Molecular mechanisms to organize neurons into circuits

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All aspects of human behaviour rely on precise wiring of billions of nerve cells into neural circuits. Brain wiring begins in the embryo, with genetically-coordinated programs that establish a blueprint of neuronal connectivity. Experience refines this map well into adulthood. The goal of my research is to identify molecular and cellular mechanisms that specify neural circuit assembly. Our approach is to identify cell recognition molecules presented at the surface of neurons that shape and wire neurons, with a focus on anatomically and genetically accessible circuits in the mouse retina and brain. The large family of recognition molecules called Clustered Protocadherins (Pcdhs) supply a massive molecular code with the potential of assigning each neuron has a unique Pcdh molecular combination, or Pcdh code. By studying the role of Pcdhs in starburst neurons that reside in the retina, we discovered that this Pcdh code controls the neuronal wiring and distribution of dendrite branches at the level of individual neurons, in a novel phenomenon called ‘neurite self-avoidance’. We propose that, by expressing different Pcdh codes, each neuron recognize and avoid their own branches through expression of the same Pcdh code. We call this neuron ‘self/non-self recognition’, which allows neurons to distribute their branches across a territory but connect with neighbouring neurons. In this proposal, we will investigate the cellular and molecular function of Pcdhs in neuron self/non-self recognition. For Objective 1, we use advanced, time-lapse microscopy to investigate the mechanism by which Pcdh regulate dendrite outgrowth and self-avoidance in developing neurons. We will test which molecular regions within Pcdh proteins that are necessary for this process, and elucidate the molecular signals. For our second objective, we will manipulate the large diversity of Pcdh members and reduce the possible Pcdh combinations available to each neuron to understand how this affects the wiring of other neuronal cell-types. We will also investigate broader roles for self/non-self recognition provided by the protocadherin code in neural wiring in the brain. The proposed research will lead to training of Highly Qualified Personnel with a variety of cutting-edge, multidisciplinary research technologies in neuroscience and molecular biology, promising to make important scientific contributions and innovations in Canada. By training in my lab, the Highly Qualified Personnel will be on track for successful careers in research and beyond. In the long-term, my research team will seek novel mechanisms of molecular recognition for circuit wiring and examine their importance in relation to circuit function. This work will make significant contributions towards understanding how individual neurons are wired, and how ensembles of neurons form complex neural circuits and how miswiring leads to neural dysfunction.