Activity-Dependent Mechanisms of Visual Map Formation & Alignment
Open AccessEfficient sensory processing is a critical function of the nervous system, which requires the establishment of precise connections. In many visual areas, neuronal connections are organized topographically, where neighboring neurons monitor adjacent regions. For instance, retinal ganglion cells (RGCs) project topographically to two image-forming areas: the superior colliculus (SC) and dorsal lateral geniculate nucleus (dLGN). The SC also receives topographically ordered inputs from the primary visual cortex (V1), which are aligned with terminals from RGCs monitoring the same region of space. Previous studies have argued that retinofugal topography is established by a combination of molecular cues, competition, and activity-dependent processes. While the molecular regulation of topographic mapping is well-understood, the mechanisms by which activity acts are unclear. Similarly, evidence exists for molecular and activity-dependent regulation of visual map alignment in the SC, but the specific mechanisms remain poorly understood.Previous pharmacological studies suggest that the formation of the retinocollicular map requires N-methyl-D-Aspartate Receptor (NMDAR) activity. However, these pharmacological studies were unable to distinguish if pre- and/or post-synaptic NMDARs are necessary for this circuit formation. Recently, a study implicated that both pre-synaptic and post-synaptic NMDARs are important for RGC terminal developmental dynamics and have distinct roles in establishing receptive field properties in the tectum. However, it remains unclear if the differential regulation of circuit development by pre- and/or post-synaptic NMDAR activity is conserved, or how pre- and/or post-synaptic NMDAR activity affects topography, in the mammalian brain. To directly test the role of pre-synaptic NMDARs in the formation of the mammalian visual map, I utilized a transgenic mouse line to specifically ablate pre-synaptic NMDAR function in RGCs (Chrnb3-Cre;GluN1fllox/flox). Calcium imaging showed that pre-synaptic NMDARs located on RGC terminals can be activated in retinorecipient areas. To ascertain disruptions in topographic map formation, I focally labeled a small subset of RGCs with DiI in adult animals and visualized the termination zones (TZs) of labeled RGCs in the dLGN and SC. I found no difference in retinocollicular or retinogeniculate map organization in these mutant animals. Additionally, I assessed if eye-specific segregation was altered in development and adult animals and found no differences in development or adult animals. Altogether, these data suggest that NMDARs expressed by RGCs are not required for retinotopic map formation or eye-specific segregation. Previous studies demonstrated that retinal inputs instruct the alignment of V1 inputs in a manner dependent on spontaneous correlated activity. However, the mechanism by which activity instructs alignment remains unclear. To assess the role of post-synaptic NMDARs in visual map alignment after retinocollicular map development, I utilized a tamoxifen-inducible conditional mouse line to specifically ablate post-synaptic NMDAR function in the SC (Tal1CreERT2;GluN1fllox/flox) during the period of visual map alignment. To determine the organization of visual map alignment, I focally labeled a small subset of V1 neurons or RGCs with DiI at P10 and visualized the TZs in the SC at P12. Interestingly, I found that corticocollicular TZs were significantly larger in Tal1CreERT2; GluN1fllox/flox mice, while retinocollicular TZs were unchanged. These data suggest that NMDARs expressed in the SC are critical for activity-driven visual map alignment. NMDARs are necessary for several forms of neuronal plasticity in the brain. However, the role of pre-synaptic and post-synaptic NMDARs in neuronal circuit development is not fully understood. In this dissertation work, I directly probed the activity-dependent mechanisms of retinorecipient map formation and visual map alignment by researching the roles of pre- and post-synaptic NMDARs, respectively. My data suggest that the regulation of visual circuit development by pre-synaptic NMDAR activity reported in the frog tectum may not be consequential for the establishment of topography in the mouse SC. Interestingly, others have determined that corticocollicular projections may be guided by molecular cues in the retina. However, my data implicate that activity from post-synaptic NMDARs plays a critical role in corticocollicular map refinement. These data open up future studies in understanding the interactions between molecules and activity during visual map alignment. Nevertheless, the activity-dependent mechanisms regarding retinocollicular map formation remains unclear. The work in this thesis contributes to our knowledge of visual system development in mammals; specifically, it is the first assessment of the role of pre-synaptic NMDARs in retinocollicular map formation and the role of post-synaptic NMDARs visual map alignment in the mouse model.
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