The Ferrier Lecture 1998. The molecular biology of consciousness investigated with genetically modified mice

The question is raised of the relevance of experimental work with the mouse and some of its genetically modified individuals in the study of consciousness. Even if this species does not go far beyond the level of 'minimal consciousness', it may be a useful animal model to examine the elementary building blocks of consciousness using the methods of molecular biology jointly with investigations at the physiological and behavioural levels. These building blocks which are anticipated to be universally shared by higher organisms (from birds to humans) may include: (i) the access to multiple states of vigilance, like wakefulness, sleep, general anaesthesia, etc.; (ii) the capacity for global integration of several sensory and cognitive functions, together with behavioural flexibility resulting in what is referred to as exploratory behaviour, and possibly a minimal form of intentionality. In addition, the contribution of defined neuronal nicotinic receptors species to some of these processes is demonstrated and the data discussed within the framework of recent neurocomputational models for access to consciousness.     

Consciousness is Cheap, Even if Symbols are Expensive; Metabolism and the Brain’s Dark Energy

Use of symbols, the key to the biosemiotics field as to many others, required bigger brains which implied a promissory note for greater energy consumption; symbols are obviously expensive. A score years before the current estimate of 18–20% for the human brain’s metabolic demand on the organism, it was known that neural tissue is metabolically dear. This paper first discusses two evolutionary responses to this demand, on both of which there is some consensus. The first, assigning care of altricial infants with burgeoning brains (and in human infants the metabolic demand peaks at 65% of the total) to “allomothers” is not unique to humans. The second, using relatively small neurons as primates do, risks misfires past a certain minimal value. Moreover, in apparent paradox, there is an increasing consensus that large “Von Economo” neurons are critical for communication. This paper’s main contribution is the discussion of two further evolutionary tricks. The first is the use of self-similarity in the cortex, both in structure and process, to allow the cortex readily—and in energetic terms, parsimoniously—to shift between states in a high-dimensional space. This leads to discussion of the kind of formalism appropriate to model these shifts, a formalism which—it is tentatively suggested—may do double duty for the modeling of symbolic thought. The second trick is the superimposition on the background “white noise” of neural firing of EEG-detected waves like gamma. The paper describes a method, using the Hilbert transform, of calculating the dips in energy consumption as the brain is transitioned by gamma waves. It is hypothesized that consciousness may be a spandrel, the incidental result of a neurodynamic imperative that the brain enter a maximally sensitive (in sensory terms) “zero power” state a few times a second. If that is the case, then there are obvious benefits for health in meditation, which can be viewed as a state of consciousness extended over time by limiting afferent stimuli.     

Quantum-like formalism for cognitive measurements

We develop a quantum formalism (Hilbert space probabilistic calculus) for measurements performed over cognitive systems. In particular, this formalism is used for mathematical modelling of the functioning of consciousness as a self-measuring quantum-like system. By using this formalism, we could predict averages of cognitive observables. Reflecting the basic idea of neurophysiological and psychological studies on a hierarchic structure of cognitive processes, we use p-adic hierarchic trees as a mathematical model of a mental space. We also briefly discuss the general problem of the choice of an adequate mental geometry.     

Identification of dermcidin in human gestational tissue and characterization of its proteolytic activity

Dermcidin (DCD) is a gene for an antimicrobial peptide DCD-1 in human sweat glands. It has become evident that the gene products of DCD exhibit a wide range of biological functions. In addition to its antimicrobial function, it is reported to be a neuronal survival factor, a putative oncogene in breast cancer and a proteolysis-inducing factor (PIF) that induces skeletal muscle proteolysis to cause cancer cachexia. Here we identified DCD in human placental tissue and determined its previously uncharacterized proteolytic activity. We also show that recombinant DCD induced an invasive phenotype in a human choriocarcinoma cell line JAR in vitro. This work suggests that DCD might participate in the regulation of placental function by means of modulating the proteolytic cascades on the trophoblastic cell surface, and might be involved in the pathophysiology of pregnancy-related disorders, as well as cancer and neuronal diseases.     

