Viral Gene Delivery Selectively Restores Feeding and Prevents Lethality of Dopamine-Deficient Mice
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Dopamine-deficient mice (DA-/- ), lacking tyrosine hydroxylase (TH) in dopaminergic neurons, become hypoactive and aphagic and die by 4 weeks of age. They are rescued by daily treatment with L-3,4-dihydroxyphenylalanine (L-DOPA); each dose restores dopamine (DA) and feeding for less than 24 hr. Recombinant adeno-associated viruses expressing human TH or GTP cyclohydrolase 1 (GTPCH1) were injected into the striatum of DA-/- mice. Bilateral coinjection of both viruses restored feeding behavior for several months. However, locomotor activity and coordination were partially improved. A virus expressing only TH was less effective, and one expressing GTPCH1 alone was ineffective. TH immunoreactivity and DA were detected in the ventral striatum and adjacent posterior regions of rescued mice, suggesting that these regions mediate a critical DA-dependent aspect of feeding behavior.
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Treatment of DA-deficient mice with L-DOPA to restore striatal DA levels to 10% of normal is sufficient to elicit normal feeding behavior and animal survival.
“However, intervention and treatment of the mice with L-DOPA to restore striatal DA levels to 10% of the levels in normal mice is sufficient to elicit normal feeding behavior and animal survival [302].”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [302]
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- Authors
- Szczypka, M. S., Mandel, R. J., Donahue, B. A., Snyder, R. O., Leff, S. E., & Palmiter, R. D.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Palmiter, Richard D
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 1999-01
- Volume
- 22
- Issue
- 1
- Pages
- 167-178
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2038432598
- Cited by
- 129
- References
- 60
- Citations by year
- 2026: 3 · 2024: 2 · 2023: 1 · 2021: 4 · 2020: 3 · 2019: 2 · 2018: 1 · 2017: 2 · 2016: 5 · 2015: 4 · 2014: 1 · 2013: 10 · 2012: 4
- FWCI
- 7.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 09172, F32HD008121, HD-08121-02)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- dopamine deficiency, tyrosine hydroxylase, GTP cyclohydrolase I, viral gene delivery, adeno-associated virus, feeding behavior, lethality, dopaminergic neurons, ventral striatum, locomotor activity, L-DOPA
- MeSH terms
- Adenoviridae, Animals, Catecholamines, Dopamine, Feeding Behavior, Genetic Vectors, GTP Cyclohydrolase, Humans, Immunohistochemistry, Isoenzymes, Levodopa, Metabolic Diseases, Mice, Inbred Strains, Motor Activity, Recombination, Genetic, Stereotyped Behavior, Tissue Distribution, Tyrosine 3-Monooxygenase, Gene Transfer Techniques, Mice
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