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The more active the fly, the faster its brain works

Borst 2017

In order to react to changes in the environment in good time, the brain must analyze the signals it receives from the eyes rapidly and accurately. For example, the ability to recognise the direction in which an approaching car is moving is vital to the survival of modern humans in cities. Using the brain of the fruit fly Drosophila as a model, scientists from the Max Planck Institute of Neurobiology study how the brain extracts this essential motion information. They have now described in detail the cells that enable downstream neurons to recognize the direction of movement. Interestingly, the characteristics of these input cells exactly match to a motion detector model they recently proposed. In addition, the cells alter their characteristics according to the animals’ state: when the fly is active, the cells respond faster to light stimuli.

Humans perceive their environment mainly through their eyes. The ability to recognize movements and their direction is something that seems almost trivial and automatic to us. However, this information has to be processed in the brain as the light-sensitive sensory cells of the retina can only register changes in contrast. The direction of a movement can only be calculated through the comparison of neighbouring signals. Various models exist for these calculations. Alexander Borst and his team at the Max Planck Institute of Neurobiology study the extent to which these models can be applied to the brain’s neuronal circuitry. Their test subject is the fruit fly Drosophila, a master of motion perception.

The genetic transmission of gene locks

Although all cells in an organism contain the same genes, only some of the genes are activated in a given cells and others remain inactive. Genes coil around histone proteins in the form of DNA threads. If a gene has to remain inactive, its histones are marked by the PRC2 enzyme so that this gene is locked down and cannot be read. When cells divide and the genes are copied, these histone marks must be placed again, at exactly the same location. The mechanism that enables transmission of this information has now been explained by Jürg Müller from the Max Planck Institute of Biochemistry in Martinsried in a study published in the journal Science.

In animals and plants, the genomic DNA in the cell nucleus is wrapped around small proteins known as histones. Jürg Müller, Leader of the Biology of Chromatin Research Group at the MPI of Biochemistry explains: “The DNA is like a big library of books. Each book contains the instruction manual for making a protein. Although the same DNA library is present in all cells, some of the books are ‘sealed’, so they cannot be read. A muscle cell requires other protein-building instructions than an intestinal cell.” An essential mechanism to prevent the expression of genes relies on the chemical marking of histone proteins to permanently “lock down” genes. In the current study, Müller and his team examined how such gene locks are transmitted during cell division. Histones play a key role in determining how accessible a gene is. When genes need to be permanently locked down, their histones are chemically modified by the enzyme PRC2. “If we imagine the histones as the binder of the book, PRC2 helps to seal that book and prevent that it gets opened and read,” explains Müller.

Publication of IMPRS-LS student Friederike Laprell

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Laprell F, Finkl K, Müller J.
Science, 2017, [Epub ahead of print].

Propagation of Polycomb-repressed chromatin requires sequence-specific recruitment to DNA.

Epigenetic inheritance models posit that during Polycomb repression, Polycomb Repressive Complex 2 (PRC2) propagates histone H3K27 tri-methylation (H3K27me3) independently of DNA sequence. We show that insertion of Polycomb Response Element (PRE) DNA into the Drosophila genome creates extended domains of H3K27me3-modified nucleosomes in the flanking chromatin and causes repression of a linked reporter gene. After excision of PRE DNA, H3K27me3 nucleosomes become diluted with each round of DNA replication and reporter gene repression is lost, whereas in replication-stalled cells, H3K27me3 levels stay high and repression persists. Hence, H3K27me3-marked nucleosomes provide a memory of repression that is transmitted in a sequence-independent manner to daughter strand DNA during replication. In contrast, propagation of H3K27 tri-methylation to newly incorporated nucleosomes requires sequence-specific targeting of PRC2 to PRE DNA.

Operation of ancient biological clock uncovered

A team of Dutch and German researchers under the leadership of Albert Heck and Friedrich Förster has discovered the operation of one of the oldest biological clocks in the world, which is crucial for life on earth as we know it. The researcher from the Max Planck Institute of Biochemistry and the Utrecht University applied a new combination of cutting-edge research techniques. They discovered how the biological clock in cyanobacteria works in detail. Important to understand life, because cyanobacteria were the first organisms on earth producing oxygen via photosynthesis. The results of their research were published in Science.

Ten years ago, researchers discovered that the biological clock in cyanobacteria consists of only three protein components: KaiA, KaiB and KaiC. These are the building blocks - the gears, springs and balances - of an ingenious system resembling a precision Swiss timepiece. In 2005, Japanese scientists published an article in Science showing that a solution of these three components in a test tube could run a 24-hour cycle for days when a bit of energy was added. However, the scientists were not able to uncover the exact operation of the system, despite its relative simplicity.

