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D Wahlsten

Publications and source records attributed to D Wahlsten.

At least 19 recordsLinked to original sources
PubMed2006

Localization of two new X-linked quantitative trait loci controlling corpus callosum size in the mouse.

Corpus callosum (CC) size is a complex trait, characterized by a gradation of values within a normal range, as well as abnormalities that include a small or totally absent CC. Among inbred mouse strains with defects of the CC, BTBR T(+)tf/J (BTBR) mice have the most extreme phenotype; all animals show total absence of the CC and severe reduction of the hippocampal commissure (HC). In contrast, the BALB/cByJ (BALB) strain has a low frequency of small CC and consistently normal HC. Reciprocal F(1) crosses between BTBR and BALB suggest the presence of X-linked quantitative trait loci (QTLs) affecting CC size. Through linkage analysis of backcross male progeny, we have localized two regions on the X chromosome, having peaks at 68.5 Mb (approximately 29.5 cM) and at 134.5 Mb (approximately 60.5 cM) that are largely responsible for the reciprocal differences, with the BTBR allele showing X-linked dominant inheritance associated with CC defects.

Agenesis of Corpus Callosum↗
PubMed2006

Recombinant inbreeding in mice reveals thresholds in embryonic corpus callosum development.

The inbred strains BALB/cWah1 and 129P1/ReJ both show incomplete penetrance for absent corpus callosum (CC); about 14% of adult mice have no CC at all. Their F(1) hybrid offspring are normal, which proves that the strains differ at two or more loci pertinent to absent CC. Twenty-three recombinant inbred lines were bred from the F(2) cross of BALB/c and 129, and several of these expressed a novel and severe phenotype after only three or four generations of inbreeding - total absence of the CC and severe reduction of the hippocampal commissure (HC) in every adult animal. As inbreeding progressed, intermediate sizes of the CC and the HC remained quite rare. This striking phenotypic distribution in adults arose from developmental thresholds in the embryo. CC axons normally cross to the opposite hemisphere via a tissue bridge in the septal region at midline, where the HC forms before CC axons arrive. The primary defect in callosal agenesis in the BALB/c and 129 strains is severe retardation of fusion of the hemispheres in the septal region, and failure to form a CC is secondary to this defect. The putative CC axons arrive at midline at the correct time and place in all groups, but in certain genotypes, the bridge is not yet present. The relative timing of axon growth and delay of the septal bridge create a narrow critical period for forming a normal brain.

Agenesis of Corpus Callosum↗
PubMed2005

Digit ratio (2D:4D) and behavioral differences between inbred mouse strains.

Digit ratio (2D:4D) is a trait, which is sexually differentiated in a variety of species. In humans, males typically have shorter second digits (2Ds) (index fingers) compared to fourth digits (4Ds) (ring fingers) whereas females' fingers are more equal in length. Smaller, more masculine, digit ratios are thought to be associated with higher prenatal testosterone levels, greater sensitivity to prenatal androgens or both. Men with more masculine digit ratios have shown increased ability, achievement and speed in sports and tend to report that they are more physically aggressive. Previous research has shown the same sexually differentiated pattern in the hind paws of laboratory mice as in human hands, males have lower 2D:4D than females. We measured hind paw digit ratio in mice of eight inbred strains. These measurements were made while blind to strain, sex and whether the paw was from the left or right side. We found large differences in digit ratio between the strains and suggest that inbred mice are a promising system for investigating the correlation between digit ratio and behavioral traits.

Analysis of Variance↗
PubMed2003

A rating scale for wildness and ease of handling laboratory mice: results for 21 inbred strains tested in two laboratories.

Rating scales for difficulty in capturing and holding mice were devised that proved to be easy to use and highly sensitive to differences among mouse strains on the A and B priority lists of the Mouse Phenome Project. The simplicity of the scales makes it feasible to rate wildness during behavioral test sessions without adding much to testing time or distracting the technician from the principal task at hand. Overall wildness and placidity ratings obtained by combining capture and hold ratings provide a good impression of the difficulties encountered while working with lab mice in the course of complex experiments. Ratings of 21 inbred strains during the course of 15 behavioral tests in two laboratories demonstrated that the SPRET/Ei, PERA/Ei, CAST/Ei and SWR/J strains were particularly difficult to handle. The NOD/LtJ strain posed no special challenge in the Edmonton laboratory but was very difficult to handle in the Portland lab. The rating scales should be useful for judging the difficulties in working with novel targeted or induced mutations in mice as well as effects of a variety of environmental treatments or drugs.

Animals↗
PubMed2003

Strain differences in three measures of ethanol intoxication in mice: the screen, dowel and grip strength tests.

