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Role of Neurotransmitters and other such Neurosignaling Molecules

Curator: Larry H Bernstein, MD, FCAP

Circuit Dynamo

Eve Marder’s quest to understand neurotransmitter signaling is more than 40 years old and still going strong.

By Anna Azvolinsky | October 1, 2015

http://www.the-scientist.com//?articles.view/articleNo/44061/title/Circuit-Dynamo/

Eve Marder has her junior-year college roommate to thank for her initial fascination with neuroscience. “She came back from the first day of an abnormal psychology course and said, ‘Eve, you have to take this course! The professor has an English accent, wears a three-piece suit, and has a dueling scar,’” recalls Marder, a professor of biology at Brandeis University in Waltham, Massachusetts. “Of course, I agreed. What could be more romantic than that?” The course focused on schizophrenia, which at the time, in 1967, was thought to stem from a genetic predisposition coupled with competing sensory inputs or stressors that the brain couldn’t turn off. “The professor, in passing, said that some people think there may be a [cellular] basis for schizophrenia, including deficient inhibition of electrochemical signals in the brain. I thought, ‘What does that mean, inhibition in the brain?’” says Marder. To find out, she read everything she could about the role of inhibitory neurotransmitters—and, in the process, decided she would become a neuroscientist.

Marder began her graduate studies in biology at the University of California, San Diego (UCSD) in 1969. “I was a molecular biologist at heart because I was intrigued by molecules and cells rather than the large systems many were studying,” she says. That same year, a new assistant professor, Allen Selverston, joined the department. “He was the only real neurobiologist in the biology department, so I decided to work with him.” In the summer of 1970, Selverston introduced Marder to the lobster stomatogastric ganglion (STG), a then-new and relatively simple model for studying neuronal connectivity that she has studied ever since.

“Every time we were really stuck—not trivially, but stuck on a deep intellectual level—that has driven us to rethink, go sideways, or turn the problem inside out and come up with something new.”

Here, Marder explains why her choice to become a scientist during the 1960s counterculture was more conservative than what her friends and peers were up to, how her penchant for beautifully written neuropharmacology papers led her to a postdoc in Paris, and why we are not training too many PhDs.

Marder’s Momentum

A political slant. Growing up in the 1960s in Westchester County, New York, at the height of the civil rights movement, Marder was involved in a local youth civil rights group. In 1965, when she entered Brandeis University as a freshman, Marder thought she wanted to be a civil rights lawyer. But during her sophomore year, a post–World War II European history course that required memorization of every country’s political parties, “all alphabet soup and boring, with an odious black textbook with double columns of text,” changed her mind. After taking the final, Marder walked out of the lecture hall and pressed her mental delete button. “I forgot all of it on purpose and changed my major to biology,” she says.

Perfect sense. “I remember in high school when we learned about respiration and photosynthesis and the other molecular machinery hiding inside things that on the surface looked solid. I realized all of these molecular dynamics were inside cells, and that is what really fascinated me—these mechanisms of biological systems. Biology just made complete sense to me.”

The road less travelled. Before graduating and heading off to grad school, Marder presented an honors thesis on muscle biochemistry. At the time, most students who did an honors science thesis were men headed to medical school. “I remember having a funny conversation with one of them my senior year. He asked if I was also applying to medical school, and after I said no, said, ‘But why not? You’d get in.’ I said, ‘But why would I want to go to medical school if I don’t want to be a doctor?’ And he just kept saying, ‘But you would get in,’ and ‘Why wouldn’t you want to be a doctor?’”

A new model. When Marder joined Selverston’s lab as his first graduate student, he had just learned how to make in vitro preparations of the STG. “It was brand new and a simple example of a pattern-generating circuit,” says Marder. The STG, just 30 neurons, controls the rhythmic movement of the lobster’s stomach muscles during digestion, similar to the circuitry that controls breathing or walking. The STG cellular circuitry continues to generate motor patterns in vitro that resemble in vivo action potentials, but without the need for external stimuli. “This was something not possible then with vertebrate neuronal preparations.”

Thinking outside the circuit. For her graduate thesis, Marder set out to identify the neurotransmitters of the STG. “It was already clear that there were a bunch of different molecules used as transmitters, but no one had any idea why there were so many. There were researchers studying GABA, dopamine, serotonin, and other neurotransmitters separately, but no one was asking why there were so many transmitters in the brain and what their functional organization was. I wanted to understand the whole circuitry,” she says. Marder was the first to describe neurotransmitters in the STG. She discovered that acetylcholine functions as both an excitatory and inhibitory transmitter in some of the STG’s neurons. “This turned into a lifelong chase into transmitters and modulators in functional circuits.”

