Stuart Maudsley

BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders

Brain-derived neurotrophic factor (BDNF) and serotonin (5-hydroxytryptamine, 5-HT) are known to regulate synaptic plasticity, neurogenesis and neuronal survival in the adult brain. These two signals co-regulate one another such that 5-HT stimulates the expression of BDNF, and BDNF enhances the growth and survival of 5-HT neurons. Impaired 5-HT and BDNF signaling is central to depression and anxiety disorders, but could also play important roles in the pathogenesis of several age-related disorders, including insulin resistance syndrome, Alzheimers disease and Huntingtons disease. Enhancement of BDNF signaling may be a key mechanism whereby cognitive stimulation, exercise, dietary restriction and antidepressant drugs preserve brain function during aging. Behavioral and pharmacological manipulations that enhance 5-HT and BDNF signaling could help promote healthy brain aging.

A novel mammalian receptor for the evolutionarily conserved type II GnRH.

Mammalian gonadotropin-releasing hormone (GnRH I: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) stimulates pituitary gonadotropin secretion, which in turn stimulates the gonads. Whereas a hypothalamic form of GnRH of variable structure (designated type I) had been shown to regulate reproduction through a cognate type I receptor, it has recently become evident that most vertebrates have one or two other forms of GnRH. One of these, designated type II GnRH (GnRH II: pGlu-His-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2), is conserved from fish to man and is widely distributed in the brain, suggesting important neuromodulatory functions such as regulating K+ channels and stimulating sexual arousal. We now report the cloning of a type II GnRH receptor from marmoset cDNA. The receptor has only 41% identity with the type I receptor and, unlike the type I receptor, has a carboxyl-terminal tail. The receptor is highly selective for GnRH II. As with the type I receptor, it couples to Gαq/11 and also activates extracellular signal-regulated kinase (ERK1/2) but differs in activating p38 mitogen activated protein (MAP) kinase. The type II receptor is more widely distributed than the type I receptor and is expressed throughout the brain, including areas associated with sexual arousal, and in diverse non-neural and reproductive tissues, suggesting a variety of functions. Surprisingly, the type II receptor is expressed in the majority of gonadotropes. The presence of two GnRH receptors in gonadotropes, together with the differences in their signaling, suggests different roles in gonadotrope functioning.

The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomized trial in young overweight women

Background:The problems of adherence to energy restriction in humans are well known.Objective:To compare the feasibility and effectiveness of intermittent continuous energy (IER) with continuous energy restriction (CER) for weight loss, insulin sensitivity and other metabolic disease risk markers.Design:Randomized comparison of a 25% energy restriction as IER (∼2710 kJ/day for 2 days/week) or CER (∼6276 kJ/day for 7 days/week) in 107 overweight or obese (mean (±s.d.) body mass index 30.6 (±5.1) kg m−2) premenopausal women observed over a period of 6 months. Weight, anthropometry, biomarkers for breast cancer, diabetes, cardiovascular disease and dementia risk; insulin resistance (HOMA), oxidative stress markers, leptin, adiponectin, insulin-like growth factor (IGF)-1 and IGF binding proteins 1 and 2, androgens, prolactin, inflammatory markers (high sensitivity C-reactive protein and sialic acid), lipids, blood pressure and brain-derived neurotrophic factor were assessed at baseline and after 1, 3 and 6 months.Results:Last observation carried forward analysis showed that IER and CER are equally effective for weight loss: mean (95% confidence interval ) weight change for IER was −6.4 (−7.9 to −4.8) kg vs −5.6 (−6.9 to −4.4) kg for CER (P-value for difference between groups=0.4). Both groups experienced comparable reductions in leptin, free androgen index, high-sensitivity C-reactive protein, total and LDL cholesterol, triglycerides, blood pressure and increases in sex hormone binding globulin, IGF binding proteins 1 and 2. Reductions in fasting insulin and insulin resistance were modest in both groups, but greater with IER than with CER; difference between groups for fasting insulin was −1.2 (−1.4 to −1.0) μU ml−1 and for insulin resistance was −1.2 (−1.5 to −1.0) μU mmol−1 l−1 (both P=0.04).Conclusion:IER is as effective as CER with regard to weight loss, insulin sensitivity and other health biomarkers, and may be offered as an alternative equivalent to CER for weight loss and reducing disease risk.

