Variations on a theme

The development of the visual system is under the control of both genetic and environmental factors. The connections are refined and cut to fit on the basis of neural activity that is constantly flickering through the visual system from the retina. Following birth, it is environmental stimulation that elicits neural activity in the visual system. Cells in the retina, LGN and V1 of newborn, visually naïve monkeys and kittens have receptive field and response properties very much like those of the adults. However, there are differences in their visual systems, such as in layer 4 of V1 where the projections from the LGN terminate. At birth, the cells in layer 4 are driven by both eyes, as projections from the LGN spread over a wide region of layer 4, whereas in the adult a layer 4 cell is driven by either eye but not by both. The adult pattern of ocular dominance columns in layer 4 is established over the first 6 weeks of life, when the LGN axons retract to establish separate, alternating zones in layer 4 that are supplied exclusively by one eye or the other (Figure 6.1).

In early life, the connections of neurons in the visual system are susceptible to change and can be affected irreversibly by unbalanced neural activity passing through them. For example, closure of the lids of one eye during the first 3 months of life leads to blindness in that eye.

Background

Increased adipose tissue mass is a common denominator in both obesity and osteoporosis. Obesity is characterized by increased fat storage in subcutaneous and visceral adipose depots resulting from an imbalance between energy intake and energy expenditure, whereas osteoporosis is associated with increased adipocyte production in bone marrow and is not necessarily associated with increased overall adiposity. In obesity a reduction of adipose tissue mass is accompanied by amelioration of the pathophysiological effects. There are currently no therapies that specifically reduce bone marrow adipocyte populations. However, bone formation decreases with increasing proportion of marrow adipocytes (Verma et al., 2002); thus, it is likely that reversal or prevention of bone marrow adiposity may improve bone quality.

In the USA, the prevalence of overweight among adults increased by 61% from 1991 to 2000; currently, more than half of all adults are considered overweight and approximately 20% are extremely overweight or obese (Flegal et al., 1998). Obesity is not just a cosmetic problem – there is much evidence indicating that higher levels of body fat are associated with an increased risk for the development of numerous adverse health consequences (Visscher & Seidell, 2001). There is also a tremendous economic burden associated with the recent rise in prevalence of obesity. The economic costs of obesity are estimated to be ∼7% of total healthcare costs in the USA (Colditz, 1999).

In the twenty-first century, obesity affects around 20–25% of the population and it is now one of the prime contributors to ill health in modern society. Obesity can cause or exacerbate a variety of health problems and it is often associated with a number of other diseases including type II diabetes mellitus, coronary heart disease and certain types of cancer. The incidence of obesity and related diseases is steadily increasing such that obesity is now regarded as a global epidemic. In recent years, major advances have been made in determining the role of the central nervous system, in particular specific hypothalamic nuclei, in regulating energy balance. From such studies it is apparent that a highly intricate neural system involving a complex interplay between a range of orexigenic and anorectic agents controls food intake and body weight. Thus, a greater understanding of the key neurotransmitter molecules, their related signal transduction pathways and molecular targets, as well as the neuronal pathways that control release of these neurotransmitters is vital if novel therapeutic targets for the treatment of obesity and related diseases are to be uncovered. This book provides a concise overview of recent developments in this field. As an introduction, Professor Bloom gives an outline of the factors that are known to play a key role in regulating energy balance and the development of obesity in humans.

Obesity is a global phenomenon, a disease which is spread by increasing urbanization and which causes major morbidity and mortality. Over the last two decades it has reached unprecedented and dramatic levels in industrially developed countries but the rise in prevalence affects almost every part of the world. It is already placing huge burdens on the health systems of many countries. Its potential to cause disability amongst working-age populations worldwide, particularly as a result of complications of diabetes, makes it imperative to work towards both preventative and curative solutions.

Yet, despite the fact that obesity has become such a widespread disease, there remains within the medical community a tradition of stigmatizing individual sufferers. Doctors and other health professionals have tended to provide what is seen as self-evident advice, namely, to consume less food and to expend more energy through physical activity. The subsequent failure of patients to lose weight, despite good advice, and in the face of complications of their condition, is then viewed as evidence of an inability to control lifestyles and to resist urges. At the root of this view lies an historical absence of knowledge of the hugely complex and fascinating innate homeostatic mechanism which controls satiety and energy balance: a mechanism that has evolved over millions of years, has seen humankind through feast and famine, and has run into trouble only since the advent of mechanization.

