elegans movement LY294002 clinical trial ( Figure 8D). We demonstrate that gap junctions between premotor interneurons and motoneurons (GJ, illustrated as cylinders in Figure 8D) are necessary

for establishing an imbalanced motoneuron output. In the absence of these couplings, an endogenous A and B motoneuron activity (yellow circles in Figure 8D) leads to an equal motoneuron output and nondirectional movement (kinking). We propose that the reciprocal activation of premotor interneurons of the forward and backward circuit (colored lines in Figure 8D) leads to the establishment and the switching between the A > B and B > A patterns through modifying the endogenous B and A motoneuron activity. We further demonstrate that UNC-7-UNC-9-mediated gap junctions in the backward circuit maintain the backward circuit at a low state by suppressing the activity of both AVA premotor interneurons and A motoneurons. They establish the intrinsic bias (>>> in Figure 8D) for a higher forward-circuit output (B > A) and are necessary for continuous forward movement. Such a bias ensures that only upon strong backward-premotor interneuron activation (input, illustrated as arrowheads in Figure 8D) is an A > B pattern established

via the increased chemical (arrows in Figure 8D) and electrical synaptic inputs to A motoneurons to permit brief backing. Our studies indicate that an endogenous activity of the C. elegans motoneurons is modulated by premotor interneurons to exhibit different output levels. It supports a notion that premotor interneurons of the forward and backward RAD001 order circuits function as organizers to establish the differential output pattern between distinct motoneuron pools. Such an operational model bears intriguing resemblance

to that of other motor systems. For example, mouse spinal cord premotor interneurons act as organizers of the oscillating motoneuron activity to establish an alternate, left-right firing pattern that permits walking and prevents hopping of the Suplatast tosilate hind limbs ( Crone et al., 2008, Lanuza et al., 2004 and Zhang et al., 2008). Critically, in both motor systems, inputs from specific interneuron pools are necessary to break the equilibrium of an otherwise synchronized motor output pattern. This study mainly focused on the role of premotor interneuron-motoneuron coupling in the backward circuit in directional movement; questions remain regarding how other circuit components contribute to such a decision-making process. How premotor interneurons of the forward circuit instruct directional motion remains elusive. UNC-7 and UNC-9 innexins mediate heterotypic gap junctions between AVB and B motoneurons (Starich et al., 2009). Restoring their expression in the forward circuit, however, did not rescue forward movement in respective innexin mutants (Figure 5A; discussion in Starich et al., 2009), whereas restoring AVA-A coupling resulted in a robust rescue (Figures 5A and 5B).