Research

fluorescent images of the nematode C. elegans

We are a sensory biology lab. We ask the following questions to better understand how animals sense their external and internal world through various sensory systems:

  • How do animals detect and distinguish various sensory cues — such as temperature, touch, light, sound, odorants and tastants  — via different types of sensory receptors? 
  • What are the molecular identities of these sensory receptors? How do they regulate sensory signaling and behavior?
  • How do neural circuits process sensory information to produce behavioral outputs?
  • How do sensory cues regulate aging and longevity? 

To address these questions, we use both C. elegans and mouse models. We study C. elegans because of its simple and well-characterized nervous system. Because many sensory receptors are evolutionarily conserved, we also investigate their roles in somatosensation, interoception and pain sensation in mammals using mouse models. We take a multidisciplinary approach, combining molecular genetics, behavioral analysis, functional imaging and electrophysiology.

Sensory Receptors

Postdoctoral fellow Zhaoyu Li conducts an optogenetics experiment.

The environment has a profound impact on animal behavior. The ability to sense environmental cues and to adjust behavior in response is essential for an animal’s life. Molecular sensors are a central player in sensory perception. These sensory receptors, which are expressed in sensory neurons/cells, detect sensory inputs and transduce them into electrical and/or chemical outputs to trigger behavioral responses. Sensory receptors may sense signals from the external world (exteroception), as well as the internal body of an animal (interoception).  In some cases, sensory receptors are also ion channels (ionotropic) that are directly activated by sensory stimuli, leading to the excitation of sensory neurons/cells. In many other cases, sensory receptors are metabotropic and require downstream signaling molecules to transduce sensory signals. Identifying sensory receptors/channels and understanding how they detect and transduce sensory information represent a major task in sensory biology research. 

C. elegans worms are a powerful genetic model for the study of various questions in neuroscience, particularly sensory neuroscience. To survive and adapt to the ever-changing environment, worms have evolved complex sensory systems. For example, worms are known to sense chemicals (e.g., odorants and tastants), touch and temperature. Recent work from our lab has greatly expanded the repertoire of sensory modalities in C. elegans. Specifically, we demonstrated that despite the lack of eyes, worms can sense light through photoreceptor neurons and engage in phototaxis behavior, enabling them to avoid lethal doses of ultraviolet light. We discovered that despite the lack of ears, worms can sense airborne sound through auditory sensory neurons and engage in phonotaxis behavior, which might help them to evade predators. We also showed that worms possess the sense of proprioception mediated by stretch-sensitive proprioceptor neurons, which allows these animals to control body posture during locomotion. Apparently, worms have evolved all of the six primary sensory modalities found in mammals. Importantly, the genes encoding sensory receptors in worms, which detect sensory stimuli, tend to be evolutionarily conserved in other species. This, together with its short generation time (~3 days) and facile genetic tools, makes C. elegans an excellent model system for identifying novel sensory receptors and sensory transduction mechanisms. 

Over the years, we have identified and characterized a number of sensory receptors/channels, including, among others, a mechano-sensing channel (TRP-4/NOMPC), a light-sensing receptor (LITE-1), an alkali-sensing receptor (TMC-1),  a cold-sensing receptor (GLR-3/GluK2) and so on. Current work involves identifying novel types of sensory receptors through genetic screens in C. elegans, and investigating how these sensory receptors detect and transduce different sensory cues to generate behavioral outputs.

Strikingly, many sensory receptors are evolutionarily conserved. For example, we recently reported that GluK2, a mammalian homolog of the C. elegans cold sensor GLR-3, also functions as a cold-sensing receptor and mediates cold sensation in dorsal root ganglion (DRG) neurons in mice. As such, another direction of our research is to identify novel mammalian sensory receptors and investigate how they control somatosensation, interoception and pain sensation in mammals using mouse models. 

Sensory Circuits

Following sensory transduction mediated by sensory neurons/cells, sensory information is further processed by downstream neural circuits to ultimately generate behavioral outputs. Identifying such sensory circuits, dissecting how they process sensory information, and characterizing how genes and an animal’s internal state and past experience regulate these processes are central to understanding how sensory cues regulate behavior. We aim to address these questions in both C. elegans and mice.  In C. elegans, benefiting from its small and well-annotated nervous system, we strive to take a rather comprehensive approach by identifying the neural circuits underlying multiple sensory behaviors, ranging from thermosensory to mechanosensory, chemosensory and photosensory behaviors, and dissecting how they process sensory inputs to produce distinct behavioral outputs. We also investigate how genes and the internal state and past experience of the animal regulate sensory processing. 

In mice, we mainly focus on somatosensory and pain behaviors. We are particularly interested in identifying the spinal and brain circuits that transmit and process distinct temperature signals, such as noxious cold and innocuous cool, to generate a perception and produce appropriate behavioral responses. To do so, we take a multidisciplinary approach, combining behavioral analysis, molecular genetics, optogenetics, calcium imaging and electrophysiology.

Sensory Regulation of Aging and Longevity

Sensory cues regulate not only an animal’s behavior, but also its physiology — such as aging. For example, temperature has a profound impact on aging. Both cold- and warm-blooded animals live longer at lower body temperatures, pointing to a general role of temperature in lifespan regulation. However, the underlying mechanisms are not well understood. We have identified a cold-sensitive channel as a thermal sensor that detects temperature decreases in the environment to extend lifespan, demonstrating that genes actively promote longevity at cold temperatures. This calls into question the century-old view that cold-dependent lifespan extension is simply a passive thermodynamic process. Besides temperature, food represents another major environmental factor that affects aging. Dietary restriction (DR) is considered one of the most effective non-genetic interventions that extend lifespan. We recently reported that food odors suppress DR-induced longevity via an olfactory circuit and a brain-to-gut signal. This highlights the striking phenomenon that not only the actual food abundance but also the perception of food abundance regulate longevity.

We are interested in identifying new genes and pathways that mediate temperature- and chemical cue-dependent regulation of lifespan and healthspan in C. elegans. Ultimately, we would like to derive a thorough understanding of how sensory cues regulate aging.

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