Brett R. Schofield - US grants

The auditory system consists of ascending pathways that transmit information from the ear to the cortex, where sound is perceived, and descending pathways from the cortex that modulate the processing and flow of ascending information. The descending pathways play a role in a wide variety of functions, including selective attention, learning, frequency selectivity, sound localization, and discrimination of speech sounds. Much of the previous work on descending pathways has focused on projections from the brainstem to the cochlea. Characterization of the morphology, physiology and transmitter chemistry of the cells that project to the cochlea has led to major advances in our understanding of this olivocochlear system. Our understanding of the remaining descending pathways, some of which involve many more cells than the olivocochlear system, lags far behind. We propose to use combinations of sensitive new anatomical tracing techniques to examine the functional organization of some of the largest components of the descending auditory pathways. Our experiments are focused on the projections from the auditory cortex to the brainstem auditory nuclei. The importance of this pathway was highlighted by recent discoveries that the cortical projections are far more extensive than previously believed, extending as far as the cochlear nucleus, which is the site of entry of auditory information into the brain. One goal of our experiments is to identify the brainstem circuits that are contacted directly by descending projections from the cortex. A second goal is to identify the anatomical relationships between the cells that give rise to the descending projections and the functional organization of auditory cortex. The results should provide insights into the types of information being transmitted by the descending projections as well as the identity of the brainstem circuits that are affected by these projections. This information will provide in turn an anatomical basis for interpreting the results from other types of studies and, eventually, help us understand the role of the descending pathways in both the normal and the diseased or damaged brain.

DESCRIPTION (provided by applicant): The auditory system consists of ascending pathways that transmit information from the ear to the cortex, where sound is perceived, and descending pathways from the cortex that modulate the processing and flow of ascending information. The descending pathways play a role in a wide variety of functions, including selective attention, learning, frequency selectivity, sound localization, and discrimination of speech sounds. Recent work has shown close ties between the descending pathways and the brainstem cholinergic system. Acetylcholine has been implicated in many of the same auditory functions just listed as well as arousal and detection of novel stimuli. Understanding the various functions of the descending and cholinergic systems has been impeded by lack of information on the underlying neuronal circuitry. The present proposal will combine multi-labeling anatomical tracing techniques with multi-labeling immunohistochemistry to identify the components and synaptic organization of these circuits. The experiments will focus on the inferior colliculus, a part of the midbrain that is involved in pathways for auditory perception as well as numerous aspects of auditory-driven behavior. The results will provide a framework for interpreting physiological and behavioral experiments, and will provide essential data for designing more advanced experiments to examine both the functions of these pathways and to determine the underlying cellular mechanisms. PUBLIC HEALTH RELEVANCE: Descending auditory pathways and the pathways that use acetylcholine as a neurotransmitter play critical roles in functions such as selective attention and discrimination of sounds in a noisy environment. Understanding and improving these functions is an important goal in persons with hearing loss, cochlear implants or various disorders such as autism or schizophrenia. The present proposal will answer important questions about the circuitry that underlies these functions.

? DESCRIPTION (provided by applicant): Acetylcholine is a neurotransmitter that plays a role in many aspects of hearing, including selective attention, learning, frequency selectivity, sound localization, and discrimination of speech sounds. It also plays a critical role in helping the bran adapt during normal development, during aging and in response to damage of the ear or central nervous system. The long term goal of this research is to understand how cholinergic inputs to brainstem auditory circuits contribute to these tasks. Recent studies have identified 4 different cholinergic systems that innervate the brainstem auditory pathways. These cholinergic systems have different functions such as arousal, setting neuronal sensitivity, or controlling the flow of auditory information (e.g., to determine whether an acoustic stimulus is consciously perceived). A major obstacle to understand cholinergic functions in the brainstem has been lack of information about which cholinergic sources contact which auditory pathways. The objective of this proposal is to identify brainstem auditory circuits that are major targets of specific brainstm cholinergic projection systems. The experiments will use recently developed viral vectors and genetically-engineered (transgenic) rats to label cholinergic circuits from identified sources. These techniques will be combined with multi-labeling anatomical tracers and immunochemistry to identify the components and synaptic organization of specific auditory circuits targeted by the cholinergic systems. The Aims focus on two brainstem areas that show high levels of cholinergic innervation: the ventral cochlear nucleus (VCN) and the inferior colliculus (IC). Together, these 2 areas process nearly all auditory information and thus contribute to all aspects of auditory function. Aim 1 will focus on the VCN, a region that receives direct input from the ear and that gives rise to multiple pathways to higher centers. The experiments will identify cholinergic inputs to specific ascending pathways. Aims 2 and 3 will focus on the IC, the largest brainstem auditory center and a major hub for integration of auditory information. Aim 2 will identify specific cell types in the IC that are targeted by cholinergic inputs. Aim 3 will idetify the circuits within the IC that are likely to be modulated by the cholinergic inputs and that could control how auditory information is processed within this integrative center. Overall, results from the three Aims will move the field forward by providing essential information for designing and interpreting future experiments with optogenetics, physiology and behavior to better understand cholinergic roles in normal hearing, during development, learning and aging and after damage to the cochlea or central auditory system.