•High-fat diet (HFD) increased neurogenesis and the fraction of POMC neurons in the adult arcuate nucleus (ArcN).•Physical exercise increased cell proliferation in the ArcN of HFD-fed ...mice.•HFD-induced increase in the amount of microglia was reduced to control levels by physical exercise.•Physical exercise reduced body weight gain due to HFD.
The hypothalamus has emerged as a novel neurogenic niche in the adult brain during the past decade. However, little is known about its regulation and the role hypothalamic neurogenesis might play in body weight and appetite control. High-fat diet (HFD) has been demonstrated to induce an inflammatory response and to alter neurogenesis in the hypothalamus and functional outcome measures, e.g. body weight. Such modulation poses similarities to what is known from adult hippocampal neurogenesis, which is highly responsive to lifestyle factors, such as nutrition or physical exercise. With the rising question of a principle of neurogenic stimulation by lifestyle in the adult brain as a physiological regulatory mechanism of central and peripheral functions, exercise is interventionally applied in obesity and metabolic syndrome conditions, promoting weight loss and improving glucose tolerance and insulin sensitivity. To investigate the potential pro-neurogenic cellular processes underlying such beneficial peripheral outcomes, we exposed adult female mice to HFD together with physical exercise and evaluated neurogenesis and inflammatory markers in the arcuate nucleus (ArcN) of the hypothalamus. We found that HFD increased neurogenesis, whereas physical exercise stimulated cell proliferation. HFD also increased the amount of microglia, which was counteracted by physical exercise. Physiologically, exercise increased food and fat intake but reduced HFD-induced body weight gain. These findings support the hypothesis that hypothalamic neurogenesis may represent a counter-regulatory mechanism in response to environmental or physiological insults to maintain energy balance.
Highlights ► Environmental enrichment rescues BDNF expression and 5HT metabolism in BDNF+/− mice. ► Environmental enrichment did not affect BDNF expression and 5HT In female mice. ► Thus, rescue ...effects of emotional phenotype by enrichment are gender-specific.
The neurotrophin brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are a central part of the molecular concepts on neuroplastic changes associated with stress, anxiety and ...depression. An increasing number of studies uses serum BDNF levels as a potential indicator for central nervous system alterations.
To analyze the relationship between brain tissue and serum BDNF and NGF levels, we used electroconvulsive shocks (ECS), an animal model of electroconvulsive therapy, and studied the temporal profile of neurotrophin expression in the hippocampus, prefrontal cortex and serum. 88 male Sprague-Dawley rats received single or serial ECS treatments and were killed between 3 hours and 14 days after the last treatment.
We found a 2.8-fold rise for BDNF (1.3-fold for NGF) in the prefrontal cortex, and a 2.2-fold rise (1.2-fold for NGF) in the hippocampus after 5 ECS sessions. The temporal expression profile and correlation analyses between tissue and serum BDNF indicate that BDNF crosses the blood-brain barrier. No such correlation was found for NGF.
The time course of central and peripheral BDNF changes may significantly differ. However, we demonstrate substantial evidence that it can be justified to measure serum BDNF levels with a time delay to monitor brain tissue neurotrophin alterations.
•High-fat diet (HFD) initiated in adolescent but not adult mice impaired flexible memory expression in the water maze.•Concurrent (long-term) physical exercise prevented the HFD-induced ...impairment.•HFD initiated in adolescent mice reduced the number of immature neurons in the hippocampus.•Long-term exercise enhanced learning abilities and increased the number of newborn neurons in the hippocampus.
