High-fat Diet and Physical Exercise Differentially Modulate Adult Neurogenesis in the Mouse Hypothalamus.

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.

Impaired detection and differentiation of briefly presented facial emotions in adults with high-functioning autism and asperger syndrome.

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.

Effects of aerobic exercise on brain metabolism and grey matter volume in older adults: results of the randomised controlled SMART trial.

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.

Exercise prevents high-fat diet-induced impairment of flexible memory expression in the water maze and modulates adult hippocampal neurogenesis in mice.

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.

[The significance of depot medication in the long-term-treatment of schizophrenia]. / Stellenwert von Depotformulierungen in der Langzeittherapie der Schizophrenie.

Relapse prevention in schizophrenia is a key aim in therapy. However, it is estimated that approximately 75% of patients with schizophrenia relapse within five years. Each relapse might worsen the disease and increase the risk of psychosocial and work-related disadvantages. A continuous long-term therapy is able to reduce this risk, but medical non-adherence, which is influenced by numerous factors, is a limitation. Naturalistic studies show that depot-antipsychotics compared with oral antipsychotics lead consistently to a better outcome, for example by reducing relapse rates or hospitalisation. Numerous meta-analyses of randomised controlled trials comparing oral versus depot-antipsychotics also show this advantages. However these results are not consistent in all meta-analyses. Results of controlled studies do not appropriately reflect the reality of daily practice. The advantages of depot-antipsychotics are shown more distinctly in naturalistic studies. The following review reflects the current therapy of schizophrenia and discusses adequately a broad application of depot-antipsychotics based on existing data. In addition, concerns and prejudices of physicians and patients against antipsychotic long-term therapy and depot-formulation are discussed and a recommendation is provided.

Reduced nerve growth factor levels in stress-related brain regions of folate-deficient mice.

Folate deficiency has been linked to neurodegenerative and stress-related diseases such as stroke, dementia and depression. The role of the neurotrophins nerve growth factor (NGF) and neurotrophin-3 (NT-3) in stress-related disorders and neurodegeneration has garnered increasing attention in recent years. Uracil misincorporation is involved in the neuropsychiatric dysfunction induced by experimental folate deprivation. However, the effects of folate deficiency on the expression of NGF and NT-3 in brain tissue have not yet been investigated. In a 2×2 design, aged mice lacking uracil-DNA N-glycosylase (Ung(-/-)) versus wild-type (Ung(+/+)) controls were subjected to a folate-deficient diet versus a regular diet for three months. Independent of genotype, folate deficiency led to decreased NGF protein levels in the frontal cortex and amygdala. In the hippocampus, NGF levels were increased in UNG(-/-) mice on the normal diet, but not under folate deficiency, while in UNG(+/+) mice, folate deprivation did not affect hippocampal NGF content. NT-3 protein concentrations were neither affected by genotype nor by folate deficiency. Altogether, the results of our study show that folate deficiency affects NGF levels in the frontal cortex, amygdala and hippocampus. The decrease in NGF content in the hippocampus in response to folate deficiency in Ung(-/-) mice may contribute to their phenotype of enhanced anxiety and despair-like behavior as well as to selective hippocampal neurodegeneration.

Changes of serum concentrations of brain-derived neurotrophic factor (BDNF) during treatment with venlafaxine and mirtazapine: role of medication and response to treatment.

INTRODUCTION: Depression, stress and antidepressant treatment have been found to modulate the expression of brain-derived neurotrophic factor (BDNF). Recent research suggests that serum BDNF concentration is reduced in depression and that antidepressant treatment leads to an increase in serum BDNF concentration. METHODS: We studied depressed patients receiving a randomized antidepressant treatment with either mirtazapine (n=29) or venlafaxine (n=27) for 28 days in a prospective design. Changes in the concentrations of serum neurotrophins in response to antidepressant treatment were assessed. RESULTS: There was a significant "treatment" by "medication" interaction effect on BDNF serum concentrations that indicated a decline of BDNF in venlafaxine-treated patients (7.82±3.75-7.18±5.64 ng/mL), while there was an increase in mirtazapine-treated patients (7.64±6.23-8.50±5.37 ng/mL). There was a trend for a "treatment" by "remission" interaction with a favourable clinical course being related to increasing serum BDNF. DISCUSSION: Changes in BDNF serum concentrations as a result of antidepressant therapy depend on the antidepressant and potentially on the clinical course.

[Assessment of benefits of drug therapies: memantine for Alzheimer's disease as an example]. / Zur Bewertung des Nutzens medikamentöser Therapieoptionen am Beispiel von Memantin bei Alzheimer Demenz.

