HR Mice Research Articles

Increased stress reactivity is associated with reduced hippocampal activity and neuronal integrity along with changes in energy metabolism

Patients suffering from major depression have repeatedly been reported to have dysregulations in hypothalamus-pituitary-adrenal (HPA) axis activity along with deficits in cognitive processes related to hippocampal and prefrontal cortex (PFC) malfunction. Here, we utilized three mouse lines selectively bred for high (HR), intermediate, or low (LR) stress reactivity, determined by the corticosterone response to a psychological stressor, probing the behavioral and functional consequences of increased vs. decreased HPA axis reactivity on the hippocampus and PFC. We assessed performance in hippocampus- and PFC-dependent tasks and determined the volume, basal activity, and neuronal integrity of the hippocampus and PFC using in vivo manganese-enhanced magnetic resonance imaging and proton magnetic resonance spectroscopy. The hippocampal proteomes of HR and LR mice were also compared using two-dimensional gel electrophoresis and mass spectrometry. HR mice were found to have deficits in the performance of hippocampus- and PFC-dependent tests and showed decreased N-acetylaspartate levels in the right dorsal hippocampus and PFC. In addition, the basal activity of the hippocampus, as assessed by manganese-enhanced magnetic resonance imaging, was reduced in HR mice. The three mouse lines, however, did not differ in hippocampal volume. Proteomic analysis identified several proteins that were differentially expressed in HR and LR mice. In accordance with the notion that N-acetylaspartate levels, in part, reflect dysfunctional mitochondrial metabolism, these proteins were found to be involved in energy metabolism pathways. Thus, our results provide further support for the involvement of a dysregulated HPA axis and mitochondrial dysfunction in the etiology and pathophysiology of affective disorders.

Oxytocin, vasopressin and estrogen receptor gene expression in relation to social recognition in female mice

Inter- and intra-species differences in social behavior and recognition-related hormones and receptors suggest that different distribution and/or expression patterns may relate to social recognition. We used qRT-PCR to investigate naturally occurring differences in expression of estrogen receptor-alpha (ERα), ER-beta (ERβ), progesterone receptor (PR), oxytocin (OT) and receptor, and vasopressin (AVP) and receptors in proestrous female mice. Following four 5min exposures to the same two conspecifics, one was replaced with a novel mouse in the final trial (T5). Gene expression was examined in mice showing high (85–100%) and low (40–60%) social recognition scores (i.e., preferential novel mouse investigation in T5) in eight socially-relevant brain regions. Results supported OT and AVP involvement in social recognition, and suggest that in the medial preoptic area, increased OT and AVP mRNA, together with ERα and ERβ gene activation, relate to improved social recognition. Initial social investigation correlated with ERs, PR and OTR in the dorsolateral septum, suggesting that these receptors may modulate social interest without affecting social recognition. Finally, increased lateral amygdala gene activation in the LR mice may be associated with general learning impairments, while decreased lateral amygdala activity may indicate more efficient cognitive mechanisms in the HR mice.

Sleep disturbances in highly stress reactive mice: Modeling endophenotypes of major depression

BackgroundNeuronal mechanisms underlying affective disorders such as major depression (MD) are still poorly understood. By selectively breeding mice for high (HR), intermediate (IR), or low (LR) reactivity of the hypothalamic-pituitary-adrenocortical (HPA) axis, we recently established a new genetic animal model of extremes in stress reactivity (SR). Studies characterizing this SR mouse model on the behavioral, endocrine, and neurobiological levels revealed several similarities with key endophenotypes observed in MD patients. HR mice were shown to have changes in rhythmicity and sleep measures such as rapid eye movement sleep (REMS) and non-REM sleep (NREMS) as well as in slow wave activity, indicative of reduced sleep efficacy and increased REMS. In the present study we were interested in how far a detailed spectral analysis of several electroencephalogram (EEG) parameters, including relevant frequency bands, could reveal further alterations of sleep architecture in this animal model. Eight adult males of each of the three breeding lines were equipped with epidural EEG and intramuscular electromyogram (EMG) electrodes. After recovery, EEG and EMG recordings were performed for two days.ResultsDifferences in the amount of REMS and wakefulness and in the number of transitions between vigilance states were found in HR mice, when compared with IR and LR animals. Increased frequencies of transitions from NREMS to REMS and from REMS to wakefulness in HR animals were robust across the light-dark cycle. Detailed statistical analyses of spectral EEG parameters showed that especially during NREMS the power of the theta (6-9 Hz), alpha (10-15 Hz) and eta (16-22.75 Hz) bands was significantly different between the three breeding lines. Well defined distributions of significant power differences could be assigned to different times during the light and the dark phase. Especially during NREMS, group differences were robust and could be continuously monitored across the light-dark cycle.ConclusionsThe HR mice, i.e. those animals that have a genetic predisposition to hyper-activating their HPA axis in response to stressors, showed disturbed patterns in sleep architecture, similar to what is known from depressed patients. Significant alterations in several frequency bands of the EEG, which also seem to at least partly mimic clinical observations, suggest the SR mouse lines as a promising animal model for basic research of mechanisms underlying sleep impairments in MD.

