Department of Biology
Massachusetts Institute of Technology
Howard Hughes Medical Institute
McGovern Institute for Brain Research


 
Research: Behavior

We are analyzing both how the nervous system controls behavior and how genes specify the functioning of a neuromuscular system. As described under "NEURAL DEVELOPMENT," the C. elegans nervous system is strikingly simple and exceptionally well described. We have studied many aspects of the functioning of the C. elegans nervous system. For example, we use a laser microbeam, pharmacology and mutations to identify which neurons control specific behaviors. In this way, we defined the complete GABAergic nervous system and the neural circuits of and the behaviors controlled by 25 of the 26 GABAergic neurons. We have analyzed a diversity of the animal’s behaviors, including egg laying, feeding, defecation, locomotion, and foraging. We have analyzed the animal’s chemosensory system and aspects of its mechanosensory systems. We discovered that C. elegans has a sense of smell and characterized its olfactory system. We have studied simple motor outputs, reflex circuits, integrated circuits within its central nervous system and behaviors that are modulated by the environment and/or experience. We have also identified and are now characterizing a two-pore potassium channel protein complex that regulates muscle contraction.


One major current focus is to understand how both the environment and experience modulate C. elegans behavior. For example, we are examining how bacteria, the animal’s standard food source, modulate locomotion and egg laying. We observed that when a worm encounters bacteria it slows its rate of locomotion (the basal slowing response), presumably to cause it to stay where the food supply is ample. We found that this behavioral response can be modulated by experience: worms that have been transiently deprived of food slow even more than do well-fed worms (the enhanced slowing response), as if "hungry" worms are taking no chances about leaving a food source. We showed that the basal slowing response and the enhanced slowing response are mediated by distinct mechanisms. For example, whereas the dopaminergic nervous system controls the basal slowing response, the serotonergic nervous system controls the enhanced slowing response. We are isolating and characterizing mutants abnormal in the enhanced slowing response. One of these mutants defined MOD-1, which encodes a novel class of serotonin (5HT) receptor. Like the mammalian 5HT-3 receptor, MOD-1 is a ligand-gated ion channel, but unlike the 5HT-3 receptor, MOD-1 conducts chloride ions and hence its activity is likely to be inhibitory rather than stimulatory. We plan to seek mammalian equivalents of MOD-1. Such a molecule could have important implications for mammalian neurobiology as well as for the therapeutic treatment of disorders caused by serotonin dysfunction, which include disorders affecting mood, sleep, pain, thermoregulation, appetite, sexual function, thirst, blood pressure, respiration, heart rate and possibly memory.

The MOD-1 protein is a serotonin-gated chloride channel, as exemplified by electrophysiological studies of voltage-clamped Xenopus oocytes. MOD-1 responds specifically to serotonin and shows a reversal potential that varies linearly with the log of the chloride concentration.

A second gene that affects the enhanced slowing response encodes MOD-5, a serotonin reuptake transporter similar to the human protein that is the target of many of the pharmaceutical agents used clinically to treat depression, including amitryptaline, Prozac and Celexa. Such serotonin reuptake transporters mediate the removal of serotonin from the synaptic cleft, so that when transporter function is blocked, serotonin remains in the cleft longer, thereby enhancing serotonergic function. Thus, whereas mod-1 mutations block the enhanced slowing response, mod-5 mutations increase the enhanced slowing response. We found that some but not all of the effects of Prozac on C. elegans are mediated through serotonin and MOD-5, and we plan to identify the other target(s) of Prozac, with the hope that this knowledge will facilitate the development of more specific therapeutic compounds. We are extending our studies of the effects of acute food deprivation from locomotion to egg laying with the goal of determining how experience and the environment coordinately control multiple behaviors. In addition, by characterizing genes that act in the enhanced slowing response downstream of the MOD-1 serotonin receptor, we are attempting to define a complete pathway for serotonin signal transduction. Finally, we are attempting to isolate mutants with defects in the pathway that stores and retrieves the "memory" of food deprivation. We hope that these studies will reveal where and how C. elegans stores, retrieves and integrates information concerning its prior exposure to food, and how it uses this information to modulate serotonergic neurotransmission and control its behavior in response to its past experience.


We are also pursuing the role of other biogenic amines, including octopamine, as possible modulators of C. elegans behavior. We found that exogenous octopamine antagonizes many of the behavioral effects of exogenous serotonin. To analyze the role of octopamine, we isolated a deletion allele of the putative tyramine-beta-hydroxylase gene tbh-1, since this enzyme is essential for the biosynthesis of octopamine. tbh-1 mutants, like wild-type animals exposed to exogenous serotonin, have reduced locomotory rates, consistent with the hypothesis that octopamine and serotonin act antagonistically. The TBH-1 protein is specifically expressed in two head interneurons. We are investigating the role of these neurons and the neural circuit in which they act.


The repeated actions of neuromodulators, such as serotonin and octopamine, can cause long-term changes in synaptic function. Studies of long-term memory formation in the sea slug Aplysia, the fruit fly Drosophila and mice have indicated a major role of the cyclic AMP response element binding protein CREB. To explore the role of CREB in C. elegans, we have isolated deletion alleles of the CREB-like gene crh-1. These mutants display defects consistent with the hypothesis that this CREB gene acts downstream of serotonin to mediate long-term changes in both behavior and development dependent upon aspects of the animal’s past experience.

Publications: Behavior

Abstracts: Behavior

The Horvitz Lab