Biology subjects

John, J. M.

Publications and source records attributed to John, J. M..

2 recordsLinked to original sources

bioRxiv2026

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

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.

neuroscience↗

bioRxiv2025

Male-specific analgesic effects of minocycline in sickle cell disease are mediated by microglia and the microbiome

Over 50% of individuals with sickle cell disease (SCD) experience chronic pain that is phenotypically distinct from their acute, vaso-occlusive crisis pain. Chronic SCD pain is commonly managed with opioid-based drugs that are associated with unwanted side effects, incomplete pain relief, and - in this population - accessibility issues. Thus, new treatments for chronic SCD pain are desperately needed. Here, we examined the analgesic efficacy of acute minocycline treatment in transgenic SCD mice. SCD mice exhibit gut dysbiosis and chronic inflammation. Therefore, we hypothesized that minocycline would provide robust analgesia in this model given the drugs antibiotic and anti-inflammatory properties respectively. Six days of minocycline treatment reversed chronic mechanical hypersensitivity only in male SCD mice. We identified two potential mechanisms underlying these sex-specific effects. First, we observed increased microgliosis only in the dorsal horn of male SCD mice. Minocycline treatment had opposite effects on microglial number in male and female SCD spinal cords. Second, minocycline treatment altered the gut microbiota in a sex-specific fashion; fecal microbiota transplant (FMT) from minocycline-treated female SCD mice induced widespread pain in recipients whereas FMT from minocycline-treated male SCD mice did not. In summary, these experiments highlight novel sex-specific mechanisms of minocycline analgesia and support future exploration of minocycline use for SCD pain management, but only in male patients.

neuroscience↗