Long-range projections link distant circuits in the brain, allowing efficient transfer of information between regions and synchronization of distributed patterns of neural activity. Understanding the functional roles of defined neuronal projection pathways requires temporally precise manipulation of their activity, and optogenetic tools appear to be an obvious choice for such experiments. However, we and others have previously shown that commonly-used inhibitory optogenetic tools have low efficacy and off-target effects when applied to presynaptic terminals. In my talk, I will present a new solution to this problem: a targeting-enhanced mosquito homologue of the vertebrate encephalopsin (eOPN3), which upon activation can effectively suppress synaptic transmission through the Gi/o signaling pathway. Brief illumination of presynaptic terminals expressing eOPN3 triggers a lasting suppression of synaptic output that recovers spontaneously within minutes in vitro and in vivo. The efficacy of eOPN3 in suppressing presynaptic release opens new avenues for functional interrogation of long-range neuronal circuits in vivo.

The emergence of large-scale brain networks, and their continual refinement, represent crucial developmental processes that can drive individual differences in cognition and which are associated with multiple neurodevelopmental conditions. But how does this organization arise, and what mechanisms govern the diversity of these developmental processes? There are many existing descriptive theories, but to date none are computationally formalized. We provide a mathematical framework that specifies the growth of a brain network over developmental time. Within this framework macroscopic brain organization, complete with spatial embedding of its organization, is an emergent property of a generative wiring equation that optimizes its connectivity by renegotiating its biological costs and topological values continuously over development. The rules that govern these iterative wiring properties are controlled by a set of tightly framed parameters, with subtle differences in these parameters steering network growth towards different neurodiverse outcomes. Regional expression of genes associated with the developmental simulations converge on biological processes and cellular components predominantly involved in synaptic signaling, neuronal projection, catabolic intracellular processes and protein transport. Together, this provides a unifying computational framework for conceptualizing the mechanisms and diversity of childhood brain development, capable of integrating different levels of analysis – from genes to cognition. (Pre-print: https://www.biorxiv.org/content/10.1101/2020.08.13.249391v1)