Intrahippocampal Corticosterone Response in Mice Selectively Bred for Extremes in Stress Reactivity: A Microdialysis Study

The hypothalamic-pituitary-adrenocortical (HPA) axis is one of the major stress hormone systems, and glucocorticoids (GCs) play a pivotal role in homeostatic processes throughout the body and brain. A dysregulation of the HPA axis, leading to an aberrant secretion of GCs, is associated with affective disorders such as major depression. In the present study, three mouse lines selectively bred for high (HR), intermediate (IR) or low (LR) stress reactivity were used to elucidate the temporal dynamics of intrahippocampal corticosterone (CORT) in response to a standardised stressor. In particular, we addressed the question of whether the distinct differences in HPA axis reactivity between the three mouse lines, as determined by plasma CORT measurements, are present in the central nervous system as well, and if the respective endophenotype is brought about by alterations in blood-brain barrier (BBB) functionality. We applied in vivo microdialysis in the hippocampus, demonstrating that the concentrations of CORT released from the adrenals in response to restraint stress are not only distinctly different in the plasma, but can also be found in the central nervous system, although the differences between the three mouse lines were attenuated, particularly between IR and LR animals. Additionally, a time lag of approximately 60 min was observed in all three lines regarding intrahippocampal peak concentrations of CORT after the onset of the stressor. Furthermore, we showed that the penetration and clearance of CORT in the hippocampal tissue was not affected by differences in BBB functionality because the multidrug resistance 1 P-glycoprotein (Mdr1 Pgp) was equally expressed in HR, IR and LR mice. Furthermore, we could exclude surgical damage of the BBB because peripherally-injected dexamethasone, which is a high affinity substrate for the Mdr1 Pgp and therefore restricted from entering the brain, could only be detected in the plasma and was virtually absent in the brain.

Dermal cysts participate in reparative regeneration of epidermis in Hr hr /Hr hr mice

One of the phenotypic effects of mutation in the Hr gene in mice is disintegration of hair follicles and their degeneration into open funnel-shaped structures (utricles) opened on skin surface and cysts located in the depth of the dermis. The aim of the current study consists in analysis of the process of reparative regeneration of skin in homozygotous mice with one of the mutant alleles of the Hr gene-Hr(hr). It is shown that epithelial cells that constitute the inner pavement of cysts take part in the process of epithelization of deep skin wounds. This indicates that the competence of ectodermal cells in relation to inductive signals from injured skin remains in Hrr homozygote mice, in spite of the significant anatomic abnormalities of the hair follicles.

Morphofunctional Evaluation of the Effect of Collagen-1-Based Dressing on Skin Regeneration after Burn Trauma in Mice of Two Genetic Strains

Morphofunctional evaluation of the effect of biological dressing with collagen-1 on healing of 3A degree burn wound in outbred and mutant Hr(hr)/Hr(hr)(hairless) mice was carried out by the histological method and optic radioautography. A pronounced stimulatory effect of the dressing on skin regeneration in mice was demonstrated. According to radioautography data, early dressing of the burn wounds in Hr(hr)/Hr(hr)mice led to active proliferation of epithelial cells in dermal cyst and vascular endotheliocytes. The possible mechanisms of the stimulatory effect of collagen-based dressing on wound healing are discussed.

