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The blood–brain barrier (BBB) is a specialized tissue interface that provides an important homeostatic and immunosurveillance role in the CNS. Unlike most microvascular tissues, which readily promote paracellular passage of solutes and macromolecules, the BBB is more analogous to polarized mucosal epithelia that restrict such permeability in order to prevent disease onset. Recent transgenic ablation studies have demonstrated that the BBB and mucosal tissues also share a requirement for astroglial-regulated barrier integrity. This review highlights the emerging concept that astroglia regulate barrier function at markedly different tissue interfaces. It also explores possible lessons that might be learnt by adopting epithelial model paradigms of the BBB. For example, novel glial-derived S-nitrosylation signals that regulate intestinal permeability in the digestive tract might provide new mechanistic insights into the function of the BBB. A better understanding of such universal mechanisms for barrier regulation will facilitate novel therapeutic strategies that target permeability disorders at CNS and mucosal tissue interfaces.
Expression of the human epidermal growth factor receptor (EGFR) in murine Schwann cells results in loss of axon–Schwann cell interactions and collagen deposition, modeling peripheral nerve response to injury and tumorigenesis. Mast cells infiltrate nerves in all three situations. We show that mast cells are present in normal mouse peripheral nerve beginning at 4 weeks of age, and that the number of mast-cells in EGFR+ nerves increases abruptly at 5–6 weeks of age as axons and Schwann cells dissociate. The increase in mast cell number is preceded and accompanied by elevated levels of mRNAs encoding the mast-cell chemoattractants Rantes, SCF and VEGF. Genetic ablation of mast cells and bone marrow reconstitution in W41 × EGFR+ mice indicate a role for mast cells in loss of axon−Schwann cell interactions and collagen deposition. Pharmacological stabilization of mast cells by disodium cromoglycate administration to EGFR+ mice also diminished loss of axon−Schwann cell interaction. Together these three lines of evidence support the hypothesis that mast cells can contribute to alterations in peripheral nerves.
The complexity of the adult brain is the result of an integrated series of developmental events that depends on appropriate timing of differentiation. The importance of transcriptional regulatory networks and epigenetic mechanisms of regulation of gene expression is becoming increasingly evident. Among these mechanisms, previous work has revealed the importance of histone deacetylation in oligodendrocyte differentiation. In this manuscript we define the region of interaction between transcription factor Yin-Yang 1 (YY1) and histone deacetylase 1, and characterize the functional consequences of YY1 overexpression on the differentiation of oligodendrocyte progenitors.
In this review, we briefly summarize what is known about the properties of the three families of gap junction proteins, connexins, innexins and pannexins, emphasizing their importance as intercellular channels that provide ionic and metabolic coupling and as non-junctional channels that can function as a paracrine signaling pathway. We discuss that two distinct groups of proteins form gap junctions in deuterostomes (connexins) and protostomes (innexins), and that channels formed of the deuterostome homologues of innexins (pannexins) differ from connexin channels in terms of important structural features and activation properties. These differences indicate that the two families of gap junction proteins serve distinct, complementary functions in deuterostomes. In several tissues, including the CNS, both connexins and pannexins are involved in intercellular communication, but have different roles. Connexins mainly contribute by forming the intercellular gap junction channels, which provide for junctional coupling and define the communication compartments in the CNS. We also provide new data supporting the concept that pannexins form the non-junctional channels that play paracrine roles by releasing ATP and, thus, modulating the range of the intercellular Ca2+-wave transmission between astrocytes in culture.
