What the cognitive neurosciences mean to me

Cognitive Neuroscience is an interdisciplinary area of research that combines measurement of brain activity (mostly by means of neuroimaging) with a simultaneous performance of cognitive tasks by human subjects. These investigations have been successful in the task of connecting the sciences of the brain (Neurosciences) and the sciences of the mind (Cognitive Sciences). Advances on this kind of research provide a map of localization of cognitive functions in the human brain. Do these results help us to understand how mind relates to the brain? In my view, the results obtained by the Cognitive Neurosciences lead to new investigations in the domain of Molecular Neurobiology, aimed at discovering biophysical mechanisms that generate the activity measured by neuroimaging instruments. In this context, I argue that the understanding of how ionic/molecular processes support cognition and consciousness cannot be made by means of the standard reductionist explanations. Knowledge of ionic/molecular meclianisms can contribute to our understanding of the human mind as long as we assume an alternative form of explanation, based on psycho-physical similarities, together with an ontological view of mentality and spirituality as embedded in physical nature (and not outside nature, as frequently assumed in western culture).

From ab initio quantum mechanics to molecular neurobiology: A cation–π binding site in the nicotinic receptor

The nicotinic acetylcholine receptor is the prototype ligand-gated ion channel. A number of aromatic amino acids have been identified as contributing to the agonist binding site, suggesting that cation–π interactions may be involved in binding the quaternary ammonium group of the agonist, acetylcholine. Here we show a compelling correlation between: (i) ab initio quantum mechanical predictions of cation–π binding abilities and (ii) EC50 values for acetylcholine at the receptor for a series of tryptophan derivatives that were incorporated into the receptor by using the in vivo nonsense-suppression method for unnatural amino acid incorporation. Such a correlation is seen at one, and only one, of the aromatic residues—tryptophan-149 of the α subunit. This finding indicates that, on binding, the cationic, quaternary ammonium group of acetylcholine makes van der Waals contact with the indole side chain of α tryptophan-149, providing the most precise structural information to date on this receptor. Consistent with this model, a tethered quaternary ammonium group emanating from position α149 produces a constitutively active receptor.

Elements of molecular neurobiology:instruction manual to 2r.e

Extensively updated, revised and illustrated this unique introductory text presents a molecular account of the structure, function and development of the brain and nervous systems. This book describes the latest research in neurobiology made possible by modern molecular biology techniques. The author synthesizes this new knowledge and demonstrates how an understanding at the molecular level can contribute towards a theory of the brain in health and disease.

Origins of molecular neurobiology:The role of the physicists

The revolution in the foundations of physics at the beginning of the twentieth century suggested to several of its most prominent workers that biology was ripe for something similar. In consequence, a number of physicists moved into biology. They were highly influential in initiating a molecular biology in the 1950s. Two decades later it seemed to several of these migrants, and those they had influenced, that the major problems in molecular biology had been solved, and that it was time to move on to what seemed to them the final problem: the nervous system, consciousness, and the age-old mind-body problem. This paper reviews this "double migration" and shows how the hopes of the first generation of physicist-biologists were both realized and dashed. No new physical principles were discovered at work in the foundations of biology or neuroscience. On the other hand, the mind-set of those trained in physics proved immensely valuable in analyzing fundamental issues in both biology and neuroscience. It has been argued that the outcome of the molecular biology of the 1950s was a change in the concept of the gene from that of "a mysterious entity into that of a real molecular object" (Watson, 1965, p.6); the gates and channels which play such crucial roles in the functioning of nervous systems have been transformed in a similar way. Studies on highly simplified systems have also opened the prospect of finding the neural correlatives of numerous behaviors and neuropathologies. This increasing understanding at the molecular level is invaluable not only in devising rational therapies but also, by defining the material substrate of consciousness, in bringing the mind-body problem into sharper focus. Copyright © Taylor & Francis Inc.

