Inborn vs. acquired anxiety in cross-breeding and cross-fostering HAB/LAB mice bred for extremes in anxiety-related behavior.

This study focused on genetically determined versus acquired factors in shaping anxiety-related behavior by combining cross-breeding and cross-fostering approaches. Via cross-breeding of HAB (high anxiety-related behavior) female and LAB (low anxiety-related behavior) male mice, we obtained F1 hybrids with intermediate anxiety levels carrying genetic characteristics of both parental lines. Pups were raised either by their biological HAB (noncross-fostered control) or foster LAB (cross-fostered) mothers. Compared to controls, 6-week-old offspring raised by LAB mothers showed lower levels of anxiety in the elevated plus-maze and open field, but not the light-dark box, tests. No differences were found in the forced swim test reflecting active versus passive coping. The behavioral changes were associated with increased stress-induced concentrations of plasma corticosterone in cross-fostered animals. The expression of the corticotropin-releasing hormone receptor type I and glucocorticoid receptor genes did not differ in limbic and hypothalamic brain areas between cross-fostered and control mice. The data suggest that LAB-typical maternal care may partially shift behavioral and neuroendocrine characteristics of F1 crosses carrying both HAB and LAB alleles from intermediate toward reduced anxiety-related behavior. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Polymorphism in Tmem132d regulates expression and anxiety-related behavior through binding of RNA polymerase II complex.

TMEM132D is a candidate gene, where risk genotypes have been associated with anxiety severity along with higher mRNA expression in the frontal cortex of panic disorder patients. Concurrently, in a high (HAB) and low (LAB) trait anxiety mouse model, Tmem132d was found to show increased expression in the anterior cingulate cortex (aCC) of HAB as compared to LAB mice. To understand the molecular underpinnings underlying the differential expression, we sequenced the gene and found two single-nucleotide polymorphisms (SNPs) in the promoter differing between both lines which could explain the observed mRNA expression profiles using gene reporter assays. In addition, there was no difference in basal DNA methylation in the CpG Island that encompasses the HAB vs. LAB Tmem132d promoter region. Furthermore, we found significantly higher binding of RNA polymerase II (POLR2A) to the proximal HAB-specific SNP (rs233264624) than the corresponding LAB locus in an oligonucleotide pull-down assay, suggesting increased transcription. Virus mediated overexpression of Tmem132d in the aCC of C57BL/6 J mice could confirm its role in mediating an anxiogenic phenotype. To model gene-environmental interactions, HAB mice exposed to enriched environment (HAB-EE) responded with decreased anxiety levels but, had enhanced Tmem132d mRNA expression as compared to standard-housed HAB (HAB-SH) mice. While LAB mice subjected to unpredictable chronic mild stress (LAB-UCMS) exhibited higher anxiety levels and had lower mRNA expression compared to standard-housed LAB (LAB-SH) mice. Chromatin immunoprecipitation revealed significantly higher binding of POLR2A to rs233264624 in HAB-EE, while LAB-UCMS had lower POLR2A binding at this locus, thus explaining the enhanced or attenuated expression of Tmem132d compared to their respective SH controls. To further investigate gene-environment interactions, DNA methylation was assessed using Illumina 450 K BeadChip in 74 panic disorder patients. Significant methylation differences were observed in two CpGs (cg26322591 and cg03283235) located in TMEM132D depending on the number of positive life events supporting the results of an influence of positive environmental cues on regulation of Tmem132d expression in mice.

Environmental manipulations generate bidirectional shifts in both behavior and gene regulation in a crossbred mouse model of extremes in trait anxiety.

