Beyond the wiring diagram: signalling through complex neuromodulator networks

Abstract

During the computations performed by the nervous system, its 'wiring diagram'--the map of its neurons and synaptic connections--is dynamically modified and supplemented by multiple actions of neuromodulators that can be so complex that they can be thought of as constituting a biochemical network that combines with the neuronal network to perform the computation. Thus, the neuronal wiring diagram alone is not sufficient to specify, and permit us to understand, the computation that underlies behaviour. Here I review how such modulatory networks operate, the problems that their existence poses for the experimental study and conceptual understanding of the computations performed by the nervous system, and how these problems may perhaps be solved and the computations understood by considering the structural and functional 'logic' of the modulatory networks.

Figure 1.

Multiplicity of neuromodulators identified in the crustacean stomatogastric ganglion. Reproduced with permission from Marder & Bucher (2001).

Figure 2.

Network of modulatory actions that shapes the contractions of the ARC muscle of Aplysia. (a) Schema of the ARC muscle (grey box), its two motorneurons B15 and B16 (circles at top) that release ACh to elicit the basal contractions of the muscle (black arrow) but also modulatory neuropeptides belonging to the SCP, MM and buccalin (BUC) families, other neurons (circles down right-hand side) that release additional modulators, and the network of the principal modulatory actions (coloured arrows). Thick arrows denote strong actions, thin arrows weaker actions. The subnetwork analysed in figure 3 is shown in red, the rest of the modulatory network in purple. Modified from Brezina et al. (2003a) and based in the first instance on the body of previous work summarized there, then brought up to date with the more recent findings of Orekhova et al. (2003), Proekt et al. (2005) and Vilim et al. (2010). (b) The diversity of ARC muscle contraction shapes produced by the various modulators. Representative contractions elicited in vitro by firing of either motor neuron B15 or B16 under control conditions (‘c’) and after exogenous application of 10⁻⁷ or 10⁻⁶ M (‘− 7’, ‘− 6’) of the modulators. Modified from Hooper et al. (1999), with the MMG2-DP traces taken from an experiment of Proekt et al. (2005). Abbreviations: MMG2-DP, myomodulin gene 2-derived peptides; FMRF, FMRFamide peptides; FRF, FRFamide peptides; 5-HT, serotonin; MCC, metacerebral cells; P-BPN, pedal–buccal projecting neurons.

Figure 3.

Analysis of the actions of modulator combinations in the Aplysia ARC muscle system. This partial analysis considers the combinatorial action of just two modulators, SCP released from motor neuron B15 and MM released from motor neuron B16, through the subnetwork of actions shown in red in figure 2a, on just two parameters, the size and the relaxation rate, of the ARC muscle contractions. (a) Representative ARC muscle contraction shapes, recorded as in figure 2b, produced by various exogenously applied steady concentrations of SCP alone (red), MM alone (blue) and both SCP and MM applied together (purple; the peak and relaxation phase of just one contraction is shown; scale bar 1 s, 500 ms). (b) Mapping from the space of all combinations of SCP and MM concentrations (over the range from 10⁻¹⁰ to 10⁻⁴ M) to the space of all combinations of the effects on contraction size and relaxation rate. The grid of small dots in the two spaces shows the steady-state mapping generated by the computational model of Brezina et al. (1996, 2003a). The larger black dots and blue and red curves show how the steady-state mapping is traversed as the SCP concentration varies in the presence of constant MM concentration (red curves) or the converse (blue curves); the letters ‘a’–‘d’ identify the mapping of the four corners of the modulator space for orientation. The large black, red, blue and purple dots mark the approximate locations of the contraction shapes in (a), right. The purple overlay then shows the dynamical trajectory through the modulator and effect spaces of the entire meal modelled in (c), in the modulator space plotting against each other the SCP and MM concentration waveforms shown in (c) and in the effect space the contraction size and relaxation rate waveforms, plotting either the entire continuous waveforms (thin purple curve) or just their values at the end of the retraction phase of each feeding cycle (small purple circles). (c) Modelled waveforms of the principal variables during an entire meal eaten by a real Aplysia in vivo, comprising 749 feeding cycles over approximately 2.5 h, during which the firing frequencies of the motorneurons B15 and B16 (top two waveforms) were recorded with chronically implanted electrodes by Horn et al. (2004) and were then used by Brezina et al. (2005) to drive the computational model of Brezina et al. (2003a). Scale bar, 30 min. (a,b) modified from Brezina et al. (2003a) and (c) from Brezina et al. (2005).