Introduction

Leptin (a 146 residue peptide) and insulin (a 30 amino acid dipeptide) are synthesized in distinct locations in the periphery but share a common function of long-term regulation of body weight and energy balance through direct alterations in hypothalamic arcuate nucleus (ARC) signaling (Sahu, 2004; Cone, 2005). Insulin is synthesized as a prohormone almost exclusively by pancreatic β-cells, and secreted into plasma in response to rising glucose levels. The mRNA for insulin has been found in some brain areas, suggesting that specific neurons may be capable of producing an ‘insulin-like’ peptide. Meanwhile leptin is synthesized and secreted mainly by adipocytes, and circulating levels are normally related to adiposity (Zhang et al., 1994; Frederich et al., 1995; Considine et al., 1996). There is some evidence that leptin is also produced by cells of the immune system such as T-cells and macrophages, bone, skeletal muscle, placenta, stomach, hypothalamus and by stellate cells of the liver. Direct administration of either hormone to the ARC has significant effects on feeding and body weight, while both hormones can cross the blood–brain barrier, probably via specific and saturable transport systems (Niswender & Schwartz, 2003; Niswender et al., 2004). Leptin and insulin stimulate proopiomelanocortin (POMC) expressing neurons in the ARC, resulting in processing of POMC to α-melanocyte-stimulating hormone (α-MSH) and subsequent activation of the melanocortin-3 and -4 receptors, leading to anorexigenic outputs.

The chapters within this book have detailed various aspects of the neurobiology of weight control. These include the genetic factors which determined the function of the body's energy regulation and the central mechanisms responsible for maintaining the body's energy balance. Particular focus has been placed on central targets such as the melanocortin and endogenous opioid systems. These systems represent two factors which control food intake: energy balance regulation and pleasure/reward. It is the metabolic demand for energy and the pleasure derived from eating palatable foods which determine when, what and how much we eat. Other chapters have dealt with peripheral generated signals such as ghrelin, leptin and insulin and their role in appetite and energy regulation. Such mechanisms provide episodic meal-by-meal signals of food consumption and the tonic signals of energy storage to the CNS. Organs such as the gut, the pancreas and adipose tissue act as both detectors and effectors in the organism energy regulation system. This diverse peripheral input allows the organism to constantly monitor its current energy status. In turn the CNS does not only adjust the expression of feeding behavior, as the last chapter shows the CNS also exerts control over the storage of energy.

Given the complexity of these systems underpinning energy regulation (episodic and tonic, peripheral and central) it may appear surprising that the state of obesity exists. However, despite the collective action of these many systems it seems many individuals experience great difficulty controlling their own body weight.

Introduction

The initial report that melanocortin peptides potently inhibit food intake after central administration was published in 1986 (Poggioli et al., 1986). Because the melanocortin receptors had not yet been cloned or shown to be expressed in the brain, there was no physiological context to fully appreciate the significance of these data. In the two decades since that first publication, a remarkable web of experimental findings has firmly established the melanocortin system as a critical component in the brain's control of energy homeostasis. A key breakthrough was the cloning and characterization of the agouti gene from the “obese yellow” mouse (Lu et al., 1994). This spontaneous mutant strain expresses a dominant agouti AY allele and has an obesity phenotype in addition to a yellow coat color. The demonstration that agouti is an antagonist of melanocortin receptors (MCR), together with the findings of ectopic brain expression of the peptide and expression of MC3R and MC4R in the brain was the genesis of the “agouti-melanocortin” hypothesis for the mechanism of obesity in AY mice. Critical elements of this hypothesis were substantiated in 1997 by a trilogy of publications. First, targeted inactivation of the gene encoding the brain-specific MC4R caused an obesity phenotype similar to that of AY mice (Huszar et al., 1997). Second, novel agonists and antagonists of the MC3/4R inhibited or stimulated feeding, respectively, when injected into the 3rd ventricle in rodents (Fan et al., 1997).

