Rectifying electrical synapses in pattern-generating circuits

by Gabrielle Gutierrez

Rectifying electrical synapses are more interesting than they might seem at first. Our recent study finds that they have the potential to allow a circuit to control how robust the circuit output is to modulation of synaptic strength.

Gap junctions allow neurons to communicate quickly by serving as a direct conduit of electrical signals. Non-rectifying gap junctions probably come to mind first for most neuroscientists when they think about electrical synapses, since they are the idealized textbook variety. The electrical current that passes through the non-rectifying type of gap junction is simply a function of the voltage difference between the coupled neurons. However, this is only the case when the two hemi-channels that form a gap junction pore have the same voltage-dependencies.

Schematic shows that neurons can express diverse gap junction subunits (top left). Rectifying gap junction conductance is a function voltage difference between two neurons (top right). Bottom panel illustrates how coupled neuron output depends on the polarity of the rectifying electrical synapse and the intrinsic properties of the coupled neurons.

We know from past electrophysiology studies that a single neuron can express a diverse set of gap junction hemi-channels, enabling it to form similarly diverse gap junction channels with another neuron. This could result in rectifying electrical synapses in which current flows asymmetrically between neurons so that current flow can either be permitted or restricted depending on whether the current is positive or negative. What we didn’t know were the consequences of electrical synapse rectification for a pattern-generating circuit of competing oscillators. Our recently published study in J. Neuroscience addressed this question and led us to conclude that rectifying electrical synapses can change how a neuronal circuit responds to modulation of its synapses – including its chemical synapses. Although we used a computational model for our study, our results indicate that rectifying electrical synapses in biological networks can be an important component in neuronal circuits that produce rhythmic patterns, such as those found in motor systems.

Gabrielle Gutierrez obtained her PhD in Neuroscience from Brandeis earlier this year, and is currently doing a postdoc with Sophie Deneuve at the Ecole Normale Superieure in Paris

Gutierrez GJ, Marder E. Rectifying electrical synapses can affect the influence of synaptic modulation on output pattern robustness. J Neurosci. 2013;33(32):13238-48.

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.

How many neurons does it take to stay cool?

The worm (nematode) C. elegans is a nice model system for studying neuroscience, combining

• genetic tools that allow genes to be turned on or off, often on a per cell basis, in the whole organism,
• tools like laser or genetic ablation that allow individual, identified cells to be selectively eliminated,
• robust behaviors that can be readily measured, and
• a well defined nervous system consisting of 302 neurons, each of which can be identified, and whoseanatomical connectivity has been established.

In a paper appearing this month in Journal of Neuroscience, Molecular and Cell Biology grad student Matthew Beverly, undergrad Sriram Anbil, and Professor of Biology Piali Sengupta examined the contribution of sensory neurons to controlling thermotaxis in C. elegans. Worms develop a memory of the temperature at which they have been cultivated, and display a robust behavior in which worms placed on a temperature gradient at temperatures higher than their cultivation temperature will crawl back towards colder temperature (negative thermotaxis – see movie). The behavior depends on TAX-4, a channel protein expressed in a subset of the sensory neurons. In this study, the Brandeis researchers asked the question “how many and which of the sensory neurons are required for the worms to perform negative thermotaxis, and are the required sensory neurons the same regardless of the temperature range examined?” (or, in my paraphrase, “how many and which neurons does it take to stay cool?”)

Worm head, showing expression of the calcim indicator GCaMP in ASI and AWA neurons (used in calcium imaging experiments)

As it turns out, the answer is complicated (and readers are encouraged to read the paper). The researchers found that in addition to the previously known thermosensory neurons AFD and AWC, the ASI neurons previously known to be involved in chemosensation play a significant role in regulating negative thermotaxis. Interestingly, the circuits used seem to be degenerate; under one condition, for example, a particular combination of AFD, AWC or ASI is necessary to generate the behavior, although at other conditions, a different combination is required to generate the same behavior.. And only a couple of degrees Celsius makes a difference — the circuit required for negative thermotaxis on a gradient centered at 8^oC above the cultivation temperature is different from a gradient centered at 6^oC above.

These and other results taken together suggest that even in the worm, a complex circuit has evolved to control crawling behaviors to cope with temperature changes, and that having degeneracy in the underlying circuits may be a common feature that ensures that behaviors crucial to survival are maintained in a variety of environmental conditions..

Beverly M, Anbil S, Sengupta P. Degeneracy and Neuromodulation among Thermosensory Neurons Contribute to Robust Thermosensory Behaviors in Caenorhabditis elegans. J Neurosci. 2011;31(32):11718-27.

How crabs deal with the chill

Chemical (and biochemical) reaction rates can increase dramatically with even small changes in temperature, but many biological systems require rhythms with a precise ordering of events. How are these rhythms maintained in organisms that can prosper in a wide range of temperatures? In a recent study published in PLoS Biology (comment). Lamont Tang, a Neuroscience grad student, and other members of the Marder lab studied this question by looking at neurons in the pyloric network of the crab Cancer borealis. They argue from a combination of experiments and computational models that even though firing frequencies change with temperature, the phase between elements of the network is maintained by balancing opposing currents with similar temperature dependencies.

graphic courtesy of Gabrielle Gutierrez

New faculty Stephen Van Hooser joins Biology Dept

Steve is back, starting this month.

Stephen Van Hooser is an alumnus of Brandeis Neuroscience Ph.D. program, graduating in 2005. After a highly productive stint as a postdoc as Duke, Steve rejoins us in May, 2010 as Biology’s newest assistant professor. The Van Hooser lab will focus on the role of visual experience in maturation and development of neural circuit, using optical and optogenetic tools.