Sarah J. Bailey

Bio: Sarah J. Bailey is an academic researcher from University of Bath. The author has contributed to research in topics: κ-opioid receptor & Buprenorphine. The author has an hindex of 17, co-authored 36 publications receiving 1263 citations. Previous affiliations of Sarah J. Bailey include University of Bristol & Newcastle University.

Inhibition by glucose or leptin of hypothalamic neurons expressing neuropeptide Y requires changes in AMP-activated protein kinase activity.

Abstract: Changes in the activity of glucose-excited and glucose-inhibited neurons within the basomedial hypothalamus are key to the central regulation of satiety. However, the molecular mechanisms through which these cells respond to extracellular stimuli remain poorly understood. Here, we investigate the role of 5′-AMP-activated protein kinase (AMPK), a trimeric complex encoded by seven distinct genes of the PRKA family, in the responses to glucose and leptin of each cell type. The activity of isolated rat basomedial hypothalamic neurons was assessed by: (1) recording cellular voltage responses under current clamp; (2) measuring intracellular free Ca2+ with fluo-3 or fura-2; and (3) developing a neuropeptide Y (NPY) promoter-driven adenovirally produced ratiometric ‘pericam’ (a green fluorescent protein-based Ca2+ sensor) to monitor [Ca2+] changes selectively in NPY-positive neurons. The stimulatory effects of decreased (0 or 1.0 vs 15 mmol/l) glucose on glucose-inhibited neurons were mimicked by the AMPK activator, 5-amino-imidazole-4-carboxamide riboside (AICAR) and blocked by the inhibitor Compound C. Similarly, AICAR reversed the inhibitory effects of leptin in the majority of glucose-inhibited neurons. The responses to glucose of Npy-expressing cells, which represented ∼40 % of all glucose-inhibited neurons, were also sensitive to Compound C or AICAR. Forced changes in AMPK activity had no effect on glucose-excited and non-glucose-responsive neurons. Changes in AMPK activity are involved in the responses of glucose-inhibited neurons to large fluctuations in glucose concentration, and possibly also to leptin. This mechanism may contribute to the acute reduction of electrical activity and Ca2+ oscillation frequency in these, but not other neurons, in the basomedial hypothalamus.

Pre- and post-synaptic abnormalities associated with impaired neuromuscular transmission in a group of patients with 'limb-girdle myasthenia'.

Abstract: The properties of neuromuscular junctions (NMJs) were studied in motor-point biopsy samples from eight patients with congenital myasthenic syndromes affecting primarily proximal limb muscles ['limb-girdle myasthenia' (LGM)]. All had moderate to severe weakness of the proximal muscles, without short-term clinical fatigability but with marked variation in strength over periods of weeks or months, with little or no facial weakness or ptosis and no ophthalmoplegia. Most had a characteristic gait and stance. All patients showed decrement of the compound muscle action potential (CMAP) on repetitive stimulation at 3 Hz, and increased jitter and blocking was detected by SFEMG, confirming the presence of impaired neuromuscular transmission. None of the patients had serum antibodies against acetylcholine receptors (AChRs). Two of the patients had similarly affected siblings. Intracellular recording from isolated nerve-muscle preparations revealed that the quantal content (the number of ACh quanta released per nerve impulse) was only approximately 50% of that in controls. However, the quantal size (amplitude of miniature end-plate currents) and the kinetic properties of synaptic potentials and currents were similar to control values. The area of synaptic contact and extent of post-synaptic folding were approximately 50% of control values. Thus, the quantal content per unit area of synaptic contact was normal. The number of AChRs per NMJ was also reduced to approximately 50% of normal, so the local AChR density was normal. Immunolabelling studies revealed qualitatively normal distributions and abundance of each of 14 proteins normally concentrated at the NMJ, including components of the basal lamina, post-synaptic membrane and post-synaptic cytoskeleton. DNA analysis failed to detect mutations in the genes encoding any of the following proteins: AChR subunits, rapsyn, ColQ, ChAT or muscle-specific kinase. Response of these patients to treatment was varied: few showed long-term improvement with pyridostigmine and some even deteriorated with treatments, while others had intolerable side-effects. Several patients showed improvement with 3,4-diaminopyridine, but this was generally only transient. Ephedrine was helpful in half of the patients. We conclude that impaired neuromuscular transmission in these LGM patients results from structural abnormalities of the NMJ, including reduced size and post-synaptic folding, rather from any abnormality in the immediate events of neuromuscular transmission.

Retinoid-Mediated Regulation of Mood : Possible Cellular Mechanisms

Abstract: Vitamin A and its derivatives, the retinoids, have long been studied for their ability to alter central nervous system (CNS) development. Increasingly, it is recognized that sufficient levels of retinoids may also be required for adult CNS function. However, excess dietary vitamin A, due to the consumption of supplements or foods rich in vitamin A, has been reported to induce psychosis. In addition, 13-cis-retinoic acid (13-cis-RA, isotretinoin), the active ingredient in the acne treatment Accutane, has been reported to cause adverse psychiatric events, including depression and suicidal ideation. Nevertheless, epidemiological studies have reported no consistent link between Accutane use and clinical depression in humans. Using an animal model, we have recently shown that 13-cis-RA induces an increase in depression-related behavior. Impairments in spatial learning and memory have also been demonstrated following 13-cis-RA treatment in mice. This review focuses on the behavioral and possible cellular effects of retinoid deficiency or excess in the adult brain in relation to altered mood. Specifically, we discuss the effect of retinoids on depression-related behaviors and whether norepinephrinergic, dopaminergic, or serotonergic neurotransmitter systems may be impaired. In addition, we consider the evidence that adult neurogenesis, a process implicated in the pathophysiology of depression, is reduced by retinoid signaling. We suggest that 13-cis-RA treatment may induce depression-related behaviors by decreasing adult neurogenesis and/or altering the expression of components of serotonergic neurotransmitter system, thereby leading to impaired serotonin signaling.