Modeling psychotic and cognitive symptoms of affective disorders: Disrupted latent inhibition and reversal learning deficits in highly stress reactive mice

Increased stress reactivity has repeatedly been reported in patients suffering from psychiatric diseases including schizophrenia and major depression. These disorders also have other symptoms in common, such as cognitive deficits and psychotic-like behavior. We have therefore investigated if increased stress reactivity is associated with these phenotypic endpoints in an animal model of affective disorders. The stress reactivity mouse model used in this study consists of three CD-1-derived mouse lines, that have been selectively bred for high (HR), intermediate (IR) or low (LR) stress reactivity. Male mice from these three breeding lines were subjected to a reversal learning task and latent inhibition (Li) was assessed using a conditioned taste aversion paradigm. Furthermore, as the dopaminergic system is involved in both Li and reversal learning, the dopamine 1 receptor (D1R), dopamine 2 receptor (D2R) and dopamine transporter (DAT) mRNA expression levels were assessed in relevant brain areas of these animals. The results demonstrate that HR mice show perseveration in the reversal learning task and have disrupted Li. Furthermore, compared to LR mice, HR mice have decreased D2R mRNA levels in the ventral tegmental area, as well as decreased D1R mRNA levels in the cingulate cortex, and an increased expression of D2R mRNA in the nucleus accumbens. Taken together, these results demonstrate that the HR mice display cognitive deficits associated with psychotic-like behavior, similar to those observed in patients suffering from schizophrenia and major depression and could be utilized in the search for better treatment strategies for these symptoms of psychiatric disorders.

Dopaminergic dysregulation in mice selectively bred for excessive exercise or obesity

Dysregulation of the dopamine system is linked to various aberrant behaviors, including addiction, compulsive exercise, and hyperphagia leading to obesity. The goal of the present experiments was to determine how dopamine contributes to the expression of opposing phenotypes, excessive exercise and obesity. We hypothesized that similar alterations in dopamine and dopamine-related gene expression may underly obesity and excessive exercise, as competing traits for central reward pathways. Moreover, we hypothesized that selective breeding for high levels of exercise or obesity may have influenced genetic variation controlling these pathways, manifesting as opposing complex traits. Dopamine, dopamine-related peptide concentrations, and gene expression were evaluated in dorsal striatum (DS) and nucleus accumbens (NA) of mice from lines selectively bred for high rates of wheel running (HR) or obesity (M16), and the non-selected ICR strain from which these lines were derived. HPLC analysis showed significantly greater neurotransmitter concentrations in DS and NA of HR mice compared to M16 and ICR. Microarray analysis showed significant gene expression differences between HR and M16 compared to ICR in both brain areas, with changes revealed throughout the dopamine pathway including D1 and D2 receptors, associated G-proteins (e.g., Golf), and adenylate cyclase (e.g., Adcy5). The results suggest that similar modifications within the dopamine system may contribute to the expression of opposite phenotypes in mice, demonstrating that alterations within central reward pathways can contribute to both obesity and excessive exercise.

Increased stress reactivity is associated with cognitive deficits and decreased hippocampal brain-derived neurotrophic factor in a mouse model of affective disorders

Cognitive deficits are a common feature of major depression (MD), with largely unknown biological underpinnings. In addition to the affective and cognitive symptoms of MD, a dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis is commonly observed in these patients. Increased plasma glucocorticoid levels are known to render the hippocampus susceptible to neuronal damage. This structure is important for learning and memory, creating a potential link between HPA axis dysregulation and cognitive deficits in depression. In order to further elucidate how altered stress responsiveness may contribute to the etiology of MD, three mouse lines with high (HR), intermediate (IR), or low (LR) stress reactivity were generated by selective breeding. The aim of the present study was to investigate whether increased stress reactivity is associated with deficits in hippocampus-dependent memory tests. To this end, we subjected mice from the HR, IR, and LR breeding lines to tests of recognition memory, spatial memory, and depression-like behavior. In addition, measurements of brain-derived neurotrophic factor (BDNF) in the hippocampus and plasma of these animals were conducted. Our results demonstrate that HR mice exhibit hippocampus-dependent memory deficits along with decreased hippocampal, but not plasma, BDNF levels. Thus, the stress reactivity mouse lines are a promising animal model of the cognitive deficits in MD with the unique feature of a genetic predisposition for an altered HPA axis reactivity, which provides the opportunity to explore the progression of the symptoms of MD, predisposing genetic factors as well as new treatment strategies.

Variation in within-bone stiffness measured by nanoindentation in mice bred for high levels of voluntary wheel running.