Elements of molecular neurobiology

This edition of the popular text incorporates recent advances in neurobiology enabled by modern molecular biology techniques. Understanding how the brain works from a molecular level allows research to better understand behaviours, cognition, and neuropathologies. Since the appearance six years ago of the second edition, much more has been learned about the molecular biology of development and its relations with early evolution. This "evodevo" (as it has come to be known) framework also has a great deal of bearing on our understanding of neuropathologies as dysfunction of early onset genes can cause neurodegeneration in later life. Advances in our understanding of the genomes and proteomes of a number of organisms also greatly influence our understanding of neurobiology. This book will be of particular interest to biomedical undergraduates undertaking a neuroscience unit, neuroscience postgraduates, physiologists, pharmacologists. It is also a useful basic reference for university libraries.

Elements of molecular neurobiology

Extensively updated, revised and illustrated this unique introductory text presents a molecular account of the structure, function and development of the brain and nervous systems. This book describes the latest research in neurobiology made possible by modern molecular biology techniques. The author synthesizes this new knowledge and demonstrates how an understanding at the molecular level can contribute towards a theory of the brain in health and disease.

Elements of molecular neurobiology

The 1980s have seen spectacular advances in our understanding of the molecular bases of neurobiology. Biological membranes, channel proteins, cytoskeletal elements, and neuroactive peptides have all been illuminated by the molecular approach. The operation of synapses can be seen to be far more subtle and complex than has previously been imagined, and the development of the brain and physical basis of memory have both been illuminated by this new understanding. In addition, some of the ways in which the brain may go wrong can be traced to malfunction at the molecular level. This study attemps a synthesis of this new knowledge, to provide an indication of how an understanding at the molecular level can help towards a theory of the brain in health and disease. The text will be of benefit to undergraduate students of biochemistry, medical science, pharmacy, pharmacology and general biology.

Biomolecular information, brain activity and cognitive functions

Molecular neurobiology has provided an explanation of mechanisms supporting mental functions as learning, memory, emotion and consciousness. However, an explanatory gap remains between two levels of description: molecular mechanisms determining cellular and tissue functions, and cognitive functions. In this paper we review molecular and cellular mechanisms that determine brain activity, and then hypothetize about their relation with cognition and consciousness. The brain is conceived of as a dynamic system that exchanges information with the whole body and the environment. Three explanatory hypotheses are presented, stating that: a) brain tissue function is coordinated by macromolecules controlling ion movements, b) structured (amplitude, frequency and phase-modulated) local field potentials generated by organized ionic movement embody cognitive information patterns, and c) conscious episodes are constructed by a large-scale mechanism that uses oscillatory synchrony to integrate local field patterns. © by São Paulo State University.

Peripheral brain-derived neurotrophic factor levels in alzheimer's disease and mild cognitive impairment: A comprehensive systematic review and meta-analysis

Alzheimer's disease (AD) is becoming a growing global problem, and there is an urgent need to identify reliable blood biomarkers of the risk and progression of this condition. A potential candidate is the brain-derived neurotrophic factor (BDNF), which modulates major trophic effects in the brain. However, findings are apparently inconsistent regarding peripheral blood BDNF levels in AD patients vs. healthy people. We thus performed a systematic review and meta-analysis of the studies that have examined peripheral BDNF levels in patients with AD or mild cognitive impairment (MCI) and healthy controls. We searched articles through PubMed, EMBASE, and hand searching. Over a total pool of 2061 potential articles, 26 met all inclusion criteria (including a total of 1584 AD patients, 556 MCI patients, and 1294 controls). A meta-analysis of BDNF levels between early AD and controls showed statistically significantly higher levels (SMD [95 % CI]: 0.72 [0.31, 1.13]) with no heterogeneity. AD patients with a low (<20) mini-mental state examination (MMSE) score had lower peripheral BDNF levels compared with controls (SMD [95 % CI]: -0.33 [-0.60, -0.05]). However, we found no statistically significant difference in blood (serum/plasma) BDNF levels between all AD patients and controls (standard mean difference, SMD [95 % CI]: -0.16 [-0.4, 0.07]), and there was heterogeneity among studies (P < 0.0001, I 2 = 85.8 %). There were no differences in blood BDNF levels among AD or MCI patients vs. controls by subgroup analyses according to age, sex, and drug use. In conclusion, this meta-analysis shows that peripheral blood BDNF levels seem to be increased in early AD and decreased in AD patients with low MMSE scores respectively compared with their age- and sex-matched healthy referents. At present, however, this could not be concluded from individual studies.

