Neural circuitry for state-dependent control of cortical auditory processing and perception

? DESCRIPTION (provided by applicant): Behavioral engagement improves perception and learning by managing the limited capacity of the nervous system to process information. Multiple brain regions contribute to controlling behavioral states, in particular frontal cortical structure that play major roles in preparatory engagement. However, the key circuit mechanisms by which specific frontal cortical regions allocate the processing resources of the brain to prospective sensory stimuli remain largely unknown. Consequently, multiple disorders with an attention deficit, such as schizophrenia, autism and ADHD remain poorly understood and treated. My long-term career goal is to understand the neuronal circuit mechanisms by which the frontal cortex communicates with sensory and neuromodulatory systems to facilitate stimulus processing and to improve behavior, and use this information to guide development of novel treatments. The immediate goal of this proposal is to define neuronal network interactions during preparatory set and to establish causal links with performance. My central hypothesis is that direct and indirect circuits cooperatively control auditory perception by competing mechanisms: direct connections increase evoked responses in AC whereas indirect circuits via LC suppress spontaneous and evoked spiking in AC. To accomplish the proposed aims, I will use a combination of powerful neurophysiological and optogenetic techniques in behaving rats. I have recently shown that plastic changes in sound representation in the auditory cortex can improve perceptual performance. I then found that preparatory set dynamically modulates evoked and spontaneous firing in the auditory cortex in order to control behavior. To determine the circuit mechanism by which preparation controls stimulus representation and performance, I recorded in behaving rats single unit activity in the medial agranular frontal cortex (maFC), a brain structure directly and indirectly connected to the auditory cortex. I identified a physiologial marker for preparatory set in maFC. For the mentored part of this award (two additional years of postdoctoral studies) I will extend this work by analyzing the role of direct projections from maFC to the auditory cortex in sensory processing and perceptual performance (Aim 1). During the independent phase (three years) I will investigate synaptic mechanisms and behavioral function of indirect connections between maFC and the auditory cortex, with a focus on noradrenergic neuromodulation (Aim 2). For this, I will learn complex optogenetic and recording techniques in the Froemke and Buszáki labs at the NYU School of Medicine, an outstanding research environment that provides all the equipment and facilities needed for the proposed aims. Dr. Dayu Lin, also at NYU, will act as a consultant. I have assembled a strong advisory committee that will oversee my progress and provide intellectual and technical input during the award period and beyond. My training plan will enable me to carry out the proposed research and to acquire the skill set and the general knowledge required for my independent career. I am confident that my studies will impart a thorough understanding of circuit interactions regulating behavioral engagement and will enable me to contribute to the development of superior treatments for psychiatric disorders.