Synaptic Mechanisms and Local Circuitry of Top-Down Control in the Inferior Colliculus

Abstract

Descending projections are a common circuit organization throughout the brain. Projections from cortical and sub-cortical regions convey contextual information via top-down control to lower-order brain regions. This top-down control plays a critical role in local processing and behavior. At the auditory midbrain, corticofugal projections from the auditory cortex descend to target the non-lemniscal shell inferior colliculus (IC). There is a limited understanding of how top-down control integrates and drives activity at individual shell IC neurons. Therefore, the biophysical properties and circuit mechanisms that allow corticofugal activity to shape IC processing are unknown. We used in vivo and in vitro electrophysiology, transgenic mouse lines, optogenetics and pharmacology across three distinct projects to elucidate the details surrounding corticofugal control at the inferior colliculus. We began to address this in Chapter 2 by characterizing how corticofugal control drives activity in dorsomedial shell neurons and how this information integrates with ascending acoustic information. We found the latency of corticofugal activity to arrive to the dorsomedial shell is near the peak of the response to ascending acoustic information, allowing for top-down control to quickly modulate responses to incoming sounds. Further, the ascending and descending pathways can integrate in a supra-linear fashion to enhance responses through NMDA receptor activity. Descending control can drive inhibition at the IC, with potential effects being to sharpen tuning or allow for sparser neuronal activity. However, this is surprising as the descending fibers are predominately glutamatergic and primarily synapse at IC glutamatergic neurons. In Chapter 3, we determined the circuitry allowing for this seemingly improbable inhibitory control through targeted electrophysiology recordings to presumptive GABAergic and glutamatergic neurons. Trains of corticofugal activation resulted in polysynaptic activity in a portion of the GABAergic neurons, while the glutamatergic neurons displayed monosynaptic activity. This suggested that corticofugal neurons drive activity in local glutamatergic neurons that then synapse at GABAergic neurons, which we tested and confirmed through pharmacological experiments. Further, we found that corticofugal activity could drive local inhibition and this inhibition supports temporal integration of corticofugal signals. Our work has focused on corticofugal activity at the dorsomedial shell IC, but the descending fibers also target the lateral shell. The lateral shell is a multi-modal region with a unique cellular organization that distinguishes it from the dorsomedial shell. In Chapter 4, we determined there is a differential cortical modulation of the dorsomedial and lateral shell. Corticofugal projections more sparsely target lateral shell neurons and drive smaller overall responses compared to the connectivity and responses at dorsomedial shell neurons. These differences are not related to basic biophysical properties of dorsomedial and lateral shell neurons, nor a difference in the number of fibers that converge at individual neurons. Overall, this work advances the field’s understanding of the synaptic mechanisms and local circuitry underlying top-down control at the inferior colliculus. There is a clearer understanding of how corticofugal activity shapes individual neurons at the dorsomedial and lateral shell to drive the local circuit, which modulates auditory responses and shapes behavior. More broadly, as top-down control is prevalent throughout the brain, we determined an example of synaptic mechanisms and circuitry that allows for top-down control to enhance ascending signals, provide inhibitory control and differentially modulate specific sub-regions. This dissertation gives further insight to the potential outcomes and computational power of top-down control at lower-order brain regions.