Targeting distinct neuronal populations with AAV vectors reveals neurogenesis-associated anxiolytic effects of JNK inhibition

In mice, AAV-PHP.eB-hSyn1 delivery of a nucleus-targeted JNK inhibitor produces an anxiolytic phenotype linked to reduced hilar mossy cells and ~two-fold more doublecortin-positive newborn granule neurons.

• Why it matters: JNK is linked to stress responses and affective behavior, but which neuronal populations mediate its behavioral effects is unclear.
• What they did: The team used blood-brain barrier-crossing AAV vectors with distinct cellular tropisms to deliver a nucleus-targeted JNK inhibitor, then compared behavior and dentate gyrus neurogenesis markers across targeting strategies.
• The result: Only AAV-PHP.eB-hSyn1 reproduced the previously reported anxiolytic outcome; other tropisms altered locomotion and depressive-like behavior, while plasma extracellular vesicle proteomics showed widespread metabolic and inflammatory changes despite neuron-restricted expression.

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