Efeitos de relevância versus repetição de estímulo lingüístico na indução da memória declarativa

In the LTP (Long-Term Potentiation) model of learning and memory formation, elaborated in the context of molecular neurobiology, the opening of NMDA (N-Metyl-D-Aspartate) channels to entry of calcium ions into the post-synaptic neuron depends on two excitatory events: the repeated activation of the post-synaptic neuron by only one pre-synaptic neuron (Alternative 1), or its concomitant activation by two or more pre-synaptic neurons (Alternative 2). With the purpose of testing these alternatives, in the context of Cognitive Psychology, we presented to 73 university students a sequence of slides, with the duration of 6 seconds each, containing sentences (one for each slide) considered as being relevant or irrelevant for the subjects. Relevant sentences (R1) were presented only one time, while irrelevant ones were divided in three groups: the first one with sentences presented only one time (I1), the second with sentences presented three times (I3) and the third with sentences presented five times (I5). We conjectured that relevant sentences presented only one time would mobilize two or more brain excitatory pathways (corresponding to Alternative 2 above), while repeated irrelevant sentences would progressively activate the same sensory pathway. After the presentation of the sentences, the subjects answered a written questionnaire with questions about each presented sentence. The results indicate a prevalence of correct answers to R1 over I1, I3 and I5, suggesting that the relevance factor has greater weight than repetition in the induction of declarative memories

Caspase-3 mediates in part hippocampal apoptosis in sepsis

The brain is one of the first organs affected during sepsis development resulting in apoptosis for a short-term and cognitive impairment for a long-term. Despite its importance, the mechanisms of brain dysfunction during sepsis are not fully elucidated. Thus, we here, in an animal model of sepsis, evaluated apoptosis in the dentate gyrus cell layer of the hippocampus to document the involvement of caspase-3 in the pathogenesis of neuronal apoptosis. Wistar rats sham-operated or submitted to the cecal ligation and perforation (CLP) procedure were killed at 12, 24, 48 h, and 10 days after surgery for the determination of caspase-3 and apoptosis rate. In a separate cohort of animals, a caspase-3-specific inhibitor was administered and animals were killed at 12 h after sepsis. An increase in the number of apoptotic cells 12, 24, and 48 h by histopathological evaluations and an increase of caspase-3 apoptotic cells 12 and 24 h after sepsis induction were observed. The caspase-3 inhibitor decreases the number of apoptotic cells by histopathological evaluations but not by immunohistochemistry evaluations. Caspase-3 is involved in part in apoptosis in the dentate gyrus cell layer of the hippocampus in septic rats submitted by CLP.

Decreased EEG synchronization in Alzheimer's disease and mild cognitive impairment

The hypothesis of a functional disconnection of neuro-cognitive networks in patients with mild cognitive impairment (MCI) and Alzheimer Dementia was investigated using baseline resting EEG data. EEG databases from New York (264 subjects) and Stockholm (155 subjects), including healthy controls and patients with varying degrees of cognitive decline or Alzheimer Dementia were analyzed using Global Field Synchronization (GFS), a novel measure of global EEG synchronization. GFS reflects the global amount of phase-locked activity at a given frequency by a single number; it is independent of the recording reference and of implicit source models. Patients showed decreased GFS values in Alpha, Beta, and Gamma frequency bands, and increased GFS values in the Delta band, confirming the hypothesized disconnection syndrome. The results are discussed within the framework of current knowledge about the functional significance of the affected frequency bands.

