Fig. 1.

Generation of LacQ140 mice and treatment paradigm.

(a) The LacO/LacIR-regulatable HD mouse model (LacQ140) was generated by crossing the Htt^LacQ140/+ mouse to the Tg^{ACTB-lacI*Scrb} mouse (Cronin et al., 2001) as previously described (Marchionini et al., 2022). The default state of the LacQ140 mouse is global repression of mHtt due to Lac Repressor binding to the Lac operators. Administration of IPTG starting from embryonic day 5 (E5) interrupts the binding between the Lac repressor and operators, resulting in a de-repressed state, and maximal expression of mHtt in LacQ140. All WT mice were Htt^LacO+/+; b-actin-LacI^R tg. (b) Mice were fed ad libitum; the lactose analog IPTG was provided in drinking water (at 10mM) which de-represses the LacQ140 allele and keeps normal mHtt expression. During embryonic development, mHtt expression levels were maintained at normal levels by administering IPTG to pregnant dams starting at embryonic day 5 (E5). IPTG was continuously administered to WT mice. IPTG was administered continuously (mHtt continuously expressed, LacQ140), withdrawn at 8 months (mHtt repressed beginning at 8 months, LacQ140_8M), withdrawn 2 at months (mHtt repressed beginning at 2 months, LacQ140_2M), or never administered (mHtt always repressed, LacQ140_A). Tissue for each group (except LacQ140_8M) was collected at 6, 9, and 12 months of age.