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Inside the Head #

Foto: IST

Neuroscientists investigate the nervous system to ultimately understand how our brains work, how we manage to think, learn, and remember, and how we coordinate our actions by transmitting signals through our body at incredible speed.

Today, neuroscience has evolved into a highly interdisciplinary area. No longer is it exclusive to biology or medicine but has strong links to disciplines such as computer science, mathematics, or physics. Consequently, neuroscientists investigate a wide range of aspects in the nervous system as they reveal the secrets of molecules, cellular processes, and neuronal circuits.

This diversity is reflected by the academic backgrounds of the neuroscientists working at IST Austria. Yet, they all have a strictly quantitative approach in common as they elucidate different aspects of the nervous system: How are memories built and the cerebral cortex developed? How do synapses communicate, how is information processed, and what is the function of specific molecules? What are the genetic and molecular bases of neurodevelopmental disorders, which interactions between specific cell types cause diseases?

Understanding the microcosm of the nervous system and its components also requires cutting-edge technologies that are able to accurately measure infinitesimal processes. The Electron Microscopy Facility provides some of the highly sophisticated equipment, allowing scientists to peek into a single neuron.

JOZSEF CSICSVARI investigates how learning leads to memory formation in the brain. In one of their projects, the Csicsvari group addressed the well-known phenomenon that sleep greatly helps to consolidate memories. In the absence of any interfering stimuli, the neuronal network is in a much better position to encode what has been learned. The research group is focusing on the hippocampus, a brain area that plays a key role in the processing of spatial information and episodic memory. During sleep, it also naturally repeats what has been learned before and sends it to other brain areas. Based on the discovery of “place cells” — i.e. spatial selective cells that have a sense of location — the group designed experiments to measure the neuronal activity in the hippocampus of rats. The animals learned where food was hidden in a maze. Csicsvari and colleagues recorded the action potential of place cells in the hippocampus during the periods of learning, sleep, and memory retrieval. The neuronal activity patterns in the sleep phase mirrored those of the learning phase and did so with more accuracy when learning took place closer to sleep. The collected data from the sleep patterns allowed actually predicting how well the animal was going to remember the locations with food. The group now aims at blocking specific spatial memories. They do so by suppressing the activity of certain place cells during sleep with optogenetic methods. These experiments produce huge amounts of data and lengthy analysis steps are necessary to process them. Future research will study how the memory traces are transferred from the hippocampus to brain regions where they are potentially stored long term.

SIMON HIPPENMEYER is one step closer to answering the fundamental question how stem cells in the developing brain produce the highly specialized neurons in the cerebral cortex — an area of the brain that commands all higher cognitive functions such as perception or language. Hippenmeyer and his team investigated a subclass of neural stem cells called radial glia progenitors or RGPs, which are responsible for producing all cortical neurons. They used a unique genetic methodology called MADM which stands for Mosaic Analysis with Double Markers. MADM provides unprecedented single-cell resolution of stem cell division pattern in vivo, and thus an unambiguous quantitative optical readout of the precise proliferation mode of cortical progenitors. By systematically applying MADM in RGPs, they discovered a remarkable feature: RGP development follows a clear and predefined “orderly” program that first leads to a great expansion of the stem cell pool. Yet at a certain stage, RGPs enter a special step in their developmental program where each consistently produces fixed units of about 8–9 neurons. This discovery implies a fine balance between RGP proliferation and differentiation into neurons, and suggests a precise mechanism to specify the cerebral cortex of the correct size and cellular composition. Hippenmeyer wants to take this research a step further to decipher the underlying cellular and molecular mechanisms, based also on human tissue: A recent breakthrough of the international neuroscientific community was the actual creation of “minibrains”, derived from human stem cells, that form a cerebral structure similar to a very early embryonic human brain. This novel medium is starting to become widely used to study brain development but also the underlying basis of neurodevelopmental disorders. PETER JONAS works on the understanding of the function of neuronal microcircuits. In line with Hopfield’s famous quote “build it, and you understand it” the Jonas group is tackling a major undertaking: they are quantitatively exploring the nanophysiology of a specific type of inhibitory interneuron to eventually build a complete mathematical model. These nerve cells — the so-called fast-spiking parvalbumin-positive GABAergic interneurons — play a central role in information processing of neuronal networks in the hippocampus. One of their jobs is to convert an excitatory input signal into an inhibitory output signal within a millisecond. Checkpoints like these are the key to preventing excitatory activity to explode, as may happen in epilepsy. To achieve this kind of speed, neurons usually require a large axon diameter and a coating with myelin, yet GABAergic interneurons have neither of these. Jonas’ research revealed a new subcellular mechanism for reliable and fast action potential transmission. It consists of a controlled increase in the density of Na+ channels and conductance, starting from the cell body to the proximal axon, where action potentials are initiated. Current research is now focusing on another part of the neuron — the presynaptic terminal — from which the Jonas group is taking direct measurements. The aim is to identify all mechanisms that contribute to the speed of signaling at the synapse. It is not surprising that high velocity comes at a cost and consumes a great amount of energy. For this reason, the Jonas group is measuring the energy requirements on a subcellular level in a unique approach to establish how much “fuel” in the form of adenosine-triphosphate or ATP is needed. One of the next intriguing questions will be which evolutionary strategy the neuron took in order to find a viable compromise between speed, reliability, and energy consumption.

