network? Hypothesis: Nicotinic and muscarinic receptors modulate Ca oscillations and gamma-frequency membrane potential oscillations by differentially affecting neuronal properties and synaptic transmission. Question 4: How is the prefrontal cortical neuronal network affected in transgenic mice with hyperactive attention deficits? Hypothesis: DA and ACh will not be able to induce or increase gamma-frequency oscillations and synchronized activity in the PFC, as a result of the absence or highly reduced fast excitatory glutamatergic and inhibitory GABAergic transmission. However, Ca and membrane potential oscillations are still present in individual neurons. Answering the questions and hypotheses addressed will gain insight into the neurophysiological basis of selective attention and the modulation of attention by dopaminergic and cholinergic systems in the brain. The results will contribute to unraveling the vast neuronal network that underlies all our cognitive faculties and provide insight into the underlying cellular and synaptic mechanisms. The group of Prof. Dr. Brussaard has ample experience in studying synapse physiology in neu

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