Obesity is currently one of the most serious threats to human health in the western civilization. A growing body of evidence suggests that obesity is associated with cognitive dysfunction. Physical exercise not only improves fitness but it has also been shown in human and animal studies to increase hippocampus-dependent learning and memory. High-fat diet (HFD)-induced obesity and physical exercise both modulate adult hippocampal neurogenesis. Adult neurogenesis has been demonstrated to play a role in hippocampus-dependent learning and memory, particularly flexible memory expression. Here, we investigated the effects of twelve weeks of HFD vs. control diet (CD) and voluntary physical activity (wheel running; -R) vs. inactivity (sedentary; -S) on hippocampal neurogenesis and spatial learning and flexible memory function in female C57Bl/6 mice assessed in the Morris water maze. HFD was initiated either in adolescent mice combined with long-term concurrent exercise (preventive approach) or in young adult mice with 14days of subsequent exercise (therapeutic approach). HFD resulted in impaired flexible memory expression only when initiated in adolescent (HFD-S) but not in young adult mice, which was successfully prevented by concurrent exercise (HFD-R). Histological analysis revealed a reduction of immature neurons in the hippocampus of the memory-impaired HFD-S mice of the preventive approach. Long-term physical exercise also led to accelerated spatial learning during the acquisition period, which was accompanied by increased numbers of newborn mature neurons (HFD-R and CD-R). Short-term exercise of 14days in the therapeutic group was not effective in improving spatial learning or memory. We show that (1) alterations in learning and flexible memory expression are accompanied by changes in the number of neuronal cells at different maturation stages; (2) these neuronal cells are in turn differently affected by HFD; (3) adolescent mice are specifically susceptible to the negative effects of HFD. Thus, physical exercise, by modulating adult neurogenesis in the hippocampus, might represent a potential preventive approach for treating cognitive impairments associated with adolescent obesity.
Although deficits in the recognition of emotional facial expressions are considered a hallmark of autism spectrum disorder (ASD), characterization of abnormalities in the differentiation of emotional ...expressions (e.g., sad vs. angry) has been rather inconsistent, especially in adults without intellectual impairments who may compensate for their deficits. In addition, previous research neglected the ability to detect emotional expressions (e.g., angry vs. neutral). The present study used a backward masking paradigm to investigate, a) the detection of emotional expressions, and b) the differentiation of emotional expressions in adults diagnosed with high functioning autism or Asperger syndrome (n = 23) compared to neurotypical controls (n = 25). Compensatory strategies were prevented by shortening the stimulus presentation time (33, 67, and 100 ms). In general, participants with ASD were significantly less accurate in detecting and differentiating emotional expressions compared to the control group. In the emotion differentiation task, individuals with ASD profited significantly less from an increase in presentation time. These results reinforce theoretical models that individuals with ASD have deficits in emotion recognition under time constraints. Furthermore, first evidence was provided that emotion detection and emotion differentiation are impaired in ASD.
•Detection and differentiation of briefly presented emotions are analyzed in ASD and HC.•Individuals with ASD are less accurate in detecting and differentiating facial emotions.•In emotion differentiation, ASD profit less from an increase in presentation time than HC.•Deficits in facial emotion processing in ASD become apparent with constrained presentation time.
New therapeutic targets for advanced colorectal cancer (CRC) are critically needed. Our laboratory recently performed an insertional mutagenesis screen in mice to identify novel CRC driver genes and, ...thus, potential drug targets. Here, we define Transmembrane 9 Superfamily 2 (TM9SF2) as a novel CRC oncogene. TM9SF2 is an understudied protein, belonging to a well conserved protein family characterized by their nine putative transmembrane domains. Based on our transposon screen we found that TM9SF2 is a candidate progression driver in digestive tract tumors. Analysis of The Cancer Genome Atlas (TCGA) data revealed that approximately 35% of CRC patients have elevated levels of TM9SF2 mRNA, data we validated using an independent set of CRC samples. RNAi silencing of TM9SF2 reduced CRC cell growth in an anchorage-independent manner, a hallmark of cancer. Furthermore, CRISPR/Cas9 knockout of TM9SF2 substantially diminished CRC tumor fitness in vitro and in vivo. Transcriptome analysis of TM9SF2 knockout cells revealed a potential role for TM9SF2 in cell cycle progression, oxidative phosphorylation, and ceramide signaling. Lastly, we report that increased TM9SF2 expression correlates with disease stage and low TM9SF2 expression correlate with a more favorable relapse-free survival. Taken together, this study provides evidence that TM9SF2 is a novel CRC oncogene.
