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Temporal spiking precision underlying memory measured by neuronal recordings and photo-stimulation

Final Report Summary - TSPUMMNRPS (Temporal spiking precision underlying memory measured by neuronal recordings and photo-stimulation)

The overall hypothesis underlying the present research program was that the variability of neuronal activity in higher cortical structures, independent of the physical features of sensory inputs, is due to brain‐derived (“cognitive”) processes. Accordingly, activity patterns (spike trains) in neuronal populations (functional cell assemblies) should show coordinated activity beyond that predicted by the time‐course of external sensory input. The results of these experiments provide an important step towards understanding how coordinated neuronal activity results in overt and cognitive behavior. According to the “cell assembly” hypothesis, information in the brain is represented by groups of synchronously firing neurons, whose membership reflects an interaction between sensory input and internally generated patterns. The requisite temporal precision of spiking to maintain the assemblies by synchronous firing is unknown. The hypothesis tested in the current work is that precise spike timing in neural networks is required for information processing in the brain. Quantitatively, the question is what temporal precision of multineuronal spiking is required to support reliable behavior. Here, we interfere with naturally‐occurring spiking by injecting noise into the brains of behaving rats or mice, and measure the precision of multi‐unit spike timing at which behavior deteriorates.
During the outgoing phase of my international outgoing fellowship, my training included hands-on tutorials on the handling of freely moving rodents (including legal and ethical, as well as practical aspects), on performing large scale in vivo recordings, handling silicon electrodes. Moreover I gained insight to the state of the art problems of systems neuroscience. My scientific maturation was also promoted by weekly lectures and seminars given by well acknowledged, highly reputed lecturers of various fields of neuroscience, who visited the host and neighboring institutes. The most significant results of my work during the reporting period are:
A major oscillatory activity that synchronizes the firing pattern of the hippocampal neurons is the theta rhythm that originates mainly from the medial septum of the thalamus. This theta rhythm is a conductor which orchestrates the individual timing of each neurons firing pattern, forming unique, highly reliable constellations of these single unit firing patterns. The significance of these complex patterns in information coding is well known, e.g. in the case of the coding of the animals spatial position. To investigate the requisite of such internal temporal precision of the assemblies in order to successfully code information, we decided to interfere with the theta rhythm generator cells in the medial septum (MS), and investigate the effect of such perturbation on the hippocampal assembly synchrony, and on the behavioral performance. To selectively perturb the activity of the GABAergic or cholinergic MS neurons, we used an optogenetical approach as suggested in the project proposal; however a number of difficulties arose. In collaboration with the Zeng group (Allen Institute, Seattle, WA) we developed a new transgenic mouse line for optogenetical experiments. The results of this project are published in a high impact journal (Nature Neuroscience), and the strains are accessible for the neuroscience community through The Jackson Laboratory.
To overcome the spatial and weight constrains mentioned above I developed a new recording system. The main principle of the device is to transmit the signal of 32 recording channels through a single data transmission wire by multiplexing them directly on the head of the animal. Using this new approach the number of simultaneously recorded channels could be increased to 96 in the case of freely moving mice, and 512 in the case of freely moving rats, which finally gives a broader picture of the behavior of larger cell assemblies. In a set of experiments I combined the new recording system with a custom designed silicon electrode, which was designed and prototyped in parallel with the multiplexing amplifier system. The first results gained in a freely moving rats using this new multiplexer amplifier system is published in a high impact journal (Science), and it’s significance and the general working principle is demonstrated through 512 channel freely moving rat two accepted, and two under-review papers in leading scientific journals (Neuron, Journal of Neuroscience, Nature).
I also investigated whether electrical stimuli delivered from the outer surface of the skull can by sufficiently high in magnitude to change the state of neuronal oscillatory networks, and thus to change temporal synchrony. These experiments led finally to a unique closed loop system where the developed circuitry can detect the evolution of epileptic seizures in real time, and deliver electrical pulses transcranially with a fine temporal precision in order to stop the initiation of the seizures. We proved that the method can successfully decrease the duration of epileptic episodes with more than 60%. I published these striking results and the methodology in one of the most prestigious scientific journals (Science). To continue these experiments I successfully applied for an EU FP7 ERC Starting grant, which will support the continuation of my work as an independent research group in the next five years.
During the one year of the return phase I established an experimental setup in Szeged allowing large-scale neuronal recordings, in combination with photo-stimulation in chronically implanted behaving rodents and cats. By experimenting with our initially chosen animal model it turned out that its suboptimal for the investigation of visual information processing in freely moving animals due to various technical reasons. The main bottleneck was the extremely long training period before achieving an acceptable yield in the chosen task performance. Moreover the necessary head fixation was an unwanted constrain that was suspected to influence the neuronal responses comparing to natural behavior. Considering these circumstances we decided to change the animal model to a freely moving non-restrained rat model. We chose the Long-Evans strain, which has higher visual acuity comparing to other strains and an innate ability to perform various spatial navigation tasks. Since it is almost impossible to train a freely moving rat to fixate its sight onto a pre-defined place, we trained them to run back and forth on a linear maze, where the optical stimuli were projected on the translucent walls and floor through a specially designed set of mirrors. With this arrangement the stationary, but trial-by-trial variable visual stimuli was perceived as a visual motion, with a velocity defined by the free motion of the animal. We found that this experimental approach is the best available to resemble natural conditions, while the experimenter has still complete control on the parameters of the stimulus. The analysis of the recorded dataset is currently in progress, we are focusing on the translation of the rendered visual information by synaptically connected neurons. The interim results are going to be presented as two posters on the Society for Neuroscience Meeting, San Diego, CA, USA, in 2013 November.
I believe, that my progress toward the objectives is in full agreement with my project proposal, and I was able to exploit almost all opportunities to gain the host institutes knowledge. I feel being on a more advanced level of scientific maturity then before this period, which makes me ready to start my reintegration and independent carrier at my home institution. To continue my experiments, and to provide adequate funding for my new independent research group, I successfully applied for the EU FP7 ERC Starting grant. The contract preparation has already been started, and expectedly the project will start in 2013 November. This financial support helps me to continue my work along the same principles and standards in the next five years.

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