Marder’s Merits

A singular vision. Marder learned a lot in graduate school, but her desire to understand the molecular underpinnings of neuronal communication remained strong. “At the time, the field was interested in working out wiring diagrams, because the scientists, who mostly came from electrical engineering, thought the neuron circuits worked like electrical circuits. My advisor echoed what many said at the time. ‘What you are doing is just pharmacology, it doesn’t really matter.’ In their minds, it only mattered whether the signal was inhibitory or excitatory; the actual signaling molecule wasn’t going to matter.”

A conservative choice. “Of the people I graduated college with, half were going to change the world, some were going to live on a commune, some guys ran away to Canada to avoid the draft, and others were going to a farm in Vermont to grow their own food. Long-term career plans were sort of weird for us—we were all counterculture. Graduate school at the time was a very conservative thing to be doing amongst my friends. When I finished my PhD, I just thought about the next step but didn’t have long-term career goals.” Marder spent a year as a postdoc in David Barker’s laboratory at the University of Oregon and then, in December 1975, with a fellowship from the Helen Hay Whitney Foundation, set off for Paris to work in JacSue Kehoe’s laboratory. “She had written, just head and shoulders, the most beautiful neuropharmacology papers. I had read every paper in the field and these were just so much better than what anyone else was doing.” There, Marder collaborated with Danielle Paupardin-Tritsch, publishing three papers, including a study of the responses of the crab STG to three different neurotransmitters.

More than on/off switches. When she came back to the U.S. in 1978, Marder joined the faculty at Brandeis as an assistant professor in the biology department and has remained there ever since. Along with her first graduate student, Judith Eisen, whom Marder credits with early successes in her lab, Marder provided the initial evidence for the existence of neuromodulators that can prompt longer-term changes influencing how neurons respond to fast-acting neurotransmitters. Eisen initially characterized the pharmacology of the synapses, figuring out which neurons had receptors for which signaling molecules.

Predicting behavior. In 1989, Marder met Larry Abbott, then a theoretical physicist at Brandeis. “It was clear that for a true mechanistic understanding of how the dynamics of the circuit arise from its components, we needed to be able to do modeling,” she recalls. With Abbott, Marder’s lab developed the “dynamic clamp,” a method that uses a computer to introduce a conductance—the ease with which an electric current can pass through a circuit—into neurons to model their behavior. They also worked out thenegative-feedback system within neurons that allows for changes in parameters while maintaining their normal function. “We were building models and they were fragile. We would change a parameter, and the model would crash. I kept saying that the cells don’t crash all the time, so how do cells balance their number of ion channels? What we came up with is a very simple way of thinking about this.”

The bigger picture. “The big themes that have come from the STG model, and partly from our lab, are that neuronal circuits are multiply modulated, that modulators reconfigure circuits, and that there have to be pretty simple global regulatory mechanisms that help neurons maintain stable electrical activity despite the fact that their ion channels—the proteins in the cell membranes that carry out electrical signaling—are being constantly replaced.”

Heterogeneity. For the last 10 years, Marder’s lab has been working to understand the extent of variability within individual nervous systems that still allows the systems to remain stable. “For quite a long time, people thought that all nervous systems had to be very tightly tuned,” she says. “And what we are seeing is that, actually, they can be quite variable and change over time and still work well enough because there is a lot of degeneracy in the way circuits are constructed.”

Marder’s Mind

The new normal. Before 1968, many life-science PhD programs had informal quotas, restricting the number of women accepted, says Marder. But that year, the draft law changed, and graduate school enrollment was no longer a valid way to defer the draft. Life-science graduate programs suddenly switched to gender parity. Marder’s class at UCSD was the first to have a large proportion of women—13 women out of a class of 30; in prior years there were only two or three women per class of 30. “There was a lot of hubbub about it. ‘What are we going to do with all these women? Civilization as we know it will end!’ was how the professors talked about it. But by May that year they had completely forgotten about it,” Marder laughs.

The big picture. “I have always been good at figuring out how to use the same nervous system to ask a bunch of different questions. And I’ve always been pretty good at finding the general principles amongst the idiosyncrasies of a neuronal system. I think that is key if you work on model organisms.”

The benefits of being stuck. “Everything important we did in the lab arose because something wasn’t working as expected. In Judith’s original work, we finally realized after getting different answers from every experiment that there were nine different possible outcomes connecting only three neurons, all consistent with our recordings. So we had to design a completely different experiment. The activity-dependent regulation work arose only because of my total frustration with having to tune conductance-based models. So every time we were really stuck—not trivially, but stuck on a deep intellectual level—that has driven us to rethink, go sideways, or turn the problem inside out and come up with something new.”

