Strain-dependent differences in corticolimbic processing of aversive or rewarding stimuli

Aberrations in the elaboration of both aversive and rewarding stimuli characterize several psychopathologies including anxiety, depression and addiction. Several studies suggest that different neurotrasmitters, within the corticolimbic system, are critically involved in the processing of positive and negative stimuli. Individual differences in this system, depending on genotype, have been shown to act as a liability factor for different psychopathologies. Inbred mouse strains are commonly used in preclinical studies of normal and pathological behaviors. In particular, C57BL/6J (C57) and DBA/2J (DBA) strains have permitted to disclose the impact of different genetic backgrounds over the corticolimbic system functions. Here, we summarize the main findings collected over the years in our laboratory, showing how the genetic background plays a critical role in modulating amminergic and GABAergic neurotransmission in prefrontal-accumbal-amygdala system response to different rewarding and aversive experiences, as well as to stress response. Finally, we propose a top-down model for the response to rewarding and aversive stimuli in which amminergic transmission in prefrontal cortex (PFC) controls accumbal and amygdala neurotransmitter response

Strain-dependent variations in stress coping behavior are mediated by a 5-HT/GABA interaction within the prefrontal corticolimbic system

Background: Serotonin and γ- Aminobutyric acid (GABA) transmission is crucial in coping strategies. Methods: Here, using mice from 2 inbred strains widely exploited in behavioral neurochemistry, we investigated whether serotonin transmission in medial prefrontal cortex and GABA in basolateral amygdala determine strain-dependent liability to stress response and differences in coping. Results: C57BL/6J mice displayed greater immobility in the forced swimming test, higher serotonin outflow in medial prefrontal cortex, higher GABA outflow in basolateral amygdala induced by stress, and higher serotonin 1A receptor levels in medial prefrontal cortex accompanied by lower GABAb receptor levels in basolateral amygdala than DBA/2J mice. In assessing whether serotonin in medial prefrontal cortex determines GABA functioning in response to stress and passive coping behavior in C57BL/6J and DBA/2J mice, we observed that selective prefrontal serotonin depletion in C57BL/6J and DBA/2J reduced stress-induced GABA outflow in basolateral amygdala and immobility in the forced swimming test. Conclusions: These results show that strain-dependent prefrontal corticolimbic serotonin/GABA regulation determines the strain differences in stress-coping behavior in the forced swimming test and point to a role of a specific neuronal system in genetic susceptibility to stress that opens up new prospects for innovative therapies for stress disorders

Lifespan modulation in mice and the confounding effects of genetic background

We are currently in the midst of a revolution in ageing research, with several dietary, genetic and pharmacological interventions now known to modulate ageing in model organisms. Excitingly, these interventions also appear to have beneficial effects on late-life health. For example, dietary restriction (DR) has been shown to slow the incidence of age-associated cardiovascular disease, metabolic disease, cancer and brain ageing in non-human primates and has been shown to improve a range of health indices in humans. While the idea that DR's ability to extend lifespan is often thought of as being universal, studies in a range of organisms, including yeast, mice and monkeys, suggest that this may not actually be the case. The precise reasons underlying these differential effects of DR on lifespan are currently unclear, but genetic background may be an important factor in how an individual responds to DR. Similarly, recent findings also suggest that the responsiveness of mice to specific genetic or pharmacological interventions that modulate ageing may again be influenced by genetic background. Consequently, while there is a clear driver to develop interventions to improve late-life health and vitality, understanding precisely how these act in response to particular genotypes is critical if we are to translate these findings to humans. We will consider of the role of genetic background in the efficacy of various lifespan interventions and discuss potential routes of utilising genetic heterogeneity to further understand how particular interventions modulate lifespan and healthspan

Intra- and inter-individual genetic differences in gene expression

Genetic variation is known to influence the amount of mRNA produced by a gene. Given that the molecular machines control mRNA levels of multiple genes, we expect genetic variation in the components of these machines would influence multiple genes in a similar fashion. In this study we show that this assumption is correct by using correlation of mRNA levels measured independently in the brain, kidney or liver of multiple, genetically typed, mice strains to detect shared genetic influences. These correlating groups of genes (CGG) have collective properties that account for 40-90% of the variability of their constituent genes and in some cases, but not all, contain genes encoding functionally related proteins. Critically, we show that the genetic influences are essentially tissue specific and consequently the same genetic variations in the one animal may up-regulate a CGG in one tissue but down-regulate the same CGG in a second tissue. We further show similarly paradoxical behaviour of CGGs within the same tissues of different individuals. The implication of this study is that this class of genetic variation can result in complex inter- and intra-individual and tissue differences and that this will create substantial challenges to the investigation of phenotypic outcomes, particularly in humans where multiple tissues are not readily available.

