Deletion of one allele of Mthfd1 (methylenetetrahydrofolate dehydrogenase 1) impairs learning in mice

The MTHFD1 gene encodes for methylenetetrahydrofolate dehydrogenase 1, an enzyme that has an important role in folate-mediated one-carbon metabolism. In people, a single nucleotide polymorphism of this gene (1958G > A; rs2236225) is associated with increased risk for bipolar disorder and schizophrenia, neural tube and other birth defects. Mice homozygous for a loss of Mthfd1 via a gene-trap mutation are not viable, and heterozygotes, though they appear healthy, have metabolic imbalances in the folate- and choline-mediated 1-carbon metabolic pathways. In this study, we evaluated cognitive function in Mthfd1gt/+ male and female mice using a behavioral battery composed of eight different tests. We found that these mice display impaired cue-conditioned learning, while other behaviors remain intact

Translational neuroscience of anorexia nervosa: A genetic and environmental interplay underlying behavioural hyperactivity in mice

Anorexia Nervosa is a severe mental illness, affecting young females more than males. Anorexia nervosa runs a chronic, relapsing course and is associated with high disability and mortality rates. The hallmark of the disease is keeping a low body weight, less than 85% of what is expected. The etiology of anorexia nervosa is complex (unknown), with risks involving environmental, temperamental, developmental and genetic factors. Though not specified in the diagnosis criteria, excessive physical activity has also been described as a prominent feature of the disorder. It plays a significant role in the development, maintenance and recovery rate of the disorder. This thesis aims at unraveling genetic and environmental factors affecting the hyperactivity behavior and the susceptibility to the activity based anorexia (ABA) model, which models this feature in rodents. Rodent studies take place under controlled genetic and environmental conditions, where the dissection of complex phenotypes is facilitated. In the thesis we report on the following novel findings. Physical activity levels prior to the restriction phase were found to highly predict the susceptibility levels across a set of eleven inbred mouse strains exposed to the ABA model. Mapping of hyperactivity behavior, by screening of the chromosome substitution (CS) panel, generated from C7BL/6J and A/J mice, in the ABA model, has shown potential quantitative trait loci (QTL) on mouse chromosomes 4, 12 and 13. Further analysis revealed a locus in the proximal region of chromosome 12, however, additional research is needed to search for candidate genes within the QTL interval that contribute to the observed phenotype. Early life events (inter- and intra- strain cross-fostering experiments in mice) were able to modulate genetic background in the highly ABA susceptible CS mouse strain 4. Change in maternal environment, of CS strain 4, was associated with significant differences in DNA methylation when compared to the mice raised by their own biological mothers. Several genes implicated in different psychiatric disorders, such as Cntnap2, showed hypermethylated regions and were related to reduced ABA susceptibility following cross-fostering. Thus, early life events may modulate genetic background susceptibility for adult maladaptive behavior via epigenetic modifications. Altogether, the studies described in this thesis suggest that the trajectory of anorexia nervosa is likely defined by an ongoing gene and environment interplay starting at an early stage. Close to the onset of illness, the role of excessive exercise or excessive physical activity as a risk factor becomes prominent and it should also be considered as a factor of illness severity. These results warrant further studies to investigate what modifications of brain structures i.e. neuronal organizations or/and connections, have occurred with the epigenetic modifications under the environmental and how these dynamic brain changes affect susceptibility to adult mal-adaptive behavior

Translational neuroscience of anorexia nervosa: A genetic and environmental interplay underlying behavioural hyperactivity in mice

