Writing on the ceiling

BrandeisNOW answers the question Who’s been writing on the Physics ceiling?

How does a hard-wired simple circuit generate multiple behaviors?

In a paper appearing in last week’s issue of Neuron, members of the Sengupta Lab and their collaborators from the Bargmann Lab describe how a fixed neural circuit produces multiple behaviors in a context-dependent manner.  The study was led by former Brandeis post-doctoral fellow Kyuhyung Kim in the Sengupta Lab (currently Assistant Professor at DGIST, Korea) and Rockefeller student Heeun Jang in the Bargmann Lab. Also involved in the study were current Brandeis MCB students Scott Neal and Danna Zeiger, and Dongshin Kim, the head of the Brandeis Microfluidics Facility.

For this study the researchers used the nematode Caenorhabditis elegans. The nervous system of C. elegans consists of only 302 neurons (in the adult hermaphrodite) whose anatomical connectivities are well-mapped. Despite its relatively small nervous system, C. elegans exhibits a wide range of behaviors in response to environmental stimuli. For instance, C. elegans exhibits varied responses to pheromones – small chemical substances used for intra-specific communication. Some pheromones are repulsive to adult hermaphrodite C. elegans but neutral to male C. elegans. However, reducing the function of the neuropeptide Y-like receptor NPR-1 results in hermaphrodites now exhibiting neutral pheromone responses and males becoming strongly attracted. The researchers asked how the sex and neuromodulatory state of the animal allows it to interpret the pheromone stimulus differently to generate distinct behavioral responses.

To answer this question, the researchers used behavioral assays, genetic manipulations of neuronal output, and in vivo measurements of pheromone-induced neuronal activity (using genetically encoded calcium sensors and customized microfluidics devices designed by the Brandeis Microfluidics Facility). They found that flexible output of a neuronal ‘hub-and-spoke’ circuit motif was responsible for generating these distinct pheromone responses under different conditions.

In this circuit, pheromone-sensing neurons ASK and ADL are connected to the central RMG motor/interneuron by gap junctions (see Figure). Jang et al. showed that in hermaphrodites with high levels of NPR-1 activity, the ADL sensory neurons respond strongly to a specific pheromone component and drive avoidance behavior via their chemical synapses to command interneurons for locomotion. However, sexual dimorphism in the circuit results in males having reduced ADL pheromone responses.  Moreover, Jang et al. showed that ADL synaptic output in males is further decreased via RMG and ASK-mediated antagonism (see Figure). As a result, males are indifferent to this pheromone.

The next issue the authors addressed is the role of NPR-1 activity in regulating pheromone responses. The Bargmann Lab had previously shown that high NPR-1 activity inhibits RMG, and under these conditions, pheromone responses of the ASK sensory neurons are low. Conversely, when NPR-1 activity is reduced or absent, ASK pheromone responses are enhanced. Jang et al. found that in the absence of NPR-1 activity, ADL chemical synaptic output in response to pheromones is antagonized by the RMG-ASK gap junction circuit. In other words, avoidance mediated by ADL chemical synaptic output is balanced by attraction mediated by the RMG-ASK gap junction circuit, resulting in hermaphrodites being neither attracted to nor avoiding this pheromone. In males with reduced NPR-1 activity the same effects are observed, however, since the ADL pheromone response is already lower in males, the RMG-ASK attraction-mediating arm “wins” resulting in attraction to pheromones.  The authors refer to these as overlapping ‘push-pull’ circuits in analogy with electronic circuits.

These results begin to explain how a small fixed circuit can generate a remarkable range of behaviors via alteration of sensory response properties as well as choice of specific synaptic output pathway as a function of neuromodulatory state and sex. The general theme of a circuit functioning differently under different neuromodulatory conditions has been extensively studied in the Marder Lab in the crustacean nervous system, and is an important principle to be kept in mind when interpreting functionality from structurally described connectomes.

Jang H(*), Kim K(*), Neal SJ, Macosko E, Kim D, Butcher RA, Zeiger DM, Bargmann CI, Sengupta P. Neuromodulatory State and Sex Specify Alternative Behaviors through Antagonistic Synaptic Pathways in C. elegans. Neuron. 2012;75(4):585-92.

Sept 18 Symposium on Stem Cell Genetics

On September 18th, 2012, the Molecular and Cell Biology graduate students supported by our  Genetics Training Grant from NIGMS will be hosting a symposium entitled “Stem Cell Genetics: Insights and Applications”. We will be joined by four distinguished scientists who will be presenting their recent work:

Rudolf Jaenisch (Whitehead Institute), our Keynote Speaker, will speak to us about the epigenetic regulation of gene expression in development and cell differentiation;
Constance Cepko (Harvard Medical School) will present her work on the development and degeneration of the vertebrate central nervous system, using the retina as a model;
Fernando Camargo (Harvard Stem Cell Institute) will talk about the molecular basis of tissue size regulation and the role of transcription factors and micro RNAs in hematopoietic stem cell fate;
Konrad Hochedlinger (MGH) will present work on mechanisms underlying pluripotency in embryonic stem cells and nuclear reprogramming.