Mice from 8 to 21 inbred strains were tested for sensitivity to ethanol intoxication using a range of doses and three different measures: the screen test, the dowel test and a test of grip strength. Strains differed under nearly all conditions. For the dowel test, two dowel widths were employed, and mice were tested immediately or 30 min after ethanol. For the dowel and screen tests, low doses failed to affect some strains, and the highest doses failed to discriminate among mice, maximally affecting nearly all. For grip strength, a single ethanol dose was used, and mice of all strains were affected. Pharmacokinetic differences among strains were significant, but these could not account for strain differences in intoxication. For doses and test conditions in the middle range, there were only modest correlations among strain means within a test. In addition, genotypic correlations across tests were modest to quite low. These results suggest that different specific versions of a test reflect the influence of different genes, and that genetic influences on different tests were also distinct.

Alcoholic Intoxication↗
PubMed2001

Behavioural testing of standard inbred and 5HT(1B) knockout mice: implications of absent corpus callosum.

Rapid advances in biotechnology have created new demands for tests of mouse behaviour having both high reliability and high throughput for mass screening. This paper discusses several statistical and psychological factors pertinent to replication of results in different laboratories, and it considers the question of which inbred strains are best for test standardization. In this context, the problem of absent corpus callosum in the 129 strains is addressed with data from a recent study of six diverse tests of behaviour, and it is shown that effects of absent corpus callosum are usually nonsignificant and/or very small. Whether any 129 substrain is to be included in the list of standard strains depends on the goal of the standardization--collecting diverse phenotypic data on most available strains by a few expert investigators (the gold standard) or refining behavioural tests in order to establish a normal range of behaviour that can be used to judge a wider range of strains or even an individual mouse.

Agenesis of Corpus Callosum↗
PubMed2001

Standardizing tests of mouse behavior: reasons, recommendations, and reality.

As more investigators with widely varying backgrounds enter the field of mouse behavioral genetics, there is a growing need to standardize some of the more popular tests because differences between laboratories in the details of behavioral testing and the pretesting environment can contribute to failures to replicate results of genetic experiments. It is argued here that we have sufficient knowledge to warrant a wise choice of a short list of standard strains and even details of apparatus and protocols for several kinds of behavioral tests. Equating the laboratory environment does not appear to be feasible. Instead, we need to learn what kinds of behavioral tests yield the most stable results in different labs and what kinds are most sensitive to the ubiquitous variations among test sites. Methods for making an informed choice of sample size for evaluating interactions between the laboratory environment and genotype are available and should be utilized in standardization trials. New resources for convenient sharing of data will greatly aid in collaborative and comparative studies involving several sites. Like the sequencing of an entire genome, test standardization is something that needs to be done only once if it is done properly, and the work will then benefit the field of behavioral and neural genetics for many years.

Animals↗
PubMed1999

Genetics of mouse behavior: interactions with laboratory environment.

Strains of mice that show characteristic patterns of behavior are critical for research in neurobehavioral genetics. Possible confounding influences of the laboratory environment were studied in several inbred strains and one null mutant by simultaneous testing in three laboratories on a battery of six behaviors. Apparatus, test protocols, and many environmental variables were rigorously equated. Strains differed markedly in all behaviors, and despite standardization, there were systematic differences in behavior across labs. For some tests, the magnitude of genetic differences depended upon the specific testing lab. Thus, experiments characterizing mutants may yield results that are idiosyncratic to a particular laboratory.

Animals↗
PubMed1999

Sex and species differences in mouse and rat forebrain commissures depend on the method of adjusting for brain size.

Sex differences in the forebrain commissures (corpus callosum, hippocampal commissure, and anterior commissure) were examined in B6D2F2 hybrid mice and Sprague-Dawley rats. Twenty-four male-female littermate pairs of mice were perfused at each of 21, 42 and 63 days of age and the midsagittal area of the commissures was measured from en bloc stained tissue. Twenty-two male-female littermate pairs of rats were examined at 110 days of age using the same methods. Male mice had larger bodies than females but no sex differences were found for mouse brain weight or commissure areas. In contrast, a significant sex difference was found for rat body, brain, corpus callosum and hippocampal commissure sizes. Four methods were used to adjust for differences in brain size (ratio, geometric, linear regression, and allometric). When the two species were analysed separately, neither mice nor rats showed significant sex differences in commissure areas relative to brain size if regression or allometric adjustments were made. Even when data from mice and rats were combined into one large group with a wide range of values, no species or sex differences were apparent after adjustments were made for brain size with either the regression or allometric methods. The use of ratios to adjust for differences in overall size is not recommended, especially because this method does not effectively remove the influence of brain size from commissure size; a substantial correlation is often present between the ratio and brain size.

Animals↗
PubMed1999

Single-gene influences on brain and behavior.

