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

Abstract

c-Jun N-terminal kinase (JNK) regulates stress responses and affective behaviour, but the neural populations mediating these effects remain unclear. Here, we delivered a nucleus-targeted JNK inhibitor to the mouse brain using blood-brain barrier-crossing adeno-associated virus vectors with distinct cellular tropisms. JNK inhibition produced strikingly different behavioural outcomes depending on the neuronal populations targeted. Only AAV-PHP.eB-hSyn1-mediated delivery reproduced the previously reported anxiolytic phenotype, whereas AAV.CAP-B10-hSyn1 increased locomotor activity and depressive-like behaviour and AAV.CAP-B10-mDlx reduced locomotion while enhancing object recognition memory. The anxiolytic response was accompanied by reduced hilar mossy cell abundance and an approximately two-fold increase in doublecortin-positive newborn granule neurons in the dentate gyrus. Notably, this phenotype mirrors our previous findings following selective JNK inhibition in adult hippocampal progenitor cells, implicating the neurogenic niche as a convergent substrate for anxiolytic responses to JNK inhibition. Proteomic analysis of plasma extracellular vesicles revealed widespread alterations in metabolic and inflammatory proteins upon JNK inhibition, despite neuron-restricted transgene expression. Together, these findings demonstrate that the behavioural and systemic consequences of JNK inhibition depend critically on the neural populations targeted and identify hippocampal neurogenesis-associated circuits involving mossy cells as candidate mediators of JNK-dependent anxiety regulation.