GAIA NOVARINO is leading a research program with a focus on inherited forms of epilepsy, intellectual disability, and autism in children. It seems that this spectrum of neurodevelopmental disorders (NDD) shares common molecular and genetic mechanisms. However, there is not one single cause but a multitude of various genetic mutations that are responsible for NDD although a group of affected people may show very similar symptoms. The presence of hundreds of different causes makes the quest for a potential cure look like a search for a needle in the haystack. Gaia Novarino and her group therefore aim to categorize genes that may be dissimilar but are contributing to same processes. A recent example is her discovery of three specific amino acids that — if not available in sufficient quantity — cause a rare form of NDD. Some patients were found to have a mutated gene that degraded these amino acids too fast, resulting in too low a level. Yet, this was not the case in other patients with the same deficiency. In her current work, Novarino therefore aims to uncover other possible factors that induce a lack of these amino acids. Another interesting question in this context is time: If a mutated gene is only active during a certain developmental window and becomes silent later in life, a potential cure would become obsolete if given too late. But if administer- ed during the developmental window, medication — in this case the lacking amino acids — could be given up until a certain age and after that point in time, the individual would be cured.

RYUICHI SHIGEMOTO seeks to understand the molecular basis of neuronal transmission in the brain mediated by neurotransmitter receptors or ion channels. In a more experimental approach, Shigemoto and his group also examine the left-right asymmetry of the brain. This so-called laterality of the brain function is well known but the molecular determinants are still largely elusive. Most humans — and also many vertebrates — have a right hemisphere dominance for spatial navigation and memory. The reason is twofold as both genetics and environmental factors play a role. In one of Shigemoto’s experiments, mice explored an enriched environment with a variety of toys (such as running wheels, tubes, etc.) as opposed to a plain standard cage. The exploration induced a higher activity in the right than in the left hippocampus, a brain region related to spatial memory formation, and the amount of connections between neurons significantly increased exclusively in the right hemisphere of the brain as a result of the environmental changes repeated for six weeks. To study the second aspect — the genetic reasons — Shigemoto worked with mutant mice that lack the left-right asymmetry. He found that the difference in their genes is critical for the formation of lateralization and examined the pathway of this development. But what is this asymmetry actually good for? There is no conclusive answer yet: some tasks are better accomplished by wild-type mice and maybe others by mutant mice. But in terms of spatial memory, laterality is indeed an evolutionary advantage.

SANDRA SIEGERT explores the compelling world of microglia. These cell types are not just the health police of the central nervous system but also play a vital role in the formation and function of the neuronal circuit, as recent research uncovered. Microglia can be activated in the presence of neuronal malfunction — leading to alteration of neuronal circuit elements — and then lay dormant again afterwards. However, modification within genes exclusively expressed in microglia could also take action causing microglia to attack healthy cells. To understand how microglia are switched on and whether they are causative for a disease, Siegert examines their role in the case of retinitis pigmentosa, a disease where the photoreceptor cells die off and which shows microglial activation. The retina represents an ideal model system to study microglial function because of the well-defined and precisely mapped neuronal circuits. Siegert combines various approaches to unravel the unknown mechanisms of microglia: Live imaging of microglial cells, which express green fluorescent protein, and photoreceptors, which express red fluorescent protein, will tell us more about the interaction of microglia and neurons during health and disease. Moreover, Siegert and her team can model the observations in “mini-retinas”, generated from induced pluripotent stem cells obtained from human skin cells. They will genetically modify the disease-associated genes of microglial cells to reveal the subsequent effects. In the long run, an understanding of the microglial system will potentially have tremendous benefits, and not just for people with degenerative eye diseases: microglia are involved in a multitude of neurodegenerative disorders like Alzheimer’s or Parkinson’s disease, to name just a few.

GAŠPER TKAČIK is a theoretical physicist and computational neuroscientist. One strand of his current interdisciplinary research investigates how the neural code works in the eye’s retina. The retina transforms light signals into sequences of spikes and silences, and these so-called action potentials are sent through the optic nerve to the brain. Together with a group of experimentalists at the Institut de la Vision in Paris, they studied these visual signals while a movie was being shown and precisely recorded the output consisting of action potential spikes. The Tkačik group developed a mathematical model to reconstruct the original movie stimulus from the recorded signals of the retina with good accuracy. For this recent experiment, the researchers used a rich artificial stimulus of dark discs moving around randomly, but decoding complete natural movies still remains very challenging. Gašper Tkačik and his colleagues are now striving to better understand the workings of the retina so that they can build improved decoders for natural movies. They are using methods from machine learning and information theory in order to quantify how precisely the retina transmits information. Results of their theoretical work may also feed into ongoing experiments of applied groups that seek to restore the vision of patients with retinal degeneration by means of a little camera coupled to a chip that stimulates retinal neurons.