Zimmer Group Research
The neural basis of behavior
One of the prime goals pursued by current neuroscientists is to gain a comprehensive understanding of how networks of neurons operate as a single brain to produce sensations, thoughts and behavior. This is a challenging endeavor because of the sheer complexity of mammalian nervous systems. To address this problem, at our lab we study the nematode C. elegans, which is equipped with a simple and anatomically well defined nervous system of just 302 neurons. Specifically, we combine powerful worm genetics, quantitative behavioral assays, and functional neuronal imaging techniques to elucidate the precise neural circuits that control oxygen chemosensory behaviors.
Research activities
An animal’s decision as to how it should respond to changes in the environment is based not only on the available sensory information, but also on internal factors such as stress, sleep/wakefulness, hunger/satiety and experience. Small molecule neurotransmitters and neuropeptides in the brain modulate neural circuits according to these conditions, so that appropriate behaviors are generated. Aberrant neuromodulation is implicated in conditions such as insomnia, obesity, or anorexia. Given the complexity of most neural systems that have been studied thus far, we lack good models to investigate how neuromodulatory alterations systemically affect the activities of networks that generate behavioral outcomes. We use the simple model organism C. elegans as a tool to solve these questions.
- Figure 1(Click to view legend)
Wild C. elegans live in soil, which is a very heterogeneous environment. As worms navigate, they are constantly challenged to evaluate their environment in order to determine the best survival tactic. The ability to locate food sources (bacteria) while avoiding pathogens, predators or other noxious conditions is far from simple. To optimize this search, nematodes have evolved a highly sophisticated repertoire of behavioral strategies. Oxygen chemotaxis is one such strategy. Local oxygen concentrations in soil range from atmospheric levels (21% O2) to toxic hypoxia (<1% O2), with soil bacteria creating a milieu of intermediate oxygen levels. When we present C. elegans with a range of oxygen concentrations in the laboratory, they show a homeostatic preference for these intermediate oxygen concentrations while avoiding both atmospheric and hypoxic conditions. Oxygen chemotaxis is regulated by various factors such as experience, nutritional status, and the genetic background of different strain isolates. It therefore serves as a tractable paradigm to study the modulation of the underlying circuits.
To study behavior, we are filming worm populations that experience downshifts and upshifts in environmental oxygen levels. Image processing and further computer analysis is used to quantify simple locomotion responses. To measure the neuronal activity of individual neurons, we use real-time fluorescence imaging of intracellular calcium levels. We employ microfabrication technologies to generate small microfluidic devices that allow the immobilization of worms onto microscope stages while the animals are being stimulated by chemical or gaseous stimuli (Movie 1).
- Figure 2(Click to view legend)
Surprisingly, all behaviors observed in the assay can be explained by the action of just two sensory neuron classes in the entire worm brain: The BAG neurons cause deceleration of locomotion rate, which may persist for several minutes after oxygen concentrations drop to preferable levels. Conversely, when oxygen concentrations rise to undesirable levels, the URX neurons trigger very brief slowing responses that last for no more than a few seconds (Figure 2). Calcium imaging demonstrated that decreasing oxygen concentrations activate BAG neurons (Figure 3, Movie 2) while increasing oxygen concentrations activate URX neurons (Figure 3). A genetic analysis of behavioral responses and neuronal calcium signals showed that the reciprocal chemosensory properties of BAG and URX are the result of differentially expressed molecular oxygen sensors of the soluble guanylate cyclase family (Zimmer et. al. 2009).
- Figure 3(Click to view legend)
These behavioral paradigms and imaging technologies are ideal tools to study the neuromodulation of circuits and behavior. Oxygen downshift and upshift elicit two distinct slowing responses that can be assigned to the activities of just one sensory neuron in each case. Thus, behavior can be studied in a robustly quantifiable manner at single cell resolution. Moreover, the imaging technologies we developed are tailor-made to mimic conditions under which behavioral experiments are performed. Thus, behavioral responses and neural activity can be directly correlated. BAG and URX share a small neural circuit of postsynaptic interneurons. The simplicity of this system, powerful worm genetics, and tractable behavioral and physiological assays, enable us to study the neuromodulation of circuits at all levels; i.e. at the level of networks, single cells, as well as single genes and molecules.
We are currently focusing on the following goals:
• To elucidate the precise functions of interneurons that connect to BAG and URX.
• To determine the mechanism by which neuropeptides mediate experience-dependent modulation of behavior.
• To investigate the mechanisms by which neural circuits integrate sensory information with other external and internal conditions, such as the availability of food and the nutritional status.