Cerebral dopamine neurotrophic factor (CDNF) affects hippocampal neuroplasticity and fear memory in rats

The role of CDNF in modulating learning and memory remains largely unexplored. Here, hippocampal CDNF overexpression significantly accelerated extinction of contextual and cued fear memory in rats. Molecularly, overexpressed CDNF was retained in the ER and upregulated mRNA levels of Perk, Atf6, and spliced Xbp1, indicating activation of UPR-related signaling.

Furthermore, CDNF overexpression increased CREB transcription and phosphorylation. Additionally, Cdnf mRNA levels correlated positively with transcript levels of Bdnf exons I, II, and IV. In primary hippocampal neurons, CDNF enhanced spontaneous bioelectrical activity, network burst complexity, and functional connectivity, as evidenced by multielectrode array and calcium imaging.

These findings suggest that CDNF facilitates fear memory extinction, potentially through UPR-related signaling and enhanced neuronal excitability and network synchronization, positioning it as a potential regulator of hippocampal-dependent plasticity. This study was supported by the Russian Science Foundation (grant number 25-15-00043). Tatiana Ilchibaeva and Anton Tsybko contributed equally to this work.

Federal Research Center Institute of Cytology and Genetics, Siberian Division of the Russian Academy of Science, Lavrentyeva av. 10, Novosibirsk, 630090, Russia Tatiana Ilchibaeva, Anton Tsybko, Dmitry Eremin, Yana Kaminskaya & Vladimir Naumenko Institute of Biology and Biomedicine, Lobachevsky State University of Nizhni Novgorod, Gagarin av. 23, Nizhny Novgorod, 603022, Russia Elena Mitroshina, Tatiana Mishchenko & Maria Vedunova The authors declare no competing interests. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Below is the link to the electronic supplementary material.

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