Subcellular distribution of biopterin in rat brain: the biochemical basis of its stability

Rat brain biopterin, the hydroxylase cofactor, was observed to distribute equally across regional subcellular fractions, rather than to codistribute neuronally with tyrosine and tryptophan hydroxylases for which it functions. Over a 24 h period with light/dark phasing, which some groups have shown to result in cycling of biopterin levels in striate and certain other regions, only the biopterin associated with the crude nuclear fraction of the striate (not associated with neurotransmitter synthesis) demonstrated a diurnal cycle. The selectivity of this perturbation response to the striate nuclear fraction suggests that (1) multiple subcellular loci of biopterin might exist independently in rat brain neurons and (2) the pterin's availability for neurotransmitter biosynthesis is limited beyond its apparent regional concentration. The demonstration of multiple independent sources of neuronal biopterin may be relevant to understanding why regional levels have been so resistant to efforts at pharmacological manipulation (only amphetamine and CRF have changed striate biopterin levels). It also shows that changes in regional hydroxylase cofactor levels may not be related to neurotransmitter synthesis, but instead may result from another presently unknown demand for the cofactor at a disparate neuronal site.     

Pareto optimality,economy–effectiveness trade-offs and ion channel degeneracy: improving population modelling for single neurons

Neurons encounter unavoidable evolutionary trade-offs between multiple tasks. They must consume as little energy as possible while effectively fulfilling their functions. Cells displaying the best performance for such multi-task trade-offs are said to be Pareto optimal, with their ion channel configurations underpinning their functionality. Ion channel degeneracy, however, implies that multiple ion channel configurations can lead to functionally similar behaviour. Therefore, instead of a single model, neuroscientists often use populations of models with distinct combinations of ionic conductances. This approach is called population (database or ensemble) modelling. It remains unclear, which ion channel parameters in the vast population of functional models are more likely to be found in the brain. Here we argue that Pareto optimality can serve as a guiding principle for addressing this issue by helping to identify the subpopulations of conductance-based models that perform best for the trade-off between economy and functionality. In this way, the high-dimensional parameter space of neuronal models might be reduced to geometrically simple low-dimensional manifolds, potentially explaining experimentally observed ion channel correlations. Conversely, Pareto inference might also help deduce neuronal functions from high-dimensional Patch-seq data. In summary, Pareto optimality is a promising framework for improving population modelling of neurons and their circuits.     

A simulation of the effect of inbreeding on crop domestication genetics with comments on the integration of archaeobotany and genetics: a reply to Honne and Heun

Archaeobotanical evidence for Near Eastern einkorn wheat, barley, and Chinese rice suggests that the fixation of key domestication traits such as non-shattering was slower than has often been assumed. This suggests a protracted period of pre-domestication cultivation, and therefore implies that both in time and in space the initial start of cultivation was separated from eventual domestication, when domesticated and wild populations would have become distinct gene pools. Archaeobotanical evidence increasingly suggests more pathways to cultivation than are represented by modern domesticated crop lines, including apparent early experiments with cultivation that did not lead to domestication, and early domesticates, such as two-grained einkorn and striate-emmeroid wheats, which went extinct in prehistory. This diverse range of early crops is hard to accommodate within a single centre of origin for all early Near Eastern cultivars, despite suggestions from genetic datasets that single origins from a single centre ought to be expected. This apparent discrepancy between archaeobotany and genetics highlights the need for modelling the expected genetic signature of different domestication scenarios, including multiple origins. A computer simulation of simple plant populations with 20 chromosomes was designed to explore potential differences between single and double origins of domesticated populations as they might appear in genomic datasets millennia later. Here we report a new simulation of a self-pollinating (2% outbreeding) plant compared to panmictic populations, and find that the general outcome is similar with multiple starts of cultivation drifting towards apparent monophyly in genome-wide phylogenetic analysis over hundreds of generations. This suggests that multiple origins of cultivation of a given species may be missed in some forms of modern genetic analysis, and it highlights the need for more complex modelling of population genetic processes associated with the origins of agriculture.     

