Vision is the sense humans rely on most to navigate the world, make decisions, and perform complex tasks. Understanding how humans see thus represents one of the most fundamental and important goals of neuroscience. The use of the mouse as a model for parsing how vision works at a fundamental level started approximately a decade ago, ushered in by the mouse's convenient size, relatively low cost, and, above all, amenability to genetic perturbations. In the course of that effort, a large cadre of new and powerful tools for in vivo labeling, monitoring, and manipulation of neurons were applied to this species. As a consequence, a significant body of work now exists on the architecture, function, and development of mouse central visual pathways. Excitingly, much of that work includes causal testing of the role of specific cell types and circuits in visual perception and behavior-something rare to find in studies of the visual system of other species. Indeed, one could argue that more information is now available about the mouse visual system than any other sensory system, in any species, including humans. As such, the mouse visual system has become a platform for multilevel analysis of the mammalian central nervous system generally. Here we review the mouse visual system structure, function, and development literature and comment on the similarities and differences between the visual system of this and other model species. We also make it a point to highlight the aspects of mouse visual circuitry that remain opaque and that are in need of additional experimentation to enrich our understanding of how vision works on a broad scale.

Neurons in layer VI of visual cortex represent one of the largest sources of nonretinal input to the dorsal lateral geniculate nucleus (dLGN) and play a major role in modulating the gain of thalamic signal transmission. However, little is known about how and when these descending projections arrive and make functional connections with dLGN cells. Here we used a transgenic mouse to visualize corticogeniculate projections to examine the timing of cortical innervation in dLGN. Corticogeniculate innervation occurred at postnatal ages and was delayed compared with the arrival of retinal afferents. Cortical fibers began to enter dLGN at postnatal day 3 (P3) to P4, a time when retinogeniculate innervation is complete. However, cortical projections did not fully innervate dLGN until eye opening (P12), well after the time when retinal inputs from the two eyes segregate to form nonoverlapping eye-specific domains. In vitro thalamic slice recordings revealed that newly arriving cortical axons form functional connections with dLGN cells. However, adult-like responses that exhibited paired pulse facilitation did not fully emerge until 2 weeks of age. Finally, surgical or genetic elimination of retinal input greatly accelerated the rate of corticogeniculate innervation, with axons invading between P2 and P3 and fully innervating dLGN by P8 to P10. However, recordings in genetically deafferented mice showed that corticogeniculate synapses continued to mature at the same rate as controls. These studies suggest that retinal and cortical innervation of dLGN is highly coordinated and that input from retina plays an important role in regulating the rate of corticogeniculate innervation.

SUMMARY Neural circuit formation demands precise timing of innervation by different classes of axons. However the mechanisms underlying such activity remain largely unknown. In the dorsal lateral geniculate nucleus (dLGN), axons from the retina and visual cortex innervate thalamic relay neurons in a highly coordinated manner, with those from the cortex arriving well after those from retina. The differential timing of retino- and corticogeniculate innervation is not a coincidence but is orchestrated by retinal inputs. Here, we identified a chondroitin sulfate proteoglycan (CSPG) that regulates the timing of corticogeniculate innervation. Aggrecan, a repulsive CSPG, is enriched in neonatal dLGN and inhibits cortical axons from prematurely entering the dLGN. Postnatal loss of aggrecan from dLGN coincides with upregulation of aggrecanase expression in the dLGN and corticogeniculate innervation and, importantly, is regulated by retinal inputs. Taken together, these studies reveal a molecular mechanism through which one class of axons coordinates the temporal targeting of another class of axons.

BackgroundThe dorsal lateral geniculate nucleus (dLGN) of the mouse thalamus has emerged as a powerful experimental system for understanding the refinement of developing sensory connections. Interestingly, many of the basic tenets for such developmental remodeling (for example, pruning of connections to form precise sensory maps) fail to take into account a fundamental aspect of sensory organization, cell-type specific wiring. To date, studies have focused on thalamocortical relay neurons and little is known about the development of retinal connections onto the other principal cell type of dLGN, intrinsic interneurons. Here, we used a transgenic mouse line in which green fluorescent protein (GFP) is expressed within dLGN interneurons (GAD67-GFP), making it possible to visualize them in acutely prepared thalamic slices in order to examine their morphology and functional patterns of connectivity throughout postnatal life.FindingsGFP-expressing interneurons were evenly distributed throughout dLGN and had highly complex and widespread dendritic processes that often crossed eye-specific borders. Estimates of retinal convergence derived from excitatory postsynaptic potential (EPSP) amplitude by stimulus intensity plots revealed that unlike relay cells, interneurons recorded throughout the first 5 weeks of life, maintain a large number (approximately eight to ten) of retinal inputs.ConclusionsThe lack of pruning onto interneurons suggests that the activity-dependent refinement of retinal connections in dLGN is cell-type specific. The high degree of retinal convergence onto interneurons may be necessary for these cells to provide both widespread and local forms of inhibition in dLGN.

