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PubMed2001

Infants' detection of contingency: a cognitive-neuroscience perspective.

Advances in developmental cognitive neuroscience have generated important and interesting data that are relevant to infants' perception of contingencies. The author discusses concepts of "binding" (i.e., the binding of stimulus properties across space, and binding of events across time) within the context of the cognitive-neuroscience approach to learning. Issues relevant to infant contingency perception are also addressed. Previously published data on infant contingency perception and discrimination learning from the author's laboratory are reinterpreted in terms of these binding concepts, as well as the development of the neural substrates that presumably underlie the perception of stimulus attributes and temporal redundancy.

Association Learning↗
PubMed2005

Estimation of the cortical connectivity by high-resolution EEG and structural equation modeling: simulations and application to finger tapping data.

Today, the concept of brain connectivity plays a central role in the neuroscience. While functional connectivity is defined as the temporal coherence between the activities of different brain areas, the effective connectivity is defined as the simplest brain circuit that would produce the same temporal relationship as observed experimentally between cortical sites. The most used method to estimate effective connectivity in neuroscience is the structural equation modeling (SEM), typically used on data related to the brain hemodynamic behavior. However, the use of hemodynamic measures limits the temporal resolution on which the brain process can be followed. The present research proposes the use of the SEM approach on the cortical waveforms estimated from the high-resolution EEG data, which exhibits a good spatial resolution and a higher temporal resolution than hemodynamic measures. We performed a simulation study, in which different main factors were systematically manipulated in the generation of test signals, and the errors in the estimated connectivity were evaluated by the analysis of variance (ANOVA). Such factors were the signal-to-noise ratio and the duration of the simulated cortical activity. Since SEM technique is based on the use of a model formulated on the basis of anatomical and physiological constraints, different experimental conditions were analyzed, in order to evaluate the effect of errors made in the a priori model formulation on its performances. The feasibility of the proposed approach has been shown in a human study using high-resolution EEG recordings related to finger tapping movements.

Algorithms↗
PubMed2003

The neuroscience of recovery and rehabilitation: what have we learned from animal research?

OBJECTIVES: To encourage rehabilitation specialists to develop a critical approach to the animal research literature that is relevant to human neurorehabilitation and to encourage clinicians to lend their perspectives to basic research. ATA SOURCES: Scientific publications cited in MEDLINE, PubMed, and PsychInfo, and professional presentations of leading neuroscience researchers. The focus was on current publications to 2001, with historical works included when appropriate. STUDY SELECTION: Studies were selected based on their relevance to the objectives. DATA EXTRACTION: Reviewed study methodology and findings and extracted key principles relevant to rehabilitation. DATA SYNTHESIS: Many themes emerging from neuroscience research are relevant to human rehabilitation, including issues related to timing of intervention and recovery, and characteristics of nervous system plasticity. CONCLUSIONS: Although animal research has many limitations, it provides a unique window on nervous system recovery and has generated important directions for future human research. Clinician involvement in basic animal research will improve the extent to which results are relevant to human rehabilitation and recovery.

Animals↗
PubMed2003

Evaluation of common gene expression patterns in the rat nervous system.

In the postgenomic era, integrating data obtained from array technologies (e.g., oligonucleotide microarrays) with published information on eukaryotic genomes is beginning to yield biomarkers and therapeutic targets that are key for the diagnosis and treatment of disease. Nevertheless, identifying and validating these drug targets has not been a trivial task. Although a plethora of bioinformatics tools and databases are available, major bottlenecks for this approach reside in the interpretation of vast amounts of data, its integration into biologically representative models, and ultimately the identification of pathophysiologically and therapeutically useful information. In the field of neuroscience, accomplishing these goals has been particularly challenging because of the complex nature of nerve tissue, the relatively small adaptive nature of induced-gene expression changes, as well as the polygenic etiology of most neuropsychiatric diseases. This report combines published data sets from multiple transcript profiling studies that used GeneChip microarrays to illustrate a postanalysis approach for the interpretation of data from neuroscience microarray studies. By defining common gene expression patterns triggered by diverse events (administration of psychoactive drugs and trauma) in different nerve tissues (telencephalic brain areas and spinal cord), we broaden the conclusions derived from each of the original studies. In addition, the evaluation of the identified overlapping gene lists provides a foundation for generating hypotheses relating alterations in specific sets of genes to common physiological processes. Our approach demonstrates the significance of interpreting transcript profiling data within the context of common pathways and mechanisms rather than specific to a given tissue or stimulus. We also highlight the use of gene expression patterns in predictive biology (e.g., in toxicogenomics) as well as the utility of combining data derived from multiple microarray studies that examine diverse biological events for a broader interpretation of data from a particular microarray study.

