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Martinez de Paz, J.M., and Macé, E.
Neuroimage, 2021, 245, 118722.
DOI: 10.1016/j.neuroimage.2021.118722

Functional ultrasound imaging: A useful tool for functional connectomics?

Functional ultrasound (fUS) is a hemodynamic-based functional neuroimaging technique, primarily used in animal models, that combines a high spatiotemporal resolution, a large field of view, and compatibility with behavior. These assets make fUS especially suited to interrogating brain activity at the systems level. In this review, we describe the technical capabilities offered by fUS and discuss how this technique can contribute to the field of functional connectomics. First, fUS can be used to study intrinsic functional connectivity, namely patterns of correlated activity between brain regions. In this area, fUS has made the most impact by following connectivity changes in disease models, across behavioral states, or dynamically. Second, fUS can also be used to map brain-wide pathways associated with an external event. For example, fUS has helped obtain finer descriptions of several sensory systems, and uncover new pathways implicated in specific behaviors. Additionally, combining fUS with direct circuit manipulations such as optogenetics is an attractive way to map the brain-wide connections of defined neuronal populations. Finally, technological improvements and the application of new analytical tools promise to boost fUS capabilities. As brain coverage and the range of behavioral contexts that can be addressed with fUS keep on increasing, we believe that fUS-guided connectomics will only expand in the future. In this regard, we consider the incorporation of fUS into multimodal studies combining diverse techniques and behavioral tasks to be the most promising research avenue.

 


 

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Schwach, J., Kolobynina, K., Brandstetter, K., Gerlach, M., Ochtrop, P., Helma, J., Hackenberger, C.P.R., Harz, H., Cardoso, M.C., Leonhardt, H., and Stengl, A.
(IMPRS-LS students are in bold)
Chembiochem, 2021, 22, 1205-1209
DOI: 10.1002/cbic.202000727

Site-Specific Antibody Fragment Conjugates for Reversible Staining in Fluorescence Microscopy

Antibody conjugates have taken a great leap forward as tools in basic and applied molecular life sciences that was enabled by the development of chemoselective reactions for the site-specific modification of proteins. Antibody-oligonucleotide conjugates combine the antibody's target specificity with the reversible, sequence-encoded binding properties of oligonucleotides like DNAs or peptide nucleic acids (PNAs), allowing sequential imaging of large numbers of targets in a single specimen. In this report, we use the Tub-tag® technology in combination with Cu-catalyzed azide-alkyne cycloaddition for the site-specific conjugation of single DNA and PNA strands to an eGFP-binding nanobody. We show binding of the conjugate to recombinant eGFP and subsequent sequence-specific annealing of fluorescently labelled imager strands. Furthermore, we reversibly stain eGFP-tagged proteins in human cells, thus demonstrating the suitability of our conjugation strategy to generate antibody-oligonucleotides for reversible immunofluorescence imaging.

 


 

graduationCongratulations on your PhD!

 

Johanna Tüshaus


Proteomic secretome analysis of primary brain cells


RG: Stefan Lichtenthaler

 


 

graduationCongratulations on your PhD!

 

Giulia Chiapparini


Structural and Biochemical Characterisation of Minimal Translesion Synthesis Complexes


RG: Christian Biertümpfel

 


 

Danny Nedialkova, head of the Max Planck Research Group "Mechanisms of Protein Biogenesis" at the Max Planck Institute (MPI) of Biochemistry, has been elected into the EMBO Young Investigator Network. As one of 26 life science researchers chosen this year, she will receive financial support and access to a range of mentoring and training programs for a period of four years, starting in January 2022. "It’s an honor and a privilege to join the Young Investigator network, and I am excited about the new possibilities this opens up for me and my team," says Danny Nedialkova.

“They have already demonstrated scientific excellence despite only recently launching their own laboratories. The EMBO Young Investigator Programme will aid them in taking their career to the next level. We look forward to supporting them during an important phase of their career.” says Michael N. Hall, EMBO Director ad interim. For the synthesis of proteins, the sequence of nucleic acids, the basic building blocks of genetic information, is translated into a specific sequence of amino acids, the basic building blocks of proteins. This is called the genetic code. Danny Nedialkova’s research explores how the genetic code is translated into the thousands of different proteins that make up each cell. Her team uses genome-wide approaches and functional genomics to investigate how protein synthesis is regulated during development and in different cell types. 

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F. Ulrich Hartl, Director at the Max Planck Institute of Biochemistry, together with his colleague Arthur L. Horwich, receives the HFSP Nakasone Prize 2022.

Biochemist F. Ulrich Hartl, together with his colleague and geneticist Arthur L. Horwich, discovered that nascent proteins often do not fold spontaneously into their functional form. Proteins which assist the folding process, known as chaperones, are needed for this process. Both researchers now receive the HFSP Nakasone Prize 2022 of the Human Frontier Science Program for this fundamental and far-reaching discovery. F. Ulrich Hartl: " I am very honored to receive this award together with my early collaborator Art Horwich and look forward to the prize ceremony in Paris." The award honors scientists for their groundbreaking discoveries in areas of the life sciences.