A worrisome trend. “I am very concerned with science right now because I think the push to have high-impact papers is having a deleterious effect on the way people design experiments, and it definitely has a deleterious effect on the way researchers write their papers. The most common critique you see from reviewers is that authors are overselling their work, and it’s because the researchers believe high-impact papers are necessary for their careers. So the science we are doing is being warped.”

A scientist in the rough. Marder recently wrote a commentary against the push to decrease the number of students accepted into science PhD programs.“We’re very bad at spotting who is going to be a good scientist and who isn’t [based on graduate-school applications],” she says. “While students are in college, they are fundamentally consumers of knowledge, and becoming a scientist means you have to learn to be a creator of new knowledge. But the tools that allow you to be a great consumer of knowledge don’t set you up for the kind of frustrations and sidewise thinking and problems that you have to confront to be a knowledge creator. You can take the best undergrad students, and they may not be the best graduate students. And the ones who complete the best PhDs may not be the ones that stay in the field. I think it comes down to drive, persistence, willingness to confront failure, creativity, passion—all of these other attributes that we can’t measure easily on an application. So to take just the top undergraduates, you’re going to be missing many of the best ones. The real problem here is that the US government is not funding enough science.”

Potential to fly. “It’s crazy right now because biology in general, and neuroscience specifically, is at this extraordinary moment in time when there is so much really wonderful science that can now be done that was inconceivable even 10 years ago. We are at this incredibly exciting moment for discovery and at the same time the field is being destroyed by extraordinary anxiety about [funding] resources. If we didn’t have this extent of resource anxiety we could be flying, but the funding situation is crippling, and we are crippling ourselves with this incredible collective anxiety.”

Greatest Hits

• Discovered that acetylcholine acts as a neurotransmitter in the crustacean stomatogastric ganglion (STG), where it functions as both an excitatory and an inhibitory signal
• Among the first to describe neuromodulators that acted differently than neurotransmitters, resulting in long-lasting effects on neuronal circuits
• Determined that neurons are robust, maintaining their electrical activity patterns despite the turnover of channels and other changes
• With colleagues, developed the “dynamic clamp,” a neurophysiological method that can finely manipulate nerve cells and simulate neuronal and muscle systems using computer-adjusted parameters
• Showed that there are multiple sets of parameters in neurons and networks that can produce similar output patterns

Eve Marder, Ph.D.
Professor of Biology
Member, US National Academy of Sciences

Modulation of Neural Networks

B.A., Brandeis University
Ph.D., University of California, San Diego

Contact Information

One of the fundamental problems in neuroscience is understanding how circuit function arises from the intrinsic properties of individual neurons and their synaptic connections. Of particular interest to us today is the extent to which similar circuit outputs can be generated by multiple mechanisms, both in different individual animals, or in the same animal over its life-time. As an experimental preparation we exploit the advantages of the central pattern generating circuits in the crustacean stomatogastric nervous system. Central pattern generators are groups of neurons found in vertebrate and invertebrate nervous systems responsible for the generation of specific rhythmic behaviors such as walking, swimming, and breathing. The central pattern generators in the stomatogastric ganglion (STG) of lobsters and crabs are ideal for many analyses because the STG has only about 30 large neurons, the connectivity is established, the neurons are easy to record from, and when the stomatogastric ganglion is removed from the animal, it continues to produce rhythmic motor patterns.

Work in the lab centers on three main questions:

1. How do neuromodulators and neuromodulatory neurons reconfigure circuits so that the same group of neurons can produce a variety of behaviorally relevant outputs?
2. How can networks be both stable over the lifetime of the animal despite ongoing turnover of membrane proteins such as channels and receptors? How is network stability maintained over long time periods? To what extent do similar network outputs result from different underlying mechanisms or solutions?.
3. How variable are the sets of parameters that govern circuit function across animals? How can animals with disparate sets of circuit parameters respond reliably to perturbations such as neuromodulators and temperature?

To address these questions we employ electrophysiological, biophysical, computational, anatomical, biochemical, and molecular techniques.

See references at bottom

Rewarding Companions

Oxytocin and social contact together modulate endocannabinoid activity in the mouse brain, which could help explain the prosocial effects of marijuana use.

By Rina Shaikh-Lesko | October 26, 2015

http://www.the-scientist.com//?articles.view/articleNo/44338/title/Rewarding-Companions/

The mammalian central nervous system is studded with receptors that bind with a small number of endogenous cannabinoids, as well as those found in marijuana. Marijuana is known to promote heightened social connection, but the mechanism for this phenomenon was not well understood. According to a paper published today (October 26) in PNAS, it is social interaction between mice plus oxytocin—the hormone involved in social bonding—that drive cannabinoid activity in the animals’ brains.

