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Molecules & Brains, led by Vincent Rehder (Biology), is concerned with the development and the application of molecular tools and probes to address fundamental questions of the development and function of the nervous system

The Molecules and Brains Research Group have started a series of noon meetings in which faculty members will be giving 10 minute presentations introducing their research and highlight possibilities for future collaborations. All interested faculty, students, and post-docs are invited to participate in this event and share in the science and the opportunities offered by the Molecules and Brains Research Group. Upcoming group meetings

Principle Investigators: Dr. Charles Derby / Binghe Wang
Title: Identification & Synthesis of Sea Hare Defensive Compounds

Abstract:
Chemical defenses play an important role in many animals. We have been examining sensory and neural mechanisms of action of chemicals defenses of sea hares against their predators. We have identified an abundant protein in the defensive ink of sea hares: escapin, an L-amino acid oxidase that uses lysine and arginine as its substrates in the production of hydrogen peroxide. We have not yet identified predators against which escapin functions, but we have identified antimicrobial actions for escapin. Interestingly and importantly, escapin's bactericidal effect is mediated by lysine but not arginine, and hydrogen peroxide does not account for this effect. Thus, escapin's other products of oxidation of lysine produce that bactericidal effect, none of which are commercially available. The aim of our proposed research is to synthesize these putative defensive compounds, and to test them against a range of natural predators of sea hares.

Principle Investigators: Lucjan Strekowski / Markus Germann
Title: Search for 5-HT7 Receptor Liglands with potential antidepressant activity

Abstract:
The serotonin (5-HT) receptors belong to the superfamily of G-protein coupled transmembrane receptors. Homology studies indicate that the receptors consist of 7 helical segments that span the lipid bilayer of the cell membrane. The detailed structures of these proteins remain unknown, which is mostly due to crystallization problems. As these receptors are important from a therapeutic point of view, medicinal chemists try to build pharmacophore or receptor models based on the structure of the 5-HT ligands. For example, the PI of this proposal has previously synthesized a large number of novel a1, 5-HT1A, and 5-HT2A receptor ligands and has established structural requirements for 5-HT1A and 5-HT2A receptor selectivity. Most recently, in collaboration with Dr. A. Bojarski of the Institute of Pharmacology , Polish Academy of Sciences, the PI has found novel molecules that are antagonists of the 5-HT7 receptor. As part of this application, work is proposed to synthesize new potential 5-HT7 ligands (Strekowski), to determine their biological activity (5-HT7 affinities) in vitro (Bojarski & Baro), to conduct structure-activity (SAR) and quantitative structure-activity (QSAR) analyses (Strekowski & Germann) and, based on the SAR and QSAR results, to conduct molecular modeling studies aimed at the better understanding of the structure of the 5-HT7 receptor (Germann). The shortterm goal of this proposal is to obtain preliminary results for a submission of a grant application to a major granting agency such as NIH. The antidepressant activity that is associated with binding of antagonists to the 5-HT7 receptor will lay a strong foundation for the search for practical antidepressant agents. Dr. D.J. Baro is the consultant on the biological aspects of the project, and she will be involved in the preparation of the external proposal as co-PI.

Principle Investigators: William Walthall / Gennady Cymbalyuk / Andrey Shilnikov
Title: Intergrating cellular and genetic analyses with mathematical modeling to investigate the cellular network controlling movement in the nematode caenorhabditis elegans

Abstract:

C. elegans moves forward by generating undulating sinuous body waves that begin at the head and propagate to the tail; alternatively the animal moves backward by generating undulating, body waves that begin at the tail and propagate to the head. Serial reconstructions of electron micrographs have revealed a connectivity diagram for the neuronal network that controls forward and backward locomotion. The network is composed of 5 interneurons that innervate 72 excitatory motor neurons that in turn innervate 19 inhibitory motor neurons and 95 body wall muscle cells. The body wall muscles form four strands that generate the traveling body wave. The pair of dorsal strands contracts in synchrony and the ventral pair contracts in synchrony. The undulating pattern of locomotion is generated by the dorsal and ventral contractile waves that are in anti-phase during either forward or backward locomotion (Chalfie et al., 1984). The animals move over different substrates and can vary their speed. However there is much to learn about the dynamics of the neuronal network controlling locomotion, the dynamics of muscular system and the dynamics of their interactions. These relationships produce and control the traveling waves once initiated. It is likely that tactile and proprioceptive feedback are involved; it is also likely that there are redundancies in the mechanisms controlling locomotion.

A paradox that has emerged from both genetic and cellular manipulations is that predicted outcomes of current models for backward movement are more accurate than similar predictions for forward movement. The goal of this proposal is to develop a more accurate means to analyze the contribution of neurons and muscles during forward and backward movement so that we can address the genetic and cellular basis for understanding why forward locomotion is more resilient to perturbations than backward locomotion. Our first aim is to create and analyze high-resolution movies that will aid our understanding of how the neural circuits coordinate waves of muscular contraction and relaxation to create coordinated patterns of locomotion. Motion analysis of the recorded locomotion patterns will be analyzed with the software developed by our team. Key kinematical characteristics will be determined for wildtype animals. These characteristics will be used to construct a mathematical model for nematode locomotion that will include the contributions of components within the neural network and the muscular network that produces the traveling body waves. To test the model we will employ two different types of experimental manipulations: laser ablation and genetic mutants that cause specific alterations in the cellular networks. Comparison between outcomes predicted by the model with those observed from the experimental manipulations will suggest new experiments and allow further improvement of the model and our understanding of locomotion control.