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In the CNS, fine processes of astrocytes often wrap around dendrites, axons and synapses, which provides an interface where neurons and astrocytes might interact. We have reported previously that selective Ca2+ elevation in astrocytes, by photolysis of caged Ca2+ by o-nitrophenyl-EGTA (NP-EGTA), causes a kainite receptor-dependent increase in the frequency of spontaneous inhibitory post-synaptic potentials (sIPSCs) in neighboring interneurons in hippocampal slices. However, tetrodotoxin (TTX), which blocks action potentials, reduces the frequency of miniature IPSCs (mIPSCs) in interneurons during Ca2+ uncaging by an unknown presynaptic mechanism. In this study we investigate the mechanism underlying the presynaptic inhibition. We show that Ca2+ uncaging in astrocytes is accompanied by a decrease in the amplitude of evoked IPSCs (eIPSCs) in neighboring interneurons. The decreases in eIPSC amplitude and mIPSC frequency are prevented by CPPG, a group II/III metabotropic glutamate receptor (mGluR) antagonist, but not by the AMPA/kainate and NMDA receptor antagonists CNQX/CPP. Application of either the group II mGluR agonist DCG IV or the group III mGluR agonist L-AP4 decreased the amplitude of eIPSCs by a presynaptic mechanism, and both effects are blocked by CPPG. Thus, activation of mGluRs mediates the effects of Ca2+ uncaging on mIPSCs and eIPSCs. Our results indicate that Ca2+-dependent release of glutamate from astrocytes can activate distinct classes of glutamate receptors and differentially modulate inhibitory synaptic transmission in hippocampal interneurons.
The level of glutathione (GSH) is often reduced in brains that are affected by neurodegeneration. It is not known, however, whether this is a cause or a consequence of the disease. Here we have examined the effects of GSH depletion on the viability of human neurons cultured in either the presence or the absence of astrocytes, both derived from NT2/D1 cells. We established that the endogenous concentration of GSH is 10 times lower in neurons than in astrocytes (1.42 versus 18.9 pmol µg protein−1) and that pure neuronal cultures begin to die by apoptosis within 24 h of GSH depletion. By contrast, neurons that are co-cultured with astrocytes remain viable for several days, even with a profoundly decreased GSH content. However, they die rapidly when challenged additionally with nitrative stress. In addition, astrocytes survive for prolonged periods of time (>12 days) under severely reduced GSH concentrations. Our study shows clear differences in the content and sensitivity to depletion of GSH in neurons and astrocytes and establishes the significance of neuronal–glial interactions for the maintenance of neuronal viability under reduced GSH content. However, with chronic GSH depletion, these interactions might not be sufficient to protect neurons from other injurious factors (i.e. reactive oxygen and nitrogen species), which indicates that defective GSH metabolism might facilitate the progression of neurodegeneration.
During the past several years, there has been increasing interest in the effects of estrogen on neural function. This enthusiasm is driven, in part, by the results of early clinical studies suggesting that estrogen therapy given after menopause may prevent, or at least delay, the onset of Alzheimer's disease in older women. However, later clinical trials of women with probable Alzheimer's disease had contrary results. Much of the current research related to estrogen and brain function is focused in two directions. One involves clinical studies that examine the potential of estrogen in protecting against cognitive decline during normal aging and against Alzheimer's disease (neuroprotection). The other direction, which is the primary focus of this review, involves laboratory studies that examine the mechanisms by which estrogen can modify the structure of nerve cells and alter the way neurons communicate with other cells in the brain (neuroplasticity). In this review, we examine recent evidence from experimental and clinical research on the rapid effects of estrogen on several mechanisms that involve synaptic plasticity in the nervous system, including hippocampal excitability, long-term potentiation and depression related to sex and aging differences, cellular neuroprotection and probable molecular mechanisms of the action of estrogen in brain tissue.
