The acetylcholine index: an electroencephalographic marker of cholinergic activity in the living human brain applied to Alzheimer's disease and other dementias.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.The cholinergic hypothesis is well established and has led to the development of pharmacological treatments for Alzheimer's disease (AD). However, there has previously been no physiological means of monitoring cholinergic activity in vivo.An electroencephalography (EEG)-based acetylcholine (Ach) index reflecting the cholinergic activity in the brain was developed using data from a scopolamine challenge study. The applicability of the Ach index was examined in an elderly population of healthy controls and patients suffering from various causes of cognitive decline.The Ach index showed a strong reduction in the severe stages of AD dementia. A high correlation was demonstrated between the Ach index and cognitive function. The index was reduced in patients with mild cognitive impairment and prodromal AD, indicating a decreased cholinergic activity. When considering the distribution of the Ach index in a population of healthy elderly subjects, an age-related threshold was revealed, beyond which there is a general decline in cholinergic activity.The EEG-based Ach index provides, for the first time, a physiological means of monitoring the cholinergic activity in the human brain in vivo. This has great potential for aiding diagnosis and patient stratification as well as for monitoring disease progression and treatment response.Icelandic Technology Development Fund/051221006 Icelandic Technology Development Fund/08120600

Acetylcholine Signaling in the Basolateral Amygdala During Reward Learning

Animal survival relies in part on the ability to learn the outcomes that environmental stimuli predict and recall those associations to make decisions later in life. Learning is not monolithic, but instead is mediated by different brain regions depending on the type of information processed. Learning can happen at happen at different speeds, and memories can vary in their longevity. Much is still unknown about the neurobiology underlying learning and memory, thus further research into these processes is necessary to build foundational understanding of these critical phenomenon, and also to develop novel treatments for patients suffering from learning and memory related disorders such as Alzheimer’s Disease, addiction, and post-traumatic stress disorder. Memories that have a positive or negative emotional association are powerful and long-lasting. The basolateral amygdala (BLA) is a brain area involved in emotional processing, including associating initially neutral cues with the appetitive or aversive stimuli they come to predict. Acetylcholine (ACh), a neuromodulator with abundant release in the BLA, is implicated in many processes throughout the brain and body, not least of which is learning and memory. The following chapters detail my exploration of the connection between BLA ACh signaling and cue-reward learning. After explaining the background behind and rationale for the approach (Chapter 1), I briefly describe the development of a cue-reward learning task used to study the role of cholinergic signaling in appetitive learning (Chapter 2). Then, I discuss experiments we performed to record (Chapter 3) and manipulate (Chapter 4) BLA cholinergic signaling during this cue-reward learning. I conclude by integrating the results from recording and manipulation studies and attempt to reconcile these results internally and with external findings to move toward a more comprehensive understanding of the effect of BLA ACh signaling during reward learning (Chapter 5). The primary behavioral paradigm used in the following chapters was a cue-reward learning task in which mice must learn to nose poke during presentation of an auditory tone to receive a food reward. In Chapter 3, we used a genetically-encoded fluorescent ACh sensor to record ACh dynamics in the BLA as animals learned the task contingency. We found that ACh was released in the BLA in response to salient events during the task and evolved with task performance. In order to isolate the source of the ACh, we also recorded calcium dynamics in the BLA-projecting cholinergic terminal fibers of nucleus basalis of Meynert (NBM), a basal forebrain nucleus that is a main contributor of ACh to the BLA. The pattern of activity in these terminal fibers was similar to that observed for ACh signaling, suggesting that the NBM is responsible, at least in part, for cue-reward ACh signaling. Importantly, these shifts in time-locking were tightly correlated to acquisition of the task contingency. We also recorded the activity of BLA output cells, which revealed they were excited following reward-retrieval initially, but their response shifted to the reward-predictive tone after acquisition. Next, in Chapter 4, we optogenetically and pharmacologically modulated cholinergic signaling in the BLA and systemically investigated the effect of manipulating cholinergic signaling on reward learning. We found that both behaviorally-contingent and non-contingent stimulation of BLA ACh release enhanced cue-reward learning. Systemic antagonism of muscarinic, but not nicotinic, ACh receptors impaired task acquisition. Interestingly, nicotine administration led to a modest improvement in performance of the cue-reward task. The studies described here advance the understanding of how ACh might be involved in cue-reward learning and challenge notions of the precise timing required for neuromodulatory input to affect the formation of associations between stimuli

Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity.