Relación entre atrofia cortical difusa y desempeño cognitivo : estudio en población mayor de 60 años en un hospital universitario en la ciudad de Bogotá

El presente trabajo tuvo como objetivo evaluar la existencia de la relación entre la atrofia cortical difusa objetivada por neuroimagenes cerebrales y desempeños cognitivos determinados mediante la aplicación de pruebas neuropsicológicas que evalúan memoria de trabajo, razonamiento simbólico verbal y memoria anterógrada declarativa. Participaron 114 sujetos reclutados en el Hospital Universitario Mayor Méderi de la ciudad de Bogotá mediante muestreo de conveniencia. Los resultados arrojaron diferencias significativas entre los dos grupos (pacientes con diagnóstico de atrofia cortical difusa y pacientes con neuroimagenes interpretadas como dentro de los límites normales) en todas las pruebas neuropsicológicas aplicadas. Respecto a las variables demográficas se pudo observar que el grado de escolaridad contribuye como factor neuroprotector de un posible deterioro cognitivo. Tales hallazgos son importantes para determinar protocoles tempranos de detección de posible instalación de enfermedades neurodegenerativas primarias.

The role of the dopaminergic neurotrophin growth/differentiation factor-5 in the developing rat ventral midbrain

Growth differentiation factor-5 (GDF-5) is a member of the transforming growth factor-β superfamily, a family of proteins that play diverse roles in many aspects of cell growth, proliferation and differentiation. GDF-5 has also been shown to be a trophic factor for embryonic midbrain dopaminergic neurons in vitro (Krieglstein et al. 1995) and after transplantation to adult rats in vivo (Sullivan et al. 1998). GDF-5 has also been shown to have neuroprotective and neurorestorative effects on adult dopaminergic neurons in the substantia nigra in animal models of Parkinson’s disease (Sullivan et al. 1997, 1999; Hurley et al. 2004). This experimental evidence has lead to GDF-5 being proposed as a neurotrophic factor with potential for use in the treatment of Parkinson’s disease. However, it is not know if GDF-5 is expressed in the brain and whether it plays a role in dopaminergic neuron development. The experiments presented here aim to address these questions. To that end this thesis is divided into five separate studies each addressing a particular question associated with GDF-5 and its expression patterns and roles during the development of the rat midbrain. Expression of the GDF-5 in the developing rat ventral mesencephalon (VM) was found to begin at E12 and peak on E14, the day that dopaminergic neurons undergo terminal differentiation. In the adult rat, GDF-5 was found to be restricted to heart and brain, being expressed in many areas of the brain, including striatum and midbrain. This indicated a role for GDF-5 in the development and maintenance of dopaminergic neurons. The appropriate receptors for GDF-5 (BMPR-II and BMPR-Ib) were found to be expressed at high levels in the rat VM at E14 and BMPR-II expression was demonstrated on dopaminergic neurons in the E13 mouse VM. GDF-5 resulted in a three-fold increase in the numbers of dopaminergic neurons in cultures of E14 rat VM, without affecting the numbers of neurones or total cells. GDF-5 was found to increase the proportion of neurons that were dopaminergic. The numbers of Nurr1-positive cells were not affected by GDF-5 treatment, but GDF-5 did increase the numbers of Nurr1- positive cells that expressed tyrosine hydroxylase (TH). Taken together this data indicated that GDF-5 increases the conversion of Nurr1-positive, TH-negative cells to Nurr1-positive, TH-positive cells. In GDF-5 treated cultures, total neurite length, neurite arborisation and somal area of dopaminergic were all significantly increased compared to control cultures. Thus this study showed that GDF-5 increased the numbers and morphological differentiation of VM dopaminergic neurones in vitro. In order to examine if GDF-5 could induce a dopaminergic phenotype in neural progenitor cells, neurosphere cultures prepared from embryonic rat VM were established. The effect of the gestational age of the donor VM on the proportion of cell types generated from neurospheres from E12, E13 and E14 VM was examined. Dopaminergic neurons could only be generated from neurospheres which were prepared from E12 VM. Thus in subsequent studies the effect of GDF-5 on dopaminergic induction was examined in progentior cell cultures prepared from the E12 rat VM. In primary cultures of E12 rat VM, GDF-5 increased the numbers of TH-positive cells without affecting the proliferation or survival of these cells. In cultures of expanded neural progenitor cells from the E12 rat VM, GDF-5 increased the expression of Nurr1 and TH, an action that was dependent on signalling through the BMPR-Ib receptor. Taken together, these experiments provide evidence that GDF-5 is expressed in the developing rat VM, is involved in both the induction of a dopaminergic phenotype in cells of the VM and in the subsequent morphological development of these dopaminergic neurons