“It was a great surprise to see how powerful the effects of social contact are on production of anandamide in select regions of the brain,” said study coauthor Daniele Piomelli, a neuroscientist at the University of California, Irvine.

The brain has two known cannabinoid receptors, types 1 and 2 (CB1 and CB2). Two main endocannabinoids bind with CB1, anandamide and 2-Arachidonoylglycerol (2-AG), as do plant cannabinoids such as tetrahydrocannabinol (THC), the main psychoactive compound in marijuana.

To study the behavioral effects of oxytocin, endocannabinoids, and social interaction, Poimelli and his colleagues isolated mice for 24 hours, then allowed them to either socialize with other mice or remain in isolation for another three hours. The researchers found that the mice that were allowed to socialize had higher levels of anandamide, but not 2-AG, in their nucleus accumbens.

“I was personally very surprised by the fact that it’s such a simple thing—just taking an animal, isolating it for three hours, then putting it back with its buddies, or not—would make such a difference in a single chemical in a specific area of the brain,” Piomelli told The Scientist.

In mice lacking an enzyme that degrades anandamide, fatty acid amid hydrolase (FAAH), the researchers observed more prosocial behavior. When the researchers used a pharmacological compound to block FAAH, they also saw prosocial behavior, even among the mice that were isolated. Piomelli and his colleagues also found that stimulating oxytocin receptors promoted the action of anandamide, while blocking oxytocin receptors seemed to stifle anandamide. “The effects of oxytocin are virtually entirely dependent on the ability of oxytocin to drive the formation of anandamide,” Piomelli said.

The finding may also point to a possible treatment for autism spectrum disorders, which can involve social-interaction difficulties. (The team initially homed in on the interaction of oxytocin and anandamide while studying autism mouse model of autism.)

“The convincing evidence that enhancing the activation of CB1 receptors by endogenously released anandamide, but not by the endocannabinoid, [2-AG] . . . could be a new strategy for ameliorating some of the unwanted symptoms of disorders like autism,” Roger Pertwee, a neuropharmacologist at the University of Aberdeen, U.K., who was not involved with the study, wrote in an email. “The important next step will be to test the clinical importance of these findings in studies performed with human autistic subjects—to test whether at least some of their autistic symptoms can be ameliorated by a FAAH inhibitor.”

Piomelli said he would like to further explore why anandamide and 2-AG appear to act so differently in relation to oxytocin. The latter endocannabinoid is much more abundant than anandamide. “Anandamide is like the little brother and 2AG is like the big brother,” Piomelli said. He and his colleagues are looking into whether 2-AG plays a role in other forms of reward-oriented behavior.

10. Wei et al., “Endocannabinoid signaling mediates oxytocin-driven social reward,” PNAS, http://dx.doi.org:/10.1073/pnas.1509795112,2015

Jacob Hooker: Weaver of Brain Science

Director of Radiochemistry, Athinoula A. Martinos Center for Biomedical Imaging; Associate Professor, Harvard Medical School. Age: 35

http://www.the-scientist.com//?articles.view/articleNo/44064/title/Jacob-Hooker–Weaver-of-Brain-Science/

As a kid growing up outside Asheville, North Carolina, Jacob Hooker spent a lot of time tinkering underneath cars with his mechanic father. But it was a guest speaker in his high school chemistry class who provided the spark that propelled him into research. Kent Hester, director of student and career services at North Carolina State University’s College of Textiles, told students about opportunities for studying textile chemistry. Hooker applied to NC State and won a $5,000-per-year North Carolina Textile Foundation merit scholarship, graduating in 2002. “That was one of the largest college-based scholarships on NC State’s campus at the time,” Hester recalls.

Hooker published four papers while at NC State, but when the time came to apply for grad school, he says he was “geographically driven” to branch out from his home state and explore the western half of the country. On a visit to the University of California, Berkeley, he met Matt Francis, a young biochemist who had just set up his lab the year before.

“From the very second I met him, I could just tell he was a very special individual,” says Francis, who develops techniques for the chemical modification of proteins. “He’s got a certain intensity and scientific sophistication to him that supersedes any kind of training he had.” While in Francis’s lab, Hooker published a technique for chemically modifying the interior surface of a viral capsid that would pave the way for viral drug-delivery methods.¹

Near the end of his PhD research, Hooker learned about radioactive label­ing and radioisotopes from Jim O’Neil at Lawrence Berkeley National Lab. Then, at a nuclear medicine meeting in the winter of 2006, he attended a presentation given by Brookhaven National Lab organic chemist Joanna Fowler about using specially synthesized radioactive molecules and positron emission tomography (PET) technology to study the neurobiology of addiction. “It was incredibly exciting that a chemist could label a small molecule and observe something fundamental about the brain using that molecule they made,” Hooker says.