Reversible airway hyperreactivity underlies the pathophysiology of asthma, yet the precise mediators of the response remain unclear. Human studies have correlated aberrant activation of T helper (Th) 2-like effector systems in the airways with disease. A murine model of airway hyperreactivity in response to acetylcholine was established using mice immunized with ovalbumin and challenged with aerosolized antigen. No airway hyperractivity occurred in severe combined immunodeficient mice. Identically immunized BALB/c mice developed an influx of cells, with a predominance of eosinophils and CD4+ T cells, into the lungs and bronchoalveolar lavage fluid at the time that substantial changes in airway pressure and resistance were quantitated. Challenged animals developed marked increases in Th2 cytokine production, eosinophil influx, and serum immunoglobulin E levels. Neutralization of interleukin (IL) 4 using monoclonal antibodies administered during the period of systemic immunization abrogated airway hyperractivity but had little effect on the influx of eosinophils. Administration of anti-IL-4 only during the period of the aerosol challenge did not affect the subsequent response to acetylcholine. Finally, administration of anti-IL-5 antibodies at levels that suppressed eosinophils to < 1% of recruited cells had no effect on the subsequent airway responses. BALB/c mice had significantly greater airway responses than C57BL/6 mice, consistent with enhanced IL-4 responses to antigen in BALB/c mice. Taken together, these data implicate IL-4 generated during the period of lymphocyte priming with antigen in establishing the cascade of responses required to generate airway hyperractivity to inhaled antigen. No role for IL-5 or eosinophils could be demonstrated

Environmental domains and range-limiting mechanisms: testing the Abundant Centre Hypothesis using southern African sandhoppers

Predicting shifts of species geographical ranges is a fundamental challenge for conservation ecologists given the great complexity of factors involved in setting range limits. Distributional patterns are frequently modelled to “simplify” species responses to the environment, yet the central mechanisms that drive a particular pattern are rarely understood. We evaluated the distributions of two sandhopper species (Crustacea, Amphipoda, Talitridae), Talorchestia capensis and Africorchestia quadrispinosa along the Namibian and South African coasts, encompassing three biogeographic regions influenced by two different oceanographic systems, the Benguela and Agulhas currents. We aimed to test whether the Abundant Centre Hypothesis (ACH) can explain the distributions of these species’ abundances, sizes and sex ratios and examined which environmental parameters influence/drive these distributions. Animals were collected during a once-off survey at 29 sites over c.3500 km of coastline. The ACH was tested using a non-parametric constraint space analysis of the goodness of fit of five hypothetical models. Distance Based Linear Modelling (DistLM) was performed to evaluate which environmental traits influenced the distribution data. Abundance, size and sex ratio showed different patterns of distribution. A ramped model fitted the abundance (Ramped North) and size (Ramped South) distribution for A. quadrispinosa. The Inverse Quadratic model fitted the size distribution of T. capensis. Beach slope, salinity, sand temperature and percentage of detritus found on the shore at the time of collection played important roles in driving the abundance of A. quadrispinosa. T. capensis was mainly affected by salinity and the morphodynamic state of the beach. Our results provided only some support for the ACH predictions. The DistLM confirmed that the physical state of the beach is an important factor for sandy beach organisms. The effect of salinity and temperature suggest metabolic responses to local conditions and a role in small to mesoscale shifts in the range of these populations

Cholinergic regulation of mood: from basic and clinical studies to emerging therapeutics.