Although gene-environment interactions are known to significantly influence psychopathology-related disease states, only few animal models cover both the genetic background and environmental manipulations. Therefore, we have taken advantage of the bidirectionally inbred high (HAB) and low (LAB) anxiety-related behavior mouse lines to generate HAB × LAB F1 hybrids that intrinsically carry both lines' genetic characteristics, and subsequently raised them in three different environments-standard, enriched (EE) and chronic mild stress (CMS). Assessing genetic correlates of trait anxiety, we focused on two genes already known to play a role in HAB vs. LAB mice, corticotropin releasing hormone receptor type 1 (Crhr1) and high mobility group nucleosomal binding domain 3 (Hmgn3). While EE F1 mice showed decreased anxiety-related and increased explorative behaviors compared to controls, CMS sparked effects in the opposite direction. However, environmental treatments affected the expression of the two genes in distinct ways. Thus, while expression ratios of Hmgn3 between the HAB- and LAB-specific alleles remained equal, total expression resembled the one observed in HAB vs. LAB mice, i.e., decreased after EE and increased after CMS treatment. On the other hand, while total expression of Crhr1 remained unchanged between the groups, the relative expression of HAB- and LAB-specific alleles showed a clear effect following the environmental modifications. Thus, the environmentally driven bidirectional shift of trait anxiety in this F1 model strongly correlated with Hmgn3 expression, irrespective of allele-specific expression patterns that retained the proportions of basic differential HAB vs. LAB expression, making this gene a match for environment-induced modifications. An involvement of Crhr1 in the bidirectional behavioral shift could, however, rather be due to different effects of the HAB- and LAB-specific alleles described here. Both candidate genes therefore deserve attention in the complex regulation of anxiety-related phenotypes including environment-mediated effects.

Real-time imaging of amygdalar network dynamics in vitro reveals a neurophysiological link to behavior in a mouse model of extremes in trait anxiety.

In humans and numerous other mammalian species, individuals considerably vary in their level of trait anxiety. This well known phenomenon is closely related to the etiology of several psychiatric disorders, but its neurophysiological basis remains poorly understood. Here, we applied voltage-sensitive dye imaging to brain slices from animals of the high (HAB), normal (NAB), and low (LAB) trait anxiety mouse model and investigated whether evoked neuronal activity propagations from the lateral (LA) to the central (CeA) amygdala differ in their relative strength among HAB, NAB, and LAB mice. For this purpose, we divided a real-time measure of neuronal population activity in the CeA by a respective measure obtained for the LA. This calculation yielded the metric "CeA/LA activity." Our data clearly demonstrate a positive correlation between trait anxiety levels evaluated by the elevated plus-maze test and CeA/LA activity. Moreover, we found reduced CeA/LA activity in HAB mice, which responded with decreased anxiety levels to an environmental enrichment and, inversely, detected increased anxiety levels and CeA/LA activity in LAB mice that experienced chronic mild stress. We did not observe differences in the spread of neuronal activity in the motor and visual cortex among HAB, NAB, and LAB animals. Collectively, these findings provide evidence that, in mammals, interindividual variability in trait anxiety is causally linked to individual variations in the physiological constitution of the LA-to-CeA circuitry that give rise to a differential regulation of neuronal signal flow through this fundamental input-output network of the amygdala.

The business case for preconception care: methods and issues.

Only a limited number of economic evaluations have addressed the costs and benefits of preconception care. In order to persuade health care providers, payers, or purchasers to become actively involved in promoting preconception care, it is important to demonstrate the value of doing so through development of a "business case". Perceived benefits in terms of organizational reputation and market share can be influential in forming a business case. In addition, it is standard to include an economic analysis of financial costs and benefits from the perspective of the provider practice, payer, or purchaser in a business case. The methods, data needs, and other issues involved with preparing an economic analysis of the likely financial return on investment in preconception care are presented here. This is accompanied by a review or case study of economic evaluations of preconception care for women with recognized diabetes. Although the data are not sufficient to draw firm conclusions, there are indications that such care may yield positive financial benefits to health care organizations through reduction in maternal and infant hospitalizations. More work is needed to establish how costs and economic benefits are distributed among different types of organizations. Also, the optimum methods of delivering preconception care for women with diabetes need to be evaluated. Similar assessments should also be conducted for other forms of preconception care, including comprehensive care.