He immediately wrote to Fowler, asking if she had an open postdoc position in her lab. “She said she didn’t, but she’d be willing to help me look for money to make one,” Hooker says. He submitted an NIH training proposal as he was finishing his PhD dissertation and got the grant. Hooker moved to Fowler’s lab in 2007. “Getting him was like winning the lottery,” says Fowler, now a professor emeritus at Brookhaven.

Fowler introduced Hooker to PET, which is used in concert with radionucleotide tracers to image molecules in the active brain. Hooker and colleagues built new radiotracers that target novel molecules to gain insights into their in vivo function. He also helped develop a new method for quickly and efficiently labeling the carbamate functional groups with carbon-11 (¹¹C), one of the most important isotopes for PET research.²

Hooker started at the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital in 2009, overseeing the construction of the center’s new MRI/PET facility while setting up his own lab. Earlier this year, Hooker and Mass General neuroscientist Marco Loggia devised a PET imaging strategy to record the activation of glial cells in the brains of chronic-pain patients.³ With other colleagues Hooker developed a novel histone deacetylase–binding radiotracer, [¹¹C]Martinostat, which could open an unprecedented window into DNA expression in the brain.⁴

“He’s the best I’ve ever seen,” Fowler says. “He’s going to ask questions we haven’t thought of before.”

References

1. J.M. Hooker et al., “Interior surface modification of bacteriophage MS2,” J Am Chem Soc, 126:3718-19, 2004. (Cited 212 times)
2. J.M. Hooker et al., “One-Pot, direct incorporation of [¹¹C]-CO2 into carbamates,” Angew Chem Int Ed, 48:3482-85, 2009. (Cited 68 times)
3. M.L. Loggia et al., “Evidence for brain glial activation in chronic pain patients,” Brain, 138:604-15, 2015. (Cited 8 times)
4. C. Wey et al., “In vivo imaging of histone deacetylases (HDACs) in the central nervous system and major peripheral organs,” J Med Chem, 57:7999-8009, 2014. (Cited 6 times)

Marder Recent Publications:

Swensen, A.M., Golowasch, J., Christie, A.E., Coleman, M.J., Nusbaum, M.P., and Marder, E. (2000) GABA and GABA responses in the stomatogastric ganglion of the crab, Cancer borealis. J. Exp. Biol.,203: 2075-2092. [abstract]

Richards, K.S. and Marder, E. (2000) The actions of crustacean cardioactive peptide on adult and developing stomatogastric ganglion motor patterns. J. Neurobiol. 44: 31-44. [abstract]

Swensen, A.M. and Marder, E. (2000) Multiple peptides converge to activate the same voltage-dependent current in a central pattern generating circuit. J. Neurosci. 20: 6752-6759. [abstract]

Marder, E. (2000) Colored Chalk. Current Biol., 10: R613. [pdf file]

Marder, E. (2000) Models identify hidden assumptions. Nature Neurosci. 3: 1198.

Marder, E. (2000) Motor pattern generation. Curr. Opin. Neurobiol. 10: 691-698. [abstract]

Nusbaum, M.P., Blitz, D.M., Swensen, A.M., Wood, D., and Marder, E. (2001) The roles of co-transmission in neural network modulation. TINS 24: 146-154. [abstract]

Marder, E. (2001) Moving rhythms. Nature, 410: 755.

Soto-Treviño, C., Thoroughman, K.A., Marder, E., and Abbott, L.F. (2001) Activity-dependent modification of inhibitory synapses in models of rhythmic neural networks. Nature Neuroscience, 4: 297-303. [abstract]

Swensen, A.M. and Marder, E. (2001) Modulators with convergent cellular actions elicit distinct circuit outputs. J. Neuroscience, 21: 4050-4058. [abstract]

Goldman, M.S., Golowasch, J., Marder, E., and Abbott, L.F. (2001) Global structure, robustness, and modulation of neuronal models. J. Neuroscience, 21: 5229-5238. [abstract]

Marder, E. and Bucher, D. (2001) Central pattern generators and the control of rhythmic movements. Current Biol., 11: R986-R996. [abstract]

Li, L., Pulver, S.R., Kelley, W.P., Thirumalai, V., Sweedler, J.V., and Marder, E. (2002) Orcokinin peptides in developing and adult crustacean stomatogastric nervous systems and pericardial organs. J. Comp. Neurol., 444:227-244.

Golowasch, J., Goldman, M., Abbott, L.F, and Marder, E. (2002) Failure of averaging in the construction of conductance-based neuron models. J. Neurophysiol., 87: 11291131. [abstract]

Thirumalai, V. and Marder, E. (2002) Colocalized neuropeptides activate a central pattern generator by acting on different circuit targets. J. Neuroscience, 22: 18741882. [abstract]

Pulver, S.R. and Marder, E. (2002) Neuromodulatory complement of the pericardial organ in the embryonic lobster, Homarus americanus. J. Comp. Neurol., 451: 79-90.