Stress, glucocorticoids and anti-depressant treatment have been found to modulate the expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Recent research suggests ...that serum BDNF concentration is reduced in depression and that successful antidepressant treatment leads to an increase in serum BDNF concentration.
We studied depressed patients receiving a standardized antidepressant treatment with either 150 mg amitriptyline (n=20) or 40 mg paroxetine (n=20) for 36 days in a prospective design. Changes in the concentrations of serum neurotrophins and salivary cortisol in response to antidepressant treatment were assessed.
Independent of clinical efficacy there was a significant 'treatment' by 'medication' interaction effect on BDNF serum concentrations that indicated a decline of BDNF by 12% in paroxetine-treated patients while there was an increase by 13% in amitriptyline-treated patients. Neither antidepressant altered NGF concentrations. The changes in cortisol and neurotrophin concentrations were not related.
Changes in BDNF serum concentrations as a result of antidepressant therapy depend on the antidepressant instead of being a general characteristic of response to antidepressant treatment.
Abstract Epidemiological studies demonstrate that affective disorders are at least twice as common in women as in men, but surprisingly, very few preclinical studies have been conducted on female ...experimental animals. Therefore, the necessity of developing valid animal models for studying the pathophysiology of stress-related disorders in women is obvious. Chronic social stress has the potential to induce depression in humans and therefore we characterize here a chronic social instability stress paradigm in female rats. This consists of a 4-week period with alternating stressful social situations, including phases of isolation and crowding, in an unpredictable manner. At the physiological level, increased adrenal weight and plasma corticosterone levels indicated hyperactivity of the hypothalamus–pituitary–adrenal axis. Elevated plasma luteinizing hormone and disruption of the estrus cycle together with increased serum prolactin levels revealed disrupted regulation of the hypothalamus–pituitary–gonadal axis. Body temperature regulation was affected during the last week of stress such that stressed rats reduced their body temperature less during the rest phase than the controls, thus exhibiting a flattened temperature curve. Behaviorally, chronically stressed rats showed reduced sucrose preference and food intake. However, we did not observe any effect of stress on performance in the forced swim test and hippocampal neurotrophin levels were similarly unaffected. Our results indicate that, by using this social instability paradigm, female rats can be kept under chronic stress for weeks without habituation, and that ultimately the animals develop a depressive-like phenotype. This model may provide a valuable tool for further analyses of the neurobiology of stress-related disorders in women and has the potential to serve as a paradigm for screening novel antidepressant drugs with special efficacy in women.
There is mounting evidence that aerobic exercise has a positive effect on cognitive functions in older adults. To date, little is known about the neurometabolic and molecular mechanisms underlying ...this positive effect. The present study used magnetic resonance spectroscopy and quantitative MRI to systematically explore the effects of physical activity on human brain metabolism and grey matter (GM) volume in healthy aging. This is a randomised controlled assessor-blinded two-armed trial (n=53) to explore exercise-induced neuroprotective and metabolic effects on the brain in cognitively healthy older adults. Participants (age >65) were allocated to a 12-week individualised aerobic exercise programme intervention (n=29) or a 12-week waiting control group (n=24). The main outcomes were the change in cerebral metabolism and its association to brain-derived neurotrophic factor (BDNF) levels as well as changes in GM volume. We found that cerebral choline concentrations remained stable after 12 weeks of aerobic exercise in the intervention group, whereas they increased in the waiting control group. No effect of training was seen on cerebral N-acetyl-aspartate concentrations, nor on markers of neuronal energy reserve or BDNF levels. Further, we observed no change in cortical GM volume in response to aerobic exercise. The finding of stable choline concentrations in the intervention group over the 3 month period might indicate a neuroprotective effect of aerobic exercise. Choline might constitute a valid marker for an effect of aerobic exercise on cerebral metabolism in healthy aging.
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