Mood disorders are highly prevalent and are the leading cause of disability worldwide. The neurobiological mechanisms underlying depression remain poorly understood, although theories regarding dysfunction within various neurotransmitter systems have been postulated. Over 50 years ago, clinical studies suggested that increases in central acetylcholine could lead to depressed mood. Evidence has continued to accumulate suggesting that the cholinergic system has a important role in mood regulation. In particular, the finding that the antimuscarinic agent, scopolamine, exerts fast-onset and sustained antidepressant effects in depressed humans has led to a renewal of interest in the cholinergic system as an important player in the neurochemistry of major depression and bipolar disorder. Here, we synthesize current knowledge regarding the modulation of mood by the central cholinergic system, drawing upon studies from human postmortem brain, neuroimaging, and drug challenge investigations, as well as animal model studies. First, we describe an illustrative series of early discoveries which suggest a role for acetylcholine in the pathophysiology of mood disorders. Then, we discuss more recent studies conducted in humans and/or animals which have identified roles for both acetylcholinergic muscarinic and nicotinic receptors in different mood states, and as targets for novel therapies

Logistic regression analysis of populations of electrophysiological models to assess proarrythmic risk.

Population-based computational approaches have been developed in recent years and helped to gain insight into arrhythmia mechanisms, and intra- and inter-patient variability (e.g., in drug responses). Here, we illustrate the use of multivariable logistic regression to analyze the factors that enhance or reduce the susceptibility to cellular arrhythmogenic events. As an example, we generate 1000 model variants by randomly modifying ionic conductances and maximal rates of ion transports in our atrial myocyte model and simulate an arrhythmia-provoking protocol that enhances early afterdepolarization (EAD) proclivity. We then treat EAD occurrence as a categorical, yes or no variable, and perform logistic regression to relate perturbations in model parameters to the presence/absence of EADs. We find that EAD formation is sensitive to the conductance of the voltage-gated Na+, the acetylcholine-sensitive and ultra-rapid K+ channels, and the Na+/Ca2+ exchange current, which matches our mechanistic understanding of the process and preliminary sensitivity analysis. The described technique: •allows investigating the factors underlying dichotomous outcomes, and is therefore a useful tool improve our understanding of arrhythmic risk;•is valid for analyzing both deterministic and stochastic models, and various phenomena (e.g., delayed afterdepolarizations and Ca2+ sparks);•is computationally more efficient than one-at-a-time parameter sensitivity analysis

Development Of Food Guide Pyramid For Individuals With Achondroplasia

AN ABSTRACT OF THE THESIS OF KATHRYN E. LAMB, for the Master of Science degree in Food and Nutrition, presented on Tuesday, November 22, 2011, at Southern Illinois University Carbondale TITLE: DEVELOPMENT OF FOOD GUIDE PYRAMID FOR INDIVIDUALS WITH ACHONDROPLASIA MAJOR PROFESSOR: Dr. Sara Long Roth Previous studies have developed food guide pyramids for different populations. However, no study has developed a food guide pyramid for individuals with achondroplasia. This study used the USDA\u27s food guide pyramid, RDA/DRI, and 2010 Dietary Guidelines to develop a food guide pyramid for individuals with achondroplasia. Although food guide pyramids for different populations exist, there was a lack of nutritional guidelines geared towards individuals with achondroplasia. As this population continues to increase (1 of 26,000), the need for nutrition information increases too. Individuals with ACH are at risk of being overweight or obese just like average sized adults; and with being the height of a child and age of an adult, it can be more of a challenge to maintain a healthy body weight. This indicates how much of a need there is for food guide pyramid for individuals with achondroplasia. Results will benefit individuals with achondroplasia along with parents, physicians, registered dietitians, and other health professionals associated with individuals with achondroplasia. Development of food guide pyramid for individuals with ACH could help develop food guide pyramids for other types of dwarfisms

Developing an entry strategy for Claus Porto to the German market

CEMSClaus Porto is the high-end and international brand of Ach Brito, a Portuguese producer of soaps and other beauty and personal care products. Claus Porto has endured and succeeded the test of time, but has faced numerous “ups and downs”. With Claus Porto at the heart of the firm (potential) value, the current vision is to growth the brand internationally. The challenge of the Business Project was to develop an entry strategy for Claus Porto to the German Market. The analysis and recommendations are described in this paper. Finally, a brief academic discussion on firm internationalization and a scoring model to measure the attractiveness of international markets are presented