Animals↗
PubMed2002

Loss of polysialic residues accelerates CNS neural precursor differentiation in pathological conditions.

Using the model of lysolecithin-induced demyelination of the corpus callosum in wild-type, NCAM-deficient, and endoneuraminidase-injected mice, we have analyzed the consequences of the loss of expression of NCAM or PSA residues on the migration and proliferation capacities of neural precursors of the subventricular zone (SVZ). We showed that the absence of PSA or NCAM delayed migration of neural precursors to the olfactory bulb and consequently enhanced their recruitment at the lesion site. Moreover, after demyelination, the lack of NCAM but not PSA promoted proliferation in the SVZ and the lesion while the lack of PSA favored the differentiation of the traced cells into the oligodendroglial fate both in the SVZ and in the lesion. As previously demonstrated in vitro (L. Decker et al., 2000, Mol. Cell. Neurosci. 16, 422-439), these data illustrate the involvement of PSA and NCAM in neural precursor motility and differentiation in the normal and injured central nervous system, suggesting distinct roles for these two molecules under pathophysiological conditions.

Animals↗
PubMed2006

Lesions of suprachiasmatic nucleus efferents selectively affect rest-activity rhythm.

The suprachiasmatic nucleus (SCN) of the hypothalamus controls circadian rhythms in behavioral, neuroendocrine and physiological functions. In this study, we test the hypothesis that caudal SCN efferents to the subparaventricular zone (SPVZ) control the rhythm in rest-activity (R-A) through projections on posterior hypothalamic area arousal systems (PHA). Small electrolytic lesions of the ventral SPVZ cause a selective loss of the circadian R-A rhythm, sparing the core body temperature rhythm. In contrast, large excitotoxic lesions of the posterior hypothalamic area (PHA) that effectively ablate populations of hypocretin and melanin concentrating hormone neurons projecting to cortex and subcortical arousal areas decrease R-A rhythm amplitude but do not disrupt circadian regulation. Since dorsomedial hypothalamic nucleus lesions have effects similar to PHA lesions (Chou, T.C., Scammell, T.E., Gooley, J.J., Gaus, S.E., Saper, C.B., Lu, J., 2003. Critical role of dorsomedial hypothalamic nucleus in a wide range of behavioral circadian rhythms. J. Neurosci. 23:10691-10702), these data support the view that the SPVZ is the principal relay nucleus for SCN signals to the multiple posterior hypothalamic arousal systems involved in generation of the R-A rhythm.

Activity Cycles↗
PubMed2005

The N-terminus of the norepinephrine transporter regulates the magnitude and selectivity of the transporter-associated leak current.

The norepinephrine (NE) transporter (NET) mediates the removal of NE from synaptic spaces and is a major target for antidepressants, amphetamine and cocaine. Previously, we have shown that syntaxin 1A (SYN 1A) supports human NET (hNET) cell surface expression, that hNET/SYN 1A interactions are direct and mediated by the hNET N-terminus, and that the hNET/SYN 1A association limits substrate-induced hNET-associated currents [Sung, U., Apparsundaram, S., Galli, A., Kahlig, K.M., Savchenko, V., Schroeter, S., Quick, M.W., Blakely, R.D., 2003. A regulated interaction of syntaxin 1A with the antidepressant-sensitive norepinephrine transporter establishes catecholamine clearance capacity. J. Neurosci. 23, 1697-1709]. These data raise the possibility that the hNET N-terminus, and potentially its interaction with SYN 1A, might regulate other hNET conductance states, including the hNET-mediated leak current. Importantly for monoamine transporters, the leak conductance has been shown to play a critical role in regulating cell membrane potential and possibly neuronal excitability [Quick, M.W., 2003. Regulating the conducting states of a mammalian serotonin transporter. Neuron 40, 537-549]. Here we demonstrate that deletion of the binding domain for SYN 1A in the NET N-terminus robustly enhances the NET-mediated leak current as well as its selectivity for Cl- permeation under particular intracellular ionic compositions. In addition, we show that the NET N-terminus coordinates the ability of intracellular Na+ and Cl- to regulate the leak conductance. These data suggest that the NET N-terminus regulates and defines the ionic specificity of the NET-mediated leak current.

Amino Acid Sequence↗
PubMed1999

Neuronal substrates participating in attentional set-shifting of rules for visually guided motor selection: a functional magnetic resonance imaging investigation.