The hierarchical structure of bone, involving micro-scale organization and interaction of material components, is a critical determinant of macro-scale mechanics. Changes in whole-bone morphology in response to the actions of individual genes, physiological loading during life, or evolutionary processes, may be accompanied by alterations in underlying mineralization or architecture. Here, we used nanoindentation to precisely measure compressive stiffness in the femoral mid-diaphysis of mice that had experienced 37 generations of selective breeding for high levels of voluntary wheel running (HR). Mice (n = 48 total), half from HR lines and half from non-selected control (C) lines, were divided into two experimental groups, one with 13-14 weeks of access to a running wheel and one housed without wheels (n = 12 in each group). At the end of the experiment, gross and micro-computed tomography (microCT)-based morphometric traits were measured, and reduced elastic modulus (E(r)) was estimated separately for four anatomical quadrants of the femoral cortex: anterior, posterior, lateral, and medial. Two-way, mixed-model analysis of covariance (ancova) showed that body mass was a highly significant predictor of all morphometric traits and that structural change is more apparent at the microCT level than in conventional morphometrics of whole bones. Both line type (HR vs. C) and presence of the mini-muscle phenotype (caused by a Mendelian recessive allele and characterized by a approximately 50% reduction in mass of the gastrocnemius muscle complex) were significant predictors of femoral cortical cross-sectional anatomy. Measurement of reduced modulus obtained by nanoindentation was repeatable within a single quadrant and sensitive enough to detect inter-individual differences. Although we found no significant effects of line type (HR vs. C) or physical activity (wheel vs. no wheel) on mean stiffness, anterior and posterior quadrants were significantly stiffer (P < 0.0001) than medial and lateral quadrants (32.67 and 33.09 GPa vs. 29.78 and 30.46 GPa, respectively). Our findings of no significant difference in compressive stiffness in the anterior and posterior quadrants agree with previous results for mice, but differ from those for large mammals. Integrating these results with others from ongoing research on these mice, we hypothesize that the skeletons of female HR mice may be less sensitive to the effects of chronic exercise, due to decreased circulating leptin levels and potentially altered endocannabinoid signaling.

Temporal aspects of HPA axis reactivity and regulation: microdialysis studies in the HR/IR/LR mouse model

Major depression (MD) is one of the most common affective disorders. Apart from vegetative and psychological symptoms, patients show profound neuroendocrine alterations often including a HPA axis dysregulation. In this study, a new animal model for affective disorders was used to elucidate the temporal aspects of HPA axis reactivity and feedback regulation. The so-called stress reactivity (SR) mouse model consists of three separate breeding lines – the high (HR), intermediate (IR) and low reactivity (LR) mouse line – with a significantly different reactivity of the HPA axis in response to stressors. In vivo microdialysis was used to monitor the increase of hippocampal corticosterone (CORT) concentrations after the onset of a stressor. Simultaneously, plasma CORT concentrations were measured via blood samplings. The experiments revealed: (i) distinct differences between the SR mouse lines regarding peak concentrations of CORT in the hippocampus and plasma (HR&gt;IR&gt;LR); (ii) all tested individuals showed this peak concentration around the same time point (45min) after the onset of the stressor, with HR mice showing the highest increase of hippocampal and plasma CORT concentrations; (iii) recordings of the circadian rhythm of CORT secretion showed a higher HPA axis activity in the HR mouse line. Thus, our findings suggest the SR model to be a promising tool for elucidating the molecular mechanisms of affective disorders and developing new treatment strategies for MD.

A novel mutation in Hr causes abnormal hair follicle morphogenesis in hairpoor mouse, an animal model for Marie Unna Hereditary Hypotrichosis

Hairpoor mice (Hr(Hp)) were derived through N-ethyl-N-nitrosourea (ENU) mutagenesis. These mice display sparse and short hair in the Hr(Hp)/+ heterozygous state and complete baldness in the Hr(Hp)/Hr(Hp) homozygous state. This phenotype was irreversible and was inherited in an autosomal semidominant manner. Hair follicles (HFs) of Hr(Hp)/+ mice underwent normal cycling and appeared normal, although smaller than those of the wild-type mice. In contrast, HFs of Hr(Hp)/Hr(Hp) mice became cyst-like structures by postnatal day (P) 21. The number and length of vibrissae decreased in a dose-dependent manner as the number of mutant alleles increased. A positional candidate gene approach was used to identify the gene responsible for the hairpoor phenotype. Genetic linkage analysis determined that the hairpoor locus is 2 cm from D14Mit34 on chromosome 14. Sequence analysis of the exons of the candidate gene hairless revealed a T-to-A transversion mutation at nucleotide position 403 (exon 2), presumably resulting in abolishment of an upstream open reading frame (uORF). In addition, we also found that the near-naked mouse (Hr(N)), a spontaneously arising mutant, harbors a A402G transition in its genome. Both mutations were in the uATG codon of the second uORF in the 5' UTR and corresponded to the mutations identified in Marie Unna Hereditary Hypotrichosis (MUHH) patients. In the present study we describe the phenotype, histological morphology, and molecular etiology of an animal model of MUHH, the hairpoor mouse.