Anorexia Nervosa is a severe mental illness, affecting young females more than males. Anorexia nervosa runs a chronic, relapsing course and is associated with high disability and mortality rates. The hallmark of the disease is keeping a low body weight, less than 85% of what is expected. The etiology of anorexia nervosa is complex (unknown), with risks involving environmental, temperamental, developmental and genetic factors. Though not specified in the diagnosis criteria, excessive physical activity has also been described as a prominent feature of the disorder. It plays a significant role in the development, maintenance and recovery rate of the disorder. This thesis aims at unraveling genetic and environmental factors affecting the hyperactivity behavior and the susceptibility to the activity based anorexia (ABA) model, which models this feature in rodents. Rodent studies take place under controlled genetic and environmental conditions, where the dissection of complex phenotypes is facilitated. In the thesis we report on the following novel findings. Physical activity levels prior to the restriction phase were found to highly predict the susceptibility levels across a set of eleven inbred mouse strains exposed to the ABA model. Mapping of hyperactivity behavior, by screening of the chromosome substitution (CS) panel, generated from C7BL/6J and A/J mice, in the ABA model, has shown potential quantitative trait loci (QTL) on mouse chromosomes 4, 12 and 13. Further analysis revealed a locus in the proximal region of chromosome 12, however, additional research is needed to search for candidate genes within the QTL interval that contribute to the observed phenotype. Early life events (inter- and intra- strain cross-fostering experiments in mice) were able to modulate genetic background in the highly ABA susceptible CS mouse strain 4. Change in maternal environment, of CS strain 4, was associated with significant differences in DNA methylation when compared to the mice raised by their own biological mothers. Several genes implicated in different psychiatric disorders, such as Cntnap2, showed hypermethylated regions and were related to reduced ABA susceptibility following cross-fostering. Thus, early life events may modulate genetic background susceptibility for adult maladaptive behavior via epigenetic modifications. Altogether, the studies described in this thesis suggest that the trajectory of anorexia nervosa is likely defined by an ongoing gene and environment interplay starting at an early stage. Close to the onset of illness, the role of excessive exercise or excessive physical activity as a risk factor becomes prominent and it should also be considered as a factor of illness severity. These results warrant further studies to investigate what modifications of brain structures i.e. neuronal organizations or/and connections, have occurred with the epigenetic modifications under the environmental and how these dynamic brain changes affect susceptibility to adult mal-adaptive behavior

Reduced brain volume and impaired memory in betaine homocysteine S-methyltransferase knockout mice

Using a mouse model, this study examined the impact of lack of betaine homocysteine S-methyltransferase (BHMT) on neurological function. Bhmt-/- mice maintained on a control diet had elevated concentrations of homocysteine, reduced total brain magnetic resonance imaging (MRI) volume, as well as impaired reference and short-term memories. The results of this study indicate that the absence of BHMT may play a role in neurological function

A Central Role for C1q/TNF-Related Protein 13 (CTRP13) in Modulating Food Intake and Body Weight

C1q/TNF-related protein 13 (CTRP13), a hormone secreted by adipose tissue (adipokines), helps regulate glucose metabolism in peripheral tissues. We previously reported that CTRP13 expression is increased in obese and hyperphagic leptin-deficient mice, suggesting that it may modulate food intake and body weight. CTRP13 is also expressed in the brain, although its role in modulating whole-body energy balance remains unknown. Here, we show that CTRP13 is a novel anorexigenic factor in the mouse brain. Quantitative PCR demonstrated that food restriction downregulates Ctrp13 expression in mouse hypothalamus, while high-fat feeding upregulates expression. Central administration of recombinant CTRP13 suppressed food intake and reduced body weight in mice. Further, CTRP13 and the orexigenic neuropeptide agouti-related protein (AgRP) reciprocally regulate each other’s expression in the hypothalamus: central delivery of CTRP13 suppressed Agrp expression, while delivery of AgRP increased Ctrp13 expression. Food restriction alone reduced Ctrp13 and increased orexigenic neuropeptide gene (Npy and Agrp) expression in the hypothalamus; in contrast, when food restriction was coupled to enhanced physical activity in an activity-based anorexia (ABA) mouse model, hypothalamic expression of both Ctrp13 and Agrp were upregulated. Taken together, these results suggest that CTRP13 and AgRP form a hypothalamic feedback loop to modulate food intake and that this neural circuit may be disrupted in an anorexic-like condition

Placental miR-340 mediates vulnerability to activity based anorexia in mice

Anorexia nervosa is characterised by self-starvation but its etiology is not completely understood. Here the authors describe how prenatal stress can induce activity-based anorexia in the offspring during early adulthood by upregulating miR-340 expression in the placenta that affects expression of nutrient transporters