Michael Thomas Roberts - US grants

Abstract The inferior colliculus (IC) is the hub of the central auditory system. Located in the midbrain, the IC receives most of the ascending output of the auditory brainstem and provides the major auditory input to the thalamocortical system. Despite this central role in auditory processing, surprisingly little is known about the identity and function of the neurons and neural circuits that make up the IC. This is largely because the diverse properties of IC neurons have made it difficult to identify neuron types using conventional anatomical and physiological approaches. This represents a critical gap in knowledge because an understanding of the key neuronal players in the IC is essential for determining how computations in IC circuits support hearing. In other brain regions, molecular genetic approaches have proven critical for identifying neuron types and probing the function of neural circuits. Following a molecular genetic approach, we have identified three Cre-driver mouse lines that use neuropeptide promoters to drive the expression of Cre recombinase in subpopulations of IC neurons: Vasoactive Intestinal Peptide (VIP)-Cre, Neuropeptide Y (NPY)-Cre, and Somatostatin (SST)-Cre. The overall objective of this proposal is to determine how these molecularly defined classes of IC neurons integrate ascending inputs and influence postsynaptic targets. To pursue this objective, we will use brain slice electrophysiology, optogenetic circuit mapping, and anatomical approaches. In Aim 1, we will determine the intrinsic physiology, morphology, axonal projections, distribution, and neurochemistry of VIP, NPY, and SST neurons. We hypothesize that VIP, NPY, and SST neurons represent separate classes of IC neurons characterized by specific physiological and anatomical properties. In Aim 2, we will use optogenetic circuit mapping to identify and assess the functional impact of ascending and commissural sources of synaptic input to VIP, NPY, and SST neurons. In addition, we will use subcellular optogenetic circuit mapping to determine the dendritic location of synaptic inputs. Our working hypothesis is that specific neuron types integrate input from multiple sources and that ascending and commissural sources of input target different regions of the dendritic tree. In Aim 3, we will determine how VIP, NPY, and SST neurons influence postsynaptic targets in the local IC, the contralateral IC, and the auditory thalamus. This aim will use a combination of optogenetic circuit mapping and paired recordings from synaptically coupled neurons. We hypothesize that local and commissural projections provide weak, modulatory synaptic input, while thalamic projections provide strong inputs that drive the activity of thalamic neurons. The expected outcome of this research is that we will determine how three molecularly defined classes of IC neurons shape the integration of auditory information within the IC and influence the output of the IC to the thalamocortical system. These results will provide a mechanistic framework for understanding how neural circuits in the IC function and will enable future investigations to determine how the same classes of IC neurons influence sound processing in vivo.

Abstract The inferior colliculus (IC) is the midbrain hub of the central auditory system. Although the IC is a critical processing center for speech, vocalizations, and other complex sounds, the neuronal mechanisms underlying computations in the IC remain largely unknown. This gap in knowledge persists because it has proven difficult to reliably identify specific classes of IC neurons. By combining molecular markers with anatomical and physiological measures, we recently overcame this obstacle and have identified two novel classes of IC principal neurons: vasoactive intestinal peptide (VIP) neurons and neuropeptide Y (NPY) neurons. VIP neurons are excitatory, glutamatergic neurons, while NPY neurons are inhibitory, GABAergic neurons. Both VIP and NPY neurons are stellate neurons with dendritic arbors that spread across the tonotopic axis of the central nucleus of the IC (ICc), and both project to multiple brain regions, including the auditory thalamus. Because they can sample input from a range of sound frequencies, it has long been hypothesized that ICc stellate neurons play important roles in sound processing, but the functional roles of stellate neurons have previously been inaccessible. By identifying VIP and NPY neurons, we possess the tools for the first time to selectively target and manipulate an excitatory and an inhibitory class of ICc stellate neurons. The overall objective of this proposal is to establish a functional wiring diagram for the inputs and outputs of VIP and NPY neurons and to determine the differences in how VIP and NPY neurons respond to sounds. To pursue this objective, we will use viral tract tracing, optogenetic circuit mapping, brain slice electrophysiology, and optogenetically-targeted in vivo recordings. In Aim 1, we will identify the ascending sources of auditory input to VIP and NPY neurons and determine how these inputs vary their synaptic strength during trains of activity. In Aim 2, we will identify the long-range targets and terminal arborization patterns of VIP and NPY neurons and determine how synaptic transmission from VIP and NPY neurons influences neurons in the auditory thalamus. In Aim 3, we will test the hypothesis that excitatory VIP neurons and inhibitory NPY neurons differ in their responses to tones and noise and to amplitude- and frequency-modulated sounds, stimuli that represent important features of speech and other vocalizations. The expected outcome of this research is that we will determine for the first time how two classes of ICc stellate neurons, one excitatory and one inhibitory, integrate ascending and descending auditory input, influence long-range postsynaptic targets, and respond to simple and complex sounds. These results will generate evidence-based hypotheses about how ICc stellate neurons contribute to sound processing and will provide a launching point for investigations into the circuit computations that underlie speech and vocalization coding in the midbrain.