Axon target matching in the developing visual system

The central nervous system (CNS) is made up of trillions of connections between specific sets of highly specialized neurons. How each individual neuron finds and connects to the correct synaptic partner remains an important and unresolved issue in neuroscience. Using the mouse visual system as a model I probed the cellular and molecular mechanisms that govern one of the key steps leading to CNS development: axon target matching. Axon target matching is the process by which axons to find and innervate their correct target nuclei in the brain. I focused on eye-to-brain connections made by retinal ganglion cells (RGCs). First, I discovered that RGC birthdate correlates with the timing of axon out growth from the eye to the brain and that the timing of axon arrival predicts the mode of axon target matching. The earlier an RGC axon innervates the brain, the more targets it innervates and ultimately the more axonal refinement must take place before it reaches the final wiring pattern. Conversely, the later an RGC axon innervates the brain the more likely it will project to only the correct targets and undergo minimal refinement. Second, I discovered that specific adhesion molecules expressed by RGC axons and/or the cells in their target nuclei are required for correct axon target matching. These include cadherin-6, contactin-4 and amyloid precursor protein. I found that a loss of a single adhesion molecule and thereby the loss of connections made by a single functionally-specialized category of RGCs to the brain, results in system-wide defects in specific visually-driven behaviors.¬ My results shed light on how sensory neurons in the mammalian visual system rely on timing of cell birth and axon outgrowth, along with specific cell adhesion molecules to form highly specialized long-range connections required for correct visually-driven perception and behavior. These results speak to possible general mechanisms of neural development in the CNS

Birthdate and Outgrowth Timing Predict Cellular Mechanisms of Axon Target Matching in the Developing Visual Pathway

How axons select their appropriate targets in the brain remains poorly understood. Here, we explore the cellular mechanisms of axon target matching in the developing visual system by comparing four transgenic mouse lines, each with a different population of genetically labeled retinal ganglion cells (RGCs) that connect to unique combinations of brain targets. We find that the time when an RGC axon arrives in the brain is correlated with its target selection strategy. Early-born, early-arriving RGC axons initially innervate multiple targets. Subsequently, most of those connections are removed. By contrast, later-born, later-arriving RGC axons are highly accurate in their initial target choices. These data reveal the diversity of cellular mechanisms that mammalian CNS axons use to pick their targets and highlight the key role of birthdate and outgrowth timing in influencing this precision. Timing-based mechanisms may underlie the assembly of the other sensory pathways and complex neural circuitry in the brain

Neuronal representation of social information in the medial amygdala of awake behaving mice

The medial amygdala (MeA) plays a critical role in processing species- and sex-specific signals that trigger social and defensive behaviors. However, the principles by which this deep brain structure encodes social information is poorly understood. We used a miniature microscope to image the Ca2+ dynamics of large neural ensembles in awake behaving mice and tracked the responses of MeA neurons over several months. These recordings revealed spatially intermingled subsets of MeA neurons with distinct temporal dynamics. The encoding of social information in the MeA differed between males and females and relied on information from both individual cells and neuronal populations. By performing long-term Ca2+ imaging across different social contexts, we found that sexual experience triggers lasting and sex-specific changes in MeA activity, which, in males, involve signaling by oxytocin. These findings reveal basic principles underlying the brain’s representation of social information and its modulation by intrinsic and extrinsic factors

Cadherin-6 Mediates Axon-Target Matching in a Non-Image-Forming Visual Circuit

SummaryNeural circuits consist of highly precise connections among specific types of neurons that serve a common functional goal. How neurons distinguish among different synaptic targets to form functionally precise circuits remains largely unknown. Here, we show that during development, the adhesion molecule cadherin-6 (Cdh6) is expressed by a subset of retinal ganglion cells (RGCs) and also by their targets in the brain. All of the Cdh6-expressing retinorecipient nuclei mediate non-image-forming visual functions. A screen of mice expressing GFP in specific subsets of RGCs revealed that Cdh3-RGCs which also express Cdh6 selectively innervate Cdh6-expressing retinorecipient targets. Moreover, in Cdh6-deficient mice, the axons of Cdh3-RGCs fail to properly innervate their targets and instead project to other visual nuclei. These findings provide functional evidence that classical cadherins promote mammalian CNS circuit development by ensuring that axons of specific cell types connect to their appropriate synaptic targets