Marder, E. (2002) Non-mammalian models for studying neural development and function. Nature, 417: 318-321. [abstract]

Marder, E. and Thirumalai, V. (2002) Cellular, synaptic, and network effects of neuromodulation. Neural Networks, 15: 479-493. [abstract]

Marder, E. and Prinz, A.A. (2002) Modeling stability in neuron and network function: the role of activity in homeostasis. BioEssays, 24:1145-1154. [abstract]

Marder, E. and Prinz, A.A. (2003) Current Compensation in neuronal homeostasis. Neuron, 37: 2-4. [abstract]

Abbott, L.F., Thoroughman, K., Prinz, A., Thirumalai, V. and Marder, E. (2003) Activity-dependent modification of intrinsic and synaptic conductances in neurons and rhythmic networks. In Van Ooyen, A., ed. Modeling Neural Development (MIT Press, Cambridge MA).

Richards, K.S., Simon, D.J., Pulver, S.R., Beltz, B.S. and Marder, E. (2003) Serotonin in the developing stomatogastric system of the lobster, Homarus americanus. J. Neurobiol. 54: 380-392. [abstract]

Prinz, A.A., Thirumalai, V. and Marder, E. (2003) The functional consequences of changes in the strength and duration of synaptic inputs to oscillatory neurons. J. Neurosci. 23: 943-954. [abstract]

Pulver, S.R., Thirumalai, V., Richards, K.S. and Marder, E. (2003) Dopamine and histamine in the developing stomatogastric system of the lobster, Homarus americanus. J. Comp. Neurol 462: 400-414. [abstract]

Bucher, D., Thirumalai, V. and Marder, E. (2003) Axonal dopamine receptors activate peripheral spike initiation in a stomatogastric motor neuron. J. Neurosci., 23: 6866-6875. [abstract]

Luther, JA, Robie AA, Yarotsky J, Reina C, Marder E, and Golowasch J. (2003) Episodic Bouts of Activity Accompany Recovery of Rhythmic Output By a Neuromodulator- and Activity-Deprived Adult Neural Network. J. Neurophysiol. 90:2720-2730. [abstract] [download article]

Li, L., Kelley, W.P., Billimoria, C.P., Christie, A.E., Pulver, S.R., Sweedler, J.V., and Marder, E. (2003) Mass spectrometric investigation of the neuropeptide complement and release in the pericardial organs of the crab, Cancer borealis. J. Neurochem, 87:642-656. [abstract]

Birmingham, J.T., Billimoria, C.P., DeKlotz, T.R., Stewart, R.A. and Marder, E. (2003) Differential and history dependent modulation of a stretch receptor in the stomatogastric system of the crab, Cancer borealis. J. Neurophysiol, 90: 3608 – 3616. [abstract]

Prinz, A.A., Billimoria, C.P, and Marder, E. (2003) An alternative to hand-tuning conductance-based models: construction and analysis of data bases of model neurons. J. Neurophysiol., 90:3998-4015. [abstract] [Download Article]

Christie, A.E., Stein, W., Quinlan, J.E., Beenhakker, M., Marder, E., and Nusbaum, M.P. (2003) Actions of a histaminergic/peptidergic projection neuron on rhythmic motor patterns in the stomatogastric nervous system of the crab, Cancer borealis. J. Comp. Neurol., 469:153 – 169 [abstract]

Mahadevan A, Lappe J, Rhyne RT, Cruz-Bermudez ND, Marder E, Goy MF. (2004) Nitric oxide inhibits the rate and strength of cardiac contractions in the lobster Homarus americanus by acting on the cardiac ganglion. J Neurosci. 24:2813-24. [abstract]

Prinz AA, Abbott LF, Marder E. (2004) The dynamic clamp comes of age. Trends Neurosci. 27:218-24.

