Anterograde Trans-Synaptic AAV Strategies for Probing Neural Circuitry

Elucidating the organization and function of neural circuits is greatly facilitated by viral tools that spread transsynaptically. Adeno-associated virus (AAV) has been shown to exhibit anterograde transneuronal spread. However, the synaptic specificity of the spread and its broad application in various neural circuits remain to be explored. Here, using anatomical, functional, and molecular approaches, we provide strong evidence for the specifically preferential spread of AAV1 to post-synaptically connected neurons. Besides glutamatergic synapses made onto excitatory and inhibitory neurons, AAV1 also transsynaptically spreads through GABAergic synapses and effectively tags spinal cord neurons receiving long-distance projections from various brain regions, but exhibits little or no spread through neuromodulatory projections (e.g. serotonergic, cholinergic, and noradrenergic). Combined with newly designed intersectional and sparse labeling strategies, AAV1 can be utilized to categorize neurons according to their input sources, morphological and molecular identities. These properties make AAV a unique anterograde transsynaptic tool for establishing a comprehensive cell-atlas of the brain.

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