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A53 Effects of hypothalamic circuitries on pathology in the ventral striatum in mouse models of huntington disease
  1. Rana Soylu-Kucharz1,2,
  2. Natalie Adlesic1,
  3. Jo Henningsen1,
  4. Marcus Davidsson3,
  5. Tomas Bjorklund3,
  6. Maria Björkqvist2,
  7. Åsa Petersén1
  1. 1Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
  2. 2Brain Disease Biomarker Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
  3. 3Molecular Neuromodulation, Department of Experimental Medical Science, Lund University, Lund, Sweden

Abstract

Background Hypothalamus with its neuroendocrine circuitry is a main regulator of metabolism, emotional control and the reward system. It is also an important region of pathology in clinical Huntington’s disease (HD) with loss of orexin neurons. Given that the hypothalamus is affected already in prodromal HD, pathology in this area may mediate early features of HD such as apathy. We hypothesize that dysfunction of hypothalamic circuitries to the ventral striatum contributes to striatal pathology and the development of altered reward-mediated behavior such as apathy.

Aim To investigate the effects of selective mutant HTT expression in the hypothalamus on striatal pathology.

Methods Wild-type mice were injected bilaterally with adeno-associated viral (AAV) vectors expressing a mutant (79Q) or a normal (18Q) HTT fragment in the hypothalamus. Stereological quantification of brains processed for DARPP-32, NeuN and cresyl violet was performed in the ventral striatum. Retrograde labelling of the hypothalamic projection neurons to ventral striatum was achieved using a novel vector design.

Results Selective hypothalamic expression of a mutant HTT fragment leads to orexin loss and a specific reduction in the number of DARPP-32 and NeuN positive neurons in the ventral striatum. Moreover, the R6/2 model of HD recapitulates these changes with a similar loss of DARPP-32 in ventral striatum. Next, we have shown successful retrograde labelling of hypothalamic projection neurons, which will be sufficient for chemogenetic modulation of hypothalamo-striatal circuitries to investigate the underlying neuronal dysfunction.

Conclusions These results suggest that hypothalamic mutant HTT expression can potentially contribute to pathological mechanisms underlying ventral striatum pathology in HD.

  • hypothalamus
  • ventral striatum
  • reward

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