Alzheimer's disease amyloid β-protein mutations and deletions that define neuronal binding/internalization as early stage nonfibrillar/fibrillar aggregates and late stage fibrils

Accumulation of amyloid β-protein (Aβ) in neurons has been demonstrated to precede its formation as amyloid plaques in the extracellular space in Alzheimer's disease (AD) patients. Consequently, intraneuronal Aβ accumulation is thought to be a critical first step in the fatal cascade of events that leads to neuronal degeneration in AD. Understanding the structural basis of neuronal binding and uptake of Aβ might lead to potential therapeutic targets that could block this binding and the subsequent neurodegeneration that leads to the pathogenesis of AD. Previously, we demonstrated that mutation of the two adjacent histidine residues of Aβ40 (H13,14G) resulted in a significant decrease in its level of binding to PC12 cells and mouse cortical/hippocampal neurons. We now demonstrate that the weakened neuronal binding follows the mutation order of H13G < H14G < H13,14G, which suggests that the primary domain for neuronal binding of Aβ40 involves histidine at position 13. A novel APP mutation (E693Δ) that produced a variant Aβ lacking glutamate 22 (E22Δ) in Japanese pedigrees was recently identified to have AD-type dementia without amyloid plaque formation but with extensive intraneuronal Aβ in transfected cells and transgenic mice expressing this deletion. Deletion of glutamate 22 of Aβ40 resulted in a 6-fold enhancement of PC12 neuronal binding that was not decreased by the H13G mutation. The dose-dependent enhanced binding of E22Δ explains the high level of intraneuronal Aβ seen in this pedigree. Fluorescence anisotropy experiments at room temperature showed very rapid aggregation with increased tyrosine rigidity of Aβ39E22Δ, Aβ41E22Δ, and Aβ42 but not Aβ40. This rigidity was decreased but not eliminated by prior treatment with dimethyl sulfoxide. Surprisingly, all peptides showed an aggregated state when evaluated by transmission electron microscopy, with Aβ39E22Δ having early stage fibrils, which was also verified by atomic force microscopy. This aggregation was not affected by centrifugation or pretreatment with organic solvents. The enhanced neuronal binding of Aβ, therefore, results from aggregate binding to neurons, which requires H13 for Aβ40 but not for E22Δ or Aβ42. These latter proteins display increased tyrosine rigidity that likely masks the H13 residue, or alternatively, the H13 residue is not required for neuronal binding of these proteins as it is for Aβ40. Late state fibrils also showed enhanced neuronal binding for E22Δ but not Aβ40 with subsequent intraneuronal accumulation in lysosomes. This suggests that there are multiple pathways of binding/internalization for the different Aβ proteins and their aggregation states or fibrillar structure.     

I research,therefore I am?: A purely scientific understanding of consciousness remains elusive,but the search for its neurological foundation continues