Goaillard JM, Schulz DJ, Kilman VL, Marder E. (2004) Octopamine modulates the axons of modulatory projection neurons. J Neurosci. 24(32):7063-73. [abstract]

Pulver SR, Bucher D, Simon DJ, Marder E. (2004) Constant amplitude of postsynaptic responses for single presynaptic action potentials but not bursting input during growth of an identified neuromuscular junction in the lobster, Homarus americanus. J Neurobiol. 2005 Jan;62(1):47-61. [abstract]

Destexhe A, Marder E.(2004) Plasticity in single neuron and circuit computations. Nature. 431:789-95. [abstract]

Prinz AA, Bucher D, Marder E. (2004) Similar network activity from disparate circuit parameters. Nat Neurosci. 7:1345-52. [abstract]

Bucher D, Prinz AA, Marder E. (2005) Animal-to-animal variability in motor pattern production in adults and during growth. J Neurosci. 25:1611-9. [abstract]

Marder E, Rehm KJ.(2005) Development of central pattern generating circuits. Curr Opin Neurobiol. 15:86-93. [abstract]

Soto-Trevino C, Rabbah P, Marder E, Nadim F. (2005) A computational model of electrically coupled, intrinsically distinct pacemaker neurons. J Neurophysiol. 94:590-604. [abstract]

Marder E, Bucher D, Schulz DJ, Taylor AL. (2005) Invertebrate central pattern generation moves along, Curr Biol. 15:R685-99. [abstract]

Billimoria CP, Li L, Marder E. (2005) Profiling of neuropeptides released at the stomatogastric ganglion of the crab, Cancer borealiswith mass spectrometry. J Neurochem. 95:191-9. [abstract]

Thirumalai V, Prinz AA, Johnson CD, Marder E. (2006) Red pigment concentrating hormone strongly enhances the strength of the feedback to the pyloric rhythm oscillator but has little effect on pyloric rhythm period. J Neurophysiol. 95:1762-70. [abstract]

Schulz DJ, Goaillard JM, Marder E. (2006) Variable channel expression in identified single and electrically coupled neurons in different animals, Nat Neurosci. 9:356-62. [abstract]

Cruz-Bermudez ND, Fu Q, Kutz-Naber KK, Christie AE, Li L, Marder E. (2006) Mass spectrometric characterization and physiological actions of GAHKNYLRFamide, a novel FMRFamide-like peptide from crabs of the genus Cancer. J Neurochem. 2006 May;97:784-99. [abstract]

Bucher D, Taylor AL, Marder E. (2006) Central pattern generating neurons simultaneously express fast and slow rhythmic activities in the stomatogastric ganglion. J Neurophysiol. 2006 Jun;95:3617-32. [abstract]

Taylor AL, Hickey TJ, Prinz AA, Marder E. (2006) Structure and visualization of high-dimensional conductance spaces. J Neurophysiol. 2006 Aug;96:891-905. [abstract]

Goaillard JM, Marder E. (2006) Dynamic clamp analyses of cardiac, endocrine, and neural function. Physiology (Bethesda). 2006 Jun; 21:197-207. Review. [abstract]

Billimoria CP, DiCaprio RA, Birmingham JT, Abbott LF, Marder E. (2006) Neuromodulation of spike-timing precision in sensory neurons. J Neurosci. 2006 May 31; 26:5910-9. [abstract]

Marder E, Goaillard JM. (2006) Variability, compensation and homeostasis in neuron and network function. Nat Rev Neurosci. 2006 Jul; 7:563-74. Review. [abstract]

Marder E, Bucher D. (2007) Understanding circuit dynamics using the stomatogastric nervous system of lobsters and crabs. Annu Rev Physiol. 2007; 69:291-316. [abstract]

Bucher D, Johnson CD, Marder E. (2007) Neuronal morphology and neuropil structure in the stomatogastric ganglion of the lobster, Homarus americanus. J Comp Neurol. 2007 Mar 10; 501:185-205. [abstract]

Fu Q, Tang LS, Marder E, Li L. (2007) Mass spectrometric characterization and physiological actions of VPNDWAHFRGSWamide, a novel B type allatostatin in the crab, Cancer borealis. J Neurochem. 2007 May;101:1099-107. [abstract]

Schulz DJ, Goaillard JM, Marder EE. (2007) Quantitative expression profiling of identified neurons reveals cell-specific constraints on highly variable levels of gene expression. Proc Natl Acad Sci U S A. 2007 Aug 7;104:13187-91. [abstract]

Cruz-Bermúdez ND, Marder E. (2007) Multiple modulators act on the cardiac ganglion of the crab, Cancer borealis. J Exp Biol. 2007Aug;210(Pt 16):2873-84. [abstract]

Marder E, Tobin AE, Grashow R. (2007) How tightly tuned are network parameters? Insight from computational and experimental studies in small rhythmic motor networks. Prog Brain Res. 2007;165:193-200. [abstract]

Cape SS, Rehm KJ, Ma M, Marder E, Li L. (2008) Mass spectral comparison of the neuropeptide complement of the stomatogastric ganglion and brain in the adult and embryonic lobster, Homarus americanus. J Neurochem. 2008 May;105:690-702. [abstract]

Rehm KJ, Taylor AL, Pulver SR, Marder E. (2008) Spectral analyses reveal the presence of adult-like activity in the embryonic stomatogastric motor patterns of the lobster, Homarus americanus. J Neurophysiol. 2008 Jun;99:3104-22. [abstract]

Marder E. (2008) The roads not taken.Curr Biol. 2008 Sep 9;18:R725-R726.