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Genetic factors regulating lung vasculature and immune cell functions associate with resistance to pneumococcal infection

Streptococcus pneumoniae is an important human pathogen responsible for high mortality and morbidity worldwide. The susceptibility to pneumococcal infections is controlled by as yet unknown genetic factors. To elucidate these factors could help to develop new medical treatments and tools to identify those most at risk. In recent years genome wide association studies (GWAS) in mice and humans have proved successful in identification of causal genes involved in many complex diseases for example diabetes, systemic lupus or cholesterol metabolism. In this study a GWAS approach was used to map genetic loci associated with susceptibility to pneumococcal infection in 26 inbred mouse strains. As a result four candidate QTLs were identified on chromosomes 7, 13, 18 and 19. Interestingly, the QTL on chromosome 7 was located within S. pneumoniae resistance QTL (Spir1) identified previously in a linkage study of BALB/cOlaHsd and CBA/CaOlaHsd F2 intercrosses. We showed that only a limited number of genes encoded within the QTLs carried phenotype-associated polymorphisms (22 genes out of several hundred located within the QTLs). These candidate genes are known to regulate TGFb signalling, smooth muscle and immune cells functions. Interestingly, our pulmonary histopathology and gene expression data demonstrated, lung vasculature plays an important role in resistance to pneumococcal infection. Therefore we concluded that the cumulative effect of these candidate genes on vasculature and immune cells functions as contributory factors in the observed differences in susceptibility to pneumococcal infection. We also propose that TGFbmediated regulation of fibroblast differentiation plays an important role in development of invasive pneumococcal disease.This work was supported by the European Union-funded Pneumopath Project HEALTH-F3-2009-222983. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer-reviewedPublisher Versio

Detection and Mapping of Quantitative Trait Loci that Determine Responsiveness

Exposure to 70% N2O evokes a robust antinociceptive effect in C57BL/6 (B6) but not in DBA/2 (D2) inbred mice. This study was conducted to identify quantitative trait loci (QTL) in the mouse genome that might determine responsiveness to N2O. Offspring from the F2 generation bred from B6 and D2 progenitors exhibited a broad range of responsiveness to N2O antinociception as determined by the acetic acid-induced abdominal constriction test. QTL analysis was then used to dissect this continuous trait distribution into component loci, and to map them to broad chromosomal regions. To this end, 24 spleens were collected from each of the following four groups: male and female F2 mice responding to 70% N2O in oxygen with 100% response (high-responders); and male and female F2 mice responding with 0% response (low-responders). Genomic DNA was extracted from the spleens and genotyped with simple sequence length polymorphism MapPairs markers. Findings were combined with findings from the earlier QTL analysis from BXD recombinant inbred mice [Brain Res 725 (1996) 23]. Combined results revealed two significant QTL that influence responsiveness to nitrous oxide on proximal chromosome 2 and distal chromosome 5, and one suggestive QTL on midchromosome 18. The chromosome 2 QTL was evident only in males. A significant interaction was found between a locus on chromosome 6 and another on chromosome 13 with a substantial effect on N2O antinociception

Nitrous Oxide: Mechanism of Its Antinociceptive Action

Nitrous oxide (N2O) is an anesthetic gas known to produce an analgesic effect at sub-anesthetic concentrations. This analgesic property of N2O can be clinically exploited in a broad range of conditions where pain relief is indicated. The mechanism of this analgesic effect was long thought to be nonspecific in nature, but a landmark study by Berkowitz and others in 1976 first implicated an opioid mechanism of action, possibly via N2O-stimulated neuronal release of endogenous opioid peptides to activate opioid receptors. N2O-induced release of opioid peptide has been demonstrated in both in vivo and in vitro preparations. Reversal of N2O-induced antinociception in animals by narcotic antagonists has been reported by a number of laboratories. Subsequent studies have utilized more selective opioid antagonists to identify the opioid receptor subtypes involved in the antinociceptive effect of N2O. Extensive pharmacological testing in the mouse abdominal constriction and rat hot plate paradigms have established that N2O-induced antinociception is mediated by κ-opioid receptors in the former and by µ- and -opioid receptors in the latter. Current studies focus on two recent developments. The poor responsiveness of the DBA/2J mouse strain to N2O has led to pharmacogenetic studies that hope to identify the underlying genetic basis for antinociceptive responsiveness to N2O. Other research suggests an involvement of nitric oxide (NO) in mediating the antinociceptive effects of N2O in both rats and mice