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.
Neural circuits in the inferior colliculus contribute to speech recognition, sound localization, hearing in noise, and other computations that are essential for hearing. The proposed research is expected to determine how two novel classes of inferior colliculus neurons process identified sources of input, influence targets in other brain regions, and respond to simple and complex sounds. These results will provide a framework for understanding how defined neural circuits in the inferior colliculus support sound processing and how auditory prostheses can more effectively engage these circuits to improve hearing for the hearing impaired.