The exploration of consciousness—the most elusive characteristic of human nature—has long been left to philosophers and artists. Using modern research tools, scientists have finally begun to subject the human mind to empirical analysis.Consciousness is the heart of human existence, yet it has proven to be an elusive subject for scientific research and analysis. Its study has largely been left to philosophers, writers and artists who have spent centuries exploring the meaning of life. Existential questions such as ‘why am I me?'' are, by their nature, difficult to answer with empirical analysis. It is therefore perhaps unsurprising that natural science has found it difficult to add detail to René Descartes general principle: cognito ergo sum. From some quarters—particularly religious ones—there has also been resistance to the ‘profane'' tools of science probing the ‘sacred heart'' of human consciousness; Pope John Paul II is reported to have proclaimed during a conference at the Vatican in the 1980s, that while scientists can have the brain, the mind belongs to God (Lane, 2009).Existential questions such as ‘why am I me?'' are, by their nature, difficult to answer with empirical analysisThe separation of mind and brain is fundamental to the study of consciousness, and requires elucidation of the relationship between the biological mechanisms of brain function and the higher-level processes—such as emotion or reason—that are enabled by them. Although the ultimate meaning of human existence remains elusive—assuming that there is one—research has begun to unravel the physical mechanisms that enable consciousness, by using brain imaging techniques together with an increasing understanding of the neuronal architecture of the brain. This approach has informed the quest to identify the neural correlates of consciousness (Crick & Koch, 1990) that were first defined by Christof Koch, Professor of Biology and Engineering at the California Institute of Technology, and Francis Crick, who is better known for his codiscovery of the DNA double helix. These correlates are defined as the minimal set of neuronal mechanisms required for a particular conscious function or ability. Their identification would be useful for assessing levels of consciousness in animals, infants and adults with brain damage or disease, who are unable to express what they are feeling in words.Koch explained that although neuronal mechanisms are necessary for consciousness, it is the information that they transmit and integrate that actually brings it into being; an idea that was first advanced by Giulio Tononi (2004), to which Koch has contributed. This theory, according to Koch, states that consciousness depends on the ability to coherently integrate information, irrespective of the information type. This has important implications: that consciousness is independent of language, vision or any other specific form of information, and can exist in any system with the required structure. From this, Koch has concluded that consciousness is not limited to humans, but could exist in a machine and many animals—a view that has led him to become a vegetarian. According to this theory, aspects of recent human evolution and culture—including language—are products of consciousness, rather than requirements for it.According to Naomi Eilan, Director of the Consciousness and Self-Consciousness Research Centre at the University of Warwick, UK, the information flows and synchronization that enable consciousness are nevertheless dependent on the physical structure of the brain. “It''s mad to think that consciousness and the brain are independent [of one another],” she said. The extent of their interdependence, however, is hotly debated. According to Eilan, scientists generally take one of three positions on the subject: “[O]ne view [is that] the brain will tell us what consciousness is, but at the other [extreme] there''s the view that it''s neither here nor there and that the brain is one thing and consciousness quite another. I''m in the middle, where the brain presupposes consciousness but does not explain it. The brain will not tell you what consciousness is, but it does tell us how various aspects of it work.”…consciousness is independent of language, vision or any other specific form of information, and can exist in any system with the required structureIn evolutionary terms, consciousness is a phenotype with an underlying genotype. It is therefore subject to the pressures of natural selection, which act at the level of the genes encoding neurological structures. These structures probably first emerged in animals for specific functions and only later became integrated into a universal continuous consciousness, according to Antonio Damasio, Director of the Brain and Creativity Institute at the University of Southern California, Los Angeles, USA. “I believe most of the phenomena of consciousness emerged as a result of specific brain complexities which were required by an improved life regulation,” he said. “But once basic consciousness emerged, its adaptive value was so remarkable that natural selection made it prevail.”​Open in a separate window© MedicalRF.com/CorbisIt is now almost universally agreed that consciousness is linked to the coherence of the electrical states of different groups of neurons, but the mechanisms underlying this are still disputed. Some researchers, such as the American psychologist Stuart Hameroff, argue that quantum mechanics must be involved through a phenomenon known as quantum coherence, which would correlate the states of subatomic particles across the brain (Hameroff, 1994). This hypothesis is questioned by others, but consciousness does seem to be generated by synchronized oscillations in the electrical states of neurons in different areas of the brain, as detected by electroencephalography.