PURPOSE: This proposal addresses the synaptic mechanisms by which thalamic afferents control the excitability of cortical neurons. It is focused on the thalamic projection to the rodent somatosensory """"""""barrel"""""""" cortex, the cortical input of tactile information originating from the whiskers. Specifically, I will seek to determine how thalamocortical afferents produce differential excitation of interneurons and principal cells, and characterize the receptor subtypes that regulate transmission from the thalamus into the cortex. I will use the mouse thalamocortical slice as a model system, and electrophysiological, morphological and imaging techniques to assay synaptic function. BACKGROUND: Somatosensory information enters the cortex via afferent projections from the thalamus. In the primary somatosensory cortex of rodents, thalamocortical afferents carry information originating from the whiskers. Here, these afferents make synapses onto both inhibitory interneurons and excitatory principal cells. Thalamocortical fibers thus distribute information between two cortical cells types, setting the initial phase of cortical processing. The divergence of thalamocortical fibers onto interneurons and principal cells provides the basis for disynaptic feed-forward inhibition in the somatosensory cortex, which is critical for enforcing the temporal precision of cortical responses to whisker stimulation. Thalamocortical afferents support this vital disynaptic circuit by producing larger inputs onto interneurons than principal cells, thereby establishing a """"""""fail-safe"""""""" to ensure feed-forward inhibition. It is not known, however, what mechanisms allow thalamocortical fibers to mediate differential input to interneurons and principal cells.
AIM 1 : Determine the mechanisms underlying the stronger input of thalamocortical afferents onto inhibitory interneurons. By recording from neurons in thalamocortical slices and stimulating the thalamus, I will determine what produces stronger inputs to inhibitory interneurons receiving input from the thalamus.
AIM 2 : Characterize the receptor subtypes responsible for synaptic transmission from the thalamus to the cortex, and determine their role in shaping the behavior of local feed-forward inhibitory circuits. PUBLIC HEALTH RELAVENCE: By determining the functional properties of transmission into the cortex using the thalamocortical system, I hope to gain insight into the mechanisms that control the balance between excitation and inhibition in thalamic recipient layers, and that contribute to the cortical discrimination of tactile stimuli. A deeper understanding of the factors that regulate cortical excitability may contribute to the development of therapies aimed at preventing epileptogenesis in cortical areas. ? ? ?
| Rudolph, Stephanie; Hull, Court; Regehr, Wade G (2015) Active Dendrites and Differential Distribution of Calcium Channels Enable Functional Compartmentalization of Golgi Cells. J Neurosci 35:15492-504 |
| Hull, Court; Regehr, Wade G (2012) Identification of an inhibitory circuit that regulates cerebellar Golgi cell activity. Neuron 73:149-58 |
| Bagnall, Martha W; Hull, Court; Bushong, Eric A et al. (2011) Multiple clusters of release sites formed by individual thalamic afferents onto cortical interneurons ensure reliable transmission. Neuron 71:180-94 |
| Hull, Court; Adesnik, Hillel; Scanziani, Massimo (2009) Neocortical disynaptic inhibition requires somatodendritic integration in interneurons. J Neurosci 29:8991-5 |
| Hull, Court; Isaacson, Jeffry S; Scanziani, Massimo (2009) Postsynaptic mechanisms govern the differential excitation of cortical neurons by thalamic inputs. J Neurosci 29:9127-36 |
