Inhibitory extracellular matrices form around mature neurons as perineuronal nets containing chondroitin sulfate proteoglycans (CSPGs) that limit axonal sprouting after CNS injury. The enzyme chondroitinase (Chase) degrades the inhibitory CSPGs and improves axonal sprouting and functional recovery after spinal cord injury (SCI) in rodents. We evaluated the effects of Chase in Rhesus monkeys that had undergone C7 spinal cord hemisection. Four weeks after hemisection, multiple intraparenchymal Chase injections targeted spinal cord circuits controlling hand function below the lesion. Hand function improved significantly in Chase-treated monkeys relative to vehicle-injected controls. Moreover, Chase significantly increased corticospinal axon growth and the number of synapses formed by corticospinal terminals in gray matter caudal to the lesion. No detrimental effects were detected. This approach appears to merit clinical translation in SCI.

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The mammalian nervous system is a complex network of interconnected cells. We review emerging techniques that use the axonal transport of adeno-associated virus (AAV) vectors to dissect neural circuits. These intersectional approaches specifically target AAV-mediated gene expression to discrete neuron populations based on their axonal connectivity, including: (a) neurons with one defined output, (b) neurons with one defined input, (c) neurons with one defined input and one defined output, and (d) neurons with two defined inputs or outputs. The number of labeled neurons can be directly controlled to trace axonal projections and examine cellular morphology. These approaches can precisely target the expression of fluorescent reporters, optogenetic ion channels, chemogenetic receptors, disease-associated proteins, and other factors to defined neural circuits in mammals ranging from mice to macaques, and thereby provide a powerful new means to understand the structure and function of the nervous system.

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