Mechanisms of plasticity in a Caenorhabditis elegans mechanosensory circuit

Abstract

Despite having a small nervous system (302 neurons) and relatively short lifespan (14-21 days), the nematode Caenorhabditis elegans has a substantial ability to change its behavior in response to experience. The behavior discussed here is the tap withdrawal response, whereby the worm crawls backwards a brief distance in response to a non-localized mechanosensory stimulus from a tap to the side of the Petri plate within which it lives. The neural circuit that underlies this behavior is primarily made up of five sensory neurons and four pairs of interneurons. In this review we describe two classes of mechanosensory plasticity: adult learning and memory and experience dependent changes during development. As worms develop through young adult and adult stages there is a shift toward deeper habituation of response probability that is likely the result of changes in sensitivity to stimulus intensity. Adult worms show short- intermediate- and long-term habituation as well as context dependent habituation. Short-term habituation requires glutamate signaling and auto-phosphorylation of voltage-dependent potassium channels and is modulated by dopamine signaling in the mechanosensory neurons. Long-term memory (LTM) for habituation is mediated by down-regulation of expression of an AMPA-type glutamate receptor subunit. Intermediate memory involves an increase in release of an inhibitory neuropeptide. Depriving larval worms of mechanosensory stimulation early in development leads to fewer synaptic vesicles in the mechanosensory neurons and lower levels of an AMPA-type glutamate receptor subunit in the interneurons. Overall, the mechanosensory system of C. elegans shows a great deal of experience dependent plasticity both during development and as an adult. The simplest form of learning, habituation, is not so simple and is mediated and/or modulated by a number of different processes, some of which we are beginning to understand.

Keywords: C. elegans; context conditioning; habituation; long-term memory; non-associative learning; short-term memory; tap-withdrawal response.

Figure 1

The circuit mediating the response to tap. The touch cells are represented by ovals (blue), the interneurons by stars (yellow), and the motor neurons by rectangles (red). All neurons are bilaterally symmetrical, except AVM and DVA. The neurons in green, PVD and DVA, contribute to both forward and backward movement and may play a role in integrating the two responses. Arrows and dashed lines denote chemical and electrical connections, respectively, thickness of lines reflects relative number of synapses [Based on data from Chalfie et al. (1985), Wicks and Rankin (1995)].

Figure 2

An example of the candidate gene approach: eat-4 encodes a glutamate vesicle transporter and is expressed on the touch cells. Worms with a mutation in eat-4 show rapid and complete habituation and slower recovery compared to wild-type worms (Rankin and Wicks, 2000).

Figure 3

Using the multi worm tracker to test a number of strains of worms uncovered new mutations affecting habituation. There was lower response probability habituation to tap in adp-1 worms (A) and greater response probability in tom-1 worms (B) (Swierczek et al., 2011).

Figure 4

(A) Representative images of GLR-1::GFP expression in interneurons of the posterior ventral nerve cord in a worm that had been given spaced training for long-term memory for habituation 24 h before and an untrained control worm. There were significantly smaller GFP clusters in the trained worms than in the control worms. (B) Representative images of the vesicles in tap sensory neuron terminals visualized with a synaptobrevin GFP marker in control and trained worms. There was no difference in measured GFP expression between the trained and control worms (Rose et al., 2003).

Figure 5

Genes tested for their role in long- and short-term memory for non-associative habituation and associative context conditioning. Three genes were tested, crh-1 which is the worm homologue of CREB, glr-1 the worm homologue of a glutamate AMPA-type receptor subunit and nmr-1 the worm homologue of an NMDA-type glutamate receptor subunit. The results indicated that nmr-1 is required for short and long-term context conditioning but not necessary for non-associative learning; crh-1 is critical for long-term but not short-term memory for both associative and non-associative memory and that glr-1 is not required for short-term non-associative learning, but required for long term as well as short- and long-term context conditioning [Based on data from Lau et al. (2013)].

Figure 6

There were changes in habituation of response probability throughout middle-age in wild-type worms. This graph shows response probability habituation for 72-, 84-, 96-, 108-, and 120-h-old (all reproductive adults) wild-type C. elegans in response to a series of 30 taps. Age was significantly related to the probability of responding to the final tap at both a 10-s ISI (A) and at a 60-s ISI (B) (Timbers et al., 2013).