Aspects of Pacemakers

Outstanding steps forward were made in the last decades in terms of identification of endogenous pacemakers and the exploration of their controllability. New "artifical" devices were developed and are now able to do much more than solely pacemaking of the heart. In this book different aspects of pacemaker - functions and interactions, in various organ systems were examined. In addition, various areas of application and the potential side effects and complications of the devices were discussed

BEHAVIOURAL PHENOTYPE AND ELECTROENCEPHALOGRAPHIC PROFILE OF ADOLESCENT AND ADULT SNAP-25+/- MUTANT MICE.

Synaptosomal-associated protein of 25 kDa (SNAP-25) is a protein that participates in the regulation of synaptic vesicle exocytosis through the formation of the soluble N-ethylmaleimide-sensitive proteine (NSF) attachment protein receptor complex and modulates voltage-gated calcium channels activity. Snap25 gene has been associated with schizophrenia, and bipolar disorder, and lower levels of SNAP-25 have been described in patients with schizophrenia. In particular several SNAP-25 intronic single polymorphisms were linked to attention de\ufb01cit hyperactivity disorder, one of the most common neuropsychiatric diseases among children and adolescents. The most animal models of this pathology, available until now, are characterized by reduced SNAP-25 level in the CNS: the coloboma mice, and the spontaneously hypertensive rats (SHR). However none of them can completely ricapitulate all the core features of the human patology. Thus we used adult SNAP-25 heterozygous (SNAP-25+/ 12) mice in comparison with age-matched wild type mice (SNAP-25+/+) to investigate at which extent the reduction of the protein levels affects neuronal network function and mouse behavior, and the possible therapeutic effect of antiepileptic drugs. We also characterized adolescent SNAP-25+/- mice (6-7 weeks) in order to evaluate if they can be considered a new ADHD animal model. Firstly we analysed general health, sensory and motor abilities, and emotional behaviour in our animals, without finding any abnormalities in heterozygous mice. Since altered SNAP-25 level were associated with cognitive deficit, we performed T-maze test for the evaluation of spatial memory, latent inhibition test for attention, conditioned taste aversion and object recognition for associative memory. SNAP-25+/- resulted impaired in associative but not in spatial memory, probably because of the heterogeneous protein expression levels in different hippocampal areas, being more expressed in CA3, known to play a key role in associative memory, than in CA1, critical for long-term spatial memory. SNAP-25+/- has been associated to disease characterized by altered social behaviour, such as schizophrenia and bipolar disorder. We tested SNAP-25 mutant mice in sociability and social novelty test. Heterozygous showed impairment both in sociability and in social recognition. Pathologies characterized by SNAP-25 alterations show signi\ufb01cantly higher incidence of epilepsy. For this reason we recorded the cortical electric activity of mice and we found that SNAP-25 levels reduction was associated with network hyperexcitability, in terms of spike activity, which did not lead to spontaneous epileptiform behaviour. Acute treatment with antiepileptic drugs and Ca2+ antagonist normalized cerebral activity. Among these drugs, sodium valproate was more effective in blocking EEG and behavioural deficits. Since it is known the correlation between EEG alteration and cognitive deficits we can hypothesize that the mnemonic and social deficit are due to the abnormal EEG profile. Adolescents SNAP-25+/- mice showed the same deficits found in the adults. They also were hyperactivite, and were not susceptible to d-amphetamine treatment. These results are in line with the characteristic phenotype of ADHD children, that display cognitive deficits, problems in socialization and hyperactivity, normalized by stimulants. Recently EEG analysis was used as diagnostic tool to discriminate ADHD from other neuropsychiatric diseases. EEG in ADHD children is characterized by spikes and alteration in spectral power bands frequency. Spectral analysis heterozygous mice EEG recordings was caharacterized by spikes, a decrease in fast waves and a parallel increase in slow waves, as occur in ADHD children. Repeated exposition to a VLP solution (0.1%) reduced all the behavioural deficit and was effective in blocking spike activity for two weeks, when discontinued. SNAP-25+/- mice seem to be a promising ADHD animal model, able to recapitulate almost all the core symptoms of the human disease. Repeated treatment with VLP resulted effective in all the tests carried out in adolescents mice, in line with recent findings of its therapeutic effects on ADHD symptoms in x-fragile syndrome

Aneuploidy in Health and Disease

Aneuploidy means any karyotype that is not euploid, anything that stands outside the norm. Two particular characteristics make the research of aneuploidy challenging. First, it is often hard to distinguish what is a cause and what is a consequence. Secondly, aneuploidy is often associated with a persistent defect in maintenance of genome stability. Thus, working with aneuploid, unstable cells means analyzing an ever changing creature and capturing the features that persist. In the book Aneuploidy in Health and Disease we summarize the recent advances in understanding the causes and consequences of aneuploidy and its link to human pathologies

