One of the preeminent models used to study the development of thalamic circuitry is the mouse visual thalamus. Most studies on this system have focused on the retinogeniculate pathway that connects retinal axons with relay neurons of the dorsal lateral geniculate nucleus (dLGN). These relay neurons transmit visual information to the visual cortex via their axonal projection to primary visual cortex but this projection also sends axon collaterals to the thalamic reticular nucleus (TRN). The TRN is a GABAergic nucleus that projects to the dorsal thalamus, including dLGN, and is the main inhibitory projection to these brain regions. Thus, there is a feedback loop between dLGN and TRN, which is known to mediate visual attention, select thalamocortical rhythms, and is involved in multiple diseases processes. However, when this loop is formed and how it develops is currently not known. Furthermore, it is unknown whether the development of these projections are regulated, like other nonretinal projections to dLGN, by retinal signaling. These questions will be addressed in three specific aims:
Aim 1 will determine when TRN terminals arrive in dLGN, when synapses onto relay neurons become functional, and how both terminal expanse and synaptic responses mature;
Aim 2 will investigate similar parameters for the innervation of TRN by dLGN, determining when terminals arrive, when synapses are made and how synaptic responses change over early development;
Aim 3 will compare the developmental time course of these projections TRN and dLGN in the presence and absence of retinal input to central visual structures in order to determine if retinal terminals coordinate the developmental timing of innervation. These experiments will utilize transgenic mice that specifically label either the projections from TRN or those from dLGN. Specifically, the GAD65 mouse will be used to visualize TRN innervation of dLGN with EGFP while the somatostatin-cre mouse will be crossed to a channelrhodopsin-2 mouse in order to photoactivate TRN terminals in electrophysiological recordings (aim 1). The corticotropin releasing hormone cre-recombinase mouse will be used to both stimulate and visualize dLGN inputs to TRN with crosses to either the channelrhodopsin-2 mouse or an Ai9 reporter line that will label this projection with TdTomato (aim 2). Finally, these experiments will be repeated after crossing all these mice into a math 5 null background to genetically remove retinal inputs (aim 3). Together, these experiments will determine how an important component of the visual system develops and they will test the hypothesis that retinal terminals in dLGN coordinate the innervation of non-retinal projections to dLGN as well as the axonal projections of dLGN relay neurons. These studies will not only advance the current understanding of the visual system but will have implications for circuit development in the thalamus as a whole.

Public Health Relevance

Inhibitory circuits of the thalamus are involved in multiple disease states including epilepsy and autism but they also direct our attention in normal situations. Since understanding the development of a circuit is critical for determining its function, we propose to determine when these connections are formed and how they mature during early development. This study will determine when an important inhibitory feedback loop develops in the visual thalamus - a structure that has been used to discover much of what we currently understand about thalamic circuitry.

National Institute of Health (NIH)
National Eye Institute (NEI)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Agarwal, Neeraj
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University of Louisville
Anatomy/Cell Biology
Schools of Medicine
United States
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