Upinder S. Bhalla, Ph.D.
Professor & Dean, NCBS, Bengaluru, India
Watching the network change during the formation of associative memory
The process of learning is measured through behavioural changes, but it is of enormous interest to understand its cellular and network basis. We used 2-photon imaging of hippocampal CA1 pyramidal neuron activity in mice to monitor such changes during the acquisition of a trace conditioning task. One of the questions in such learning is how the network retains a trace of a brief conditioned stimulus (a sound), until the arrival of a delayed unconditioned stimulus (a puff of air to the eye). During learning, the mice learn to blink when the tone is presented, well before the arrival of the air puff.
The mice learnt this task in 20-50 trials. We observed that in this time-frame the cells in the network changed the time of their peak activity, such that their firing times tiled the interval between sound and air puff. Thus the cells seem to form a relay of activity. We also observed an evolution in functional connectivity in the network, as measured by groupings of correlated cells. These groupings were stable till the learning protocol commenced, and then changed. Thus we have been able to observe two aspects of network learning: changes in activity (relay firing), and changes in connectivity (correlation groups).
Ganesh Sambasivam, Ph.D.
CSO & Co-Founder, Anthem Biosciences India
Preclinical Outsourcing to India
The outsourcing segment is witnessing rapid changes with respect to the nature of work outsourced and the location. Cost is the major driver but other considerations such as infrastructure and government policies can also be important drivers for decision making. The last couple of years have been a trying time for all CROs. The global economic meltdown has hit research budgets especially hard. The new challenges facing Contract Research Organizations call for a radically revised approach and a new model that would push the boundaries of this business further and would blur the line between client and vendor further. I believe the term Contract Research Organization (CRO), is a misnomer to begin with (often confused with Clinical Research Organization), has now morphed into a new type of company viz Contract Innovation Services (CIS). Clients are no longer just happy to outsource odds and ends of the development piece but are looking to their vendors for a massive amount of innovation input. This input is increasingly across both the chemistry and discovery domains. This new paradigm calls for CIS companies to develop new platforms, create intellectual propertythat is of service to clients andinnovate processes to meet new found customer expectations.
Rohit Manchanda, Ph.D.
Professor, Biomedical Engineering Group, IIT-Bombay, India
Modelling the syncytial organization and neural control of smooth muscle: insights into autonomic physiology and pharmacology
We have been studying computationally the syncytial organization and neural control of smooth muscle in order to help explain certain puzzling findings thrown up by experimental work. This relates in particular to electrical signals generated in smooth muscles, such as synaptic potentials and spikes, and how these are explicable only if three-dimensional syncytial biophysics are taken fully into account. In this talk, I shall provide an illustration of outcomes and insights gleaned from such an approach. I shall first describe our work on the mammalian vas deferens, in which an analysis of the effects of syncytial coupling led us to conclude that the experimental effects of a presumptive gap junction uncoupler, heptanol, on synaptic potentials were incompatible with gap junctional block and could best be explained by a heptanol-induced inhibition of neurotransmitter release, thus compelling a reinterpretation of the mechanism of action of this agent. I shall outline the various lines of evidence, based on indices of syncytial function, that we adduced in order to reach this conclusion. We have now moved on to our current focus on urinary bladder biophysics, where the questions we aim to address are to do with mechanisms of spike generation. Smooth muscle cells in the bladder exhibit spontaneous spiking and spikes occur in a variety of distinct shapes, making their generation problematic to explain. We believe that the variety in shapes may owe less to intrinsic differences in spike mechanism (i.e., in the complement of ion channels participating in spike production) and more to features imposed by syncytial biophysics. We focus especially on the modulation of spike shape in a 3-D coupled network by such factors as innervation pattern, propagation in a syncytium, electrically finite bundles within and between which the spikes spread, and some degree of pacemaker activity by a sub-population of the cells. I shall report two streams of work that we have done, and the tentative conclusions these have enabled us to reach: (a) using the NEURON environment, to construct the smooth muscle syncytium and endow it with synaptic drive, and (b) using signal-processing approaches, towards sorting and classifying the experimentally recorded spikes.
