Establishing a national strategy for shared research resources in biomedical sciences.

Contemporary science has become increasingly multi-disciplinary and team-based, resulting in unprecedented growth in biomedical innovation and technology over the last several decades. Collaborative research efforts have enabled investigators to respond to the demands of an increasingly complex 21st century landscape, including pressing scientific challenges such as the COVID-19 pandemic. A major contributing factor to the success of team science is the mobilization of core facilities and shared research resources (SRRs), the scientific instrumentation and expertise that exist within research organizations that enable widespread access to advanced technologies for trainees, faculty, and staff. For over 40 years, SRRs have played a key role in accelerating biomedical research discoveries, yet a national strategy that addresses how to leverage these resources to enhance team science and achieve shared scientific goals is noticeably absent. We believe a national strategy for biomedical SRRs-led by the National Institutes of Health-is crucial to advance key national initiatives, enable long-term research efficiency, and provide a solid foundation for the next generation of scientists.

Retinal inputs signal astrocytes to recruit interneurons into visual thalamus.

Inhibitory interneurons comprise a fraction of the total neurons in the visual thalamus but are essential for sharpening receptive field properties and improving contrast-gain of retinogeniculate transmission. During early development, these interneurons undergo long-range migration from germinal zones, a process regulated by the innervation of the visual thalamus by retinal ganglion cells. Here, using transcriptomic approaches, we identified a motogenic cue, fibroblast growth factor 15 (FGF15), whose expression in the visual thalamus is regulated by retinal input. Targeted deletion of functional FGF15 in mice led to a reduction in thalamic GABAergic interneurons similar to that observed in the absence of retinal input. This loss may be attributed, at least in part, to misrouting of interneurons into nonvisual thalamic nuclei. Unexpectedly, expression analysis revealed that FGF15 is generated by thalamic astrocytes and not retino-recipient neurons. Thus, these data show that retinal inputs signal through astrocytes to direct the long-range recruitment of interneurons into the visual thalamus.

Developmental Remodeling of Thalamic Interneurons Requires Retinal Signaling.

The dorsal lateral geniculate nucleus (dLGN) of the mouse is a model system to study the development of thalamic circuitry. Most studies focus on relay neurons of dLGN, yet little is known about the development of the other principal cell type, intrinsic interneurons. Here we examined whether the structure and function of interneurons relies on retinal signaling. We took a loss-of-function approach and crossed GAD67-GFP mice, which express GFP in dLGN interneurons, with math5 nulls (math5-/-), mutants that lack retinal ganglion cells and retinofugal projections. In vitro recordings and 3-D reconstructions of biocytin-filled interneurons at different postnatal ages showed their development is a multistaged process involving migration, arbor remodeling, and synapse formation. Arbor remodeling begins during the second postnatal week, after migration to and dispersion within dLGN is complete. This phase includes a period of exuberant branching where arbors grow in number, complexity, and field size. Such growth is followed by branch pruning and stabilization, as interneurons adopt a bipolar architecture. The absence of retinal signaling disrupts this process. The math5-/- interneurons fail to branch and prune, and instead maintain a simple, sparse architecture. To test how such defects influence connectivity with dLGN relay neurons, we used DHPG [(RS)-3,5-dihydroxyphenylglycine], the mGluR1,5 agonist that targets F2 terminals. This led to substantial increases in IPSC activity among WT relay neurons but had little impact in math5-/- mice. Together, these data suggest that retinal signaling is needed to support the arbor elaboration and synaptic connectivity of dLGN interneurons.SIGNIFICANCE STATEMENT Presently, our understanding about the development of the dorsal lateral geniculate nucleus is limited to circuits involving excitatory thalamocortical relay neurons. Here we show that the other principal cell type, intrinsic interneurons, has a multistaged developmental plan that relies on retinal innervation. These findings indicate that signaling from the periphery guides the maturation of interneurons and the establishment of inhibitory thalamic circuits.