The central hypothesis of our proposed work is that neuronal microcircuit functions are dependent upon the localized concentrations of neurotransmitters or neuromodulators in which the microcircuit is embedded. Cortex neural microcircuit function depends on the specific extracellular signaling molecules which permeate the microcircuit. The function of a microcircuit is defined as the transformation of afferent synaptic input into spiking output. Changes in concentration of neuromodulators, such as acetylcholine (ACh), are known to affect changes in the intrinsic properties of individual neurons and interactions among groups of interconnected neurons. We propose to test our hypothesis by developing a novel, implantable device comprised of multiple microdialysis (D) probes and a microelectrode array (MEA). The D probes will be used to precisely control and measure the ACh concentration profile in a local area (~2 mm) where the MEA is recording electrical neural activity (spikes and local field potential). As an initial proof of principle, we will implant the device in rat barrel cortex and measure response to repeated stimulation of whiskers. Experiments aimed toward identifying the potential role implant damage may play with respect to data interpretation are proposed. Integrating these techniques, the central hypothesis will be tested by pursuing two separate aims. Aim 1 seeks to delineate changes in neural action potentials to a repeated whisker stimulus due to changes in local acetylcholine concentration gradient in anesthetized rats. Aim 2 focuses on measuring changes in awake, behaving cortex function due to changes in local acetylcholine concentration gradient. Successful completion of these studies will result in definite short-term advances and open new opportunities for long-term progress towards understanding neural microcircuit dysfunction in Alzheimer's disease. Additional benefits can be envisioned in other neurodegenerative diseases controlled by other neurotransmitters such as dopamine (Parkinson's) and norepinephrine. Two significant short-term advances are 1) new technological tools for integrated study of multi-site chemical and electrical properties of cortex microcircuits, and 2) new fundamental understanding of how changes in local concentration of neuromodulators may control cortical function/dysfunction. Another practical benefit of our work is likely to be a new quantitative explanation for the trial-o-trial variability often observed in studies of sensory cortex function. These advances will open new avenues of research with greater control of the molecular content of the extracellular space.