Targeting distinct neuronal populations with AAV vectors reveals neurogenesis-associated anxiolytic effects of JNK inhibition
- 1Turku Bioscience Centre, University of Turku and Abo Akademi University
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.
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BibTeX
@misc{jokela2026targeting,
title = {{Targeting distinct neuronal populations with AAV vectors reveals neurogenesis-associated anxiolytic effects of JNK inhibition}},
author = {A. Jokela and N. Tiwari and D. Flinkman and S. Abyari and P. Deshpande and J. M. John and E. Coffey},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.30.763057},
url = {https://www.biorxiv.org/content/10.64898/2026.10.30.763057v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Targeting distinct neuronal populations with AAV vectors reveals neurogenesis-associated anxiolytic effects of JNK inhibition
AU - A. Jokela
AU - N. Tiwari
AU - D. Flinkman
AU - S. Abyari
AU - P. Deshpande
AU - J. M. John
AU - E. Coffey
PY - 2026
DA - 2026/10/30
PB - bioRxiv
DO - 10.64898/2026.10.30.763057
UR - https://www.biorxiv.org/content/10.64898/2026.10.30.763057v1
AB - 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.
ER -