Journal article
Diphtheria toxin treatment of Pet-1-Cre floxed diphtheria toxin receptor mice disrupts thermoregulation without affecting respiratory chemoreception
Neuroscience, Vol.279, pp.65-76
10/24/2014
DOI: 10.1016/j.neuroscience.2014.08.018
PMCID: PMC4443915
PMID: 25171790
Abstract
In genetically-modified
Lmx1b
f/f/p
mice, selective deletion of LMX1B in
Pet-1
expressing cells leads to failure of embryonic development of serotonin (5-HT) neurons. As adults, these mice have a decreased hypercapnic ventilatory response and abnormal thermoregulation. This mouse model has been valuable in defining the normal role of 5-HT neurons, but it is possible that developmental compensation reduces the severity of observed deficits. Here we studied mice genetically modified to express diphtheria toxin receptors (DTR) on
Pet-1
expressing neurons (
Pet-1-Cre
/Floxed DTR or Pet1/DTR mice). These mice developed with a normal complement of 5-HT neurons. As adults, systemic treatment with 2 – 35 μg diphtheria toxin (DT) reduced the number of tryptophan hydroxylase immunoreactive (TpOH-ir) neurons in the raphe nuclei and ventrolateral medulla by 80%. There were no effects of DT on baseline ventilation (V
E
) or the ventilatory response to hypercapnia or hypoxia. At an ambient temperature (T
A
) of 24°C, all Pet1/DTR mice dropped their body temperature (T
B
) below 35°C after DT treatment, but the latency was shorter in males than females (3.0 ± 0.37 vs 4.57 ± 0.29 days, respectively; p < 0.001). One week after DT treatment, mice were challenged by dropping T
A
from 37°C to 24°C, which caused T
B
to decrease more in males than in females (29.7 ± 0.31°C vs 33.0 ± 1.3°C, p < 0.01). We conclude that the 20% of 5-HT neurons that remain after DT treatment in Pet1/DTR mice are sufficient to maintain normal baseline breathing and a normal response to CO
2
, while those affected include some essential for thermoregulation, in males more than females. In comparison to models with deficient embryonic development of 5-HT neurons, acute deletion of 5-HT neurons in adults leads to a greater defect in thermoregulation, suggesting that significant developmental compensation can occur.
Details
- Title: Subtitle
- Diphtheria toxin treatment of Pet-1-Cre floxed diphtheria toxin receptor mice disrupts thermoregulation without affecting respiratory chemoreception
- Creators
- Verónica Cerpa - Departments of Neurology and Cellular & Molecular Physiology, Yale University, New Haven, CT 06520Amalia Gonzalez - Departments of Neurology and Cellular & Molecular Physiology, Yale University, New Haven, CT 06520George B Richerson - Departments of Neurology and Cellular & Molecular Physiology, Yale University, New Haven, CT 06520
- Resource Type
- Journal article
- Publication Details
- Neuroscience, Vol.279, pp.65-76
- DOI
- 10.1016/j.neuroscience.2014.08.018
- PMID
- 25171790
- PMCID
- PMC4443915
- NLM abbreviation
- Neuroscience
- ISSN
- 0306-4522
- eISSN
- 1873-7544
- Grant note
- DOI: 10.13039/100000002, name: NIH, award: 2U54NS041069, P01HD36379, P20NS076916, R01HD052772; name: VAMC; name: Beth L. Tross Epilepsy Research Fund
- Language
- English
- Date published
- 10/24/2014
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Neurosurgery
- Record Identifier
- 9984020603002771
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