Rhythmicity in Mice Selected for Extremes in Stress Reactivity: Behavioural, Endocrine and Sleep Changes Resembling Endophenotypes of Major Depression

BackgroundDysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, including hyper- or hypo-activity of the stress hormone system, plays a critical role in the pathophysiology of mood disorders such as major depression (MD). Further biological hallmarks of MD are disturbances in circadian rhythms and sleep architecture. Applying a translational approach, an animal model has recently been developed, focusing on the deviation in sensitivity to stressful encounters. This so-called ‘stress reactivity’ (SR) mouse model consists of three separate breeding lines selected for either high (HR), intermediate (IR), or low (LR) corticosterone increase in response to stressors.Methodology/Principle FindingsIn order to contribute to the validation of the SR mouse model, our study combined the analysis of behavioural and HPA axis rhythmicity with sleep-EEG recordings in the HR/IR/LR mouse lines. We found that hyper-responsiveness to stressors was associated with psychomotor alterations (increased locomotor activity and exploration towards the end of the resting period), resembling symptoms like restlessness, sleep continuity disturbances and early awakenings that are commonly observed in melancholic depression. Additionally, HR mice also showed neuroendocrine abnormalities similar to symptoms of MD patients such as reduced amplitude of the circadian glucocorticoid rhythm and elevated trough levels. The sleep-EEG analyses, furthermore, revealed changes in rapid eye movement (REM) and non-REM sleep as well as slow wave activity, indicative of reduced sleep efficacy and REM sleep disinhibition in HR mice.Conclusion/SignificanceThus, we could show that by selectively breeding mice for extremes in stress reactivity, clinically relevant endophenotypes of MD can be modelled. Given the importance of rhythmicity and sleep disturbances as biomarkers of MD, both animal and clinical studies on the interaction of behavioural, neuroendocrine and sleep parameters may reveal molecular pathways that ultimately lead to the discovery of new targets for antidepressant drugs tailored to match specific pathologies within MD.

Cognitive abilities and hippocampal neuronal integrity of mice selected for extremes in stress reactivity: a novel animal model for cognitive deficits in depression

