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This chapter examines the relation between the blood–brain barrier (BBB) and perivascular cells. It explains that the BBB is a dynamic interface between blood and brain which restricts the entry of plasma constituents that could interfere negatively with brain function while allowing substances which are essential for brain metabolism and function to enter the brain. The chapter discusses the structural basis for the BBB, the polarity of brain endothelial cells, and carrier-mediated transport of nutrients.

This chapter traces the development of the field of enzyme replacement. It explores the major remaining problem — i.e., treatment of lysosomal storage diseases with a major neurologic component, because of insulation of the brain from the therapeutic enzyme by the blood-brain barrier.

Cephalopod molluscs such as octopus, squid, and cuttlefish are among the most advanced invertebrates known, with large brains and highly developed sensory and motor capabilities. This chapter reviews recent high-resolution electron microscopic studies of the blood–brain interface in Sepia which demonstrate that the blood–brain barrier is formed by a novel restricting junction, between vascular pericytes in arterial vessels, and between perivascular glial cells in capillaries and venous vessels. The filtering properties of the junction appear to be determined by the extracellular matrix within the intercellular cleft, and a model is proposed by which adsorbed plasma proteins cross-link the matrix and reduce its effective mesh size. Electron microscopic examination of electron-dense tracer distribution in octopus and squid brains confirms that a blood–brain barrier to protein is also present in these groups. There is considerable variability in the structure and permeability of junctional zones in different tissues and species. This may reflect the combinations possible by subtle alterations in the two major components: the membranous elements of the junction and the material packing the intercellular cleft.

This chapter focuses on the potential roles of the sensory circumventricular organs in central autonomic control. These specialized structures are not only able to collect and integrate information but are also able to transmit output signals to autonomic control centers in the hypothalamus and the medulla. The chapter describes the specialized anatomical and physiological features of the sensory circumventricular organs and reviews an expanding literature that suggests important roles for these structures in the regulation of diverse autonomic systems controlling body fluids, metabolism, reproduction and immune regulation.

Stroke is the fifth leading cause of mortality and the major cause of long-term disability in the United States. Epidemiological studies report sex differences in ischemic stroke occurrence, mortality and functional recovery. In younger demographics, the overall incidence of stroke is higher in men than younger women, but in the elderly population, stroke rates are higher in older women compared to age-matched men, indicating an interaction of age and sex as important modifiers of disease. The increased risk for stroke in older women is attributed to loss of ovarian hormones, principally estrogens. However, estrogen/estradiol therapy is not always neuroprotective for stroke, especially in aging populations. Age-related changes in central and peripheral immune cells and the blood–brain barrier may play a crucial role in modifying stroke outcomes and the effects of estrogens. This chapter discusses the role of estrogens as a stroke protectant in younger females in contrast to its anomalous effects in the aging brain. Furthermore, the chapter describes age-related changes in support cells in the brain and in the periphery and evaluates the evidence that age-associated inflammation underlies the switch in estrogens neuroprotective action in young females to its neurotoxic effects in older females.

This chapter deals with brain temperature as a physiological parameter, which is determined primarily by neural metabolism, regulated by cerebral blood flow, and affected by various environmental factors and drugs. First, normal fluctuations in brain temperature that are induced by salient environmental stimuli and occur during motivated behavior at stable normothermic conditions are examined. On the basis of thermorecording data obtained in animals, the range of physiological fluctuations in brain temperature, their underlying mechanisms, and relations to body temperatures are described. The temperature dependence of neural activity and the dual “functions” of temperature as a reflection of metabolic brain activity and as a factor that affects this activity are considered. Third, pharmacological brain hyperthermia is discussed, focusing on the effects of psychomotor stimulants, highly popular drugs of abuse that increase brain metabolism, diminish heat dissipation, and may induce pathological brain overheating. The role of brain hyperthermia in leakage of the blood-brain barrier, development of brain edema, acute abnormalities of neural cells, and neurotoxicity, is also examined.