Rehm KJ, Deeg KE, Marder E. (2008) Developmental regulation of neuromodulator function in the stomatogastric ganglion of the lobster, Homarus americanus. J Neurosci. 2008 Sep 24;28:9828-39. [abstract] [free PMC article]

Marder E. (2009) Electrical synapses: rectification demystified. Curr Biol. 2009 Jan 13;19:R34-5. Review.

Taylor AL, Goaillard JM, Marder E. (2009) How multiple conductances determine electrophysiological properties in a multicompartment model. J Neurosci. 2009 Apr 29;29:5573-86. [abstract] [free PMC article]

Ma M, Szabo TM, Jia C, Marder E, Li L. (2009) Mass spectrometric characterization and physiological actions of novel crustacean C-type allatostatins.Peptides. 2009 Sep;30:1660-8. [abstract]

Grashow R, Brookings T, Marder E. (2009) Reliable neuromodulation from circuits with variable underlying structure. Proc Natl Acad Sci U S A. 2009 Jul 14;106:11742-6. [abstract] [free PMC article]

Tobin AE, Cruz-Bermúdez ND, Marder E, Schulz DJ. (2009) Correlations in ion channel mRNA in rhythmically active neurons.PLoS One. 2009 Aug 25;4:e6742. [abstract] [free PMC article]

Goaillard JM, Taylor AL, Schulz DJ, Marder E. (2009) Functional consequences of animal-to-animal variation in circuit parameters.Nat Neurosci. 2009 Nov;12:1424-30. [abstract] [free PMC article]

Marder E, Tang LS. Coordinating different homeostatic processes. Neuron. 2010 Apr 29;66(2):161-3. [abstract]

Goaillard JM, Taylor AL, Pulver SR, Marder E. Slow and persistent postinhibitory rebound acts as an intrinsic short-term memory mechanism. J Neurosci. 2010 Mar 31;30(13):4687-92. [abstract]

Marder E. Why so long? Curr Biol. 2010 May 25;20(10):R426.

Grashow R, Brookings T, Marder E. Compensation for variable intrinsic neuronal excitability by circuit-synaptic interactions. J Neurosci. 2010 Jul 7;30(27):9145-56. [abstract]

Tang LS, Goeritz ML, Caplan JS, Taylor AL, Fisek M, Marder E. Precise temperature compensation of phase in a rhythmic motor pattern.PLoS Biol. 2010 Aug 31;8(8). pii: e1000469. [abstract]

Marder E, Kettenmann H, Grillner S. Impacting our young. Proc Natl Acad Sci U S A. 2010 Dec 14; 107(50):21233. Epub 2010 Nov 22.

Marder E, Taylor AL. Multiple models to capture the variability in biological neurons and networks. Nat Neurosci. 2011 Feb;14(2):133-8. [abstract]

Marder E. Variability, compensation, and modulation in neurons and circuits. Proc Natl Acad Sci U S A. 2011 Sep 13;108 Suppl 3:15542-8. [abstract]

Kispersky T, Gutierrez GJ, Marder E. Functional connectivity in a rhythmic inhibitory circuit using Granger causality. (2011) Neural Syst Circuits 1:9. [full paper]

Szabo TM, Chen R, Goeritz ML, Maloney RT, Tang LS, Li L, Marder E. Distribution and physiological effects of B-type allatostatins (myoinhibitory peptides, MIPs) in the stomatogastric nervous system of the crab Cancer borealis. (2011) J Comp Neurol. 2011 Sep 1;519(13):2658-76. [abstract]

Brookings T, Grashow R, Marder E. Statistics of neuronal identification with open- and closed-loop measures of intrinsic excitability. (2012) Front Neural Circuits. 6:19. [abstract]

Callaway, E.M. and Marder, E. (2012) Common Features of Diverse Circuits.  Current Opinion in Neurobiology 22: 565-567.

Marder, E. (2012) Neuromodulation of neuronal circuits: back to the future.  Neuron, 76: 1-11.  PMC3482119 [abstract]

Tang, L.S., Taylor, A.L., Rinberg, A., and Marder, E. (2012) Robustness of a rhythmic circuit to short and long-term temperature changes.  J. Neurosci., 32: 10075-10085.  NIHMS395465. [abstract]

Kispersky, T., Caplan, J., and Marder, E. (2012) Increase in sodium conductance decreases firing rate and gain in model neurons. J. Neurosci., 32: 10995– 10995. PMC3427781 [abstract]