To investigate the neuronal substrates participating in attentional set-shifting for motor selection rules, a functional magnetic resonance imaging study was performed during hand-shape selection tasks. During the session, six right-handed subjects were required to make one of three hand-shapes using their right hands, in response to the hand-shape images on a video screen, following one of the three predefined rules of win, lose, and tie. The selection rules were consistently applied in three conditions (win, tie, and lose), and changed alternately in one condition (alternate win-lose). Thus the alternate win-lose condition requires the shift of rules for motor selection. This alternate condition compared with the win, tie, and lose conditions showed activation in the left middle frontal gyrus, the bilateral inferior frontal gyri, and the left posterior fusiform and lingual gyri. These activation patterns in the prefrontal cortex were similar to those observed during the performance of the Wisconsin Card Sorting Test (WCST), which requires a typical set-shifting ability from one perceptual dimension to another (Berman et al., 1995. Neuropsychologia 33, 1027-1046; Nagahama et al., 1996. Brain 119, 1667-1675; Konishi et al., 1998. Nature Neuroscience 1, 80-84.). Our data may indicate that the dorsolateral prefrontal cortex including the middle and inferior frontal gyri are important in attentional set-shifting of both perceptual and non-perceptual characteristics. Another activation in the fusiform and lingual gyri may have reflected the increased attentional demand for visual processing in the light of a current rule for motor selection.

Adult↗
PubMedDate not supplied

Single-file diffusion and neurotransmitter transporters: Hodgkin and Keynes model revisited.

Norepinephrine transporters (NETs) use the Na gradient to remove norepinephrine (NE) from the synaptic cleft of adrenergic neurons following NE release from the presynaptic terminal. By coupling NE to the inwardly directed Na gradient, it is possible to concentrate NE inside cells. This mechanism, which is referred to as co-transport or secondary transport (Läuger, 1991, Electrogenic Ion Pumps, Sinauer Associates) is apparently universal: Na coupled transport applies to serotonin transporters (SERTs), dopamine transporters (DATs), glutamate transporters, and many others, including transporters for osmolites, metabolites and substrates such as sugar. Recently we have shown that NETs and SERTs transport norepinephrine or serotonin as if Na and the transmitter permeated through an ion channel together 'Galli et al., 1998, PNAS 95, 13260-13265; Petersen and DeFelice, 1999, Nature Neurosci. 2, 605-610'. These data are paradoxical because it has been difficult to envisage how NE, for example, would couple to Na if these ions move passively through an open pore. An 'alternating access' model is usually evoked to explain coupling: in such models NE and Na bind to NET, which then undergoes a conformational change to release NE and Na on the inside. The empty transporter then turns outward to complete the cycle. Alternating-access models never afford access to an open channel. Rather, substrates and co-transported ions are occluded in the transporter and carried across the membrane. The coupling mechanism we propose is fundamentally different than the coupling mechanism evoked in the alternating access model. To explain coupling in co-transporters, we use a mechanism first evoked by 'Hodgkin and Keynes (1955) J. Physiol. 128, 61-88' to explain ion interactions in K-selective channels. In the Hodgkin and Keynes model, K ions move single-file through a long narrow pore. Their model accounted for the inward/outward flux ratio if they assumed that two K ions queue within the pore. We evoke a similar model for the co-transport of transmitter and Na. In our case, however, coupling occurs not only between like ions but also between unlike ions (i.e. the transmitter and Na ). We made a replica of the Hodgkin and Keynes mechanical model to test our ideas, and we extended the model with computer simulations using Monte Carlo methods. We also developed an analytic formula for Na coupled co-transport that is analogous to the single-file Ussing equation for channels. The model shows that stochastic diffusion through a long narrow pore can explain coupled transport. The length of the pore amplifies the Na gradient that drives co-transport.

Computer Simulation↗
PubMed1997

The analysis of saccadic eye movements from gap and overlap paradigms.

This protocol describes the acquisition and evaluation of saccadic eye movement data for use in basic neuroscience research and clinical application. The experimental protocol requires the subject to make saccadic eye movements in response to visual stimuli presented, in random order, on consecutive trials. The gap and overlap paradigms are described together with the instruction to generate pro- or antisaccades. The protocol includes the description of saccade detection, the determination of the beginning, the end, the size, and the velocity of a saccade, the exact way of calculating the proportion of different kinds of trials, and the treatment of erratic or artifact trials. Relevant variables are defined. The results obtained from a large number (300) of subjects of different ages (8-65 years) are described and analysed with respect to their development with age. The protocol allows to test a subject's saccadic status in many different circumstances in particular with respect to diagnostic help in neurology, psychiatry and psychology.