Management of chronic pain is a real challenge, and current treatments that focus on blocking neurotransmission in the pain pathway have resulted in limited success. Activation of glial cells has been widely implicated in neuroinflammation in the CNS, leading to neurodegeneration in conditions such as Alzheimer's disease and multiple sclerosis. The inflammatory mediators released by activated glial cells, such as tumor necrosis factor-α and interleukin-1β not only cause neurodegeneration in these disease conditions, but also cause abnormal pain by acting on spinal cord dorsal horn neurons in injury conditions. Pain can also be potentiated by growth factors such as brain-derived growth factor and basic fibroblast growth factor, which are produced by glia to protect neurons. Thus, glial cells can powerfully control pain when they are activated to produce various pain mediators. We review accumulating evidence that supports an important role for microglial cells in the spinal cord for pain control under injury conditions (e.g. nerve injury). We also discuss possible signaling mechanisms, in particular mitogen-activated protein kinase pathways that are crucial for glial-mediated control of pain. Investigating signaling mechanisms in microglia might lead to more effective management of devastating chronic pain.
What is the self? There is no single or simple answer to that question. The term, which is a term of art (as a freestanding noun, the word “self” is hardly ever used in ordinary English) is used in a range of sometimes conflicting ways; so many that some philosophers despair at finding any unifying element underlying its disparate uses and therefore recommend that we discontinue using it at all as the name for a philosophical problem (Olson 1999). I suspect that these philosophers are right to this extent: there is no single sense or even a closely related set of senses, unifying all or even most of the central uses of the term. There is therefore no problem of the self. Nevertheless, there are a number of problems of the self. In this chapter, we shall consider just one.
The problem of the self upon which I want to focus is, briefly, this: why is the self singular? This is not the first problem that generally comes to mind when we consider the problem of the self. However, it is a problem that is especially pressing for us. Consider the evidence from neuroscience, reviewed in earlier chapters, that the mind consists of a multitude of discrete modules and mechanisms. Consider, too, the extended mind hypothesis, according to which mind can include or incorporate a set of tools external to the self.
In the previous chapters, I have argued that neuroscience (and allied fields) can shed light on some of the perennial questions of moral theory and moral psychology: the nature of self-control and the degree to which agents should be held responsible for their actions. In this chapter, I explore another puzzle in moral psychology: the nature and existence of self-deception.
Self-deception is a topic of perennial fascination to novelists and everyone else interested in human psychology. It is fascinating because it is at once puzzling and commonplace. The puzzle it poses arises when we observe people apparently sincerely making claims that seem obviously false, and against which they apparently possess sufficient evidence. The man whose wife suddenly has many mysterious meetings, starts to receive unexplained gifts and is reportedly seen in a bar on the other side of town with a strange man has every reason to suspect her of infidelity. If he refrains from asking her questions, or is satisfied with the flimsiest of explanations, and fails to doubt her continued faithfulness, he is self-deceived. Self-deception is, apparently, common in the interpersonal sphere, but it is also a political phenomenon. Western supporters of Soviet communism were often, and perhaps rightly, accused of self-deception, when they denied the repression characteristic of the regime.
We say that someone is self-deceived, typically, when they possess sufficient evidence for a claim and yet continue, apparently sincerely, to assert the opposite.
In the last chapter, we set out the objections that seem to underlie the presumption in favor of traditional means of changing minds (hereafter, “the presumption”). In this chapter we shall consider these objections in detail. Before we begin treating them, however, we need to consider another, more general, question, one that cuts across all the other objections and across a range of possible neurological interventions. Many people – laypeople, philosophers, bioethicists and neuroscientists – have importantly different responses to actual and potential neuroscientific (as well as medical) interventions, depending upon what they are being used for. Interventions to treat diseases and impairments are regarded as significantly more permissible (perhaps even obligatory) than interventions aimed at enhancing normal capacities. Treating disease is generally regarded as an intrinsically worthwhile activity, and we are therefore under a (possibly defeasible) obligation to engage in it, but enhancing already normal capacities is a luxury, which is at best permissible, and not obligatory, and at worst impermissible. Different thinkers make different uses of the treatment/enhancement distinction. For some, it marks the difference between the kinds of medical interventions which it is incumbent upon the state to provide, and the kinds of interventions which can permissibly be bought and sold, but need not be provided as a matter of justice; for others, it marks the difference between interventions which are permissible, and those which ought to be banned.