The endogenous opioid system, initially characterized over 30 years ago, is a primary example of a multifunctional neural system involved in a wide range of basic homeostatic behaviors, including pain control, sexual behavior, learning and memory, reward, addiction and motivation, immune function, thermoregulatory, cardiovascular and respiratory processes, and as this review indicates, the regulation of energy balance through the modulation of food intake. Given the complexity and breadth of both the endogenous opioid system itself and the complex nature of energy regulation, this review is designed to inform the reader of the systematic steps taken by the field as a whole to understand their interaction. Thus, this review will focus on: (a) discovery and characterization of the endogenous opioids and their receptors, (b) early evidence involving the opioid system in ingestive behavior, (c) the role of opioids in rewarding aspects of food intake, (d) the role of macronutrient choice in opioid-induced feeding, (e) the specific roles of opiate receptor subtypes and specific brain sites in regulating opioid-induced feeding, (f) molecular mechanisms governing opioid-induced feeding, and (g) interactions of opioid-induced feeding with dopamine and other orexigenic neuropeptides.

Discovery and characterization of the endogenous opioids and their receptors

The existence of an endogenous receptor in animals that bound opiates was reported in 1973 (Pert & Snyder, 1973; Simon et al., 1973; Terenius, 1973). Shortly thereafter, it became apparent that multiple subtypes (mu, delta and kappa) of the receptor existed (Martin et al., 1976; Lord et al., 1977).

Introduction

The hypothalamus is a critical integrator of peripheral and central signals that mediate energy homeostasis. Over the last two decades, substantial progress has been made in elucidating the details of how neural, hormonal and nutrient signals from the gut and adipose tissue act on specific hypothalamic pathways to control energy balance and various physiologic processes. These hypothalamic circuits affect not only appetite, but through their diverse projections to the autonomic nervous system, brainstem and higher centers also influence motivational and motor function, and the endocrine system via the pituitary gland. Although the details of the interacting factors and effector mechanisms remain an area of active research, it is clear that neuropeptides at the level of the hypothalamus modulate key aspects of feeding behavior, energy expenditure and neuroendocrine function (Grill & Kaplan, 2002). In this chapter, we provide an overview of the hypothalamic circuitry within a framework for understanding its role as a sensor, integrator and effector of energy homeostasis and diverse physiologic processes.

Classical role of the hypothalamus in feeding regulation

A crucial involvement of the base of the diencephalon in energy homeostasis was first suggested by clinical observations in patients with pituitary tumors associated with excessive fat deposition and hypogonadism (Bramwell, 1888; Frolich, 1901). Several animal studies confirmed the importance of this region in body weight regulation, but it was not until the experiments of Hetherington and Ranson that the role of the hypothalamus rather than that of the pituitary gland was firmly established.

Summary

Obesity is an epidemic in the USA and worldwide. Despite a rapid increase in the burden of obesity, scientific evidence indicates that body adiposity is a tightly regulated physiological variable. Current models implicate a classical endocrine feedback loop in the process termed energy homeostasis. Both the pancreatic β cell-derived hormone insulin and the adipocyte-derived hormone leptin are secreted in proportion to fat mass and, thus, signal the status of body energy stores to the hypothalamus. Key hypothalamic nuclei contain neurons that respond directly to insulin and leptin and integrate these and other signals in order to regulate food intake and energy homeostasis through a series of complex neuronal circuits.

Although the personal, societal and economic costs of obesity are staggering, the medical research community has yet to develop definitive therapies. Recent advances in our understanding of the interactions of insulin and leptin with hypothalamic target neurons has shed light upon potential pathophysiological mechanisms and therefore therapeutic targets. In this chapter, basic mechanisms of energy homeostasis will be presented in the context of an adiposity negative feedback model with the hormones insulin and leptin serving an important role. This model will then be extended and discussed in the context of the pathophysiology of obesity.

Introduction

Obesity is an international health epidemic (Kopelman, 2000; Mokdad et al., 2001) afflicting 1.7 billion people worldwide (James, 2003) and has surpassed infectious disease and under-nutrition as the major threat to health in most parts of the world.