After the approval of a drug, which represents a first assessment, independent institutions and medical professional associations provide further evaluations. Here, the question is to be asked whether common or diverging evaluation methods exist that can have an impact on the result. In principle, two methods are used: meta-analyses and responder analyses. Meta-analyses and the resulting effect sizes have to be interpreted according to the field of application (for example, the type and severity degree of a disease) with medical expertise. Omitting this can lead to incorrect evaluations and to a discrepancy of evaluation results. In the case of memantine, the merely biometric evaluation of meta-analyses performed by the IQWiG led to a denial of the benefit, while the same data, considering clinical routine, led professional associations to recommend memantine for moderate to severe Alzheimer´s disease. In contrast to meta-analyses, responder analyses directly show the benefit of a therapy option in the presence of significant group differences, as the selected responder criteria are based on the indication. The corresponding results of the responder analyses on memantine were also acknowledged by the IQWiG and led to a positive evaluation of memantine. This discrepancy of evaluation results illustrates the fact that statistical procedures are necessary when evaluating drug and non-drug therapy options but, that the interpretation of the results with medical expertise is essential.

The impact of environmental enrichment on sex-specific neurochemical circuitries - effects on brain-derived neurotrophic factor and the serotonergic system.

Experimental evidence in mice indicates that environmental conditions affect females and males differently. However, in a recent study analyzing the heterozygous mutation of brain-derived neurotrophic factor (BDNF), both sexes presented a similar emotional phenotype, which became obvious only under impoverished, but not in enriched conditions suggesting an "enrichment-induced" rescue. To investigate the basis of this behavioral "rescue" effect, we analyzed neurochemical changes (BDNF expression, serotonergic changes, and corticosterone) in the hippocampus, frontal cortex and hypothalamus of animals housed under respective conditions. In male mice, enrichment induced an increase of BDNF expression in the hippocampus of both BDNF heterozygous (BDNF(+/-)) and wild-types. Notably, in enriched-reared BDNF(+/-) mice BDNF mRNA and protein increased to levels comparable to those of wild-types in impoverished environment. In the frontal cortex of males, only wild-types presented an enrichment-induced increase of BDNF mRNA, while no effect of environment could be detected in BDNF protein levels of the male hypothalamus. A further male-specific effect of "environment" is the significant reduction of hypothalamic 5-hydroxyindoleacetic acid in enriched-housed wild-types. In female mice, environmental enrichment did not affect BDNF expression in the hippocampus and hypothalamus. However, comparable to males, an enrichment-induced increase of BDNF mRNA was detected in the frontal cortex of wild-types only. In contrast to males, no influence of environment on serotonergic parameters was observed. Male and female corticosterone levels were neither affected by "genotype" nor by "environment". In conclusion, we propose that the rescue of the emotional phenotype by environmental enrichment in BDNF(+/-) mice is directed by distinct mechanisms in males and females. Only in male BDNF(+/-) mice the rescue is related to an increase in hippocampal BDNF expression suggesting that enrichment triggers different neuronal systems in a gender-specific manner.

[The development of depression: the role of brain-derived neurotrophic factor]. / Entstehung von Depression : Die Rolle des "brain-derived neurotrophic factor"

An association between the presence of psychosocial stress, its pathological processing and the development of depression is well documented. This review reports and discusses studies suggesting a reduced release of brain-derived neurotrophic factor (BDNF) under stress as a possible mechanism. The studies show a reduction of BDNF secretion in stressful situations, a decreased blood concentration in depression and a normalization of BDNF by successful antidepressant therapy. As a possible mechanism of BDNF action, a reactivation of neuroplasticity is being discussed, especially in hippocampal and cortical networks. On the other hand, methodological limitations, such as the impossibility of determining the cerebral BDNF concentration in vivo and ruling out a variety of possible confounders, may restrict the significance of the studies. The question of whether the ascertained changes of BDNF levels are causally involved in the pathophysiology of depression or whether they are just an epiphenomenal result of depression-induced stress is still under debate.

[The importance of depressive syndromes for incipient Alzheimer-type dementia in advanced age]. / Die Bedeutung depressiver Syndrome bei beginnender Demenz vom Alzheimer-Typ im höheren Lebensalter.

Based on epidemiological data on the risk for dementia conveyed by depression, we report recent findings on the effects of depressive disorders on cognition in later life and its relationship to incipient Alzheimer's disease. We review the current literature on possible mechanisms underlying the depression-dementia association. The findings summarized in this review underline the central importance of depressive disorders for the diagnosis and treatment of psychiatric disorders in later life.

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.

Correlations and discrepancies between serum and brain tissue levels of neurotrophins after electroconvulsive treatment in rats.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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.

Chronic social instability stress in female rats: a potential animal model for female depression.

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.

Gender-dependent association of a functional NGF polymorphism with anxiety-related personality traits.

