Johannes Fuss

Voluntary exercise induces anxiety-like behavior in adult C57BL/6J mice correlating with hippocampal neurogenesis.

Several studies investigated the effect of physical exercise on emotional behaviors in rodents; resulting findings however remain controversial. Despite the accepted notion that voluntary exercise alters behavior in the same manners as antidepressant drugs, several studies reported opposite or no effects at all. In an attempt to evaluate the effect of physical exercise on emotional behaviors and brain plasticity, we individually housed C57BL/6J male mice in cages equipped with a running wheel. Three weeks after continuous voluntary running we assessed their anxiety‐ and depression‐like behaviors. Tests included openfield, dark‐light‐box, elevated O‐maze, learned helplessness, and forced swim test. We measured corticosterone metabolite levels in feces collected over a 24‐h period and brain‐derived neurotrophic factor (BDNF) in several brain regions. Furthermore, cell proliferation and adult hippocampal neurogenesis were assessed using Ki67 and Doublecortin. Voluntary wheel running induced increased anxiety in the openfield, elevated O‐maze, and dark‐light‐box and higher levels of excreted corticosterone metabolites. We did not observe any antidepressant effect of running despite a significant increase of hippocampal neurogenesis and BDNF. These data are thus far the first to indicate that the effect of physical exercise in mice may be ambiguous. On one hand, the running‐induced increase of neurogenesis and BDNF seems to be irrelevant in tests for depression‐like behavior, at least in the present model where running activity exceeded previous reports. On the other hand, exercising mice display a more anxious phenotype and are exposed to higher levels of stress hormones such as corticosterone. Intriguingly, numbers of differentiating neurons correlate significantly with anxiety parameters in the openfield and dark‐light‐box. We therefore conclude that adult hippocampal neurogenesis is a crucial player in the genesis of anxiety.

Deletion of Running-Induced Hippocampal Neurogenesis by Irradiation Prevents Development of an Anxious Phenotype in Mice

Recent evidence postulates a role of hippocampal neurogenesis in anxiety behavior. Here we report that elevated levels of neurogenesis elicit increased anxiety in rodents. Mice performing voluntary wheel running displayed both highly elevated levels of neurogenesis and increased anxiety in three different anxiety-like paradigms: the open field, elevated O-maze, and dark-light box. Reducing neurogenesis by focalized irradiation of the hippocampus abolished this exercise-induced increase of anxiety, suggesting a direct implication of hippocampal neurogenesis in this phenotype. On the other hand, irradiated mice explored less frequently the lit compartment of the dark-light box test irrespective of wheel running, suggesting that irradiation per se induced anxiety as well. Thus, our data suggest that intermediate levels of neurogenesis are related to the lowest levels of anxiety. Moreover, using c-Fos immunocytochemistry as cellular activity marker, we observed significantly different induction patterns between runners and sedentary controls when exposed to a strong anxiogenic stimulus. Again, this effect was altered by irradiation. In contrast, the well-known induction of brain-derived neurotrophic factor (BDNF) by voluntary exercise was not disrupted by focal irradiation, indicating that hippocampal BDNF levels were not correlated with anxiety under our experimental conditions. In summary, our data demonstrate to our knowledge for the first time that increased neurogenesis has a causative implication in the induction of anxiety.

In vivo voxel based morphometry: Detection of increased hippocampal volume and decreased glutamate levels in exercising mice☆

Voluntary exercise has tremendous effects on adult hippocampal plasticity and metabolism and thus sculpts the hippocampal structure of mammals. High-field (1)H magnetic resonance (MR) investigations at 9.4 T of metabolic and structural changes can be performed non-invasively in the living rodent brain. Numerous molecular and cellular mechanisms mediating the effects of exercise on brain plasticity and behavior have been detected in vitro. However, in vivo attempts have been rare. In this work a method for voxel based morphometry (VBM) was developed with automatic tissue segmentation in mice using a 9.4 T animal scanner equipped with a (1)H-cryogenic coil. The thus increased signal to noise ratio enabled the acquisition of high resolution T2-weighted images of the mouse brain in vivo and the creation of group specific tissue class maps for the segmentation and normalization with SPM. The method was used together with hippocampal single voxel (1)H MR spectroscopy to assess the structural and metabolic differences in the mouse brain due to voluntary wheel running. A specific increase of hippocampal volume with a concomitant decrease of hippocampal glutamate levels in voluntary running mice was observed. An inverse correlation of hippocampal gray matter volume and glutamate concentration indicates a possible implication of the glutamatergic system for hippocampal volume.