…aspects of recent human evolution and culture—including language—are products of consciousness, rather than requirements for itFor electrical coherence to occur, structures that can synchronize disparate brain regions must have evolved at some stage. Prime candidates are the calcium-binding (calbindin) positive cells in the thalamus—a structure that relays signals relating to spatial and motor awareness between the cerebral cortex and midbrain, as well as regulating sleep and alertness. Calbindin proteins modulate the flow of calcium within neurons, affecting synaptic activity and neuronal activation. The calbindin positive cells in the thalamus can thereby facilitate high-frequency oscillations in different regions of the cortex (Joliot et al, 1994). According to Koch, such cells might be crucial messengers for consciousness, enabling effective interactions between different cortical regions. In support of this, when calbindin positive thalamic cells lose their ability to activate other neurons—as a result of injury or disease—these patients are in a vegetative state even when their cortical tissue is intact.The above observation is an example of how the study of brain-damaged patients can shed light on the underlying mechanisms of consciousness. It also led to the development of a possible treatment for such patients. Niko Schiff and colleagues found that deep-brain electrical stimulation of the central thalamus restored some behavioural responsiveness in a patient who had been minimally conscious for 6 years (Schiff et al, 2007).In evolutionary terms, consciousness is a phenotype with an underlying genotypeSudden recovery from prolonged states of minimal consciousness can also indicate which structures of the brain are required for normal states of awareness and activity. A study by Henning Voss and colleagues in New York and New Zealand found evidence that axonal regrowth led to the dramatic recovery of speech in a patient who had been in a minimally conscious state for 19 years after a road accident in 1984 (Voss et al, 2006). Axonal regrowth was shown by use of a new imaging technique, Diffusion Tensor Imaging (DTI), as the patient quickly regained the ability to talk with increasing fluency over a period of a few days. DTI is a form of magnetic resonance imaging (MRI) that forms images by observing the Brownian motion of water molecules. It showed axons sprouting from neurons in the intact part of the cortex. Further evidence came from positron emission tomography scans of the same brain areas, showing increased glucose metabolism that seemed to be linked with the neuronal regrowth, which would explain the patient''s recovery.Sudden recovery from prolonged states of minimal consciousness can also indicate which structures of the brain are required for normal states of awareness and activityKoch noted that this and other neuroimaging studies of vegetative state or minimally conscious patients have found that even a prolonged loss of consciousness can be reversed. Another important question is whether consciousness can be detected when patients are in a persistent vegetative state and cannot communicate verbally or by movement. Observing responses to stimuli in specific brain areas is not sufficient to assess the level of consciousness, as these reactions can occur without consciousness, as they do during sleep.To address this question, Adrian Owen and colleagues in the UK and Belgium conducted an ingenious experiment with a female patient who was incapable of responding to external stimuli. The researchers asked the patient to imagine playing tennis while they observed her in an MRI scanner. They found that the same cortical areas were activated as when normal individuals perform the same task (Owen et al, 2006). Koch points out that the task could not have been performed by unconscious processing of external stimuli, as the patient was only imagining the action.This result does not conclusively show that the patient was conscious, as the neural correlates of thought processes remain unclear. However, the above observation suggests that the patient might be more than minimally conscious, as she had been diagnosed. Owen''s colleague, Steven Laureys, has since been involved in several studies indicating that almost half of people with disorders of consciousness are wrongly diagnosed as being in a vegetative state. According to Laureys, these findings might indicate that some patients have had their life support turned off as a result of such misdiagnoses, even though they could have subsequently regained consciousness, to some extent.At present, this suggestion is controversial and does no more than provide a source of acute uncertainty for the families and doctors of such patients. In future, however, brain imaging could help clinicians to make more accurate diagnoses. In one of the most striking examples so far, Christine Ecker and colleagues at King''s College and University College, London, UK, have identified characteristic structural features of the brain that can be used to reliably diagnose autism spectrum disorder (ASD; Ecker et al, 2010). They used MRI to measure certain brain features in patients with ASD—such as the thickness and degree of folding in particular areas of the cortex—and combined this information to obtain a correlate picture of the brain changes that are unique to ASD. This was an important development, as ASD is complex and associated with many cortical features that have previously been difficult to categorize. By using this new approach, ASD can now be clearly distinguished from other conditions and accurate, rapid diagnosis in early life could make a notable difference for sufferers.“the study of consciousness is now moving from the domain of philosophy and metaphysics into the empirical domain of science”This work might also guide research on the genetic and neurological bases of ASD, by identifying the anatomical features and ultimately individual proteins that are implicated in the disorder. Some of the cortical regions involved seem to be unique, which resonates with more general research into various aspects of consciousness.This type of applied research into consciousness is at the opposite end of the spectrum to the ongoing attempts to unite the scientific and philosophical approaches to studying the subject. Indeed, as Koch noted, “the study of consciousness is now moving from the domain of philosophy and metaphysics into the empirical domain of science.”This move is creating the ultimate challenge for multidisciplinary research; it requires the interaction of two fields with little history or experience of collaboration. According to Bill Brewer, who specializes in the philosophy of perception at Warwick University, UK, “this is a massive philosophical question in itself: what is the relationship between philosophical and scientific approaches to mental phenomena in general and conscious experience in particular?” Brewer believes that such efforts will ultimately prove successful; “My own opinion, having been part of a number of interdisciplinary projects concerned with such matters, is that there is no general abstract recipe for fruitful collaboration. It requires long periods of open-minded mutual learning, teaching and open-ended discussion of very specific questions and issues in the various different fields until it eventually becomes clear that a good deal in the disciplinary boundaries is arbitrary and all parties are actually concerned with the same fundamental problems in ways that merge into a continuum of approaches.”Whether this will lead to a full understanding of consciousness and whether science has something to say about the ‘meaning'' of our existence remains to be seen.     