Dietary (n-3) Fatty Acids and Brain Development

Abstract: The (n-3) fatty acids are essential dietary nutrients, and one of their important roles is providing docosahexaenoic acid [22:6(n-3)] (DHA) for growth and function of nervous tissue. Reduced DHA is associated with impairments in cognitive and behavioral performance, effects which are particularly important during brain development. Recent studies suggest that DHA functions in neurogenesis, neurotransmission, and protection against oxidative stress. These functions relate to the roles of DHA within the hydrophobic core of neural membranes and effects of unesterified DHA. Reviewed here are some of the recent studies that have begun to elucidate the role of DHA in brain development and function. A better understanding of development and age-specific changes in DHA transfer and function in the developing brain may provide important insight into the role of DHA in developmental disorders in infants and children, as well as at other stages of the lifespan.

Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity

Abstract: A subset of neurons in the brain, known as 'glucose-excited' neurons, depolarize and increase their firing rate in response to increases in extracellular glucose. Similar to insulin secretion by pancreatic beta-cells, glucose excitation of neurons is driven by ATP-mediated closure of ATP-sensitive potassium (K(ATP)) channels. Although beta-cell-like glucose sensing in neurons is well established, its physiological relevance and contribution to disease states such as type 2 diabetes remain unknown. To address these issues, we disrupted glucose sensing in glucose-excited pro-opiomelanocortin (POMC) neurons via transgenic expression of a mutant Kir6.2 subunit (encoded by the Kcnj11 gene) that prevents ATP-mediated closure of K(ATP) channels. Here we show that this genetic manipulation impaired the whole-body response to a systemic glucose load, demonstrating a role for glucose sensing by POMC neurons in the overall physiological control of blood glucose. We also found that glucose sensing by POMC neurons became defective in obese mice on a high-fat diet, suggesting that loss of glucose sensing by neurons has a role in the development of type 2 diabetes. The mechanism for obesity-induced loss of glucose sensing in POMC neurons involves uncoupling protein 2 (UCP2), a mitochondrial protein that impairs glucose-stimulated ATP production. UCP2 negatively regulates glucose sensing in POMC neurons. We found that genetic deletion of Ucp2 prevents obesity-induced loss of glucose sensing, and that acute pharmacological inhibition of UCP2 reverses loss of glucose sensing. We conclude that obesity-induced, UCP2-mediated loss of glucose sensing in glucose-excited neurons might have a pathogenic role in the development of type 2 diabetes.

Minireview: vitamin D receptor: new assignments for an already busy receptor. - eScholarship

Abstract: With its discovery in 1920, the molecule vitamin D achieved prominence as a nutritionally essential vitamin important for calcium homeostasis, particularly in the intestine and bone. Then in 1932, the elucidation of vitamin D's chemical structure revealed that this vitamin was in fact a steroid. But it was not until the late 1960s that it was appreciated that the steroid vitamin D was a precursor of a new steroid hormone, 1alpha,25(OH)2-vitamin D3 [1alpha,25(OH)2D3], that is produced by the kidney acting as an endocrine gland. The discovery in 1969 of the nuclear vitamin D receptor (VDR) for 1alpha,25(OH)2D3 initiated a two-decade-long proliferation of reports that collectively described the broad sphere of influence of the vitamin D endocrine system that is defined by the presence of the VDR in over 30 tissue/organs of man. The new genomic frontiers defined by the cellular presence of the VDR include the immune system's B and T lymphocytes, hair follicle, muscle, adipose tissue, bone marrow, and cancer cells. Unexpectedly in the mid 1980s, a new world of 1alpha,25(OH)2D3-mediated rapid responses (RR) was discovered. These were responses that occurred too rapidly (minutes to an hour) to be explained as the simple consequence of the nuclear VDR regulating gene transcription. Some RR examples include the rapid intestinal absorption of calcium (transcaltachia), secretion of insulin by pancreatic beta-cells, opening of voltage-gated Ca2+ and Cl- channels in osteoblasts, and the rapid migration of endothelial cells. The question then arose as to whether there was a second receptor, apart from the nuclear VDR, which responded to the presence of 1alpha,25(OH)2D3 to generate RR? After some false starts, it now appears that the classic VDR, long known to reside in the cell nucleus, in some cells is also associated with caveolae present in the plasma membrane. Furthermore, the chemical properties of the conformationally flexible 1alpha,25(OH)2D3 allow it to generate different shaped ligands for the VDR that are selective either for genomic or for RR. This minireview summarizes a proposed conformational ensemble model of the VDR that provides insight into how different ligand shapes of 1alpha,25(OH)2D3 acting through the VDR in different cellular locations can selectively mediate both genomic and RR.