The NINDS 2021-2026 Strategic Plan: Partnership and cross-cutting principles.

The 2021-2026 Strategic Plan of the National Institute of Neurological Disorders and Stroke began with a vision, a mission, and strategic objectives elaborated from within the institute. This plan is a collaborative product of the institute and its many stakeholders, emphasizing cross-cutting operational principles including scientific rigor, communication, workforce culture, and equity.

An evolving view of retinogeniculate transmission.

The thalamocortical (TC) relay neuron of the dorsoLateral Geniculate Nucleus (dLGN) has borne its imprecise label for many decades in spite of strong evidence that its role in visual processing transcends the implied simplicity of the term "relay". The retinogeniculate synapse is the site of communication between a retinal ganglion cell and a TC neuron of the dLGN. Activation of retinal fibers in the optic tract causes reliable, rapid, and robust postsynaptic potentials that drive postsynaptics spikes in a TC neuron. Cortical and subcortical modulatory systems have been known for decades to regulate retinogeniculate transmission. The dynamic properties that the retinogeniculate synapse itself exhibits during and after developmental refinement further enrich the role of the dLGN in the transmission of the retinal signal. Here we consider the structural and functional substrates for retinogeniculate synaptic transmission and plasticity, and reflect on how the complexity of the retinogeniculate synapse imparts a novel dynamic and influential capacity to subcortical processing of visual information.

Prolonged synaptic currents increase relay neuron firing at the developing retinogeniculate synapse.

The retinogeniculate synapse, the connection between retinal ganglion cells (RGC) and thalamic relay neurons, undergoes robust changes in connectivity over development. This process of synapse elimination and strengthening of remaining inputs is thought to require synapse specificity. Here we show that glutamate spillover and asynchronous release are prominent features of retinogeniculate synaptic transmission during this period. The immature excitatory postsynaptic currents exhibit a slow decay time course that is sensitive to low-affinity glutamate receptor antagonists and extracellular calcium concentrations, consistent with glutamate spillover. Furthermore, we uncover and characterize a novel, purely spillover-mediated AMPA receptor current from immature relay neurons. The isolation of this current strongly supports the presence of spillover between boutons of different RGCs. In addition, fluorescence measurements of presynaptic calcium transients suggest that prolonged residual calcium contributes to both glutamate spillover and asynchronous release. These data indicate that, during development, far more RGCs contribute to relay neuron firing than would be expected based on predictions from anatomy alone.

Functional convergence of on-off direction-selective ganglion cells in the visual thalamus.

In the mouse visual system, multiple types of retinal ganglion cells (RGCs) each encode distinct features of the visual space. A clear understanding of how this information is parsed in their downstream target, the dorsal lateral geniculate nucleus (dLGN), remains elusive. Here, we characterized retinogeniculate connectivity in Cart-IRES2-Cre-D and BD-CreER2 mice, which labels subsets of on-off direction-selective ganglion cells (ooDSGCs) tuned to the vertical directions and to only ventral motion, respectively. Our immunohistochemical, electrophysiological, and optogenetic experiments reveal that only a small fraction (<15%) of thalamocortical (TC) neurons in the dLGN receives primary retinal drive from these subtypes of ooDSGCs. The majority of the functionally identifiable ooDSGC inputs in the dLGN are weak and converge together with inputs from other RGC types. Yet our modeling indicates that this mixing is not random: BD-CreER+ ooDSGC inputs converge less frequently with ooDSGCs tuned to the opposite direction than with non-CART-Cre+ RGC types. Taken together, these results indicate that convergence of distinct information lines in dLGN follows specific rules of organization.

Planning and Implementing Strategically: Year 1 of the NINDS 2021-2026 Strategic Plan.

At the end of 2020, the National Institute of Neurological Disorders and Stroke, an institute of the National Institutes of Health, completed an 18 month-long strategic planning process that involved and engaged diverse internal and external biomedical and general stakeholders. The Institute published and disseminated its 2021-2026 Strategic Plan online in December 2020. Now, 1 year into its implementation, this progress report presents accomplishments to date, new initiatives and opportunities, and a preview of the metrics and benchmarks we will use to gauge the future progress of the strategic plan's implementation.

CD47 Protects Synapses from Excess Microglia-Mediated Pruning during Development.

Microglia regulate synaptic circuit remodeling and phagocytose synaptic material in the healthy brain; however, the mechanisms directing microglia to engulf specific synapses and avoid others remain unknown. Here, we demonstrate that an innate immune signaling pathway protects synapses from inappropriate removal. The expression patterns of CD47 and its receptor, SIRPα, correlated with peak pruning in the developing retinogeniculate system, and mice lacking these proteins exhibited increased microglial engulfment of retinogeniculate inputs and reduced synapse numbers in the dorsal lateral geniculate nucleus. CD47-deficient mice also displayed increased functional pruning, as measured by electrophysiology. In addition, CD47 was found to be required for neuronal activity-mediated changes in engulfment, as microglia in CD47 knockout mice failed to display preferential engulfment of less active inputs. Taken together, these results demonstrate that CD47-SIRPα signaling prevents excess microglial phagocytosis and show that molecular brakes can be regulated by activity to protect specific inputs.

Functional Convergence at the Retinogeniculate Synapse.

Precise connectivity between retinal ganglion cells (RGCs) and thalamocortical (TC) relay neurons is thought to be essential for the transmission of visual information. Consistent with this view, electrophysiological measurements have previously estimated that 1-3 RGCs converge onto a mouse geniculate TC neuron. Recent advances in connectomics and rabies tracing have yielded much higher estimates of retinogeniculate convergence, although not all identified contacts may be functional. Here we use optogenetics and a computational simulation to determine the number of functionally relevant retinogeniculate inputs onto TC neurons in mice. We find an average of ten RGCs converging onto a mature TC neuron, in contrast to >30 inputs before developmental refinement. However, only 30% of retinogeniculate inputs exceed the threshold for dominating postsynaptic activity. These results signify a greater role for the thalamus in visual processing and provide a functional perspective of anatomical connectivity data.

Refinement of the retinogeniculate synapse by bouton clustering.

Mammalian sensory circuits become refined over development in an activity-dependent manner. Retinal ganglion cell (RGC) axons from each eye first map to their target in the geniculate and then segregate into eye-specific layers by the removal and addition of axon branches. Once segregation is complete, robust functional remodeling continues as the number of afferent inputs to each geniculate neuron decreases from many to a few. It is widely assumed that large-scale axon retraction underlies this later phase of circuit refinement. On the contrary, RGC axons remain stable during functional pruning. Instead, presynaptic boutons grow in size and cluster during this process. Moreover, they exhibit dynamic spatial reorganization in response to sensory experience. Surprisingly, axon complexity decreases only after the completion of the thalamic critical period. Therefore, dynamic bouton redistribution along a broad axon backbone represents an unappreciated form of plasticity underlying developmental wiring and rewiring in the CNS.