As traditional behavioral genetics analysis merges with neurogenetics, the field of neurobehavioral genetics, focusing on single-gene effects, comes into being. New biotechnology has greatly accelerated gene discovery and the study of gene function in relation to brain and behavior. More than 7,000 genes in mice and 10,000 in humans have now been documented, and extensive information about the genetics of several species is readily available on the World Wide Web. Based on knowledge of the DNA sequence of a gene, a targeted mutation with the capacity to disable it can be created. These knockouts--also called null mutants--are employed in the study of a wide range of phenotypes, including learning and memory, appetite and obesity, and circadian rhythms. The era of examining single-gene effects from a reductionistic perspective is waning, and research with interacting arrays of genes in various environmental contexts is demonstrating a need for systems-oriented theory.

Animals↗
PubMed1998

Timing and origin of the first cortical axons to project through the corpus callosum and the subsequent emergence of callosal projection cells in mouse.

A precise knowledge of the timing and origin of the first cortical axons to project through the corpus callosum (CC) and of the subsequent emergence of callosal projection cells is essential for understanding the early ontogeny of this commissure. By using a series of mouse embryos and fetuses of the hybrid cross B6D2F2/J weighing from 0.36 g to 1.0 g (embryonic day E15.75-E17.25), we examined the spatial and temporal distribution of callosal projection cells by inserting crystals of the lipophilic dye (DiI: 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate) into the contralateral white matter just lateral to the midsagittal plane. Around 0.4 g or E15.8, retrogradely labeled cells were found restricted to a discrete cluster continuously distributed from the most ventral part of presumptive cingulate cortex to the hippocampus. During subsequent development, however, the tangential distribution of these labeled cells in ventromedial cortex did not extend further dorsally, and in fetuses where the CC became distinct from the hippocampal commissure (HC), labeled axons of cells in the ventral cingulate cortex were observed to intersect the callosal pathway and merge with labeled axons of the HC derived from cells in the hippocampus. The first cortical axons through the CC crossed the midline at about 0.64 g or E16.4, and these axons originated from a scattered neuronal population in the dorsal to lateral part of the presumptive frontal cortex. The earliest callosal cells were consistently located in the cortical plate and showed an immature bipolar appearance, displaying an ovoid- or pearl-shaped perikaryon with an apical dendrite coursing in a zig-zagging manner toward the pial surface and a slender axon directed toward the underlying white matter. Callosal projection cells spread progressively with development across the tangential extent of the cerebral cortex in both lateral-to-medial and rostral-to-caudal directions. In any cortical region, the first labeled cells appeared in the cortical plate and their number in the subplate was insignificant compared to that in the cortical plate. Thus, these results clarify that the CC is pioneered by frontal cortical plate cells, and the subsequent ontogeny of callosal projection cells proceeds according to the gradient of cortical maturation.

Animals↗
PubMed1997

Retarded formation of the hippocampal commissure in embryos from mouse strains lacking a corpus callosum.

A precise description of the timing and route traveled by axons traversing the telencephalic midline through the ventral hippocampal commissure (HC) is essential for understanding the role it plays in the formation of the corpus callosum (CC). A normal baseline of HC development was described in B6D2F2 hybrid mice and then compared with two inbred strains of mice displaying callosal agenesis, BALB/cWah1 (50% CC defect) and 129/J (70% CC defect), their F2 hybrid (C129F2-33% CC defect), and a recombinant inbred strain (RI-1-100% CC defect) derived from pairs of C129F2 mice. Embryos weighing from 0.25 g to 0.70 g (E14.5-E17) were collected and fixed by perfusion. Axon tracts were labeled using crystals of the lipophilic dyes DiI and DiA inserted into the hippocampal fimbria and cerebral cortex. HC axons in B6D2F2 mice first cross the midline at about 0.350 g body weight (E14.8) by traveling over the dorsal septum and along the pia membrane lining the longitudinal fissure. Earlier crossing was prevented by the presence of a deep cleft formed by the longitudinal fissure extending down into the septal region. Subsequent axons fasciculated along existing axons, gradually building the dorsoventral height of the HC to about 200 microns by 0.600 g. The earliest callosal axons from frontal cortex crossed the midline at 0.620 g and were clearly seen fasciculating along and between existing hippocampal axons at the dorsal surface of the HC as they crossed. In the acallosal strains, HC formation was delayed by the continued presence of the cleft deep in the septal region. This delay in time of crossing was correlated with later CC defect expression. Initial HC crossing occurred at about 0.470 g (E16.25) in BALB mice and about 0.520 g (E16.5) in 129 mice. In the RI-1 embryos, first HC crossing was estimated at about 0.750 g (E17.5), although several older embryos showed no crossing. These results show the importance of the HC for successful CC formation and suggest that absent CC arises as a consequence of a developmental defect which affects the formation of the hippocampal commissure prior to arrival of CC axons at midplane.