Synapse formation in the CNS is a complex process that involves the dynamic interplay of numerous signals exchanged between pre- and postsynaptic neurons as well as perisynaptic glia. Members of the neurotrophin family, which are widely expressed in the developing and mature CNS and are well-known for their roles in promoting neuronal survival and differentiation, have emerged as key synaptic modulators. However, the mechanisms by which neurotrophins modulate synapse formation and function are poorly understood. Here, we summarize our work on the role of neurotrophins in synaptogenesis in the CNS, in particular the role of these signaling molecules and their receptors, the Trks, in the development of excitatory and inhibitory hippocampal synapses. We discuss our results that demonstrate that postsynaptic TrkB signaling plays an important role in modulating the formation and maintenance of NMDA and GABAA receptor clusters at central synapses, and suggest that neurotrophin signaling coordinately modulates these receptors as part of mechanism that promotes the balance between excitation and inhibition in developing circuits. We also discuss our results that demonstrate that astrocytes promote the formation of GABAergic synapses in vitro by differentially regulating the development of inhibitory presynaptic terminals and postsynaptic GABAA receptor clusters, and suggest that glial modulation of inhibitory synaptogenesis is mediated by neurotrophin-dependent and -independent signaling. Together, these findings extend our understanding of how neuron–glia communication modulates synapse formation, maintenance and function, and set the stage for defining the cellular and molecular mechanisms by which neurotrophins and other cell–cell signals direct synaptogenesis in the developing brain.
The brain is remarkably responsive to its interactions with the environment, and its morphology is altered by experience in measurable ways. Histological examination of the brains of animals exposed to either a complex (‘enriched’) environment or learning paradigm, compared with appropriate controls, has illuminated the nature of experience-induced morphological plasticity in the brain. For example, this research reveals that changes in synapse number and morphology are associated with learning and are stable, in that they persist well beyond the period of exposure to the learning experience. In addition, other components of the nervous system also respond to experience: oligodendrocytes and axonal myelination might also be permanently altered, whereas changes in astrocytes and cerebrovasculature are more transient and appear to be activity- rather than learning-driven. Thus, experience induces multiple forms of plasticity in the brain that are apparently regulated, at least in part, by independent mechanisms.
Neurogenesis, the generation of new neurons from neural precursor cells (NPCs), is a multi-step process that includes the proliferation of NPCs, fate determination, migration, and neuronal maturation. Neurogenesis is regulated by several extrinsic factors, such as enriched environment, physical exercise, hormones and stress, many of which also induce the expression of neurotrophins. In this review, we summarize studies on the role of neurotrophins in neurogenesis during development and in adults. We discuss the functional significance of neurogenesis in learning and memory, and how neurotrophins regulate this process. In this context, we describe recent experiments linking adult neurogenesis to long-term synaptic plasticity in the hippocampal dentate gyrus. Further study of the relationship between neurotrophins, adult neurogenesis and dentate synaptic plasticity might provide new insights into the mechanisms by which gene–environment interactions control cognition and brain plasticity.
By
Dai Rees, Fellow of the Royal Academy of Medicine, a Fellow of the Royal Society and a member of Academia Europea,
Barbro Westerholm, Professor of Drug Epidemiology Karolinska Institute, Director General of the Swedish National Board of Health and Welfare; Member of Parliament (Liberal Party) and Chairman of the Parliamentary Committtee on Research Ethics; President Swedish Association of Senior Citizens
Steven Rose began this book with a commentary on the spectacular advances in the neurosciences over recent years, the claims for their implications, and possible aspirations for the future. The chapters that followed have explained and explored many of these aspects in some detail. We now approach this concluding chapter with somewhat different perspectives because, unlike other authors, we have no personal distinction or first-hand knowledge in modern neuroscience or any of the cognate disciplines brought into the discussion such as philosophy, law or social sciences. We come from other areas of science, and from the oversight of medical research linked to issues of public interest and government policy. One of us (DR) has been more concerned with practical applications and industry, and the other (BW) with the parliamentary process and with public sensitivities to ethics and welfare. It is natural for us to look, as it were, down the other end of the telescope to ask questions not so much about neuroscience, philosophy, law, or social sciences in themselves, but about how the new developments might impact on everyday life.
The guided tour of the new brain sciences has certainly made us think again about humanity's understanding of itself and what this means for the norms and dynamics of social behaviour, for example how criminal responsibility should be decided in law; about the scope we already have through the use of drugs and which it seems will soon be greatly expanded by genetic engineering and stem cell technology, to redesign not only ourselves and our children but other people such as those that the politically powerful might think in need of ‘improvement’; and about the moral questions as to whether, if, how, and when, these new abilities may be used.