Voluntary exercise and caloric restriction enhance hippocampal dendritic spine density and BDNF levels in diabetic mice

Diabetes may adversely affect cognitive function, but the underlying mechanisms are unknown. To investigate whether manipulations that enhance neurotrophin levels will also restore neuronal structure and function in diabetes, we examined the effects of wheel running and dietary energy restriction on hippocampal neuron morphology and brain‐derived neurotrophic factor (BDNF) levels in db/db mice, a model of insulin resistant diabetes. Running wheel activity, caloric restriction, or the combination of the two treatments increased levels of BDNF in the hippocampus of db/db mice. Enhancement of hippocampal BDNF was accompanied by increases in dendritic spine density on the secondary and tertiary dendrites of dentate granule neurons. These studies suggest that diabetes exerts detrimental effects on hippocampal structure, and that this state can be attenuated by increasing energy expenditure and decreasing energy intake. Published 2009 Wiley‐Liss, Inc.

A NEURAL SIGNALING TRIUMVIRATE THAT INFLUENCES AGEING AND AGE-RELATED DISEASE: INSULIN/IGF-1, BDNF AND SEROTONIN

The ageing process and its associated diseases all involve perturbed energy metabolism, oxidative damage, and an impaired ability of the organism and its cells to cope with adversity. We propose that some specific signaling pathways in the brain may be important determinants of health during ageing. Among such specific signaling modalities are those activated in neurons by insulin-like growth factors (IGFs), brain-derived neurotrophic factor (BDNF) and serotonin. This triumvirate may be particularly important because of their cooperative influence on energy metabolism, food intake, stress responses and cardiovascular function. The health benefits to the periphery and central nervous system of dietary restriction and exercise may be mediated by this triumvirate of signals in the brain. At the molecular level, BDNF, serotonin and IGFs can all stimulate the production of proteins involved in cellular stress adaptation, growth and repair, neurogenesis, learning and memory and cell survival. The importance of this triumvirate is emphasized when it is seen that their general roles in energy metabolism, stress adaptation and disease resistance are conserved among diverse organisms consistent with important roles in the ageing process.

“Control” laboratory rodents are metabolically morbid: Why it matters

Failure to recognize that many standard control rats and mice used in biomedical research are sedentary, obese, glucose intolerant, and on a trajectory to premature death may confound data interpretation and outcomes of human studies. Fundamental aspects of cellular physiology, vulnerability to oxidative stress, inflammation, and associated diseases are among the many biological processes affected by dietary energy intake and exercise. Although overfed sedentary rodents may be reasonable models for the study of obesity in humans, treatments shown to be efficacious in these animal models may prove ineffective or exhibit novel side effects in active, normal-weight subjects.

Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets

Huntingtons disease is a fatal neurodegenerative disorder caused by an expanded polyglutamine repeat in huntingtin (HTT) protein. We previously showed that calorie restriction ameliorated Huntingtons disease pathogenesis and slowed disease progression in mice that model Huntingtons disease (Huntingtons disease mice). We now report that overexpression of sirtuin 1 (Sirt1), a mediator of the beneficial metabolic effects of calorie restriction, protects neurons against mutant HTT toxicity, whereas reduction of Sirt1 exacerbates mutant HTT toxicity. Overexpression of Sirt1 improves motor function, reduces brain atrophy and attenuates mutant-HTT–mediated metabolic abnormalities in Huntingtons disease mice. Further mechanistic studies suggested that Sirt1 prevents the mutant-HTT–induced decline in brain-derived neurotrophic factor (BDNF) concentrations and the signaling of its receptor, TrkB, and restores dopamine- and cAMP-regulated phosphoprotein, 32 kDa (DARPP32) concentrations in the striatum. Sirt1 deacetylase activity is required for Sirt1-mediated neuroprotection in Huntingtons disease cell models. Notably, we show that mutant HTT interacts with Sirt1 and inhibits Sirt1 deacetylase activity, which results in hyperacetylation of Sirt1 substrates such as forkhead box O3A (Foxo3a), thereby inhibiting its pro-survival function. Overexpression of Sirt1 counteracts the mutant-HTT–induced deacetylase deficit, enhances the deacetylation of Foxo3a and facilitates cell survival. These findings show a neuroprotective role for Sirt1 in mammalian Huntingtons disease models and open new avenues for the development of neuroprotective strategies in Huntingtons disease.