Adolescent↗
PubMed2003

The automatic and controlled information-processing dissociation: is it still relevant?

The purpose of this paper is to examine the "dual-process" information-processing model of Schneider and Shiffrin (Schneider, W., and Shiffrin, R. M., Psychol. Rev. 84: 1-66, 1977; see also Shiffrin, R. M., and Schneider, W., Psychol. Rev. 84: 127-190, 1977) in light of the research data that have accumulated since the model was introduced more than 20 years ago. First, a brief introduction of the basic model of automatic and controlled information processing will be given. Second, some alternatives to the basic model that were developed over the last two decades will be reviewed. Third, data from neuropsychology and cognitive neuroscience that have a bearing upon this framework will be considered. Finally, some comments on the current usefulness of the dual-process framework for neuropsychological research will be offered.

Alzheimer Disease↗
PubMedDate not supplied

The sources of visual information to the primate frontal lobe: a novel role for the superior parietal lobule.

Reaching movements are performed in order to bring the hand to targets of interest. It is widely believed that the distributed cortical network underlying visual reaching transforms the information concerning the spatial location of the target into an appropriate motor command. Modern views decompose this process into sequences of coordinate transformations between informational domains. The set of cortical areas and pathways by which the information on target location is relayed from the visual areas of the occipital lobe to the motor areas of the frontal lobe have, so far, been poorly understood. Recent data from different fields of neuroscience offer the basis for a new definition of the cortical system subserving reaching and, at the same time, for a reconsideration of the nature of the underlying visuo-to-motor transformation.

Animals↗
PubMed2004

Stage-specific and opposing roles of BDNF, NT-3 and bFGF in differentiation of purified callosal projection neurons toward cellular repair of complex circuitry.

Cellular repair of neuronal circuitry affected by neurodegenerative disease or injury may be approached in the adult neocortex via transplantation of neural precursors ("neural stem cells") or via molecular manipulation and recruitment of new neurons from endogenous precursors in situ. A major challenge for potential future approaches to neuronal replacement will be to specifically direct and control progressive differentiation, axonal projection and connectivity of neural precursors along a specific neuronal lineage. This goal will require a progressively more detailed understanding of the molecular controls over morphologic differentiation of specific neuronal lineages, including neurite outgrowth and elongation, in order to accurately permit and direct proper neuronal integration and connectivity. Here, we investigate controls over the morphologic differentiation of a specific prototypical lineage of cortical neurons: callosal projection neurons (CPN). We highly enriched CPN to an essentially pure population, and cultured them at three distinct stages of development from embryonic and postnatal mouse cortex by retrograde fluorescence labelling, followed by fluorescence-activated cell sorting. We find that specific peptide growth factors exert direct stage-specific positive and negative effects over the morphologic differentiation and process outgrowth of CPN. These effects are distinct from the effects of these growth factors on CPN survival [Catapano et al. (2001)J. Neurosci., 21, 8863-8872]. These data may be critical for the future goal of directing lineage-specific neuronal differentiation of transplanted or endogenous precursors/"stem cells" toward cellular repair of complex cortical circuitry.

Aging↗
PubMed1998

H.M. revisited: relations between language comprehension, memory, and the hippocampal system.

Three studies tested the claim that H.M. exhibits a "pure memory deficit" that has left his ability to comprehend language unimpaired relative to memory-normal controls. In Study 1, H.M. and memory-normal controls of comparable intelligence, education, and age indicated whether sentences were ambiguous or unambiguous, and H. M. detected ambiguities significantly less often than controls. In Study 2, participants identified the two meanings of visually presented sentences that they knew were ambiguous, and relative to controls, H.M. rarely discovered the ambiguities without help and had difficulty understanding the first meanings, experimenter requests, and his own output. Study 3 replicated these results and showed that they were not due to brain damage per se or to cohort effects: Unlike H.M., a patient with bilateral frontal lobe damage detected the ambiguities as readily as young and same-cohort older controls. These results bear on two general classes of theories in use within a wide range of neurosciences and cognitive sciences: The data favor "distributed-memory theories" that ascribe H.M.'s deficit to semantic-level binding processes that are inherent to both language comprehension and memory, over "stages-of-processing theories," where H.M.'s defective storage processes have no effect on language comprehension.

Adult↗
PubMed2005

Memorization and association on a realistic neural model.

