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Mutant huntingtin expression in the hypothalamus promotes ventral striatal neuropathology

Soylu Kucharz, Rana LU ; Adlesic, Natalie LU ; Davidsson, Marcus LU ; Björklund, Tomas LU ; Björkqvist, Maria LU orcid and Petersén, Åsa LU (2023)
Abstract
Huntington’s disease is a fatal neurodegenerative disorder caused by an expanded CAG triplet repeat in the huntingtin (HTT) gene. Previous research focused on neuropathology in the striatum and its association with a typical movement disorder. Direct effects of mutant HTT (mHTT) in the striatum may cause neuropathology, although non-cell autonomous effects have also been suggested. Important non-motor features of HD include psychiatric symptoms and metabolic dysfunction, which may be linked to hypothalamic neuropathology. As hypothalamic neurons project to the ventral striatum, we hypothesized that expression of mHTT in the hypothalamus leads to disrupted neurotransmission in the ventral striatum and causes pathology.
The overall aim... (More)
Huntington’s disease is a fatal neurodegenerative disorder caused by an expanded CAG triplet repeat in the huntingtin (HTT) gene. Previous research focused on neuropathology in the striatum and its association with a typical movement disorder. Direct effects of mutant HTT (mHTT) in the striatum may cause neuropathology, although non-cell autonomous effects have also been suggested. Important non-motor features of HD include psychiatric symptoms and metabolic dysfunction, which may be linked to hypothalamic neuropathology. As hypothalamic neurons project to the ventral striatum, we hypothesized that expression of mHTT in the hypothalamus leads to disrupted neurotransmission in the ventral striatum and causes pathology.
The overall aim of this study was to investigate the impact of mHTT expression in the hypothalamus on ventral striatal neuropathology and its contribution to non-HD motor symptoms. We demonstrate that selective expression of mHTT in the hypothalamus leads to the loss of dopamine and cAMP-regulated phosphoprotein (DARPP-32) immunopositive neurons in the ventral striatum in mice. Contrary to the effects of direct expression of mHTT in the hypothalamus, selective overexpression of mHTT in the ventral striatum does not affect body weight. Selective expression of mHTT in the ventral striatum leads to mHTT inclusion formation and loss of DARPP-32 neurons without affecting motor activity or anxiety-like behavior. We show that DARPP-32 neuron loss in the ventral striatum is recapitulated in the R6/2 mouse model of HD. Chemogenetic activation of hypothalamic neurons projecting to the ventral striatum had a blunted response in the R6/2 mice compared to wild-type mice, indicating a disrupted hypothalamus-ventral striatal circuitry. In summary, the expression of mHTT in the hypothalamus may impact the development of ventral striatal pathology in mice. This opens the possibility that non-cell-autonomous effects in the reward circuitry play a role in HD. (Less)
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author
; ; ; ; and
organization
publishing date
type
Working paper/Preprint
publication status
published
subject
publisher
bioRxiv
DOI
10.1101/2023.03.04.530949
language
English
LU publication?
yes
id
90ad1da6-f1eb-4091-bb20-374c82c9d8fc
date added to LUP
2023-03-10 10:45:22
date last changed
2023-03-10 15:34:05
@misc{90ad1da6-f1eb-4091-bb20-374c82c9d8fc,
  abstract     = {{Huntington’s disease is a fatal neurodegenerative disorder caused by an expanded CAG triplet repeat in the huntingtin (HTT) gene. Previous research focused on neuropathology in the striatum and its association with a typical movement disorder. Direct effects of mutant HTT (mHTT) in the striatum may cause neuropathology, although non-cell autonomous effects have also been suggested. Important non-motor features of HD include psychiatric symptoms and metabolic dysfunction, which may be linked to hypothalamic neuropathology. As hypothalamic neurons project to the ventral striatum, we hypothesized that expression of mHTT in the hypothalamus leads to disrupted neurotransmission in the ventral striatum and causes pathology. <br/>The overall aim of this study was to investigate the impact of mHTT expression in the hypothalamus on ventral striatal neuropathology and its contribution to non-HD motor symptoms. We demonstrate that selective expression of mHTT in the hypothalamus leads to the loss of dopamine and cAMP-regulated phosphoprotein (DARPP-32) immunopositive neurons in the ventral striatum in mice. Contrary to the effects of direct expression of mHTT in the hypothalamus, selective overexpression of mHTT in the ventral striatum does not affect body weight. Selective expression of mHTT in the ventral striatum leads to mHTT inclusion formation and loss of DARPP-32 neurons without affecting motor activity or anxiety-like behavior. We show that DARPP-32 neuron loss in the ventral striatum is recapitulated in the R6/2 mouse model of HD. Chemogenetic activation of hypothalamic neurons projecting to the ventral striatum had a blunted response in the R6/2 mice compared to wild-type mice, indicating a disrupted hypothalamus-ventral striatal circuitry. In summary, the expression of mHTT in the hypothalamus may impact the development of ventral striatal pathology in mice. This opens the possibility that non-cell-autonomous effects in the reward circuitry play a role in HD.}},
  author       = {{Soylu Kucharz, Rana and Adlesic, Natalie and Davidsson, Marcus and Björklund, Tomas and Björkqvist, Maria and Petersén, Åsa}},
  language     = {{eng}},
  month        = {{03}},
  note         = {{Preprint}},
  publisher    = {{bioRxiv}},
  title        = {{Mutant huntingtin expression in the hypothalamus promotes ventral striatal neuropathology}},
  url          = {{http://dx.doi.org/10.1101/2023.03.04.530949}},
  doi          = {{10.1101/2023.03.04.530949}},
  year         = {{2023}},
}