Higher-order (HO) thalamic nuclei make up most of the thalamus [5], and have recently begun to be appreciated as important contributors to early sensory processing [1,6,8,9,13,16], but their inputs to primary sensory cortex are not well understood. HO nuclei contain heterogeneous neuronal sub-populations with differential connectivity, clouding our understanding of the messages they transmit and how these messages contribute to each stage of cortical processing. In the somatosensory system, the Posterior Medial nucleus (POm) is known to receive both cortical and sub-cortical information [4,5,14], but it is not known which inputs drive activity in POm neurons projecting to S1, nor how this circuit affects S1 activity. In the analogous HO visual pathway, Pulvinar (Pulv) also coordinates communication between cortical areas [1,6], and receives sub- cortical input from the Superior Colliculus [5]. Similarly, despite known contributions of Pulv to processing in V1 [8,9], it is not known what areas drive the Pulv projection to V1 nor how this pathway affects targets in V1. The proposed experiments aim to dissect these circuits by means of an intersectional anatomical and physiological approach, mapping and characterizing synaptic inputs and outputs of the HO thalamic nuclei of mice. This analysis will employ newly developed, sub-population-specific viral strategies [25,26] to deliver fluorescent reporters and optogenetic probes to the projection groups in question, in combination with intracellular recordings in vitro that will clarify what areas are driving activity in HO cells projecting to primary cortex, how these inputs coordinate, and whether HO projections drive or modulate responses in S1 and V1. While each of these two circuits alone is of interest to understanding information processing in sensory systems, and both systems are central platforms for studying systems neuroscience, this project will compare across both sensory modalities, providing a way to compare/contrast the underlying patterns of functional connectivity. HO thalamic nuclei are known to have several features in common [4,5], and HO (but not FO) nuclei are shrunken with fewer neurons in schizophrenic patients [17-19]. The current proposal to probe the nature and organization of HO thalamic input to primary sensory cortex will both provide insight into thalamo- cortical relationships in early sensory processing as well as elucidate circuit-level mechanisms that may underlie deficits seen in schizophrenia and other disease states. Data will also be useful in guiding future in vivo analyses of the same circuits. The major training goal of this proposal is to learn how to use circuit-specific optogenetics techniques along with allied skills that will assist in designing and executing neuroscience experiments that bridge cells, circuits, and sensory systems, and help me develop as an independent researcher.
HO thalamic nuclei have been shown to contribute meaningfully to early sensory processing in the visual and somatosensory systems [1,6,8,9,13,16], their relevance to human health has been established [5,10- 12], and they have been implicated in psychiatric disorders such as schizophrenia [17-19], yet their specific connectivity and contributions to information processing remain unknown. The current proposal to probe the nature and organization of HO thalamic input to primary sensory cortex will both provide insight into thalamo- cortical relationships in early sensory processing as well as elucidate circuit-level mechanisms that may underlie deficits seen in schizophrenia and other disease states. The current proposal also will support technical and professional development toward the goal of becoming an independent researcher and exploring circuit-level phenomena in the future.
