Towards humane end points: behavioural changes precede clinical signs of disease in a Huntington's disease model.

The number of animals used in science is increasing, bringing a concomitant obligation to minimize suffering. For animals with progressive conditions, euthanasia at a 'humane end point' is advised if the end point is scientifically valid, predictive and accurate. Our aim was to test the hypothesis that behavioural changes would reliably precede clinical signs of disease in a progressive neurological model, using retrospective analysis. We observed 100 pair-housed female R6/1 transgenic Huntington's disease (HD) mice and 28 pair-housed female wild-type (WT) mice in standard- or resource-enriched cages. Disease progression was monitored until one member of each HD pair reached a pre-defined end point based on pathological symptoms (HD end). This mouse was then euthanized together with its cage mate (HD other) and any matched WT pairs. At euthanasia, HD mice had significantly greater absolute and relative organ weights, and significantly higher alpha1 acid glycoprotein concentrations than WT mice, indicating reduced welfare. HD mice initially showed significantly greater use of cage resources than WT mice but this declined progressively. Steeper declines, and earlier cessation, in the use of some climbing and exploration resources occurred in the HD end mice compared with the HD other mice. Behavioural change can be an early indicator of disease onset.

Haplotype sharing suggests that a genomic segment containing six genes accounts for the pulmonary adenoma susceptibility 1 (Pas1) locus activity in mice.

The pulmonary adenoma susceptibility 1 (Pas1) locus affects inherited predisposition and resistance to chemically induced lung tumorigenesis in mice. The A/J and C57BL/6J mouse strains carry the susceptibility and resistance allele, respectively. We identified and genotyped 65 polymorphisms in the Pas1 locus region in 29 mouse inbred strains, and delimited the Pas1 locus to a minimal region of 468 kb containing six genes. That region defined a core Pas1 haplotype with 42 tightly linked markers, including intragenic polymorphisms in five genes (Bcat1, Lrmp, Las1, Ghiso, and Kras2) and amino-acid changes in three genes (Lrmp, Las1, Lmna-rs1). In (A/J x C57BL/6J)F1 mouse lung tumors, the Lmna-rs1 gene was completely downregulated, whereas allele-specific downregulation of the C57BL/6J-derived allele was observed at the Las1 gene, suggesting the potential role of these genes in tumor suppression. These results indicate a complex multigenic nature of the Pas1 locus, and point to a functional role for both intronic and exonic polymorphisms of the six genes of the Pas1 haplotype in lung tumor susceptibility.

Effects of dopaminergic cell degeneration on electrophysiological characteristics and GAD65/GAD67 expression in the substantia nigra: different action on GABA cell subpopulations.

The motor disturbances occurring in Parkinson's disease have been partially attributed to a hyperactivity of gamma-aminobutyric acid (GABA)-ergic nigral cells largely in the substantia nigra pars reticulata (SNr) secondary to the degeneration of dopaminergic nigrostriatal neurons. However, some aspects of this response remain unclear. In this work, different electrophysiological and neurochemical parameters were studied in GABAergic cells of the SN after unilateral nigrostriatal dopaminergic lesion using 6-hydroxydopamine injection in rats. Our data showed that 1) the SN under normal conditions contains different subsets of GABAergic cells according to their firing pattern and glutamic acid decarboxylase mRNA levels, and 2) the response of these GABAergic cell subgroups was different after the ipsi- and contralateral dopaminergic cell degeneration. These findings indicate a complex regulation of nigral GABAergic activity after nigrostriatal dopaminergic degeneration that probably involves local mechanisms, the nigro-striato-nigral loop, as well as interhemispheric mechanisms whose anatomical basis remains unstudied.

A new locus for resistance to gamma-radiation-induced thymic lymphoma identified using inter-specific consomic and inter-specific recombinant congenic strains of mice.

Mice of the C57BL/6J inbred strain develop thymic lymphomas at very high frequency after acute gamma-irradiation, while mice of several inbred strains derived from the wild progenitor of the Mus spretus species and their F1 hybrids with C57BL/6J appear extremely resistant. Analysis of the genetic determinism of the gamma-radiation-induced thymic lymphoma (RITL) resistance with the help of inter-specific consomic strains (ICS), which carry a single introgressed Mus spretus chromosome on a C57BL/6J genetic background, provide significant evidence for the existence of a thymic lymphoma resistance (Tlyr1) locus on chromosome 19. The subsequent analysis of the backcross progeny resulting from a cross between consomic mice heterozygous for the Mus spretus chromosome 19 and C57BL/6J mice, together with the study of inter-specific recombinant congenic strains (IRCS), suggest that this Tlyr1 locus maps within the D19Mit60-D19Mit40 chromosome interval. In addition to the discovery of a new locus controlling RITL development, our study emphasizes the value of ICS and IRCS for the genetic analysis of cancer predisposition.

Cancer modifier alleles inhibiting lung tumorigenesis are common in inbred mouse strains.

Lung tumor susceptibility in inbred mouse strains is caused by the susceptibility allele at the pulmonary adenoma susceptibility 1 (Pas1(s)) locus. However, after urethane treatment, most strains carrying the Pas1(s) allele show an intermediate (1-4 tumors/mouse) instead of a highly susceptible (15-30 tumors/mouse) lung tumor phenotype. To test the hypothesis that strains displaying the intermediate lung tumor phenotype carry dominant or codominant resistance alleles at pulmonary adenoma resistance (Par) loci, we crossed mice of intermediate susceptibility or resistance to lung tumorigenesis with the highly susceptible A/J strain. Eleven F(1) hybrids were treated with urethane to induce lung tumorigenesis. The A/J strain developed 35.3 tumors/mouse, while its F(1) hybrid with C57BL/6J mice (null allele at Par loci) developed 22.8 tumors/mouse due to the Pas1 allele dosage effect. F(1) hybrids of strains 129/SvJ, CBA/J, ST/J and LP/J (Pas1(s)) and of SPW, DBA/2J and C57L/J (Pas1(r)) mice showed significant reduction in lung tumor multiplicity (i.e., 0.3-12.8 tumors/mouse) compared to A/J and (A/J x C57BL/6J)F(1) mice. These results indicate that resistance alleles at Par loci are common in inbred mouse strains and account for the lung tumorigenesis intermediate phenotype of strains carrying the Pas1(s) allele.