Sex differences in a transgenic rat model of Huntington's disease: decreased 17β-estradiol levels correlate with reduced numbers of DARPP32+ neurons in males

Abstract

Recent clinical studies have highlighted that female sex hormones represent potential neuroprotective mediators against damage caused by acute and chronic brain diseases. This evidence has been confirmed by experimental studies documenting the protective role of female sex hormones both in vitro and in vivo, although these studies did not specifically focus on Huntington's disease (HD). We therefore investigated the onset and course of HD in female and male transgenic (tg) HD (CAG(n51)) and control rats across age and focused on three aspects: (i) behavioral and physiological alterations (energy expenditure, home-cage activity, emotional disturbance and motor dysfunction), (ii) morphological markers (numbers and characteristics of striatal DARPP32(+) medium-sized spiny neurons (MSNs) and dopamine receptor autoradiography) and (iii) peripheral sex hormone levels as well as striatal estrogen receptor expression. Independent of their sex, tgHD rats exhibited increased levels of food intake, elevated home-cage activity scores and anxiolytic-like behavior, whereas only males showed an impairment of motor function. In line with the latter finding, loss and atrophy of DARPP32(+) MSNs were apparent only in male tgHD rats. This result was associated with a decreased striatal dopamine D1 receptor density and lower plasma levels of 17beta-estradiol at the age of 14 months. As DARPP32(+) MSNs expressed both alpha- and beta-estrogen receptors and showed a correlation between cell numbers and 17beta-estradiol levels, our findings suggest sex-related differences in the HD phenotype pointing to a substantial neuroprotective effect of sex hormones and opening new perspectives on the therapy of HD.

A Novel BACHD Transgenic Rat Exhibits Characteristic Neuropathological Features of Huntington Disease

“…Compared with the already existing fragment tgHD rats BACHD rats show an earlier onset and a faster progression of motor deficits without the need to breed for homozygosity as heterozygous tgHD rats show only subtle deficits . Recently, a milder phenotype in tgHD rats as originally described has been reported (Casteels et al, 2011;Antonsen et al, 2012;Blockx et al, 2012). Also, while striatal atrophy was found in some groups of old tgHD rats (von Hörsten et al, 2003;, other studies revealed little or no evidence for atrophy (Winkler et al, 2006;Bode et al, 2008;Blockx et al, 2011).…”

“…The stability of CAG repeat expansions is of critical importance for therapeutic studies, since the age of onset of HD inversely correlates with the number of CAG repeats (Duyao et al, 1993;Stine et al, 1993). In total, 100 samples from different brain regions or peripheral tissue were collected from transgenic rats with ages of up to 18 months of four generations and both genders to verify the stability of the polyglutamine stretch in our transgenic rat model.…”

Estriol‐mediated neuroprotection in multiple sclerosis localized by voxel‐based morphometry

“…Therefore, we hypothesize that the relatively modest effect on localized GM sparing using VBM may be due to a lack of direct neuroprotective effects of natalizumab. Estrogens, in contrast, have been shown to be neuroprotective in a variety of neurologic disease models (Bode et al., 2008; Engler‐Chiurazzi, Brown, Povroznik, & Simpkins, 2017; Spence & Voskuhl, 2012; Suzuki, Brown, & Wise, 2009), including estriol treatment on cognitive electrophysiologic and neuropathologic outcomes in the MS model (Ziehn, Avedisian, Dervin, O'Dell, & Voskuhl, 2012). …”

“…Further, we have shown that treatment with estrogens and estrogen receptor ligands prevented both cortical and cerebellar GM atrophy by MRI, which correlated with preserving axons, neurons, and synapses in EAE (Itoh et al., 2017; Kim et al., 2018; MacKenzie‐Graham et al., 2012). Consistent with this, treatment with estrogens has been associated with neuroprotection in mouse models of ischemic stroke, Alzheimer's disease, Parkinson's disease, and Huntington's disease (Bode et al., 2008; Morissette, Al Sweidi, Callier, & Di Paolo, 2008; Suzuki et al., 2009; Yue et al., 2005). …”

The Ventral Striatopallidum and Extended Amygdala in Huntington Disease

“…Among all Huntington animal models generated until now (and including the two extensively studied R6/2 and YAC128 mice), the tgHD rat is unique as it shows most prominent accumulation of htt aggregates in structures of the VSP and the EA (Niescery et al, 2009;Petrasch-Parwez et al, 2007). Moreover, it presents very early and ongoing emotional changes, which partly may be associated with dysfunctions of the VSP and EA (Bode et al, 2008;Faure et al, 2011;Nguyen et al, 2006). The distribution of htt accumulates in the medioventral striatum including the olfactory tubercle ( Fig.…”