Egidio D’Angelo, MD, Ph.D.
Full Professor of Physiology & Director, Brain Connectivity Center, University of Pavia, Italy
Realistic modeling: new insight into the functions of the cerebellar network
Realistic modeling is an approach based on the careful reconstruction of neurons synapses starting from biological details at the molecular and cellular level. This technique, combined with the connection topologies derived from histological measurements, allows the reconstruction of precise neuronal networks. Finally, the advent of specific software platforms (PYTHON-NEURON) and of super-computers allows large-scale network simulation to be performed in reasonable time. This approach inverts the logics of older theoretical models, which anticipated an intuition on how the network might work. In realistic modeling, network properties “emerge” from the numerous biological properties embedded into the model.
This approach is illustrated here through an outstanding application of realistic modeling to the cerebellar cortex network. The neurons (over 105) are reproduced at a high level of detail generating non-linear network effects like population oscillations and resonance, phase-reset, bursting, rebounds, short-term and long-term plasticity, spatiotemporal redistrbution of input patterns. The model is currently being used in the context of he HUMAN BRAIN PROJECT to investigate the cerebellar network function.
Correspondence should be addressed to
Dr. EgidioD’Angelo,
Laboratory of Neurophysiology
Via Forlanini 6, 27100 Pavia, Italy
Phone: 0039 (0) 382 987606
Fax: 0039 (0) 382 987527
dangelo@unipv.it
Acknowledgments
This work was supported by grants from European Union to ED (CEREBNET FP7-ITN238686, REALNET FP7-ICT270434) and by grants from the Italian Ministry of Health to ED (RF-2009-1475845).
Deepthy Menon, Ph.D.
Associate Professor, Centre for Nanosciences & Molecular Medicine, Health Sciences Campus, Amrita University, Kochi, India
Nanobioengineering of implant materials for improved cellular response and activity
Deepthy Menon, Divyarani V V, Chandini C Mohan, Manitha B Nair, Krishnaprasad C & Shantikumar V Nair
Abstract
Current trends in biomaterials research and development include the use of surfaces with topographical features at the nanoscale (dimensions < 100 nm), which influence biomolecular or cellular level reactions in vitro and in vivo. Progress in nanotechnology now makes it possible to precisely design and modulate the surface properties of materials used for various applications in medicine at the nanoscale. Nanoengineered surfaces, owing to their close resemblance with extracellular matrix, possess the unique capacity to directly affect protein adsorption that ultimately modulates the cellular adhesion and proliferation at the site of implantation. Taking advantage of this exceptional ability, we have nanoengineered metallic surfaces of Titanium (Ti) and its alloys (Nitinol -NiTi), as well as Stainless Steel (SS) by a simple hydrothermal method for generating non-periodic, homogeneous nanostructures. The bio- and hemocompatibility of these nanotextured metallic surfaces suggest their potential use for orthopedic, dental or vascular implants. The applicability of nanotextured Ti implants for orthopedic use was demonstrated in vivo in rat models, wherein early-stage bone formation at the tissue-implant interface without any fibrous tissue intervention was achieved. This nanoscale topography also was found to critically influence bacterial adhesion in vitro, with decreased adherence of staphylococcus aureus. The same surface nanotopography also was found to provide enhanced proliferation and functionality of vascular endothelial cells, suggesting its prospective use for developing an antithrombotic stent surface for coronary applications. Clinical SS & NiTi stents were also modified based on this strategy, which would offer a suitable solution to reduce the probability of late stent thrombosis associated with bare metallic stents. Thus, we demonstrate that nanotopography on implant surfaces has a critical influence on the fate of cells, which in turn dictates the long term success of the implant.
Acknowledgement: Authors gratefully acknowledge the financial support from Department of Biotechnology, Government of India through the Bioengineering program.