The link between neural activity and the refinement of projections from retina to the dorsal lateral geniculate nucleus (dLGN) of thalamus is based largely on studies that disrupt presynaptic retinogeniculate activity. Postsynaptic mechanisms responsible for implementing the activity-dependent remodeling in dLGN remain unknown. We tested whether L-type Ca 2ϩ channel activity in the form of synaptically evoked plateau potentials in dLGN cells is needed for remodeling by using a mutant mouse that lacks the ancillary ␤ 3 subunit and, as a consequence, has highly reduced L-type channel expression and attenuated L-type Ca 2ϩ currents. In the dLGNs of ␤ 3 -null mice, glutamatergic postsynaptic activity evoked by optic tract stimulation was normal, but plateau potentials were rarely observed. The few plateaus that were evoked required high rates of retinal stimulation, but were still greatly attenuated compared with those recorded in age-matched wild-type mice. While ␤ 3 -null mice exhibit normal stage II and III retinal waves, their retinogeniculate projections fail to segregate properly and dLGN cells show a high degree of retinal convergence even at late postnatal ages. These structural and functional defects were also accompanied by a reduction in CREB phosphorylation, a signaling event that has been shown to be essential for retinogeniculate axon segregation. Thus, postsynaptic L-type Ca 2ϩ activity plays an important role in mediating the refinement of the retinogeniculate pathway.

BackgroundThe dorsal lateral geniculate nucleus (dLGN) of the mouse has become a model system for understanding thalamic circuit assembly. While the development of retinal projections to dLGN has been a topic of extensive inquiry, how and when nonretinal projections innervate this nucleus remains largely unexplored. In this study, we examined the development of a major nonretinal projection to dLGN, the ascending input arising from cholinergic neurons of the brainstem. To visualize these projections, we used a transgenic mouse line that expresses red fluorescent protein exclusively in cholinergic neurons. To assess whether retinal input regulates the timing and pattern of cholinergic innervation of dLGN, we utilized the math5-null (math5−/−) mouse, which lacks retinofugal projections due to a failure of retinal ganglion cell differentiation.ResultsCholinergic brainstem innervation of dLGN began at the end of the first postnatal week, increased steadily with age, and reached an adult-like pattern by the end of the first postnatal month. The absence of retinal input led to a disruption in the trajectory, rate, and pattern of cholinergic innervation of dLGN. Anatomical tracing experiments reveal these disruptions were linked to cholinergic projections from parabigeminal nucleus, which normally traverse and reach dLGN through the optic tract.ConclusionsThe late postnatal arrival of cholinergic projections to dLGN and their regulation by retinal signaling provides additional support for the existence of a conserved developmental plan whereby retinal input regulates the timing and sequencing of nonretinal projections to dLGN.

The biodistribution of AAVHSC7, AAVHSC15, and AAVHSC17 following systemic delivery was assessed in cynomolgus macaques (Macaca fascicularis). Animals received a single intravenous (IV) injection of a self-complementary AAVHSC-enhanced green fluorescent protein (eGFP) vector and tissues were harvested at two weeks post-dose for anti-eGFP immunohistochemistry and vector genome analyses. IV delivery of AAVHSC vectors produced widespread distribution of eGFP staining in glial cells throughout the central nervous system, with the highest levels seen in the pons and lateral geniculate nuclei (LGN). eGFP-positive neurons were also observed throughout the central and peripheral nervous systems for all three AAVHSC vectors including brain, spinal cord, and dorsal root ganglia (DRG) with staining evident in neuronal cell bodies, axons and dendritic arborizations. Co-labeling of sections from brain, spinal cord, and DRG with anti-eGFP antibodies and cell-specific markers confirmed eGFP-staining in neurons and glia, including protoplasmic and fibrous astrocytes and oligodendrocytes. For all capsids tested, 50 to 70% of glial cells (S100-β+) and on average 8% of neurons (NeuroTrace+) in the LGN were positive for eGFP expression. In the DRG, 45 to 62% of neurons and 8 to 12% of satellite cells were eGFP-positive for the capsids tested. eGFP staining was also observed in peripheral tissues with abundant staining in hepatocytes, skeletal- and cardio-myocytes and in acinar cells of the pancreas. Biodistribution of AAVHSC vector genomes in the central and peripheral organs generally correlated with eGFP staining and were highest in the liver for all AAVHSC vectors tested. These data demonstrate that AAVHSCs have broad tissue tropism and cross the blood-nerve and blood-brain-barriers following systemic delivery in nonhuman primates, making them suitable gene editing or gene transfer vectors for therapeutic application in human genetic diseases.

Adjustments in neural activity can drive cortical plasticity, but the underlying circuit components remain unclear. In this issue of Neuron, Barnes et al. (2015) show that visual deprivation-induced homeostatic plasticity invokes specific changes among select categories of V1 neurons.