A central open question of computational neuroscience is to identify the data structures and algorithms that are used in mammalian cortex to support successive acts of the basic cognitive tasks of memorization and association. This letter addresses the simultaneous challenges of realizing these two distinct tasks with the same data structure, and doing so while respecting the following four basic quantitative parameters of cortex: the neuron number, the synapse number, the synapse strengths, and the switching times. Previous work has not succeeded in reconciling these opposing constraints, the low values of synapse strengths that are typically observed experimentally having contributed a particular obstacle. In this article, we describe a computational scheme that supports both memory formation and association and is feasible on networks of model neurons that respect the widely observed values of the four quantitative parameters. Our scheme allows for both disjoint and shared representations. The algorithms are simple, and in one version both memorization and association require just one step of vicinal or neighborly influence. The issues of interference among the different circuits that are established, of robustness to noise, and of the stability of the hierarchical memorization process are addressed. A calculus therefore is implied for analyzing the capabilities of particular neural systems and subsystems, in terms of their basic numerical parameters.

Algorithms↗
PubMed2005

An overlooked connection: serotonergic mediation of estrogen-related physiology and pathology.

BACKGROUND: In humans, serotonin has typically been investigated as a neurotransmitter. However, serotonin also functions as a hormone across animal phyla, including those lacking an organized central nervous system. This hormonal action allows serotonin to have physiological consequences in systems outside the central nervous system. Fluctuations in estrogen levels over the lifespan and during ovarian cycles cause predictable changes in serotonin systems in female mammals. DISCUSSION: We hypothesize that some of the physiological effects attributed to estrogen may be a consequence of estrogen-related changes in serotonin efficacy and receptor distribution. Here, we integrate data from endocrinology, molecular biology, neuroscience, and epidemiology to propose that serotonin may mediate the effects of estrogen. In the central nervous system, estrogen influences pain transmission, headache, dizziness, nausea, and depression, all of which are known to be a consequence of serotonergic signaling. Outside of the central nervous system, estrogen produces changes in bone density, vascular function, and immune cell self-recognition and activation that are consistent with serotonin's effects. For breast cancer risk, our hypothesis predicts heretofore unexplained observations of the opposing effects of obesity pre- and post-menopause and the increase following treatment with hormone replacement therapy using medroxyprogesterone. SUMMARY: Serotonergic mediation of estrogen has important clinical implications and warrants further evaluation.

Journal Article↗
PubMed2001

SB-277011 GlaxoSmithKline.

It is presumed that GlaxoSmithKline has taken over from SmithKline Beecham in investigating the highly selective dopamine D3 antagonist SB-277011 and its analogs for the potential treatment of schizophrenia [284490] following the merger of Glaxo Wellcome and SmithKline Beecham in December 2000 [394715]. In June 2000, it was reported that novel 2,3,4,5-tetrahydro-1H-benzazepines and 2,3-dihydro-1H-isoindoles, including SB-277011, had shown high affinity and selectivity for the dopamine D3 receptor. All compounds were suggested to have further potential roles in the treatment of drug abuse and psychosis [372205]. In November 2000, data presented at the 30th Neuroscience meeting in New Orleans, LA, demonstrated that D3 receptor blockade with SB-277011 specifically altered neurochemical effects in the nucleus accumbens without the non-selective effects, such as catalepsy, seen with some other antagonists [390460].

Animals↗
PubMed1992

The identification of a cis-acting element involved in cyclic 3',5'-adenosine monophosphate regulation of bovine vasopressin gene expression.

Cyclic adenosine 3',5'-monophosphate (cAMP) has been implicated as an intracellular messenger mediating osmotic regulation of expression of the gene encoding the neuropeptide vasopressin (VP) in the hypothalamus. We have used a heterologous transient transfection system to demonstrate that cAMP regulates the bovine VP gene promoter following transfection into CV1 cells. Mutational analysis identified a bovine VP cAMP-responsive element (BVP-CRE) 120-112 base-pairs upstream of the start of transcription. DNase I footprint analysis using nuclear protein extract from CV1 cells showed protection at the site of the BVP-CRE. Protection of the BVP-CRE was also observed using purified AP1 protein, while there was a weak interaction with the BVP-CRE using purified rat CREB protein. Nuclear proteins purified from the rat supraoptic nucleus bind to the BVP-CRE. As transgenic mouse studies have shown that the bovine VP gene is subject to appropriate physiological regulation in the mouse hypothalamus (Ang, H. L., Funkhouser, J., Carter, D. A., Ho, M. Y., and Murphy, D. (1991) Soc. Neurosci. Abstr. 513, 12), these data indicate a role for the BVP-CRE element in mediating VP gene expression in vivo. These data demonstrate that cAMP regulates bovine VP gene expression in vitro via a cis-acting element within the VP promoter, and this activation may be mediated by members of the AP1/ATF/CREB family of transcription factors.

Animals↗