Event Abstract Back to Event Cognitive abilities and hippocampal neuronal integrity of mice selected for extremes in stress reactivity: a novel animal model for cognitive deficits in depression Alana Knapman1*, Sebastian Kaltwasser1, Michael Czisch1, Rainer Landgraf1 and Chadi Touma1 1 Max Planck Institute of Psychiatry, Germany Cognitive deficits are a common feature of major depressive disorders, with largely unknown biological underpinnings. It has repeatedly been reported that patients suffering from major depression have a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, with an increased reactivity commonly seen in melancholic depression, leading to increased amounts of circulating cortisol. Increased glucocorticoid levels are known to cause damage to the hippocampus, a structure that is crucial in learning and memory, creating a potential link between HPA axis dysregulation and cognitive deficits in depression. It was therefore our aim to establish if a dysregulation of the HPA axis could contribute to the underlying cause of the cognitive deficits as well as depression-like behaviour. In order to test this hypothesis, three CD-1 derived mouse lines were used, that were selectively bred for high (HR), intermediate (IR) and low (LR) stress reactivity, respectively. These mice were subjected to a cognitive test battery, focusing on hippocampus-dependent tasks. In accordance with our hypothesis, we found that HR mice, whose hippocampus most probably has been subjected to larger amounts of corticosterone than that of IR and LR mice, show both spatial and object memory deficits. LR mice, on the other hand, demonstrate superior cognitive abilities compared to HR and IR mice. Furthermore, the integrity of hippocampal neurons was investigated by means of proton magnetic resonance spectroscopy. This revealed that HR mice have a decreased level of N-acetylaspartate, a marker for neuronal integrity, compared to both IR and LR mice, in the right hippocampus. This initial cognitive test battery demonstrates that the stress reactivity mouse lines are a promising tool for modelling cognitive deficits in depression and to further our understanding of the biological underpinnings as well as exploring new treatment strategies for these symptoms. Conference: 41st European Brain and Behaviour Society Meeting, Rhodes Island, Greece, 13 Sep - 18 Sep, 2009. Presentation Type: Poster Presentation Topic: Poster presentations Citation: Knapman A, Kaltwasser S, Czisch M, Landgraf R and Touma C (2009). Cognitive abilities and hippocampal neuronal integrity of mice selected for extremes in stress reactivity: a novel animal model for cognitive deficits in depression. Conference Abstract: 41st European Brain and Behaviour Society Meeting. doi: 10.3389/conf.neuro.08.2009.09.195 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 10 Jun 2009; Published Online: 10 Jun 2009. * Correspondence: Alana Knapman, Max Planck Institute of Psychiatry, Muenchen, Germany, knapman@mpipsykl.mpg.de Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Alana Knapman Sebastian Kaltwasser Michael Czisch Rainer Landgraf Chadi Touma Google Alana Knapman Sebastian Kaltwasser Michael Czisch Rainer Landgraf Chadi Touma Google Scholar Alana Knapman Sebastian Kaltwasser Michael Czisch Rainer Landgraf Chadi Touma PubMed Alana Knapman Sebastian Kaltwasser Michael Czisch Rainer Landgraf Chadi Touma Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Genes, Hormones and the Brain: Modeling Clinically Relevant Endophenotypes of Major Depression in Mice Selected for Extremes in Stress Reactivity

Event Abstract Back to Event Genes, Hormones and the Brain: Modeling Clinically Relevant Endophenotypes of Major Depression in Mice Selected for Extremes in Stress Reactivity Chadi Touma1*, Rupert Palme2, Florian Holsboer1 and Rainer Landgraf1 1 Max Planck Institute of Psychiatry, Germany 2 University of Veterinary Medicine, Austria Affective disorders are among the most prevalent and costly diseases of the central nervous system. In recent years, it has become evident that alterations of the stress hormone system, in particular dysfunctions of the HPA axis, play a prominent role in the aetiology of major depression. Therefore, we aimed to generate a new animal model comprising these neuroendocrine core symptoms in order to unravel the mechanisms underlying increased or decreased stress reactivity. Starting from a population of outbred mice, two breeding lines were established according to the outcome of a “stress reactivity test” (SRT), consisting of a 15-min restraint period and tail blood samplings immediately before and after the stressor. Mice showing a high or a low secretion of corticosterone in the SRT were selected for the “high reactivity” (HR) and the “low reactivity” (LR) breeding line, respectively. Additionally, a third breeding line with an “intermediate reactivity” (IR) in the SRT was established. Already in the first generation, significant differences in HPA axis reactivity between HR, IR, and LR mice were observed. These differences remained stable across all subsequent generations and could be increased by selective inbreeding. Repeated testing in the SRT furthermore proved that the observed differences in stress responsiveness are already present early in life and can be regarded as a robust genetic predisposition. Emotional behaviour testing, sleep EEG measurements and morphometric, neuroendocrine, and gene expression findings also point to similarities with depressive patients. Taken together, our results indicate that distinct mechanisms influencing the function and regulation of the HPA axis seem to mediate the respective behavioural and neurobiological endophenotypes. Thus, the generated HR/IR/LR mouse lines are a valuable model to elucidate the molecular-genetic underpinnings of altered stress reactivity and thereby improve our understanding of affective disorders. Conference: 41st European Brain and Behaviour Society Meeting, Rhodes Island, Greece, 13 Sep - 18 Sep, 2009. Presentation Type: Poster Presentation Topic: Poster presentations Citation: Touma C, Palme R, Holsboer F and Landgraf R (2009). Genes, Hormones and the Brain: Modeling Clinically Relevant Endophenotypes of Major Depression in Mice Selected for Extremes in Stress Reactivity. Conference Abstract: 41st European Brain and Behaviour Society Meeting. doi: 10.3389/conf.neuro.08.2009.09.323 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 15 Jun 2009; Published Online: 15 Jun 2009. * Correspondence: Chadi Touma, Max Planck Institute of Psychiatry, Munich, Germany, chadi.touma@uni-osnabrueck.de Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Chadi Touma Rupert Palme Florian Holsboer Rainer Landgraf Google Chadi Touma Rupert Palme Florian Holsboer Rainer Landgraf Google Scholar Chadi Touma Rupert Palme Florian Holsboer Rainer Landgraf PubMed Chadi Touma Rupert Palme Florian Holsboer Rainer Landgraf Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Differential response to a selective cannabinoid receptor antagonist (SR141716: rimonabant) in female mice from lines selectively bred for high voluntary wheel-running behaviour