Many proteins need help to fold into their functional form. Helper proteins, known as chaperones, perform this task. This process of assisted folding was discovered by Prof. F. Ulrich Hartl, Director at the Max Planck Institute of Biochemistry in Martinsried, together with his colleague, the American Arthur L. Horwich from the Howard Hughes Medical Institute in Yale, USA. Hartl and his team have been investigating the structure and function of molecular chaperones ever since. Protein aggregations, which are associated with many neurodegenerative diseases such as Parkinson's, Alzheimer's, and Huntington's chorea, can be traced back to malfunctions of the chaperones, among other things. The detailed knowledge of molecular functions and malfunctions of the folding helpers should enable the development of new therapeutic approaches. 

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Markov, D.A., Petrucco, L., Kist, A.M., and Portugues, R.
Nat Commun, 2021, 12, 6694.
(IMPRS-LS students are in bold)
doi: 10.1038/s41467-021-26988-0

A cerebellar internal model calibrates a feedback controller involved in sensorimotor control

Animals must adapt their behavior to survive in a changing environment. Behavioral adaptations can be evoked by two mechanisms: feedback control and internal-model-based control. Feedback controllers can maintain the sensory state of the animal at a desired level under different environmental conditions. In contrast, internal models learn the relationship between the motor output and its sensory consequences and can be used to recalibrate behaviors. Here, we present multiple unpredictable perturbations in visual feedback to larval zebrafish performing the optomotor response and show that they react to these perturbations through a feedback control mechanism. In contrast, if a perturbation is long-lasting, fish adapt their behavior by updating a cerebellum-dependent internal model. We use modelling and functional imaging to show that the neuronal requirements for these mechanisms are met in the larval zebrafish brain. Our results illustrate the role of the cerebellum in encoding internal models and how these can calibrate neuronal circuits involved in reactive behaviors depending on the interactions between animal and environment.

 


 

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Klein, A.S., Dolensek, N., Weiand, C., and Gogolla, N.
Science, 2021, 374, 1010-1015.
 doi: 10.1126/science.abj8817

Fear balance is maintained by bodily feedback to the insular cortex in mice

How does the brain maintain fear within an adaptive range? We found that the insular cortex acts as a state-dependent regulator of fear that is necessary to establish an equilibrium between the extinction and maintenance of fear memories in mice. Whereas insular cortex responsiveness to fear-evoking cues increased with their certainty to predict harm, this activity was attenuated through negative bodily feedback that arose from heart rate decelerations during freezing. Perturbation of body-brain communication by vagus nerve stimulation disrupted the balance between fear extinction and maintenance similar to insular cortex inhibition. Our data reveal that the insular cortex integrates predictive sensory and interoceptive signals to provide graded and bidirectional teaching signals that gate fear extinction and illustrate how bodily feedback signals are used to maintain fear within a functional equilibrium.

 


 

Fear is essential for survival, but must be well regulated to avoid harmful behaviors such as panic attacks or exaggerated risk taking. Scientists at the Max Planck Institute of Neurobiology have now demonstrated in mice that the brain relies on the body’s feedback to regulate fear. The brain’s insular cortex strongly reacts to stimuli signaling danger. However, when the body freezes in response to fear, the heartbeat slows down leading to attenuated insular cortex activity. Processing these opposing signals helps the insular cortex to keep fear in balance. The body’s reactions are thus actively used to regulate emotions and are much more than passive emotional responses.

We usually experience fear as extremely unpleasant. Nevertheless, this emotion has a crucial function: it prevents us from engaging in too risky behaviors. However, this only works if fear is kept within a healthy range. Too intense fear can severely impair our daily lives, as in the case of anxiety disorders or panic attacks. So how can fear be kept in balance? It seems obvious that bodily signals may play a crucial role, as fear causes noticeable changes in our bodies: the heart beats faster or breathing becomes shallower. However, how exactly the brain processes this information to ultimately regulate emotions like fear is still largely unknown. 

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Chrustowicz, J., Sherpa, D., Teyra, J., Siong Loke, M., Popowicz, G., Basquin, J., Sattler, M., Rajan Prabu, J., Sidhu, S.S., and Schulman, B.A.
J Mol Biol,2021, 167347.
doi: 10.1016/j.jmb.2021.167347

Multifaceted N-degron recognition and ubiquitylation by GID/CTLH E3 ligases

N-degron E3 ubiquitin ligases recognize specific residues at the N-termini of substrates. Although molecular details of N-degron recognition are known for several E3 ligases, the range of N-terminal motifs that can bind a given E3 substrate binding domain remains unclear. Here, we discovered capacity of Gid4 and Gid10 substrate receptor subunits of yeast "GID"/human "CTLH" multiprotein E3 ligases to tightly bind a wide range of N-terminal residues whose recognition is determined in part by the downstream sequence context. Screening of phage displaying peptide libraries with exposed N-termini identified novel consensus motifs with non-Pro N-terminal residues binding Gid4 or Gid10 with high affinity. Structural data reveal that conformations of flexible loops in Gid4 and Gid10 complement sequences and folds of interacting peptides. Together with analysis of endogenous substrate degrons, the data show that degron identity, substrate domains harboring targeted lysines, and varying E3 ligase higher-order assemblies combinatorially determine efficiency of ubiquitylation and degradation.