Joint University Program for Air Transportation Research, 1988-1989

The research conducted during 1988 to 1989 under the NASA/FAA-sponsored Joint University Program for Air Transportation Research is summarized. The Joint University Program is a coordinated set of three grants sponsored by NASA Langley Research Center and the Federal Aviation Administration, one each with the Massachusetts Institute of Technology, Ohio University, and Princeton University. Completed works, status reports, and annotated bibliographies are presented for research topics, which include computer science, guidance and control theory and practice, aircraft performance, flight dynamics, and applied experimental psychology. An overview of the year's activities for each university is also presented

Forward and Reverse Engineering of Cellular Decision-Making

Cells reside in highly dynamic environments to which they must adapt. Throughout its lifetime, an individual cell receives numerous chemical and mechanical signals, communicated through dense molecular networks, and eliciting a diverse array of responses. A large number of these signals necessitate discrete, all-or-none responses. For instance, a cell receiving proliferation signals must respond by committing to the cell-cycle and dividing, or by not initiating the process at all; that is, the cell must not adopt an intermediate route. Analogously, a stem-cell receiving signals for different lineages must commit exclusively to one of these lineages. How individual cells integrate multiple, possibly conflicting, noisy inputs, and make discrete decisions is poorly understood. Detailed insight into cellular decision-making can enable cell-based therapies, shed light on diseases arising out of dysregulation of control, and suggest practical design strategies for implementing this behavior in synthetic systems for research and industrial use. In this thesis, we have employed both mathematical modeling and experiments to further elucidate the mechanistic underpinnings of decision-making in cells. First, we describe a computational study that assesses the entire space of minimal networks to identify topologies that can not only make decisions but can do so robustly in the dynamic and noisy cellular environment. Second, via model-driven, quantitative experiments in a megakaryocyte erythroid progenitor line, we demonstrate that a simple network with mutual antagonism and autoregulation captures the dynamics of the master transcription factors at the level of individual cells. Expansion of this model to account for extrinsic cues reconciles the competing stochastic and instructive theories of hematopoietic lineage commitment, and implicates cytokine receptors in broader regulatory roles. Third, to assess the impact of specific genetic perturbations on the distribution of the population, and on commitment trajectories of individual cells, we implemented the core mutual antagonism and autoregulation topology synthetically in yeast cells. Our approach of using orthogonal variants of a single core protein represents a general, modular design strategy for building synthetic circuits, and model-driven experiments elucidate how gene dosage, repression strength, and promoter architecture can modulate decision-making behavior

25th Annual Computational Neuroscience Meeting: CNS-2016

Abstracts of the 25th Annual Computational Neuroscience Meeting: CNS-2016 Seogwipo City, Jeju-do, South Korea. 2–7 July 201

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

Robot-assisted fMRI assessment of early brain development

Preterm birth can interfere with the intra-uterine mechanisms driving cerebral development during the third trimester of gestation and often results in severe neuro-developmental impairments. Characterizing normal/abnormal patterns of early brain maturation could be fundamental in devising and guiding early therapeutic strategies aimed at improving clinical outcome by exploiting the enhanced early neuroplasticity. Over the last decade the morphology and structure of the developing human brain has been vastly characterized; however the concurrent maturation of brain function is still poorly understood. Task-dependent fMRI studies of the preterm brain can directly probe the emergence of fundamental neuroscientific notions and also provide clinicians with much needed early diagnostic and prognostic information. To date, task-fMRI studies of the preterm population have however been hampered by methodological challenges leading to inconsistent and contradictory results. In this thesis I present a modular and flexible system to provide clinicians and researchers with a simple and reliable solution to deliver computer-controlled stimulation patterns to preterm infants during task-fMRI experiments. The system is primarily aimed at studying the developing sensori-motor system as preterm infants are often affected by neuro-motor dysfunctions such as cerebral palsy. Wrist and ankle robotic stimulators were developed and firstly used to study the emerging somatosensory “homunculus”. The wrist robotic stimulator was then used to characterize the development of the sensori-motor system throughout the mid-to-late preterm period. An instrumented pacifier system was also developed to explore the potential sensorimotor modulation of early sucking activity; however, despite its clear potential to be employed in future fMRI studies, results have not yet been obtained on preterm infants. Functional difficulties associated with prematurity are likely to extend to multi-sensory integration, and the olfactory system currently remains under-investigated despite its clear developmental importance. A custom olfactometer was developed and used to assess its early functionality.Open Acces