This chapter discusses antigen processing, presentation, and T cell interaction. The central nervous system (CNS) is protected by a blood-brain barrier (BBB) designed to minimize the passage of immune cells and macromolecules into the brain parenchyma. In the normal CNS parenchyma antigen-presenting cells (APCs) are functionally inactivated and lack expression of major histocompatibility complex (MHC) molecules. Nevertheless, the CNS is routinely surveyed by activated T lymphocytes. Perivascular macrophages situated adjacent to the endothelium cells of the blood vessels take up and present antigens to T lymphocytes. Most cells of the brain parenchyma are immunologically quiescent in the healthy CNS, but can be stimulated to become facultative APCs that process and present antigens via their MHC molecules to T lymphocytes in neuroinflammatory diseases.

Although the CNS has conventionally been viewed as an immunologically privileged site, the importance of immunological responses in the pathogenesis of CNS disease has become increasingly apparent over the last few decades. Indeed, the concept of CNS isolation from the immune system is hard to reconcile with the favourable outcome of encephalitides commonly complicating some exanthemata, such as mumps, and with the brisk cerebrospinal fluid pleocytosis, which almost invariably accompanies brain infection; neither observation suggests that CNS invasion by infective agents proceeds unhindered by immune response. However, whilst absolute immune privilege can no longer be sustained, is has become clear that there are fundamental differences between the mechanisms of immunity in the CNS and those elsewhere in the body. In order to understand the part inflammation plays in both pathogenesis and repair, it is necessary to consider briefly both the principles of the systemic immune response and the blood–brain barrier, which protects nervous tissues from the systemic circulation.

Neurodegenerative diseases lead to significant morbidity and mortality. Although medical care for other disorders (e.g., cardiovascular disease and cancer) has improved, neurodegenerative diseases have become more prevalent as the population ages. Understanding of the scientific underpinnings of neurodegenerative diseases has advanced greatly over the last thirty years. However, with a few exceptions, very few effective treatments are available to delay the onset or affect the course of these diseases. This Forum convened leaders in the field of neurodegeneration from different disciplines and tasked them with defining areas in need of more attention. A time frame of 5–20 years was the goal within which to develop more effective diagnostics and treatments. This chapter identifies eight key areas to address. With significant progress in each area, substantial changes in the diagnosis and treatment of neurodegenerative diseases should be possible over the next twenty years. Given the current cost of these diseases to society and the increase in their prevalence with no additional progress, a major worldwide effort should be made to address these issues immediately.

This chapter examines the influence of development on the inflammatory response in the central nervous system (CNS). It analyses the influence of the blood–brain barrier on brain inflammation, the leucocytes in the CNS, and the refractory nature of the brain. The findings suggest that while leucocyte traffic into the normal brain takes place as part of normal physiology, it is clear that the brain has evolved mechanisms to restrict the acute inflammatory response.

Pesticides are often designed to interfere with the functions of the nervous system in pests, such as insects. But the brain biochemistry is similar in humans, and pesticide exposure can therefore cause toxicity to children’s brain development. This risk is almost never examined, however. When pregnant women are exposed at work or at home, the pesticides are shared with the fetus. Studies in several counties now show that community use of pesticides may harm brain development and cause lasting damage. We also know that over 200 chemicals, including many pesticides, solvents, metals and many other industrial compounds, can cause brain toxicity in adults. We must therefore assume that they are able to cross the blood-brain barrier and cause toxicity to developing brains. But even for pesticides designed to be neurotoxic, there is no systematic testing.

In this chapter, the current understanding of the mechanisms of endocrine disruption on the brain and nervous system are presented. Because the overwhelming majority of mechanistic studies on EDCs have focused on the actions mediated by nuclear hormone receptors, this mechanisms is described in detail. The chapter also discusses the classic transcriptional mechanisms of steroid action and the impact of EDCs on rapid signaling (non-genomic) mechanisms. It presents an overview of the enzymes and pathways involved in the biosynthesis of steroid hormones, which are critical to proper functioning of the HPA and HPG axis, and the neuroactive steroids synthesized and active in the mammalian brain. The potential for EDCs to alter metabolic enzymes, with a focus on possible targets in the metabolic blood-brain barrier, is presented as a potential, though largely unexplored, mode of EDC action in the brain.