HdhQ150/+ animals displayed impaired CRF task acquisition and performance at 44-52 weeks of
age (Chapter 5), which is the first report of such an impairment in the HdhQ150 mouse model of HD, to my current knowledge. This deficit was not observed in HdhQ150/+ mice at 13 weeks of
age in the current work (Chapter 3), which suggests that onset of this deficit in heterozygous HdhQ150 animals occurs between 13 and 44-52 weeks of age. The validity of this conclusion is questionable, however, because of the different genders of animals used in the two experiments assessing CRF performance in HdhQ150/+ animals; Chapter 3 utilised female mice whereas Chapter
5 used male animals. Thus, it is possible that the differences in HdhQ150/+ CRF task performance
identified between the time points examined resulted from sex-dependent variations in cognitive ability. A number of sex-dependent differences in cognition have been reported outside of HD mouse models (Bowman et al., 2009; Duvoisin et al., 2010; Yue et al., 2011; Breitberg et al., 2013; Jasarevic et al., 2013; Sanches et al., 2013; Suwalska and Lojko, 2014), including variation in age-related cognitive decline (Zanos et al., 2015). Similarly, gender has previously been shown to differentially affect behavioural phenotypes in a variety of HD mouse models, with sex-dependent differences observed in cognitive ability and depressive symptoms in R6/1 mice (Renoir et al., 2011; Mo et al., 2013; Mo et al., 2014), circadian dysfunction in BACHD mice (Kuljis et al., 2016), and anxiety in HdhQ140 animals (Dorner et al., 2007). Therefore, examination of CRF task performance in both male and female HdhQ150/+ mice at 13
and 44-52 weeks of age may be necessary to establish whether the deficit observed at 44-52 weeks of age results from age- or sex-dependent changes in cognitive ability.
It is also possible that the abnormal CRF task performance observed in HdhQ150/+ animals in the
current work is not a cognitive deficit but a motivational deficit, which may be the result of decreased palatability to the food reward, as discussed in Chapter 5.4.1. In order to elucidate which of these behavioural phenotypes accounts for the CRF task performance deficit, examination of HdhQ150/+ mice lick cluster response to the Yazoo® strawberry flavoured
milkshake reward and performance in the progressive ratio task may be required. Unpublished data from our laboratory (Brooks et al., unpublished) demonstrates that HdhQ150/+ animals
display equivalent levels of palatability for sucrose pellets as their wild-type counterparts at 17- 26 weeks of age (Figure 6.1), which suggests that a decreased hedonic response to the food
172 reward is unlikely to be responsible for the CRF task performance impairment observed in the current work. However, palatability to the Yazoo® strawberry flavoured milkshake reward used in the current study has yet to be performed in HdhQ150/+ animals.
Figure 6.1. The mean weight of sucrose pellets consumed (g/kg) by Hdh+/+ and HdhQ150/+ animals (Brooks et al., unpublished). Hdh+/+ (n = 13) and HdhQ150/+ (n = 11) mice consumed an
equivalent weight of sucrose pellets at 17-26 weeks of age (main effect of genotype: t(22) = 0.633, p = 0.533). Values shown are mean ± S.E.M.
Conditional and optogenetic studies have demonstrated that the direct and indirect pathways of the basal ganglia (see Chapter 1.1.2.2) play opposing roles in reward and motivation; conditional knockout of striatopallidal neurons of the indirect pathway causes an increase in drug reinforcement in the conditioned place preference paradigm (Durieux et al., 2009) while activation of these neurons by optogenetic means leads to a decrease in drug reward (Lobo et al., 2010), which suggests that the indirect pathway inhibits drug reinforcement, and therefore inhibits the rewarding effect of drug-use. Conversely, optogenetic activation of striatonigral neurons of the direct pathway results in an increase in drug reinforcement (Lobo et al., 2010) while blockade of this pathway causes a decrease in drug reinforcement (Hikida et al., 2010), suggesting that activation of the direct pathway facilitates drug reinforcement, and thus reward. Based upon this evidence, and evidence that the indirect pathway first undergoes degeneration in HD (Reiner et al., 1988), one would anticipate that HdhQ150/+ animals would display a
phenotype of increased palatability and motivation, which is opposite to the potential motivation phenotype observed in the current work. However, recent evidence of separate
0 20 40 60 80 100 120 A XIS T IT LE
Weight of sucrose pellets consumed
W ei gh t (g /k g)
173 dorsal and ventral striatonigral DRD1 neuron-dependent circuits for the metabolic and hedonic responses to sugar (Tellez et al., 2016) suggests that HdhQ150/+ animals would display healthy
levels of palatability and motivation to the milkshake food reward, as DRD1 neurons of the direct striatonigral pathway are resistant to degeneration until the later stages of HD (Reiner et al., 1988). It is clear from these studies that the neuroanatomical basis of hedonic response is likely to be complex and is not yet fully understood, making it difficult to hypothesise how the striatal cell loss observed in mouse models of HD may affect motivation and hedonistic responses in the animals. Furthermore, previous reports demonstrate that HdhQ150/+ mice do not present with
significant striatal neuron number loss until after 70 weeks of age (Heng et al., 2007), which is beyond the age that animals were examined in the current study, suggesting that neuron loss is unlikely to cause the potential motivational abnormality observed in HdhQ150/+ animals.
However, the presence of striatal NIIs (Tallaksen-Greene et al., 2005) and heightened levels of reactive gliosis (Lin et al., 2001) have been demonstrated in HdhQ150/+ mice at the ages examined
in the current work, suggesting that pathological damage to specific subpopulations of striatal neurons could account for the motivational deficits observed. Thus, examining NII formation, reactive gliosis, and gene expression levels in the distinct subpopulations of neurons in the direct and indirect pathways of the basal ganglia may be worthwhile in future studies investigating motivation in HdhQ150/+ mice, as opposed to investigating transcriptional level changes across all
cell types in the striatum, which occurred in the current work.