Modulation of taste sensitivity by GLP-1 signaling

In many sensory systems, stimulus sensitivity is dynamically modulated through mechanisms of peripheral adaptation, efferent input, or hormonal action. In this way, responses to sensory stimuli can be optimized in the context of both the environment and the physiological state of the animal. Although the gustatory system critically influences food preference, food intake and metabolic homeostasis, the mechanisms for modulating taste sensitivity are poorly understood. In this study, we report that glucagon‐like peptide‐1 (GLP‐1) signaling in taste buds modulates taste sensitivity in behaving mice. We find that GLP‐1 is produced in two distinct subsets of mammalian taste cells, while the GLP‐1 receptor is expressed on adjacent intragemmal afferent nerve fibers. GLP‐1 receptor knockout mice show dramatically reduced taste responses to sweeteners in behavioral assays, indicating that GLP‐1 signaling normally acts to maintain or enhance sweet taste sensitivity. A modest increase in citric acid taste sensitivity in these knockout mice suggests GLP‐1 signaling may modulate sour taste, as well. Together, these findings suggest a novel paracrine mechanism for the regulation of taste function.

Exendin-4 improves glycemic control, ameliorates brain and pancreatic pathologies, and extends survival in a mouse model of Huntington's disease.

OBJECTIVE—The aim of this study was to find an effective treatment for the genetic form of diabetes that is present in some Huntingtons disease patients and in Huntingtons disease mouse models. Huntingtons disease is a neurodegenerative disorder caused by a polyglutamine expansion within the huntingtin protein. Huntingtons disease patients exhibit neuronal dysfunction/degeneration, chorea, and progressive weight loss. Additionally, they suffer from abnormalities in energy metabolism affecting both the brain and periphery. Similarly to Huntingtons disease patients, mice expressing the mutated human huntingtin protein also exhibit neurodegenerative changes, motor dysfunction, perturbed energy metabolism, and elevated blood glucose levels. RESEARCH DESIGN AND METHODS—Huntingtons disease mice were treated with an FDA-approved antidiabetic glucagon-like peptide 1 receptor agonist, exendin-4 (Ex-4), to test whether euglycemia could be achieved, whether pancreatic dysfunction could be alleviated, and whether the mice showed any neurological benefit. Blood glucose and insulin levels and various appetite hormone concentrations were measured during the study. Additionally, motor performance and life span were quantified and mutant huntingtin (mhtt) aggregates were measured in both the pancreas and brain. RESULTS—Ex-4 treatment ameliorated abnormalities in peripheral glucose regulation and suppressed cellular pathology in both brain and pancreas in a mouse model of Huntingtons disease. The treatment also improved motor function and extended the survival time of the Huntingtons disease mice. These clinical improvements were correlated with reduced accumulation of mhtt protein aggregates in both islet and brain cells. CONCLUSIONS—Targeting both peripheral and neuronal deficits, Ex-4 is an attractive agent for therapeutic intervention in Huntingtons disease patients suffering from diabetes.

Gonadotropin-Releasing Hormone (GnRH) Antagonists Promote Proapoptotic Signaling in Peripheral Reproductive Tumor Cells by Activating a Gαi-Coupling State of the Type I GnRH Receptor

Gonadotropin-releasing hormone (GnRH) receptor agonists are extensively used in the treatment of sex hormone-dependent cancers via the desensitization of pituitary gonadotropes and consequent decrease in steroid sex hormone secretion. However, evidence now points to a direct inhibitory effect of GnRH analogs on cancer cells. These effects appear to be mediated via the Gαi-type G protein, in contrast to the predominant Gαq coupling in gonadotropes. Unlike Gαq coupling, Gαi coupling of the GnRH receptor can be activated by both agonists and antagonists. This unusual pharmacology suggested that the receptor involved in the cancer cells may not be the classical gonadotrope type I GnRH receptor. However, we have previously shown that a functional type II GnRH receptor is not present in man. In the present study, we show that GnRH agonists and selective GnRH antagonists exert potent antiproliferative effects on JEG-3 choriocarcinoma, benign prostate hyperplasia (BPH-1), and HEK293 cells stably expressing the type I GnRH receptor. This antiproliferative action occurs through a Gαi-mediated activation of stress-activated protein kinase pathways, resulting in caspase activation and transmembrane transfer of phosphatidlyserine to the outer membrane envelope. Structurally related antagonistic GnRH analogs displayed divergent antiproliferative efficacies but demonstrated equal efficacies in inhibiting GnRH-induced Gαq-based signaling. Therefore the ability of GnRH receptor antagonists to exert an antiproliferative effect on reproductive tumors may be dependent on ligand-selective activation of the Gαi-coupled form of the type I GnRH receptor.