Exercise is a naturally rewarding behaviour in human beings and can be associated with feelings of euphoria and analgesia. The endocannabinoid system may play a role in the perception of neurobiological rewards during and after prolonged exercise. Mice from lines that have been selectively bred for high voluntary wheel running (high runner or HR lines) may have evolved neurobiological mechanisms that increase the incentive salience of endurance-type exercise. Here, we test the hypothesis that endocannabinoid signalling has been altered in the four replicate HR lines as compared with four nonselected control lines. After 18 days of acclimation to cages with attached wheels, we injected mice with rimonabant (SR141716), a selective cannabinoid CB1 receptor antagonist. During the time of normal peak running, each mouse received, in a randomized order, intraperitoneal injection of rimonabant (0.1 or 3.0 mg/kg) or vehicle, over 9 days. Drug response was quantified as wheel revolutions, time and speed 10-70 min postinjection. Rimonabant decreased running in all mice; however, female HR mice differentially decreased running speed and distance (but not time) as compared with control females. We conclude that altered endocannabinoid signalling plays a role in the high wheel running of female HR mice.

Mice selected for high versus low stress reactivity: A new animal model for affective disorders

Affective disorders such as major depression are among the most prevalent and costly diseases of the central nervous system, but the underlying mechanisms are still poorly understood. In recent years, it has become evident that alterations of the stress hormone system, in particular dysfunctions (hyper- or hypo-activity) of the hypothalamic-pituitary-adrenal (HPA) axis, play a prominent role in the development of major depressive disorders. Therefore, we aimed to generate a new animal model comprising these neuroendocrine core symptoms in order to unravel parameters underlying increased or decreased stress reactivity. Starting from a population of outbred mice (parental generation: 100 males and 100 females of the CD-1 strain), two breeding lines were established according to the outcome of a 'stress reactivity test' (SRT), consisting of a 15-min restraint period and tail blood samplings immediately before and after exposure to the stressor. Mice showing a very high or a very low secretion of corticosterone in the SRT, i.e. animals expressing a hyper- or a hypo-reactivity of the HPA axis, were selected for the 'high reactivity' (HR) and the 'low reactivity' (LR) breeding line, respectively. Additionally, a third breeding line was established consisting of animals with an 'intermediate reactivity' (IR) in the SRT. Already in the first generation, i.e. animals derived from breeding pairs selected from the parental generation, significant differences in the reactivity of the HPA axis between HR, IR, and LR mice were observed. Moreover, these differences were found across all subsequent generations and could be increased by selective breeding, which indicates a genetic basis of the respective phenotype. Repeated testing of individuals in the SRT furthermore proved that the observed differences in stress responsiveness are present already early in life and can be regarded as a robust genetic predisposition. Tests investigating the animal's emotionality including anxiety-related behavior, exploratory drive, locomotor activity, and depression-like behavior point to phenotypic similarities with behavioral changes observed in depressive patients. In general, HR males and females were 'hyperactive' in some behavioral paradigms, resembling symptoms of restlessness and agitation often seen in melancholic depression. LR mice, on the other hand, showed more passive-aggressive coping styles, corresponding to signs of retardation and retreat observed in atypical depression. Several morphometric and neuroendocrine findings further support this view. For example, monitoring the circadian rhythm of glucocorticoid secretion revealed clearly increased trough levels in HR mice, resulting in a flattened diurnal rhythm, again adding to the neuroendocrine similarities to patients suffering from melancholic depression. Taken together, our results suggest that distinct mechanisms influencing the function and regulation of the HPA axis are involved in the respective behavioral and neurobiological endophenotypes. Thus, the generated HR/IR/LR mouse lines can be a valuable model to elucidate molecular genetic, neuroendocrine, and behavioral parameters associated with altered stress reactivity, thereby improving our understanding of affective disorders, presumably including the symptomatology and pathophysiology of specific subtypes of major depression.