Much of the interest and anxiety provoked by new and developing neuroscientific technologies is centered around two issues: the extent to which these technologies might allow their users to read the thoughts of people, and (as if that prospect was not disturbing enough) the extent to which these technologies might actually be used to control people. Some commentators believe that one or both of these issues are pressing, in the sense that the relevant technologies will soon be available; some even believe that these technologies already exist. In this chapter, we will ask how worried we should be. Are these technologies imminent? And if they are, are they as threatening as they appear?
MIND READING AND MIND CONTROLLING
There has been a great deal of interest in the possibility of “brain reading” as a lie detection technology. The problems with existing lie detectors are well known: they produce high rates both of false positives and of false negatives, and they can be “beaten” by people who deliberately heighten their responses to control questions, which are used to establish a baseline for comparison. In its overview of current lie-detection techniques, the US National Research Council concluded that there is “little basis for the expectation that a polygraph test could have extremely high accuracy” (National Research Council 2003: 212). The reasons for this conclusion are many: because the responses measured are not uniquely involved in deception, because they include responses that can be deliberately controlled and because the technology is difficult to implement in the real-world.
One scenario which simultaneously fascinates and horrifies many people is the prospect that our memories could be altered by others. The number of films depicting this kind of scenario bears witness to its fascination; think of Total Recall, Eternal Sunshine of the Spotless Mind or Dark City. The prospect of losing our memories, or having them replaced with false recollections, exerts such power over us because we all recognize, more or less clearly, that our memories are, in some sense, us: our very identities (in one sense of that multiply ambiguous term) are constituted by our past experiences insofar as we can recall them and insofar as they shape our present behavior, thoughts and desires.
The so-called memory criterion of personal identity was originally proposed by John Locke, the great seventeenth-century English philosopher. Locke argued that a person at time t was the same person as an individual at some earlier time if at t they are able to remember experiences of that earlier individual. Locke's criterion came under attack almost immediately, and with good reason: philosophers like Thomas Reid pointed out that the memory criterion was circular. Memory presupposes personal identity, and therefore cannot constitute it. I can only remember things that actually happened to me; that's part of the very definition of memory (if I seem to remember being abducted by aliens, but I was never in fact abducted by aliens, I don't actually remember being abducted by aliens; “remember” is a success word and is only appropriately applied when the event actually happened, and the recollection is appropriately caused by the event).
Can neuroscience, and the other sciences of the mind, shed light on one of the oldest and most difficult of all philosophical problems, the problem of free will and moral responsibility? Some scientists believe it can. In their popular writings, these scientists often express the opinion that the sciences of the mind have shown that free will – and therefore moral responsibility – is an illusion. They argue, roughly, as follows: the sciences of the mind demonstrate that our thoughts, intentions, and (therefore) our actions are the product of deterministic processes, in the following sense: given the initial conditions (say, our genetic endowment at birth and the environment into which we were born), we had to act as we did. But if we were determined to act as we did, then we were not free, or morally responsible. Richard Dawkins, the great evolutionary biologist, has recently compared our practices of praising, blaming and punishing to Basil Fawlty's behavior in flogging his car for breaking down, in the TV series Fawlty Towers:
Doesn't a truly scientific, mechanistic view of the nervous system make nonsense of the very idea of responsibility, whether diminished or not? Any crime, however heinous, is in principle to be blamed on antecedent conditions acting through the accused's physiology, heredity and environment. Don't judicial hearings to decide questions of blame or diminished responsibility make as little sense for a faulty man as for a Fawlty car?
In the late 1960s, a new field of philosophical and moral enquiry came into existence. Bioethics, as it soon came to be called, quickly mushroomed: it developed its own journals, its own professional associations, its own conferences, degree programs and experts. It developed very rapidly for many reasons, but no doubt the main impetus was that it was needed. The problems and puzzles that bioethics treats were, and are, urgent. Bioethics developed at a time when medical technology, a kind of technology in which we are all – quite literally – vitally interested, was undergoing significant growth and developing unprecedented powers; powers that urgently needed to be regulated. The growth in life-saving ability, the development of means of artificial reproduction, the rapid accumulation of specialist knowledge, required new approaches, concentrated attention, new focuses and sustained development; in short, a new discipline. Bioethics was born out of new technical possibilities – new reproductive technologies, new abilities to intervene in the genetic substrate of traits, new means of extending life – and the pressing need to understand, to control and to channel these possibilities.
