Feedback and feedforward gating of sensory signaling through timing in the thalamocortical loop - Feedback and feedforward gating of sensory signaling through timing in the thalamocortical loop Nearly all sensory experience begins in the periphery, generating sensory signals travelling through the thalamus before reaching neocortex. Despite numerous anatomical and functional investigations into the feedforward projections from thalamus to primary sensory cortex (TC), significantly less is known about the extensive reciprocal corticothalamic (CT) feedback pathway that provides ~40% of input to the thalamus. One proposed role of CT feedback is to control the salience of ascending sensory signals relative to background activity, thereby regulating the selective detectability and discriminability of sensory stimuli, but this has not been explicitly tested due to the complexity of the underlying circuit, the difficulty in disentangling loops of this nature, and the only recent availability of tools designed to specifically target key elements of the circuit. This project will utilize a range of tools to precisely measure and optogenetically manipulate elements of the TC-CT circuit in the whisker somatosensory pathway of the awake head-fixed mouse during tactile perception, to develop the set of rules by which cortical feedback gates signal processing in the thalamocortical circuit. First, the effect of L6CT feedback projections on sensory signaling in the thalamus will be determined (Aim 1). L6CT neurons will be optogenetically manipulated while recording extracellular population spiking activity in L6CT and across both VPm and TRN, while delivering controlled sensory stimuli. Second, the effect of L6CT feedback on sensory signaling in S1 cortex will be determined (Aim 2). In a range of targeted optogenetic manipulations, activity in thalamus will be forced to desired baseline firing rates via a novel real-time closed-loop optogenetic control framework, while recording across cortical laminae. Third, the bi-directional, corticothalamic control of the salience of sensory evoked activity in the perception of sensory inputs will be assessed (Aim 3). Mice will be trained in tactile tasks while monitoring population single unit activity across thalamus and cortex in the presence of optogenetic manipulation of L6CT neuron activity. Significance. The feedforward thalamocortical circuit is thought to play a dynamic and pivotal role in controlling perceptually relevant information flow, but corticothalamic input to thalamus is extensive, providing an exquisite level of control of the signal processing of the pathway that is very poorly understood. Success in this project could provide a significant advance in the understanding of basic function in all sensory pathways, and provide a set of rules by which feedback acts to dynamically gate the signal processing that is vital for navigating complex environments. Broader Impacts. Feedback loops play critical roles in a range of neurological diseases and disorders, from the complex feedback loops involved in Parkinson’s disease, to the excitability of circuits involved in certain forms of epilepsy, to the interaction between brain structures in traumatic brain injury, and many others. Success in this project could therefore shed light on a fundamental principle critical for shaping function in normal and disease states.