By
Hilary Rose, Feminist Sociologist of science; Professor Emerita of Social Policy University of Bradford; Visiting Professor of Sociology City University, London
Consciousness has recently become an immensely fashionable theme within the new-found cultural popularity of the natural sciences. However, what is immediately noticeable about the proliferation over the past decade of books and journals with ‘consciousness’ in their titles or invoked in their texts is that they seem to be drawn to the cultural glamour of the concept, but with little sense that the concept of consciousness has an entirely other history. Consciousness seems to lie around in the culture like a sparkling jewel irresistible to the neurotheorists. There seems to be no recognition amongst the many biologists, artificial intelligencers, physicists and philosophers who have played in print with their new toy that the concept of consciousness is part of other discourses. Above all I want to underline that while for these neurotheorists consciousness is located within the individual human organism – and sometimes just the brain within that – the older tradition, coming from the humanities and social theory, sees it as located in subjectivity and intersubjectivity within a historical context. As David Lodge (2002) has pointed out, novelists may approach consciousness more readily than neuroscientists. The methodological individualism expressed in the objectivist language of the natural sciences erases both ‘me’ and ‘you’; by contrast in social theory both agency and structure are crucial. For social theory there can be no development of individual consciousness without a social context.
By
Sir Dai Rees, Fellow of the Royal Academy of Medicine, a Fellow of the Royal Society and a member of Academia Europea,
Steven Rose, Professor of Biology and Director of the Brain and Behaviour Research Group The Open University, Walton Hall, Milton Keynes MK7 6AA, UK
By
Sir Dai Rees, Fellow of the Royal Academy of Medicine, a Fellow of the Royal Society and a member of Academia Europea,
Steven Rose, Professor of Biology and Director of the Brain and Behaviour Research Group The Open University, Walton Hall, Milton Keynes MK7 6AA, UK
In 1953, the same year in which he had operated on the brain of the famous amnesic H. M., the American neurosurgeon W. B. Scoville described the major achievements of contemporary neurosurgery, while at the same time disclosing his aspirations for the future:
We have isolated, by the ‘undercutting’ technique, the anterior cingulate gyrus and the posterior orbital cortex in a series of fractional lobotomies performed on schizophrenic and neurotic patients. More recently, we have both stimulated and resected bilaterally various portions of the rhinencephalon in carrying out medial temporal lobectomies on schizophrenic patients and certain epileptic patients … orbital isolation has given a most gratifying improvement in depression, psychoneuroses, and tension states … Who knows but that in future years neurosurgeons may apply direct selective shock therapy to the hypothalamus, thereby relegating psychoanalysis to that scientific limbo where perhaps it belongs? And who knows if neurosurgeons may even carry out selective rhinencephalic ablations in order to raise the threshold for all convulsions, and thus dispense with pharmaceutical anticonvulsants?
(Scoville, 1954).
One doesn't need to be a neuroanatomist, with a detailed understanding of these brain structures to appreciate the optimistic tone. These were, no doubt, the high days of psychosurgery. They began in the 1930s when the Portuguese neurologist Egas Moniz attempted to treat mental illness by severing neural tracts in the frontal cortex. The approach became astonishingly widespread, apparently not without support from the popular press. Moniz was even awarded the Nobel Prize in 1949 for developing it.
By
Stephen Sedley, Professor of Law Warwick University and the University of Wales at Cardiff; Judicial Visitor Warwick University and the University of Wales at Cardiff
When a defendant claims in an English court that his offence was not murder but manslaughter by reason of diminished responsibility, the judge has to explain to the jury that:
Where a person kills or is party to the killing of another, he shall not be convicted of murder if he was suffering from such abnormality of mind (whether arising from a condition of arrested or retarded development of mind or any inherent causes or induced by disease or injury) as substantially impaired his mental responsibility for his acts or omissions in doing or being a party to the killing.
This provision was introduced into the law of England and Wales by Act of Parliament in 1957. It had by then been part of the judge-made law of Scotland for many years. Both jurisdictions had also for centuries reduced murder to manslaughter in cases of provocation. Provocation too was recognised by Parliament in 1957, but its classic formulation, which judges are still required to use, was given to a jury by Lord Devlin as a trial judge in 1949:
Provocation is some act, or series of acts, done by the dead man to the accused which would cause in any reasonable person, and actually causes in the accused, a sudden and temporary loss of self-control, rendering the accused so subject to passion as to make him or her for the moment not master of his mind.
The preceding chapter described how developments in the knowledge and potencies of stem cells are now holding out the promise of transplantation replacement therapies to restore organ functions that have been damaged or diseased, for example in Parkinson's disease, various types of heart disease and diabetes. Since these developments are currently drawing significant attention not only from biologists but also from the media, ethicists, governments, politicians, and indeed the general public, this chapter will explore the ethical issues causing concern. For further explanation of concepts and terminology, the reader is referred back to the previous chapter.