William Faulkner
How could the scientists resolve the working of the individual pieces? “In the end, the trick to understand the ticking biological clock in cyanobacteria was to literally make time stop”, tells research leader Albert Heck from Utrecht University. “Or as William Faulkner, Nobel Prize Laureate in Literature said: ‘Only when the clock stops does time come to life.’ Faulkner spoke taking a pause in the constant haste of life. That was also the trick here. We slowed the biological clock by running it in the fridge for a week. In the literal sense we have frozen the time.”

Publication of IMPRS-LS student Jan Rieckmann

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Rieckmann, J.C., Geiger, R., Hornburg, D., Wolf, T., Kveler, K., Jarrossay, D., Sallusto, F., Shen-Orr, S.S., Lanzavecchia, A., Mann, M., and Meissner, F.
Nat Immunol, 2017, [Epub ahead of print].

Social network architecture of human immune cells unveiled by quantitative proteomics.

The immune system is unique in its dynamic interplay between numerous cell types. However, a system-wide view of how immune cells communicate to protect against disease has not yet been established. We applied high-resolution mass-spectrometry-based proteomics to characterize 28 primary human hematopoietic cell populations in steady and activated states at a depth of >10,000 proteins in total. Protein copy numbers revealed a specialization of immune cells for ligand and receptor expression, thereby connecting distinct immune functions. By integrating total and secreted proteomes, we discovered fundamental intercellular communication structures and previously unknown connections between cell types. Our publicly accessible (http://www.immprot.org/) proteomic resource provides a framework for the orchestration of cellular interplay and a reference for altered communication associated with pathology.

Stocking up on spare parts

Neurodegenerative diseases such as Alzheimer‘s or Parkinson‘s, but also strokes or other types of traumatic brain damage, result in the death of nerve cells in the brain. Since the mammalian brain is capable of replacing nerve cells only in certain restricted regions, such nerve-cell loss is in most cases permanent. Similarly, the capacity to form new nerve cells in the mature brain is limited to specific areas. The cells responsible for neurogenesis in the mature brain are called adult neural stem cells, but little is known about their developmental origins. Now an international research collaboration led by Magdalena Götz, Professor of Physiological Genomics at LMU’s Biomedical Center and Director of the Institute for Stem Cell Research at the Helmholtz Zentrum Munich, has demonstrated that the mode of division of stem cells has a profound influence on the numbers of adult neural stem cells formed during embryonic development. The new findings appear in the journal Neuron.

Publication of IMPRS-LS student Ramya Balaji

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Balaji, R., Bielmeier, C., Harz, H., Bates, J., Stadler, C., Hildebrand, A., and Classen, A.K.
Sci Rep, 2017, 7, 42786.

Calcium spikes, waves and oscillations in a large, patterned epithelial tissue.

While calcium signaling in excitable cells, such as muscle or neurons, is extensively characterized, calcium signaling in epithelial tissues is little understood. Specifically, the range of intercellular calcium signaling patterns elicited by tightly coupled epithelial cells and their function in the regulation of epithelial characteristics are little explored. We found that in Drosophila imaginal discs, a widely studied epithelial model organ, complex spatiotemporal calcium dynamics occur. We describe patterns that include intercellular waves traversing large tissue domains in striking oscillatory patterns as well as spikes confined to local domains of neighboring cells. The spatiotemporal characteristics of intercellular waves and oscillations arise as emergent properties of calcium mobilization within a sheet of gap-junction coupled cells and are influenced by cell size and environmental history. While the in vivo function of spikes, waves and oscillations requires further characterization, our genetic experiments suggest that core calcium signaling components guide actomyosin organization. Our study thus suggests a possible role for calcium signaling in epithelia but importantly, introduces a model epithelium enabling the dissection of cellular mechanisms supporting the initiation, transmission and regeneration of long-range intercellular calcium waves and the emergence of oscillations in a highly coupled multicellular sheet.

Publication of IMPRS-LS student Sara Santarelli

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Santarelli, S., Zimmermann, C., Kalideris, G., Lesuis, S.L., Arloth, J., Uribe, A., Dournes, C., Balsevich, G., Hartmann, J., Masana, M., Binder, E.B., Spengler, D., and Schmidt, M.V.
Psychoneuroendocrinology, 2017, 78, 213-221.

An adverse early life environment can enhance stress resilience in adulthood.