Agenesis of Corpus Callosum↗
PubMed1997

Increased axon number in the anterior commissure of mice lacking a corpus callosum.

Relatively few behavioral deficits are apparent in subjects with hereditary absence of the corpus callosum (CC). The anterior commissure (AC) has been suggested to provide an extracallosal route for the transfer of interhemispheric information in subjects with this congenital defect. Anterior commissure size, axon number, axon diameter, and neuronal distribution were compared between normal mice and those with complete CC absence. No difference in midsagittal AC area was found between normals and acallosals, nor were differences found in the numbers or diameters of myelinated axons. However, axon counts indicated an 17% increase or about 70,000 more unmyelinated axons in the AC of acallosal mice, and the mean diameter of unmyelinated axons was slightly less than in normal mice (0.24 vs 0.26 microm). This decrease in axon diameter enabled more axons to pass through the AC without increasing its midsagittal area. The topographical distribution of neurons sending axons through the AC, assessed with lipophilic dyes, was qualitatively similar for almost all the known regions of origin of the anterior commissure in normal and acallosal mice. There was a pronounced deficit of AC cells in the anterior piriform cortex of BALB/c mice, but this occurred whether or not the mouse suffered absent CC. Although the increase in AC axon number is far smaller than the number of CC axons that fail to reach the opposite hemisphere, the higher number of axons present in the AC of acallosal mice may contribute to the functional compensation for the loss of the CC.

Agenesis of Corpus Callosum↗
PubMed1997

Leilani Muir versus the philosopher king: eugenics on trial in Alberta.

The Province of Alberta in Canada was the only jurisdiction in the British Empire where a eugenic sterilization law was passed (in 1928) and vigorously implemented. The pace of sterilization orders accelerated during the Nazi era and remained high after World War II, terminating only in 1972 when the Sexual Sterilization Act was repealed. The Alberta Eugenics Board operated away from public and legislative scrutiny, and many things done in the name of eugenics were clearly illegal. Eugenics was put on trial in Alberta in 1995 and a judge of the Court of Queen's Bench ruled in 1996 that the government had wrongly sterilized Leilani Muir. After hearing evidence about the history of the eugenics movement, the origins of Alberta's Sexual Sterilization Act, the operation of the Eugenics Board, and details of Muir's life, Madam Justice Joanne B. Veit found that 'the damage inflicted by the operation was catastrophic', the 'wrongful stigmatization of Ms. Muir as a moron ... has humiliated Ms. Muir every day of her life', and 'the circumstances of Ms. Muir's sterilization were so high-handed and so contemptuous of the statutory authority to effect sterilization, and were undertaken in an atmosphere that so little respected Ms. Muir's human dignity that the community's, and the court's, sense of decency is offended'. Veit awarded Muir damages of $740,780 CAD and legal costs of $230,000 CAD. The order for Muir's sterilization was signed by John M. MacEachran, founder of the Department of Philosophy and Psychology at the University of Alberta and chairman of the Eugenics Board from 1929 to 1965. An exponent of Platonic idealism, MacEachran believed sterilization of children with a low IQ test score was a means of 'raising and safeguarding the purity of the race'. However, the Alberta Sterilization Act was passed and implemented with cavalier disregard for the principles of genetics as well as the rights of children.

Adult↗
PubMed1997

Sex differences in the human corpus callosum: myth or reality?

It has been claimed that the human corpus callosum shows sex differences, and in particular that the splenium (the posterior portion) is larger in women than in men. Data collected before 1910 from cadavers indicate that, on average, males have larger brains than females and that the average size of their corpus callosum is larger. A meta-analysis of 49 studies published since 1980 reveals no significant sex difference in the size or shape of the splenium of the corpus callosum, whether or not an appropriate adjustment is made for brain size using analysis of covariance or linear regression. It is argued that a simple ratio of corpus callosum size to whole brain size is not an appropriate way to analyse the data and can create a false impression of a sex difference in the corpus callosum. The recent studies, most of which used magnetic resonance imaging (MRI), confirm the earlier findings of larger average brain size and overall corpus callosum size for males. The widespread belief that women have a larger splenium than men and consequently think differently is untenable. Causes of and means to avoid such a false impression in future research are discussed.

Corpus Callosum↗
PubMed1995

A precision surgical approach for complete or partial callosotomy in the mouse.

The corpus callosum (CC) of mice was completely transsected with a thin tungsten knife using a three-cut approach through the dorsal cerebrum just lateral to midline. This method results in almost total transsection of the CC throughout its entire rostrocaudal extent. Advantages of this approach include minimal bleeding and extracallosal damage as well as the possibility of selective transsection of only anterior, middle, or posterior parts of the CC. The technique can be readily adapted to any other rodent species.

Animals↗