Much of the current ethical and societal debate is about spare embryos ‘left over’ from in vitro fertilisation (IVF) procedures, and the even more revolutionary alternative of embryos created specifically for the purpose by transfer of a cell nucleus from the patient's mature tissue (for example the skin) to a donor egg from which the nucleus has been removed. Cells from the latter would be ‘autologous’ (meaning: from the same organism) with the patient, holding out the promise of eliminating or at least substantially reducing the problem of graft rejection which normally bedevils transplantation surgery. This would have important benefits, for example for the sensitive human brain in the treatment of patients suffering from neurological or neurodegenerative disorders and handicaps, by improving on its natural advantage of suffering less violent immune reactions than other organs.
This chapter considers the contributions that new biological research in the areas of behavioural genetics, brain anatomy and neurochemistry may make to our understanding of and responses to male violence against women as a public health problem. It also tests recent claims that the new biology can seek out and treat the dangerously femicidal and violence-prone.
FEMINISM AND THE PROBLEM OF FEMICIDE
‘Femicide’ is the ‘misogynous killing of women by men’ (Radford and Russell, 1992). The term points at the politics of woman killing at both the individual level and that of governance. It covers the many forms it takes – marital, stranger and serial killings as well as racist and homophobic killings of women. This said, however, most of the research discussed in this chapter homes in on either marital femicide (wife or partner killing, often called uxoricide) or the much rarer ‘lust driven’ serial killing of women by men. The rate of general homicide overall in England and Wales is relatively low – 15 per million of the population, with men showing higher rates of victimisation than women at all ages. On average 70% of homicide victims in England and Wales are males and 30% are females. Women less frequently kill and they are much more likely than are men to be killed by a partner. On average in England and Wales, two women are killed by male partners or ex-partners each week (Criminal Statistics, 2001).
As portrayed in pharmaceutical company advertisements, the typical nervous problems seen in both psychiatry and general practice from the 1960s through to the early 1990s took the form of an anxious woman in her twenties or early middle years. The exhortation was to treat her with benzodiazepines (such as Valium), marketed as tranquillisers. In contrast, during this period, advertisements for antidepressants typically featured much older women. However, in the 1990s young or middle-aged women with nervous problems were portrayed in the advertisements as depressed, with the exhortation to treat these problems with selective serotonin reuptake inhibiting (SSRI) antidepressants such as Prozac. By the end of the 1990s anxiety seemed all but forgotten by the advertisers. But, post 11 September 2001, the ‘typical’ woman is once again likely to be viewed as anxious, with exhortations to treat her with SSRI drugs, which seem now to have become anxiolytics. What is happening here? Are the biological bases of nervous problems really changing so quickly, or is this a matter of marketing of available new drugs, along with changes in nomenclature and fashion? There is arguably more to this than just a matter of changing fashions in the labels we put on nervous problems. In the past decade or so, pharmaceutical companies have developed abilities to change the very language we use to describe our most intimate experiences.
We are discovering more and more about human genotypes and about the connections between genotype and behaviour. Do these advances in genetic information threaten our free will? This chapter offers a philosopher's perspective on the question.
Whether or not genetic discoveries do really threaten free will, many feel threatened, and it is not difficult to see why. If genetic advances enable us to predict with increasing accuracy and reliability what people will do, this seems to undermine the pretensions of individual autonomy and agency. In what sense do I choose for myself what I do, if you can say reliably in advance what that choice will be?
The free will dilemma is a hardy philosophical perennial. After thousands of years of work there is still no generally accepted solution, no clear demonstration that free will really is possible. A philosopher may well wonder how new genetic knowledge could make things any worse, or indeed make things any different.
The sceptical dilemma and diminished responsibility
To see why a philosopher might suspect that genetic information could not possibly make the problem of free will any worse than it already is, we need to consider the classic free will dilemma, an argument with three very plausible premises and a depressing conclusion. First, everything that happens in the world is either determined or not. Second, if everything is determined, there is no free will.
By
Sir Dai Rees, Fellow of the Royal Academy of Medicine, a Fellow of the Royal Society and a member of Academia Europea,
Steven Rose, Professor of Biology and Director of the Brain and Behaviour Research Group The Open University, Walton Hall, Milton Keynes MK7 6AA, UK