The impact of the glial spatial buffering on the K+ Nernst potential

Astrocytes play a critical role in CNS metabolism, regulation of volume and ion homeostasis of the interstitial space. Of special relevance is their clearance of K⁺ that is released by active neurons into the extracellular space. Mathematical analysis of a modified Nernst equation for the electrochemical equilibrium of neuronal plasma membranes, suggests that K⁺ uptake by glial cells is not only relevant during neuronal activity but also has a non-neglectable impact on the basic electrical membrane properties, specifically the resting membrane potential, of neurons and might be clinically valuable as a factor in the genetics and epigenetics of the epilepsy and tuberous sclerosis complex.     

Visual shape recognition with contour propagation

A neural architecture is presented that encodes the visual space inside and outside of a shape. The contours of a shape are propagated across an excitable neuronal map and fed through a set of orientation columns, thus creating a pattern which can be viewed as a vector field. This vector field is then burned as synaptic, directional connections into a propagation map, which will serve as a “shape map”. The shape map identifies its own, preferred input when it is translated, deformed, scaled and fragmented, and discriminates other shapes very distinctively. Encoding visual space is much more efficient for shape recognition than determining contour geometry only.     

Theory of Mind in Dreaming: Awareness of Feelings and Thoughts of Others in Dreams.

If the awareness of what others are thinking and the ability to attribute feelings to others characterizes both waking and dreaming consciousness, it suggests that a social species like man has a state-independent need for a theory of mind; that is, an ability to know that others have feelings. The authors performed 2 studies, the first of which consisted of 35 participants who submitted 320 dream reports containing more than 1,200 dream characters and the second consisted of 24 participants who submitted 151 dream reports with 543 dream events. Participants reported that as subjects in their own dreams they were aware that their dream characters had feelings and thoughts about them. This finding shows that awareness of what others are feeling is a robust aspect of consciousness that is maintained despite the changed chemistry and changed activation patterns of the brain's neuronal connections during dreaming. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Erythropoietin Increases Neuronal NDPKA Expression,and NDPKA Up-Regulation as well as Exogenous Application Protects Cortical Neurons from In Vitro Ischemia-Related Insults

Using proteomics, we identified nucleoside diphosphate kinase A (NDPKA; also known as NME/NM23 nucleoside diphosphate kinase 1: NME1) to be up-regulated in primary cortical neuronal cultures by erythropoietin (EPO) preconditioning. To investigate a neuroprotective role of NDPKA in neurons, we used a RNAi construct to knock-down and an adenoviral vector to overexpress the protein in cortical neuronal cultures prior to exposure to three ischemia-related injury models; excitotoxicity (l-glutamic acid), oxidative stress (hydrogen peroxide), and in vitro ischemia (oxygen-glucose deprivation). NDPKA down-regulation had no effect on neuronal viability following injury. By contrast, NDPKA up-regulation increased neuronal survival in all three-injury models. Similarly, treatment with NDPKA recombinant protein increased neuronal survival, but only against in vitro ischemia and excitotoxicity. These findings indicate that the NDPKA protein may confer a neuroprotective advantage following injury. Furthermore, as exogenous NDPKA protein was neuroprotective, it suggests that a cell surface receptor may be activated by NDPKA leading to a protective cell-signaling response. Taken together both NDPKAs intracellular and extracellular neuroprotective actions suggest that the protein is a legitimate therapeutic target for the design of drugs to limit neuronal death following stroke and other forms of brain injury.     