Predicting the future is a dangerous business. Nevertheless, it seems safe to predict that the relatively new field dubbed neuroethics will undergo a similarly explosive growth. Neuroethics seems a safe bet, for three reasons: first because the sciences of the mind are experiencing a growth spurt that is even more spectacular than the growth seen in medicine over the decades preceding the birth of bioethics.
There are two basic ways to go about changing someone's mind. What we might call the traditional way involves the presentation of evidence and argument. This way of going about things raises ethical problems of its own, all of which are familiar: Under what circumstances is it permissible to present false evidence? If it's in the person's own interests to come to have a false belief, must we nevertheless present them with the truth? What if we know that the available evidence is misleading? Can we hide the evidence in the interests of the truth? These questions and others like them constitute a small part of the traditional turf of moral philosophy.
Traditional psychotherapy is, in many ways, an extension of this familiar method of changing minds. The goal of the earliest fully developed method of psychotherapy, Freudian psychoanalysis, is truth, and the concomitant extension of the power of rational thought over libidinal impulse. “Where id was, there ego shall be,” Freud famously wrote: the powerful unconscious drives of the id, the forces that tyrannize the neurotic patient, shall be replaced by the conscious forces of the rational ego, the I. To be sure, psychoanalysis does not take a direct route to truth. It does not seek to change minds by argument, or at least not by argument alone. Freud thought that it was not sufficient for the patient simply to be told the truth regarding his or her neuroses and their origins.
Neuroethics is a new field. The term itself is commonly, though erroneously, believed to have been coined by William Safire (2002), writing in The New York Times. In fact, as Safire himself acknowledges, the term predates his usage. The very fact that it is so widely believed that the term dates from 2002 is itself significant: it indicates the recency not of the term itself, but of widespread concern with the kinds of issues it embraces. Before 2002 most people saw no need for any such field, but so rapid have been the advances in the sciences of mind since, and so pressing have the ethical issues surrounding them become, that we cannot any longer dispense with the term or the field it names.
Neuroethics has two main branches; the ethics of neuroscience and the neuroscience of ethics (Roskies 2002). The ethics of neuroscience refers to the branch of neuroethics that seeks to develop an ethical framework for regulating the conduct of neuroscientific enquiry and the application of neuroscientific knowledge to human beings; the neuroscience of ethics refers to the impact of neuroscientific knowledge upon our understanding of ethics itself.
One branch of the “ethics of neuroscience” concerns the conduct of neuroscience itself; research protocols for neuroscientists, the ethics of withholding incidental findings, and so on.
In the preceding chapters, we considered difficult questions concerning the ethical permissibility or desirability of various ways of intervening into the minds of human beings. In examining these questions, we took for granted the reliability of the ethical theories, principles and judgments to which we appealed. But some thinkers have argued that the sciences of the mind are gradually revealing that we cannot continue to do so. Neuroscience and social psychology, these thinkers claim, show that our ethical judgments are often, perhaps even always, unjustified or irrational. These sciences are stripping away the layers of illusion and falsehood with which ethics has always clothed itself. What lies beneath these illusions? Here thinkers diverge. Some argue for a revisionist view, according to which the lesson of the sciences of the mind is that all moral theories but one are irrational; on this revisionist view, the sciences of the mind provide decisive support for one particular ethical theory. Some argue for an eliminativist view, according to which the sciences of the mind show that all moral theories and judgments are unjustified. In this chapter, we shall assess these twin challenges.
How is this deflation of morality supposed to take place? The neuroscientific challenge to ethics focuses upon our intuitions. Neuroscience, its proponents hold, shows that our moral intuitions are systematically unreliable, either in general or in some particular circumstances.