Thalamic reticular nucleus regulation of behavioral flexibility through modulation of a thalamocortical circuit

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PROJECT ABSTRACT Behavioral flexibility, as modeled by reversal learning, is critical to achieving desired outcomes in the face of an ever-changing environment, but is impaired across numerous neuropsychiatric conditions. Damage to the lateral orbitofrontal cortex (LOFC) or mediodorsal thalamus (MD) produce similar reversal learning impairments, suggesting the two regions interact to promote optimal behavior. While it is unknown how information exchange occurs between these regions to support behavioral flexibility, one region that may regulate communication between LOFC and MD is the thalamic reticular nucleus (TRN). TRN is the main source of inhibitory input to the thalamus, has roles in sleep and sensory selection, and affects thalamic output based on integration of feedforward information from the cortex and feedback information from the thalamus. While TRN’s anatomical and functional interactions with sensory thalamus are well-characterized, it is unknown how TRN interacts with associative thalamic nuclei and their cortical targets. This lack of information limits our understanding of how the brain processes higher order cognition across thalamic and cortical structures. This project will 1) characterize the effects of TRN manipulation on MD and LOFC activity, 2) identify the effects of TRN inhibition on behavioral flexibility and cell-type specific LOFC activity, and 3) determine whether TRN integrates prefrontal cortex (PFC) inputs to MD. The impact of optogenetic stimulation of TRN on coordinated MD and LOFC neural activity will be assessed in Aim 1a using fiber photometry. In addition, the impact of optogenetic inhibition of TRN on activity in a) LOFC excitatory neurons and b) LOFC neurons receiving projections from MD will be examined using a trans-synaptic, dual-color fiber photometry approach (Aim 1b). To assess the impact of TRN on behavioral flexibility and cell-type specific LOFC activity, TRN will be optogenetically inhibited during reversal learning (Aim 2a), and cell-type specific LOFC activity (Aim 2b) will be quantified using an immunohistochemical approach. Finally, I will examine the overlap of different PFC inputs to TRN→MD projecting neurons to determine whether associative-projecting TRN has the anatomical organization to permit PFC integration (Aim 3). This research will uncover novel insight into TRN’s interactions with associative thalamic structures and their cortical targets, as well as determine whether TRN is necessary for behavioral flexibility. The overall results of this proposal will identify innovative ways in which the brain performs long range coordination of neuronal activity to support associative learning.