Transneuronal viruses are powerful tools for tracing neuronal circuits or delivering genes to specific neurons in the brain. While there are multiple retrograde viruses, few anterograde viruses are available. Further, available anterograde viruses often have limitations such as retrograde transport, high neuronal toxicity, or weak signals. We developed an anterograde viral system based on a live attenuated vaccine of yellow fever – YFV-17D. Replication-deficient or packaging-deficient mutants of YFV-17D can be reconstituted in the brain, leading to efficient synapse-specific and anterograde-only transneuronal spreading, which can be controlled to achieve either monosynaptic or polysynaptic tracing. Moreover, inducible transient replication of YFV-17D mutant is sufficient to induce permanent transneuronal genetic modifications without causing neuronal toxicity. The engineered YFV-17D systems can be used to express fluorescent markers, sensors or effectors in downstream neurons, thus providing versatile tools for mapping and functionally controlling neuronal circuits.

Although the hippocampus is generally considered a cognitive center for spatial representation, learning, and memory, increasing evidence supports its roles in regulating locomotion. However, the neuronal mechanisms of the hippocampal regulation of locomotion and exploratory behavior remain unclear. In this study, we found that the inhibitory hippocampal synaptic projection to the medial septum (MS) bi-directionally controls the locomotor speed of mice. The activation of the MS-projecting interneurons in the hippocampus or the activation of the hippocampus-originated inhibitory synaptic terminals in the MS decreased locomotion and exploratory behavior. On the other hand, the inhibition of the hippocampus-originated inhibitory synaptic terminals in the MS increased locomotion. Unlike the septal projecting interneurons, the activation of the hippocampal interneurons projecting to the retrosplenial cortex did not change animal locomotion. Therefore, this study reveals a specific long-range inhibitory synaptic output from the hippocampus to the medial septum in the regulation of animal locomotion.

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Astrocytes are integral functional components of brain circuits. They ensheath the connections between neurons to form tripartite synapses. They react to local neuronal activities and release signaling molecules to regulate synaptic transmission. Their dysfunctions impair synaptic functions and are implicated in neuropsychiatric disorders. Increasing evidence indicates that astrocytes are diverse and they have distinct features and functions in different circuits. However, selectively targeting and controlling astrocytes in a circuit-specific manner is technically challenging. Recently we constructed a series of anterograde transneuronal viral vectors based on the yellow fever vaccine YFV-17D. These YFV-17D derivatives express fluorescent proteins almost exclusively in neurons. However, we find that YFV-17D carrying DNA recombinase Cre infect astrocytes associated with the traced neuronal pathways and express Cre to turn on reporter genes. The targeting of astrocytes is at a whole-brain level but specific to the neuronal circuits traced. Therefore, YFV-17D vectors carrying DNA recombinases provide tools for selectively and genetically targeting pathway-specific astrocytes. This new technology will also allow us to reveal the roles of astrocytes in specific neuronal circuits in normal brain functions and diseases.