Fifty-one kilobase HSV-1 plasmid vector can be packaged using a helper virus-free system and supports expression in the rat brain

Herpes simplex virus type 1 (HSV-1) plasmid vectors have a number of attractive features for gene transfer into neurons. In particular, the large size of the HSV-1 genome suggests that HSV-1 vectors might be designed to accommodate large inserts. We now report the construction and characterization of a 51 kb HSV-1 plasmid vector. This vector was efficiently packaged into HSV-1 particles using a helper virus-free packaging system. The structure of the packaged vector DNA was verified by both Southern blot and PCR analyses. A vector stock was microinjected into the rat striatum, the rats were sacrificed at 4 days after gene transfer, and numerous X-gal positive striatal cells were observed. This 51 kb vector was constructed using general principles that may support the routine construction of large vectors. Potential applications of such HSV-1 vectors include characterizing large promoter fragments or genomic clones and co-expressing multiple genes.     

Dopamine-containing small intensely fluorescent cells and sympathetic ganglion function

This article reviews some of the neuropharmacology of the dopamine (DA)-containing small intensely fluorescent cells of sympathetic ganglia. The major metabolite of DA found in the ganglia is 3,4-dihydroxyphenylacetic acid (DOPAC). DOPAC content appears to be a direct reflection of DA synthesis. DA synthesis can be enhanced by muscarinic agonists and diminished by muscarinic antagonists. Neuroleptic drugs stimulate DA synthesis in the ganglion, which suggests that a local negative neuronal feedback loop might operate within the ganglion. There may be a correlation between deficient DA synthesis in spontaneous hypertensive rats and the development of hypertension. It is possible that some of the peripheral side effects of drugs that act on dopaminergic neurons in the brain might originate from the drugs' action on peripheral dopaminergic neuronal systems such as the sympathetic ganglion.     

Tau Aggregation in Alzheimer's Disease

The crucial role of the neuronal Tau protein in microtubule stabilization and axonal transport suggests that too little or too much Tau might lead to neuronal dysfunction. The presence of a hyper-phosphorylated but non-aggregated molecule as a toxic species that might sequester normal Tau is discussed. We present recent in vitro results that might allow to dissect the role of individual phosphorylation sites on its structure and function. We also discuss in this review the role of phosphorylation for the aggregation of the neuronal Tau protein, and compare it to the aggregation induced by external poly-anions.     

Fat tissue: an underappreciated source of stem cells for biotechnology

Adipose tissue can be harvested in large amounts with minimal morbidity. It contains numerous cells types, including adipocytes, preadipocytes, vascular endothelial cells and vascular smooth muscle cells; it also contains cells that have the ability to differentiate into several lineages, such as fat, bone, cartilage, skeletal, smooth, and cardiac muscle, endothelium, hematopoietic cells, hepatocytes and neuronal cells. Cloning studies have shown that some adipose-derived stem cells (ADSCs) have multilineage differentiation potential. ADSCs are also capable of expressing multiple growth factors, including vascular endothelial growth factor and hepatocyte growth factor. Early, uncontrolled, non-randomized clinical research, applying fresh adipose-derived cells into a cranial defect or undifferentiated ADSCs into fistulas in Crohn's disease, has shown healing and an absence of side effects. The combination of these properties, and the large quantity of cells that can be obtained from fat, suggests that this tissue will be a useful tool in biotechnology.