Introduction

The discovery of ghrelin, a 28 amino-acid peptide hormone, has generated a substantial amount of attention for a number of reasons. Initially, ghrelin was heralded as the long sought endogenous ligand for the orphan growth hormone secretagogue receptors (GHS-Rs). Indeed, like growth hormone secretagogues (GHS), ghrelin targeted these receptors to potently increase the release of growth hormone (GH) both in vitro and in vivo. Soon, however, it became evident that ghrelin was implicated in a variety of physiological processes that include cell proliferation, metabolism, cell protection, reproduction, etc. Of these, the effects of ghrelin on food intake and metabolism have had the biggest impact; unlike other peripheral signals associated with energy balance, ghrelin increases appetite and leads to the accumulation of body fat. Indeed, the stimulatory effects of ghrelin on food intake and its apparent opposite relation to the anorectic hormone, leptin, have been proposed as the ying/yang model for hormonal regulation of energy balance. Nevertheless, the more is known about ghrelin, the more it becomes obvious that ghrelin produces its metabolic effects via a multitude of central and peripheral mechanisms that work in parallel to modulate the effects of ghrelin in energy regulation. This chapter will review the literature regarding the effects of ghrelin on energy balance. Energy balance implies the regulation of both food intake and energy expenditure, therefore we will discuss both topics in relation to ghrelin. A description of the possible central routes of ghrelin actions on energy balance within the brain will follow.

Introduction

Animals have been used extensively as surrogates for the study of factors that contribute to the development and persistence of obesity in human beings. Each model has its own set of advantages and disadvantages in relation to its similarities and differences from humans. In fact, obesity rarely occurs in feral animals outside of the pre-hibernating period. For the majority of individuals obesity is a relatively recent event in human history because food availability was generally limited and a relatively high degree of physical activity was required to procure sufficient food to maintain survival. The switch from hunter-gatherer to agricultural societies has allowed increasing numbers of individuals to obtain food with reduced expenditure of energy. In the developed world, the prevalence of obesity has increased precipitously in the last 20–30 years as the availability of cheap, highly palatable, energy-dense food has become more widely available and physical activity has declined (Popkin & Doak, 1999). Clearly, the gene pool has not changed substantially over such a short period of time to explain the rapid increase in obesity prevalence. Thus, environmental factors must be the critical variable which has promoted the current epidemic of human obesity. Animal models of obesity have become a useful tool in our quest to understand the factors contributing to the recent obesity epidemic in humans. Although other animals differ from humans in many ways, they share many common physiological properties that assure their survival during periods of famine.

This chapter is concerned with the consequences of two broad principles applicable to hearing (as well as to perception in general): (1) there is an obligatory interpretation of sensory input in terms of events and conditions normally associated with stimulation; and (2) individuals are not aware of the nature of the neurophysiological responses to stimuli as such. The implications of these principles for the sone scale of loudness and the mel scale of pitch will be discussed, and evidence will be presented suggesting that the judgments used for the construction of these scales of sensory magnitude are based upon familiarity with physical scales correlated with the changes in stimulation.

Sensory input and perception

In the previous chapter on auditory localization, we saw how differences in acoustic input to the two ears are perceived in terms of associated external conditions and events without awareness of the aspects of sensory stimulation leading to this perception. Thus, when the sound radiated by a source reaches one ear before the other, listeners hear only a single sound located on the side of the leading ear: the difference in time of stimulation can be inferred by those having some knowledge of acoustics, but even then only one off-center sound is perceived. Also, we have seen that interaural spectral amplitude differences approximating those produced by the head and pinna for sources at different azimuths are perceived in an obligatory manner in terms of location rather than spectral mismatch.

As in the earlier editions, the present text emphasizes the interconnectedness of areas in auditory perception. These linkages are especially evident in the chapters dealing with acoustic sequences, pitch and infrapitch, loudness, and the restoration of portions of signals obliterated by extraneous sounds. In addition, the chapter on speech describes how processes employed for the perception of brief nonverbal sounds are used for the organization of syllables and words, along with an overlay of special linguistic mechanisms.

The basic format of the book remains unchanged, but all chapters have been updated. Among the additions are new sections in Chapter 1 describing the principles underlying functional imaging of the brain based on the hemodynamic techniques of fMRI and PET, and the electrodynamic techniques of EEG and MEG. New information concerning pitch and infrapitch appears in Chapter 3, and additional information concerning speech processing is incorporated into Chapter 7. Suggested additional reading now appears at the end of each chapter.

It is hoped that this text will be of value to research scientists and to professionals dealing with sound and hearing. No detailed specialized knowledge is assumed, since basic information necessary for understanding the material covered is provided. It may be used for advanced undergraduate and graduate courses in behavioral sciences, neurobiology, music, audio engineering, and the health sciences and professions.