A runner's high depends on cannabinoid receptors in mice.

Significance A runner’s high is a subjective sense of well-being some humans experience after prolonged exercise. For decades, it was hypothesized that exercise-induced endorphin release is solely responsible for a runner’s high, but recent evidence has suggested that endocannabinoids also may play a role. Here, we demonstrate that wheel running increases endocannabinoids and reduces both anxiety and sensation of pain in mice. Ablation of cannabinoid receptor 1 receptors on GABAergic neurons inhibits running-induced anxiolysis, and pharmacological blockage of central and peripheral cannabinoid receptors inhibits analgesia. We thus show for the first time to our knowledge that cannabinoid receptors are crucial for main aspects of a runner’s high. Exercise is rewarding, and long-distance runners have described a runner’s high as a sudden pleasant feeling of euphoria, anxiolysis, sedation, and analgesia. A popular belief has been that endogenous endorphins mediate these beneficial effects. However, running exercise increases blood levels of both β-endorphin (an opioid) and anandamide (an endocannabinoid). Using a combination of pharmacologic, molecular genetic, and behavioral studies in mice, we demonstrate that cannabinoid receptors mediate acute anxiolysis and analgesia after running. We show that anxiolysis depends on intact cannabinoid receptor 1 (CB1) receptors on forebrain GABAergic neurons and pain reduction on activation of peripheral CB1 and CB2 receptors. We thus demonstrate that the endocannabinoid system is crucial for two main aspects of a runners high. Sedation, in contrast, was not influenced by cannabinoid or opioid receptor blockage, and euphoria cannot be studied in mouse models.

The puzzle box as a simple and efficient behavioral test for exploring impairments of general cognition and executive functions in mouse models of schizophrenia

Deficits in executive functions are key features of schizophrenia. Rodent behavioral paradigms used so far to find animal correlates of such deficits require extensive effort and time. The puzzle box is a problem-solving test in which mice are required to complete escape tasks of increasing difficulty within a limited amount of time. Previous data have indicated that it is a quick but highly reliable test of higher-order cognitive functioning. We evaluated the use of the puzzle box to explore executive functioning in five different mouse models of schizophrenia: mice with prefrontal cortex and hippocampus lesions, mice treated sub-chronically with the NMDA-receptor antagonist MK-801, mice constitutively lacking the GluA1 subunit of AMPA-receptors, and mice over-expressing dopamine D2 receptors in the striatum. All mice displayed altered executive functions in the puzzle box, although the nature and extent of the deficits varied between the different models. Deficits were strongest in hippocampus-lesioned and GluA1 knockout mice, while more subtle deficits but specific to problem solving were found in the medial prefrontal-lesioned mice, MK-801-treated mice, and in mice with striatal overexpression of D2 receptors. Data from this study demonstrate the utility of the puzzle box as an effective screening tool for executive functions in general and for schizophrenia mouse models in particular.

Endocannabinoids and voluntary activity in mice: Runner's high and long-term consequences in emotional behaviors

The endocannabinoid system participates in the regulation of physical activity, although its role is not yet fully understood. Here, we highlight the impact of endocannabinoid signalling on voluntary wheel running in mice and discuss potential mechanisms involved such as hippocampal neurogenesis. Running-induced short-term and long-term alterations of emotional behaviors are scrutinized with regard to the question how endocannabinoids might be involved. While endocannabinoids seem to contribute to the motivational aspects of voluntary running in rodents, influencing the total distance covered most likely via CB1 receptors, they are less involved in the long-term changes of emotional behavior induced by voluntary exercise.

Resting Is Rusting A Critical View on Rodent Wheel-Running Behavior

Physical exercise is known to exert various beneficial effects on brain function and bodily health throughout life. In biomedical research, these effects are widely studied by introducing running wheels into the cages of laboratory rodents. Yet, although rodents start to run in the wheels immediately, and perform wheel-running excessively on a voluntary basis, the biological significance of wheel-running is still not clear. Here, we review the current literature on wheel-running and discuss potentially negative side-effects that may give cause for concern. We particularly emphasize on analogies of wheel-running with stereotypic and addictive behavior to stimulate further research on this topic.