INTRODUCTION: Nerve growth factor (NGF) has been shown to be involved in anxiety behaviour and the expression of conditioned fear in mice. METHODS: We have tested a total of 337 (age: 39.2 +/- 14.6 years) unrelated subjects of German descent (166 males; 171 females) who were carefully screened for psychiatric health. The self-ratable State-Trait Anxiety Inventory, which enables anxiety to be quantified as a comparatively stable personality trait was applied and a recently described non-synonymous NGF SNP (rs6330,c.104C > T,p.Ala35Val) was examined. RESULTS: In the trait-related anxiety score, a significant gender-dependent effect of the genotype was observed (F=4.580, df=2, p=0.011) with higher levels of trait anxiety in females with C/C genotype when compared to females with T/T and C/T genotypes and an opposite effect in males. DISCUSSION: Our findings support the hypothesis that anxiety relates to a genetic variation of NGF and that genes modulate behaviour in a gender-dependent manner. Since anxiety and attention deficit hyperactivity disorder are related to NGF, the present results may represent a common biological link for the gender-specific occurrence and comorbidity of the diseases.

Age-dependent time course of cerebral brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3 in APP23 transgenic mice.

Neurotrophins, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3), have repeatedly been shown to be involved in the pathophysiology of Alzheimer's disease (AD). Recent studies have claimed that these neurotrophic factors are important tools for therapeutic intervention in neurodegenerative diseases. So far, little is known about the age- and disease-modulated time course of cerebral neurotrophins. Therefore, we have studied protein concentrations of BDNF, NGF, and NT-3 in different brain areas and sciatic nerve, a neurotrophin-transporting peripheral nerve, in a well-characterized AD model of amyloid precursor protein-overexpressing rodents (APP23 mice) at the ages of 5.0, 10.5, and 20.0 months. In APP23 mice, there was a significant increase of BDNF and NGF in the frontal and occipital cortices (for BDNF also in the striatum) of old 20.0-month-old mice (with respect to median values up to 8.2-fold), which was highly correlated with amyloid concentrations of these brain areas. Median values of NGF and NT-3 showed up to a 6.0-fold age-dependent increase in the septum that was not detectable in APP23 mice. Hippocampus, olfactory bulb, and cerebellum (except NT-3) did not show substantial age- or genotype-related regulation of neurotrophins. In the sciatic nerve, BDNF and NGF levels are increased in5-month-old APP23 mice and decrease with age to control levels. In conclusion, APP23 mice show a genotype-dependent increase of cortical BDNF and NGF that is highly correlated with amyloid concentrations and may reflect an amyloid-related glia-derived neurotrophin secretion or an altered axonal transport of these neurotrophic factors.

Serum concentrations of nerve growth factor and brain-derived neurotrophic factor in depressed patients before and after antidepressant treatment.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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.

Neurotrophic factors--a tool for therapeutic strategies in neurological, neuropsychiatric and neuroimmunological diseases?

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) belong to the protein family of neurotrophins. They both display profound neuromodulatory functions and are essentially involved in the survival and homeostatic maintenance of central and peripheral neurons during development and adulthood. Moreover, NGF and BDNF are known to modulate immune cell function and thus serve as mediators in the reciprocal cross talk between neurons and immune cells. Neurotrophic factors have been implicated in pathophysiological mechanisms of many diseases of the nervous and the immune system, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), neuropathy, pain, allergic bronchial asthma (BA) and neurotrophic keratitis. For all these diseases research has reached the point of creating strategies for therapeutic intervention with neurotrophins. In this review, we present an overview of the pathophysiology, therapeutic interventions and strategies concerning NGF and BDNF in the mentioned diseases.

Beta/A4-Amyloid increases nerve growth factor production in rat primary hippocampal astrocyte cultures.

Nerve growth factor (NGF), a member of the neurotrophin family, is an essential mediator of neuronal activity and synaptic plasticity of basal forebrain cholinergic neurons (BFCN). In processes of chronic degeneration of BFCN like in Alzheimer's disease (AD), characterized among others by amyloid containing plaques, NGF has been shown to improve cognitive decline and rescue BFCN but also to reduce survival of hippocampal neurons via p75 neurotrophin receptor (p75). Little is known about the mechanisms of NGF regulation in glial cells under pathological conditions in AD. This study investigates the influence of amyloid administration on the NGF protein secretion in rat primary hippocampal astrocytes. Astrocytes were stimulated with "aged" beta/A4-Amyloid (1-40), and NGF was measured in different fractions, such as supernatant, vesicles, and cytosol fraction. Treatment with amyloid at a final concentration of 10 microM for 72 h led to increased NGF protein levels up to 30-fold increase compared to unstimulated controls. This observation may be an endogenous neuroprotective mechanism possibly contributing to a delay of amyloid-dependent loss of cholinergic neurons or contribute to accelerated neuronal death by activation of p75 within Alzheimer pathology.