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Hypothalamic expression of mutant huntingtin contributes to the development of depressive-like behavior in the BAC transgenic mouse model of Huntingtons disease

Hult Lundh, Sofia LU ; Nilsson, Nathalie LU ; Soylu, Rana LU ; Kirik, Deniz LU and Petersén, Åsa LU (2013) In Human Molecular Genetics 22(17). p.3485-3497
Abstract
Psychiatric symptoms such as depression and anxiety are important clinical features of Huntingtons disease (HD). However, the underlying neurobiological substrate for the psychiatric features is not fully understood. In order to explore the biological origin of depression and anxiety in HD, we used a mouse model that expresses the human full-length mutant huntingtin, the BACHD mouse. We found that the BACHD mice displayed depressive- and anxiety-like features as early as at 2 months of age as assessed using the Porsolt forced swim test (FST), the sucrose preference test and the elevated plus maze (EPM). BACHD mice subjected to chronic treatment with the anti-depressant sertraline were not different to vehicle-treated BACHD mice in the FST... (More)
Psychiatric symptoms such as depression and anxiety are important clinical features of Huntingtons disease (HD). However, the underlying neurobiological substrate for the psychiatric features is not fully understood. In order to explore the biological origin of depression and anxiety in HD, we used a mouse model that expresses the human full-length mutant huntingtin, the BACHD mouse. We found that the BACHD mice displayed depressive- and anxiety-like features as early as at 2 months of age as assessed using the Porsolt forced swim test (FST), the sucrose preference test and the elevated plus maze (EPM). BACHD mice subjected to chronic treatment with the anti-depressant sertraline were not different to vehicle-treated BACHD mice in the FST and EPM. The behavioral manifestations occurred in the absence of reduced hippocampal cell proliferation/neurogenesis or upregulation of the hypothalamicpituitaryadrenal axis. However, alterations in anxiety- and depression-regulating genes were present in the hypothalamus of BACHD mice including reduced mRNA expression of neuropeptide Y, tachykinin receptor 3 and vesicular monoamine transporter type 2 as well as increased expression of cocaine and amphetamine regulated transcript. Interestingly, the orexin neuronal population in the hypothalamus was increased and showed cellular atrophy in old BACHD mice. Furthermore, inactivation of mutant huntingtin in a subset of the hypothalamic neurons prevented the development of the depressive features. Taken together, our data demonstrate that the BACHD mouse recapitulates clinical HD with early psychiatric aspects and point to the role of hypothalamic dysfunction in the development of depression and anxiety in the disease. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Human Molecular Genetics
volume
22
issue
17
pages
3485 - 3497
publisher
Oxford University Press
external identifiers
  • wos:000322921400008
  • scopus:84881580793
ISSN
0964-6906
DOI
10.1093/hmg/ddt203
language
English
LU publication?
yes
id
c0306676-bf3e-4717-9704-db7b6af0fb3b (old id 4103214)
date added to LUP
2013-11-07 14:20:40
date last changed
2019-06-11 01:11:44
@article{c0306676-bf3e-4717-9704-db7b6af0fb3b,
  abstract     = {Psychiatric symptoms such as depression and anxiety are important clinical features of Huntingtons disease (HD). However, the underlying neurobiological substrate for the psychiatric features is not fully understood. In order to explore the biological origin of depression and anxiety in HD, we used a mouse model that expresses the human full-length mutant huntingtin, the BACHD mouse. We found that the BACHD mice displayed depressive- and anxiety-like features as early as at 2 months of age as assessed using the Porsolt forced swim test (FST), the sucrose preference test and the elevated plus maze (EPM). BACHD mice subjected to chronic treatment with the anti-depressant sertraline were not different to vehicle-treated BACHD mice in the FST and EPM. The behavioral manifestations occurred in the absence of reduced hippocampal cell proliferation/neurogenesis or upregulation of the hypothalamicpituitaryadrenal axis. However, alterations in anxiety- and depression-regulating genes were present in the hypothalamus of BACHD mice including reduced mRNA expression of neuropeptide Y, tachykinin receptor 3 and vesicular monoamine transporter type 2 as well as increased expression of cocaine and amphetamine regulated transcript. Interestingly, the orexin neuronal population in the hypothalamus was increased and showed cellular atrophy in old BACHD mice. Furthermore, inactivation of mutant huntingtin in a subset of the hypothalamic neurons prevented the development of the depressive features. Taken together, our data demonstrate that the BACHD mouse recapitulates clinical HD with early psychiatric aspects and point to the role of hypothalamic dysfunction in the development of depression and anxiety in the disease.},
  author       = {Hult Lundh, Sofia and Nilsson, Nathalie and Soylu, Rana and Kirik, Deniz and Petersén, Åsa},
  issn         = {0964-6906},
  language     = {eng},
  number       = {17},
  pages        = {3485--3497},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Hypothalamic expression of mutant huntingtin contributes to the development of depressive-like behavior in the BAC transgenic mouse model of Huntingtons disease},
  url          = {http://dx.doi.org/10.1093/hmg/ddt203},
  volume       = {22},
  year         = {2013},
}