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Peer-reviewedCC BY-NC-ND 4.0Molecular Psychiatry

Experimental change in temperament: Conversion of the low exploratory phenotype into highly explorative by overexpression of GDNF in the rat striatum

  • Jaanus Harro1,2,3
  • Aet O’Leary1,4
  • Marianna Norden3,5
  • Kristi Liiver3
  • Margus Kanarik1
  • J. Arturo García-Horsman6
  • Sven Sakson2
  • Pilleriin Kupper1
  • Karita Laugus1
  • Sirin Korulu1,3
  • Indrek Teino2,7
  • Tõnis Org7,8
9 more authors
  • Ilmari Parkkinen6
  • Tanel Kaart9
  • Päivi Lindholm2
  • Sophie Imbeault3
  • Helen Poska3
  • Brandon K. Harvey10
  • Mikko Airavaara6
  • Ruth Shimmo3
  • Mart Saarma2
10 affiliations
  1. 1Division of Neuropsychopharmacology, Institute of Chemistry, University of Tartu, Ravila 14A Chemicum, 50411 Tartu, Estonia
  2. 2Institute of Biotechnology, HiLIFE, University of Helsinki, Viikinkaari 5D, 00790 Helsinki, Finland
  3. 3School of Natural Sciences and Health, Tallinn University, Narva 25, 10120 Tallinn, Estonia
  4. 4Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Heinrich-Hoffmann-Straße 10, 60528 Frankfurt am Main, Germany
  5. 5Institute of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia 15, 12618 Tallinn, Estonia
  6. 6Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00014 Helsinki, Finland
  7. 7Institute of Molecular and Cell Biology, University of Tartu, Riia 23, 50107 Tartu, Estonia
  8. 8Institute of Genomics, University of Tartu, Riia 23B, 50107 Tartu, Estonia
  9. 9Institute of Veterinary Medicine and Animal Sciences, Estonian University of Life Sciences, Fr. R. Kreutzwaldi 1, 51006 Tartu, Estonia
  10. 10National Institute on Drug Abuse, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224 USA
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Abstract

Major vulnerability factors for psychiatric disorders such as depression, that often prevent complete remission and lead to relapses, are temperamental. In a rat model of clustered persistent high-anxiety/low-motivation, we have found that overexpression of glial cell line-derived neurotrophic factor (GDNF) by intra-striatally administered adeno-associated virus vector completely converts the passive coping style of low exploratory rats into an active one, similar to high exploratory rats. This conversion of the behavioural strategy developed gradually over repeated testing, and was associated with increased catecholamine metabolism in several brain regions and changes in the regulation of serotonin neurotransmission. An increase in dopamine transporter availability in the striatum was necessary for the phenotype conversion. Associated changes in striatal gene expression included key regulators of monoamine storage and epitranscriptomic regulation. The increase in GDNF signalling also caused alterations in levels and regional covariation of oxidative metabolism, suggestive of a reorganization of neural activity throughout the brain. Thus, neurotrophic factors, GDNF in particular, may play a pivotal role in the development, persistence and alteration of temperament/personality traits, and therefore constitute a potential target for treatment of chronic, relapsing psychiatric disorders.

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Cite

BibTeXRIS
BibTeX
@article{harro2026experimental,
  title = {{Experimental change in temperament: Conversion of the low exploratory phenotype into highly explorative by overexpression of GDNF in the rat striatum}},
  author = {Jaanus Harro and Aet O’Leary and Marianna Norden and Kristi Liiver and Margus Kanarik and J. Arturo García-Horsman and Sven Sakson and Pilleriin Kupper and Karita Laugus and Sirin Korulu and Indrek Teino and Tõnis Org and Ilmari Parkkinen and Tanel Kaart and Päivi Lindholm and Sophie Imbeault and Helen Poska and Brandon K. Harvey and Mikko Airavaara and Ruth Shimmo and Mart Saarma},
  journal = {Molecular Psychiatry},
  year = {2026},
  month = jul,
  doi = {10.1038/s41380-026-03753-7},
  url = {https://doi.org/10.1038/s41380-026-03753-7},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Experimental change in temperament: Conversion of the low exploratory phenotype into highly explorative by overexpression of GDNF in the rat striatum
AU  - Jaanus Harro
AU  - Aet O’Leary
AU  - Marianna Norden
AU  - Kristi Liiver
AU  - Margus Kanarik
AU  - J. Arturo García-Horsman
AU  - Sven Sakson
AU  - Pilleriin Kupper
AU  - Karita Laugus
AU  - Sirin Korulu
AU  - Indrek Teino
AU  - Tõnis Org
AU  - Ilmari Parkkinen
AU  - Tanel Kaart
AU  - Päivi Lindholm
AU  - Sophie Imbeault
AU  - Helen Poska
AU  - Brandon K. Harvey
AU  - Mikko Airavaara
AU  - Ruth Shimmo
AU  - Mart Saarma
PY  - 2026
DA  - 2026/07/10
JO  - Molecular Psychiatry
DO  - 10.1038/s41380-026-03753-7
UR  - https://doi.org/10.1038/s41380-026-03753-7
AB  - Major vulnerability factors for psychiatric disorders such as depression, that often prevent complete remission and lead to relapses, are temperamental. In a rat model of clustered persistent high-anxiety/low-motivation, we have found that overexpression of glial cell line-derived neurotrophic factor (GDNF) by intra-striatally administered adeno-associated virus vector completely converts the passive coping style of low exploratory rats into an active one, similar to high exploratory rats. This conversion of the behavioural strategy developed gradually over repeated testing, and was associated with increased catecholamine metabolism in several brain regions and changes in the regulation of serotonin neurotransmission. An increase in dopamine transporter availability in the striatum was necessary for the phenotype conversion. Associated changes in striatal gene expression included key regulators of monoamine storage and epitranscriptomic regulation. The increase in GDNF signalling also caused alterations in levels and regional covariation of oxidative metabolism, suggestive of a reorganization of neural activity throughout the brain. Thus, neurotrophic factors, GDNF in particular, may play a pivotal role in the development, persistence and alteration of temperament/personality traits, and therefore constitute a potential target for treatment of chronic, relapsing psychiatric disorders.
SN  - 1359-4184
SN  - 1476-5578
ER  -