Chronic stress is a major risk factor for depression. Interestingly, not all individuals develop psychopathology after chronic stress exposure. In contrast to the prevailing view that stress effects are cumulative and increase stress vulnerability throughout life, the match/mismatch hypothesis of psychiatric disorders. The match/mismatch hypothesis proposes that individuals who experience moderate levels of early life psychosocial stress can acquire resilience to renewed stress exposure later in life. Here, we have tested this hypothesis by comparing the developmental effects of 2 opposite early life conditions, when followed by 2 opposite adult environments. Male Balb/c mice were exposed to either adverse early life conditions (limited nesting and bedding material) or a supportive rearing environment (early handling). At adulthood, the animals of each group were either housed with an ovariectomized female (supportive environment) or underwent chronic social defeat stress (socially adverse environment) for 3 weeks. At the end of the adult manipulations, all of the animals were returned to standard housing conditions. Then, we compared the neuroendocrine, behavioral and molecular effects of the interaction between early and adult environment. Our study shows that early life adversity does not necessarily result in increased vulnerability to stress. Specific endophenotypes, like hypothalamic-pituitary-adrenal axis activity, anxiety-related behavior and glucocorticoid receptor expression levels in the hippocampus were not significantly altered when adversity is experienced during early life and in adulthood, and are mainly affected by either early life or adult life adversity alone. Overall our data support the notion that being raised in a stressful environment prepares the offspring to better cope with a challenging adult environment and emphasize the role of early life experiences in shaping adult responsiveness to stress.

Understanding the brain with the help of artificial intelligence

How does consciousness arise? Researchers suspect that the answer to this question lies in the connections between neurons. Unfortunately, however, little is known about the wiring of the brain. This is due also to a problem of time: tracking down connections in collected data would require man-hours amounting to many lifetimes, as no computer has been able to identify the neural cell contacts reliably enough up to now. Scientists from the Max Planck Institute of Neurobiology in Martinsried plan to change this with the help of artificial intelligence. They have trained several artificial neural networks and thereby enabled the vastly accelerated reconstruction of neural circuits.

Neurons need company. Individually, these cells can achieve little, however when they join forces neurons form a powerful network which controls our behaviour, among other things. As part of this process, the cells exchange information via their contact points, the synapses. Information about which neurons are connected to each other when and where is crucial to our understanding of basic brain functions and superordinate processes like learning, memory, consciousness and disorders of the nervous system. Researchers suspect that the key to all of this lies in the wiring of the approximately 100 billion cells in the human brain.

To be able to use this key, the connectome, that is every single neuron in the brain with its thousands of contacts and partner cells, must be mapped. Only a few years ago, the prospect of achieving this seemed unattainable. However, the scientists in the Electrons – Photons – Neurons Department of the Max Planck Institute of Neurobiology refuse to be deterred by the notion that something seems “unattainable”. Hence, over the past few years, they have developed and improved staining and microscopy methods which can be used to transform brain tissue samples into high-resolution, three-dimensional electron microscope images. Their latest microscope, which is being used by the Department as a prototype, scans the surface of a sample with 91 electron beams in parallel before exposing the next sample level. Compared to the previous model, this increases the data acquisition rate by a factor of over 50. As a result an entire mouse brain could be mapped in just a few years rather than decades.

Although it is now possible to decompose a piece of brain tissue into billions of pixels, the analysis of these electron microscope images takes many years. This is due to the fact that the standard computer algorithms are often too inaccurate to reliably trace the neurons’ wafer-thin projections over long distances and to identify the synapses. For this reason, people still have to spend hours in front of computer screens identifying the synapses in the piles of images generated by the electron microscope.

However the Max Planck scientists led by Jörgen Kornfeld have now overcome this obstacle with the help of artificial neural networks. These algorithms can learn from examples and experience and make generalizations based on this knowledge

Publication of IMPRS-LS student Ryan Sherrard

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Sherrard, R., Luehr, S., Holzkamp, H., McJunkin, K., Memar, N., and Conradt, B.
Genes Dev, 2017, 31, 209-222.

miRNAs cooperate in apoptosis regulation during C. elegans development.

Programmed cell death occurs in a highly reproducible manner during Caenorhabditis elegans development. We demonstrate that, during embryogenesis, miR-35 and miR-58 bantam family microRNAs (miRNAs) cooperate to prevent the precocious death of mothers of cells programmed to die by repressing the gene egl-1, which encodes a proapoptotic BH3-only protein. In addition, we present evidence that repression of egl-1 is dependent on binding sites for miR-35 and miR-58 family miRNAs within the egl-1 3' untranslated region (UTR), which affect both mRNA copy number and translation. Furthermore, using single-molecule RNA fluorescent in situ hybridization (smRNA FISH), we show that egl-1 is transcribed in the mother of a cell programmed to die and that miR-35 and miR-58 family miRNAs prevent this mother from dying by keeping the copy number of egl-1 mRNA below a critical threshold. Finally, miR-35 and miR-58 family miRNAs can also dampen the transcriptional boost of egl-1 that occurs specifically in a daughter cell that is programmed to die. We propose that miRNAs compensate for lineage-specific differences in egl-1 transcriptional activation, thus ensuring that EGL-1 activity reaches the threshold necessary to trigger death only in daughter cells that are programmed to die.