Transgender Transitioning and Change of Self-Reported Sexual Orientation

Objective Sexual orientation is usually considered to be determined in early life and stable in the course of adulthood. In contrast, some transgender individuals report a change in sexual orientation. A common reason for this phenomenon is not known. Methods We included 115 transsexual persons (70 male-to-female “MtF” and 45 female-to-male “FtM”) patients from our endocrine outpatient clinic, who completed a questionnaire, retrospectively evaluating the history of their gender transition phase. The questionnaire focused on sexual orientation and recalled time points of changes in sexual orientation in the context of transition. Participants were further asked to provide a personal concept for a potential change in sexual orientation. Results In total, 32.9% (n =  23) MtF reported a change in sexual orientation in contrast to 22.2% (n =  10) FtM transsexual persons (p =  0.132). Out of these patients, 39.1% (MtF) and 60% (FtM) reported a change in sexual orientation before having undergone any sex reassignment surgery. FtM that had initially been sexually oriented towards males ( = androphilic), were significantly more likely to report on a change in sexual orientation than gynephilic, analloerotic or bisexual FtM (p  =  0.012). Similarly, gynephilic MtF reported a change in sexual orientation more frequently than androphilic, analloerotic or bisexual MtF transsexual persons (p  =  0.05). Conclusion In line with earlier reports, we reveal that a change in self-reported sexual orientation is frequent and does not solely occur in the context of particular transition events. Transsexual persons that are attracted by individuals of the opposite biological sex are more likely to change sexual orientation. Qualitative reports suggest that the individuals biography, autogynephilic and autoandrophilic sexual arousal, confusion before and after transitioning, social and self-acceptance, as well as concept of sexual orientation itself may explain this phenomenon.

Twenty years of endocrinologic treatment in transsexualism: analyzing the role of chromosomal analysis and hormonal profiling in the diagnostic work-up

OBJECTIVE To demonstrate that adequate pubertal history, physical examination, and a basal hormone profile is sufficient to exclude disorders of sexual development (DSD) in adult transsexuals and that chromosomal analysis could be omitted in cases of unremarkable hormonal profile and pubertal history. DESIGN Retrospective chart analysis. SETTING Endocrine outpatient clinic of a psychiatric research institute. PATIENT(S) A total of 475 subjects (302 male-to-female transsexuals [MtF], 173 female-to-male transsexuals [FtM]). Data from 323 (192 MtF/131 FtM) were collected for hormonal and pubertal abnormalities. Information regarding chromosomal analysis was available for 270 patients (165 MtF/105 FtM). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Pubertal abnormalities, menstrual cycle, and hormonal irregularities in relation to chromosomal analysis conducted by karyotype or hair root analysis. RESULT(S) In the MtF group, 5.2% of the patients reported pubertal irregularities and 5.7% hormonal abnormalities, and in the FtM group 3.8% and 19.1%, respectively. Overall chromosomal abnormality in both groups was 1.5% (2.9% in the FtM and 0.6% in the MtF group). The aneuploidies found included one gonosomal aneuploidy (45,X[10]/47,XXX[6]/46,XX[98]), two Robertsonian translocations (45,XXder(14;22)(q10;q10)), and one Klinefelter syndrome (47,XXY) that had already been diagnosed in puberty. CONCLUSION(S) Our data show a low incidence of chromosomal abnormalities and thus question routine chromosomal analysis at the baseline evaluation of transsexualism, and suggest that it be considered only in cases of abnormal history or hormonal examination.

Exercise Boosts Hippocampal Volume by Preventing Early Age-Related Gray Matter Loss

Recently, a larger hippocampus was found in exercising mice and men. Here we studied the morphological underpinnings in wheel running mice by longitudinal magnetic resonance imaging. Voxel‐based morphometry revealed that running increases hippocampal volume by inhibiting an early age‐related gray matter loss. Disruption of neurogenesis‐related neuroplasticity by focalized irradiation is sufficient to block positive effects of exercise on macroscopic brain morphology.