Neuronal responses to stress and injury in C. elegans

Abstract

The nervous system plays critical roles in the stress response. Animals can survive and function under harsh conditions, and resist and recover from injuries because neurons perceive and respond to various stressors through specific regulatory mechanisms. Caenorhabditis elegans has served as an excellent model to discover fundamental mechanisms underlying the neuronal response to stress. The basic physiological processes that C. elegans exhibits under stress conditions are similar to those observed in higher organisms. Many molecular pathways activated by environmental and cellular stresses are also conserved. In this review, we summarize major findings in examining neuronal responses to hypoxia, oxidative stress, osmotic stress, and traumatic injury. These studies from C. elegans have provided novel insights into our understanding of neuronal responses to stress at the molecular, cellular, and circuit levels.

Keywords: Axon regeneration; Hypoxia; Neurodegeneration; Osmotic stress; Oxidative stress; Stress response; Traumatic injury.

Fig. 1. C. elegans stress responses to acute or chronic stress stimuli

(A) Acute stress stimuli trigger fast response via the nervous system. Sensory neurons perceive environmental cues such as oxygen levels or osmolarity via their molecular sensors and prompt a behavioral response, such as moving away from the harmful environment. (B) Chronic stress stimuli trigger slow adaptive response. Accumulating cellular stressors induce specific molecular pathways that enable systemic response.

Fig. 2. C. elegans stress responses in the nervous system

Chronic hypoxia engages latent neural circuits and makes animals more sensitive to gustatory cues; chronic oxidative stress modulates neuronal gene expression (SKN-1 and NLG-1) to reduce synaptic transmission at NMJs. Upon removal from osmotic shock, C. elegans engages in a sleep-like quiescent behavior which is beneficial for survival.

Fig. 3. Cellular and molecular responses to traumatic neuronal injury in C. elegans

In C. elegans, three types of neuronal injury models have been studied, including neurotoxic stress using mec-4(d) mutants, neuronal cytoskeletal stress/disruption using colchicine treatment or β-spectrin mutants, and laser-assisted axon injury.

Fig. 4. Opposing neuronal responses to different types of injury

Injury at or near the soma of the neuron triggers a high calcium surge from the ER, which leads to neuronal death. Local neurite injury also triggers a calcium transient and this calcium signal spreads to the soma to promote neuronal regeneration. It is speculated that the increased levels of calcium or the duration of calcium stimulation might determine neuronal death or survival.