The talks will take place in the Shapiro Campus Center Theater, and we also invite you to join us at the subsequent Poster Session and Reception. Current and former trainees supported by the Genetics Training Grant will be presenting posters from 3:40 to 5:00 PM on the 2nd floor of the Shapiro Science Center. In addition, all life sciences graduate students are encouraged to present posters.

The entire event is free and open to the public. For planning purposes, we ask anyone attending the symposium and/or presenting a poster to pre-register at http://www.bio.brandeis.edu/gtg_symposium/ by September 10th, 2012. You can also visit this website to see the symposium schedule, and to see the list of poster titles after registration is complete.

Please join us for this exciting symposium showcasing genetics at Brandeis!

Blanca Carbajal-Gonzalez
Marissa Donovan
Adam Johnston
Cara Pina
Andy Russell
Mike Spellberg

What a failed drug does (and is there hope for latrepirdine?)

Latrepirdine (Dimebon) was initially used as an antihistamine drug in Russia. It was later found to be neuroprotective, and entered phase II clinical trials in the US for both Alzheimer’s disease and Huntington’s disease. However, Dimebon failed in a US-based phase II replication trial of a prior successful Russian phase II trial of mild-to-moderate AD. Given the initial promise of the drug and split results,  as well as the lack of treatments for neurodegenerative diseases, there in is significant interest in understanding the underlying molecular mechanism(s) for the drug’s effects.

In a paper appearing this week in Molecular Psychiatry, Brandeis researchers in the Petsko-Ringe lab, including postdoc Shulin Ju and undergraduate Jessica Liken ’11, used yeast models of neurodegenerative disease associated proteins to show that Dimebon specifically protects yeast from the cytotoxiciy of α-synuclein, a protein involved in Parkinson’s disease. They further showed that protection is mediated through its up-regulation of autophagy pathway. In collaboration with Sam Gandy‘s group at Mount Sinai School of Medicine, these findings were further confirmed and validated in neuronal cell and animal models.

Given these observations, disparities in the contribution of α-synuclein to the neuropathology between the Russian and US Dimebon studies might also explain, at least in part, the inconsistency of the cognitive benefit in the two trials. If this speculation is correct, then it may be interesting to test for benefits of Dimebon in treating synucleinopathies such as Parkinson’s disease, Lewy body dementia, REM sleep disorder and/or multiple system atrophy.

see also: press release from Mt. Sinai Alzheimer’s Diesease Research Center

Steele JW (*), Ju S(*), Lachenmayer ML(*), Liken J, Stock A, Kim SH, Delgado LM, Alfaro IE, Bernales S, Verdile G, Bharadwaj P, Gupta V, Barr R, Friss A, Dolios G, Wang R, Ringe D, Protter AA, Martins RN, Ehrlich ME, Yue Z, Petsko GA, Gandy S. Latrepirdine stimulates autophagy and reduces accumulation of alpha-synuclein in cells and in mouse brain. Molecular psychiatry. 2012.

Steele JW(*), Lachenmayer ML(*), Ju S, Stock A, Liken J, Kim SH, Delgado LM, Alfaro IE, Bernales S, Verdile G, Bharadwaj P, Gupta V, Barr R, Friss A, Dolios G, Wang R, Ringe D, Fraser P, Westaway D, St George-Hyslop PH, Szabo P, Relkin NR, Buxbaum JD, Glabe CG, Protter AA, Martins RN, Ehrlich ME, Petsko GA, Yue Z, Gandy S. Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer’s mouse model. Molecular psychiatry. 2012.

Bite Sci-zed Videos

Alex Dainis ’11 (Biology / Film, Television and Interactive Media) explains and entertains in her “Bite SCI-zed” youtube videos about science.

Memorandum of Understanding between the Brandeis Materials Research Science and Engineering Center (MRSEC) and the Robot Research Initiative (RRI), Chonnam National University, South Korea

 

Dr. Jong-Oh Park (left) and Dr. Seth Fraden pause in front of the MOU banner during the inauguration ceremony.

On August 10, 2012 Dr. Jong-Oh Park and Dr. Sukho Park, Director and Principal Investigator of the Robot Research Initiative (RRI), respectively, visited Brandeis as part of an inauguration ceremony of the Memorandum of Understanding (MOU) between the Brandeis Materials Research Science and Engineering Center (MRSEC) (Director: Seth Fraden, PhD) and the RRI (Director: Jong-Oh Park, Dr.-Ing). The RRI is a world leader in the field of robotics, focusing on microscale engineering applications and surgery, while the Brandeis MRSEC program focusses on biomaterials and active matter. The two institutions have agreed to work together to transform cutting-edge biophysical science into engineering applications for drug delivery.

Collaboration between the two institutions was first established on March 1, 2012, with a three-year subcontract (KRW  120,000,000 / yr) awarded to the MRSEC by the RRI for the development of micro-swimming robots based on synthetic cilia (PI: Dongshin Kim, co-PI: Zvonimir Dogic). Dr. Fraden welcomed the new Memorandum, saying that it would fortify the collaboration efforts of both institutions.

As part of the exchange program laid out by the MOU, Dr. Sukho Park is planning to visit Brandeis in 2013 to spend a year working on the development of micro-actuators based on microtubules and active hydrogels. There are opportunities for the exchange of students between our two universities.

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