The Near-Naked Hairless (HrN) Mutation Disrupts Hair Formation but Is Not Due to a Mutation in the Hairless Coding Region

Near-naked hairless (Hr(N)) is a semi-dominant, spontaneous mutation that was suggested by allelism testing to be allelic with mouse Hairless (Hr). Hr(N) mice differ from other Hr mutants in that hair loss appears as the postnatal coat begins to emerge, rather than as an inability to regrow hair after the first catagen and that the mutation displays semi-dominant inheritance. We sequenced the Hr cDNA in Hr(N)/Hr(N) mice and characterized the pathological and molecular phenotypes to identify the basis for hair loss in this model. Hr(N)/Hr(N) mice exhibit dystrophic hairs that are unable to emerge consistently from the hair follicle, whereas Hr(N)/+ mice display a sparse coat of hair and a milder degree of follicular dystrophy than their homozygous littermates. DNA microarray analysis of cutaneous gene expression demonstrates that numerous genes are downregulated in Hr(N)/Hr(N) mice, primarily genes important for hair structure. By contrast, Hr expression is significantly increased. Sequencing the Hr-coding region, intron-exon boundaries, 5'- and 3'-untranslated region, and immediate upstream region did not reveal the underlying mutation. Therefore, Hr(N) does not appear to be an allele of Hr but may result from a mutation in a closely linked gene or from a regulatory mutation in Hr.

Effect of level of dysfunction of the melanocortin-4 receptor (MC4R) on overconsumption and binge-like eating of a palatable dessert in mice.

Dysfunction of the melanocortin-4 receptor (MC4R) leads to hyperphagia and overweight and has been correlated with obesity and binge-eating in humans. We examined in mice the effect of MC4R dysfunction on development of overconsumption and body weight gain. Wild type (WT) mice, homozygous MC4R knockout (MC4RKO), and carrier (MC4RHET) mice were provided with ad libitum access to moist chow (1:1 powdered Purina 5001 to tap water, 1.67 kcal/g) and daily 8 h access to sugar fat whip (SFW; 2:1 vegetable shortening to sugar, 7.35 kcal/g). MC4RKO mice increased their caloric intake and gained weight. This is indicative of a role of MC4R in maintaining caloric balance and adjusting to the consumption of palatable foods. MC4RHET mice ate similarly to WT mice, which, unlike rats, maintained caloric balance. This suggests that studies of MC4RKO mice may be a more valid model of human overconsumption. We also examined the effect of MC4R dysfunction on binge-like eating patterns in a protocol similar to Corwin's group (Dimitriou et al., 2000). We provided female mice either daily (low restriction, LR) or every-other-day (high restriction, HR) 2 h access to SFW. HR mice of all genotypes showed evidence of binge-like eating, but only MC4RKO mice gained weight. This suggests that a lack of MC4R functioning may not be necessary for the development of binge-like eating, but may be associated with the obesity related to it.

Advantages of Using Hairless Mice Versus Haired Mice to Test Sunscreen Efficacy Against Photoimmune Suppression¶

We tested the hypothesis that the strain of mice used in sunscreen protection experiments may influence immune protection. Ultraviolet (UV) dose–response curves were done in the presence or absence of a sun protection factor (SPF) 15 sunscreen using SKH1:hrBR or C3H/HeN mice. SKH1:hrBR mice showed a higher sensitivity to the suppressive effects of UV radiation (50% immune suppression equal to 5.2 kJ/m2 UVB in SKH1:hrBR mice versus 18.5 kJ/m2 in C3H mice). Immune protection factors (IPF) and an erythema protection factor (Ery-PF) for SKH1:hr mice were derived. The Ery-PF in hairless mice was 13.5, which was similar to the SPF of 15 measured in humans. When IPF were calculated as a ratio of minimal immune suppressive doses, the IPF for the SKH1:hrBR mice was 8.23 and the IFP for the C3H/HeN mice was 1.92. When IPF were estimated using the entire UV dose–response range, they were equal to 9.01 for SKH1:hrBR mice and 1.79 for the C3H/HeN mice. Because IPF and SPF can be measured directly in hairless mice, we suggest that the use of hairless mice may provide a better model to measure sunscreen efficacy, especially when the use of human volunteers is inappropriate, unethical or impossible.