Stable neural circuits in the brain can generate a vast array of flexible behavioral responses. This behavioral diversity arises from the interplay of genes, the nervous system, the environment, and experience. We study these relationships in the nematode worm Caenorhabditis elegans, where we can define the circuits for specific behaviors in detail. The nervous system of C. elegans consists of just 302 neurons with reproducible functions, morphologies, and synaptic connections. At some level, the map of neuronal connectivity encodes the behavioral potential of the animal. We use this map to study the roles of neurons in behaviors, the functions of genes that affect neuronal development and behavior, and the performance of this neuronal network under different conditions.
A Circuit for Olfactory Behavior
We want to understand how the activity of each neuron in a circuit contributes to an animal's behavior. To achieve this goal, we first asked how neurons detect stimuli, respond to them, and relay information to other neurons. A systematic study of the C. elegans nervous system has led to the identification of olfactory neurons and interneurons that control food- and odor-evoked behaviors. We use genetically encoded calcium indicators to monitor the activity of these neurons, and we alter the flow of information by activating or inhibiting neurons, or by eliminating or restoring synaptic connections between them with precise genetic manipulations. These experiments have provided a view of information relay in the olfactory circuit. One class of olfactory neurons is activated by odor removal and suppressed by odor addition. The olfactory neurons release the neurotransmitter glutamate to inhibit one interneuron target and activate another interneuron target. As a result, one interneuron signals odor onset, and the other interneuron signals odor offset. At both a molecular level and a logical level, information processing by this circuit resembles information flow from vertebrate photoreceptors to their targets, the OFF-bipolar and ON-bipolar neurons, suggesting a conserved or convergent strategy for sensory information processing.
The transformation of sensory information into behavior involves a variety of behavioral strategies. Odor chemotaxis, for example, can occur by a probabilistic turning strategy that integrates olfactory information over many seconds. But, it can also occur by a deterministic steering strategy that is tightly coupled to locomotion at a sub-second timescale. In the first case, the relevant motor action is a reversal and large reorientation; in the second case, a subtle change in head angle. The circuits for these strategies can be distinguished only if we track neuronal activity and behavior at the same time. To achieve these goals, we have developed microfluidic arenas that allow simultaneous monitoring of an animal’s behavior and neuronal activity in controlled chemical environments. These arenas can be used to examine multiple animals simultaneously, providing the opportunity to map the probabilities of different kinds of motor events, as well as their dependence on sensory inputs, genes, and particular sensory neurons and interneurons.
Olfaction and Olfactory Learning
C. elegans shows multiple forms of olfactory learning: it avoids odors that were previously paired with starvation, and approaches odors that were previously paired with food. It can also learn to avoid odors associated with pathogenic or toxic food sources, a learned behavior similar to mammalian conditioned taste aversion. We found that a behavioral switch from attraction to repulsion can occur within a single olfactory neuron. A particular olfactory neuron can send two opposite signals—one favoring attraction, the other favoring avoidance—and can switch rapidly between these two signaling modes. Other forms of olfactory learning occur at different stages of the circuit. Feedback from interneurons onto sensory neurons shapes the sensory response to odor, providing instructive information that initiates olfactory adaptation. In pathogen learning, the neuromodulator serotonin alters odor preferences at a circuit level. These results reveal functional plasticity associated with the fixed anatomy of the nervous system.
Neuromodulatory Signals Remodel Circuits
Behaviors are often organized into discrete, long-lasting motivational states. For example, foraging animals alternate between sleeping, feeding, exploration, and active migration states that each last for minutes to hours. Transitions between behavioral states can be induced by external stimuli, but also occur spontaneously, suggesting that they can be internally generated. We have asked what kinds of molecular and circuit mechanisms generate and maintain three foraging states in C. elegans called roaming, dwelling, and leaving. Our results indicate that neuropeptides and small-molecular neuromodulators such as serotonin play important roles in behavioral state transitions. Different neuromodulators can either initiate a behavioral state, or stabilize a pre-existing state. The relevant modulatory circuits differ from the classical wiring diagram of the worm nervous system in two ways. First, the effects of the modulators are expressed over minutes, whereas classical synapses operate in less than a second. Second, the neurons that make and detect the neuromodulators are generally not connected through anatomically-defined synapses, but instead form a longer-range network that is orthogonal to the classical wiring diagram. We are currently determining how this wireless network resets the properties of the fast circuits to modify behavioral outcomes.
Neuromodulators allow one individual to generate a variety of behaviors, and may also drive behavioral differences between individuals. We have mapped a number of heritable behavioral traits that differ among wild C. elegans strains, or that differ between wild strains and laboratory strains. Several genes that generate natural variability in foraging behavior encode receptors for neuromodulators or neuropeptides. Altered activity in these neuromodulatory pathways may change the animal’s propensity to enter different behavioral states, thereby allowing different individuals to behave differently from one another.
Some of the neuromodulators that affect C. elegans behavior are highly conserved in evolution, with behavioral functions that appear analogous or homologous. For example, neuropeptides related to oxytocin and vasopressin regulate reproductive behavior in C. elegans and in mammals; adrenaline-like biogenic amines regulate arousal levels; serotonin regulates behavioral responses to food. Neuromodulators may represent ancient behavioral regulators whose slow functions are maintained in parallel to those of classical synapses.
This work has been supported in part by grants from the G. Harold and Leila Y. Mathers Foundation and Ellison Medical Foundation.
As of December 11, 2013
