Correction: Elucidation of molecular kinetic schemes from macroscopic traces using system identification.

[This corrects the article DOI: 10.1371/journal.pcbi.

Elucidation of molecular kinetic schemes from macroscopic traces using system identification.

Overall cellular responses to biologically-relevant stimuli are mediated by networks of simpler lower-level processes. Although information about some of these processes can now be obtained by visualizing and recording events at the molecular level, this is still possible only in especially favorable cases. Therefore the development of methods to extract the dynamics and relationships between the different lower-level (microscopic) processes from the overall (macroscopic) response remains a crucial challenge in the understanding of many aspects of physiology.

Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs.

Atypical antipsychotic drugs, such as clozapine and risperidone, have a high affinity for the serotonin 5-HT(2A) G protein-coupled receptor (GPCR), the 2AR, which signals via a G(q) heterotrimeric G protein. The closely related non-antipsychotic drugs, such as ritanserin and methysergide, also block 2AR function, but they lack comparable neuropsychological effects. Why some but not all 2AR inhibitors exhibit antipsychotic properties remains unresolved.

Beyond the wiring diagram: signalling through complex neuromodulator networks.

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.

Distinct mechanisms produce functionally complementary actions of neuropeptides that are structurally related but derived from different precursors.

Many bioactive neuropeptides containing RFamide at their C terminus have been described in both invertebrates and vertebrates. To obtain insight into the functional logic of RFamide signaling, we investigate it here in the feeding system of Aplysia. We focus on the expression, localization, and actions of two families of RFamide peptides, the FRFamides and FMRFamide, in the central neuronal circuitry and the peripheral musculature that generate the feeding movements.

Feedback from peripheral musculature to central pattern generator in the neurogenic heart of the crab Callinectes sapidus: role of mechanosensitive dendrites.

The neurogenic heart of decapod crustaceans is a very simple, self-contained, model central pattern generator (CPG)-effector system. The CPG, the nine-neuron cardiac ganglion (CG), is embedded in the myocardium itself; it generates bursts of spikes that are transmitted by the CG's five motor neurons to the periphery of the system, the myocardium, to produce its contractions. Considerable evidence suggests that a CPG-peripheral loop is completed by a return feedback pathway through which the contractions modify, in turn, the CG motor pattern.

Distinct inhibitory neurons exert temporally specific control over activity of a motoneuron receiving concurrent excitation and inhibition.

Recent work suggests that concurrent excitation and inhibition originating in central pattern generators (CPGs) may be used to control rhythmic motoneuronal activity. The specific roles that the inhibition plays in such cases are not well understood, however, in part because of the lack of identification of presynaptic inhibitory neurons. Here we demonstrate that, in the Aplysia feeding CPG, inhibitory inputs may be critical for flexible control of the activity of motoneurons in different forms of behavior.

A method for decoding the neurophysiological spike-response transform.

Many physiological responses elicited by neuronal spikes-intracellular calcium transients, synaptic potentials, muscle contractions-are built up of discrete, elementary responses to each spike. However, the spikes occur in trains of arbitrary temporal complexity, and each elementary response not only sums with previous ones, but can itself be modified by the previous history of the activity. A basic goal in system identification is to characterize the spike-response transform in terms of a small number of functions-the elementary response kernel and additional kernels or functions that describe the dependence on previous history-that will predict the response to any arbitrary spike train.

State dependence of network output: modeling and experiments.

Emerging experimental evidence suggests that both networks and their component neurons respond to similar inputs differently, depending on the state of network activity. The network state is determined by the intrinsic dynamical structure of the network and may change as a function of neuromodulation, the balance or stochasticity of synaptic inputs to the network, and the history of network activity. Much of the knowledge on state-dependent effects comes from comparisons of awake and sleep states of the mammalian brain.

Predicting adaptive behavior in the environment from central nervous system dynamics.

To generate adaptive behavior, the nervous system is coupled to the environment. The coupling constrains the dynamical properties that the nervous system and the environment must have relative to each other if adaptive behavior is to be produced. In previous computational studies, such constraints have been used to evolve controllers or artificial agents to perform a behavioral task in a given environment.

Functional penetration of variability of motor neuron spike timing through a modulated neuromuscular system.

Variability of the neuronal spike pattern is usually thought of in terms of the information that the different interspike intervals might be encoding. However, the very presence of the variability can have other kinds of functional significance. Here we consider the example of the B15/B16-ARC neuromuscular system of Aplysia, a model system for the study of neuromuscular modulation and control.

Regulation of the crab heartbeat by FMRFamide-like peptides: multiple interacting effects on center and periphery.

We are studying the functional "logic" of neuromodulatory actions in a simple central pattern generator (CPG)-effector system, the heart of the blue crab Callinectes sapidus. The rhythmic contractions of this heart are neurogenic, driven by rhythmic motor patterns generated by the cardiac ganglion (CG). Here we used anatomical and physiological methods to examine the sources and actions on the system of the FMRFamide-like peptides (FLPs) TNRNFLRFamide (F(1)), SDRNFLRFamide (F(2)), and GYNRSFLRFamide, an authentic Callinectes FLP.

Decoding modulation of the neuromuscular transform.

When modulators of neuromuscular function alter the motor neuron spike patterns that elicit muscle contractions, it is predicted that they will also retune correspondingly the connecting processes of the neuromuscular transform. Here we confirm this prediction by analyzing data from the cardiac neuromuscular system of the blue crab. We apply a method that decodes the contraction response to the spike pattern in terms of three elementary building-block functions that completely characterize the neuromuscular transform.

Regulation of the crab heartbeat by crustacean cardioactive peptide (CCAP): central and peripheral actions.

In regulating neurophysiological systems, neuromodulators exert multiple actions at multiple sites in such a way as to control the activity in an integrated manner. We are studying how this happens in a simple central pattern generator (CPG)-effector system, the heart of the blue crab Callinectes sapidus. The rhythmic contractions of this heart are neurogenic, driven by rhythmic motor patterns generated by the cardiac ganglion (CG).

Variability of motor neuron spike timing maintains and shapes contractions of the accessory radula closer muscle of Aplysia.

The accessory radula closer (ARC) muscle of Aplysia has long been studied as a typical "slow" muscle, one that would be assumed to respond only to the overall, integrated spike rate of its motor neurons, B15 and B16. The precise timing of the individual spikes should not much matter. However, but real B15 and B16 spike patterns recorded in vivo show great variability that extends down to the timing of individual spikes.

Cycle-to-cycle variability as an optimal behavioral strategy.

Aplysia feeding behavior is highly variable from cycle to cycle. In some cycles, when the variability causes a mismatch between the animal's movements and the requirements of the feeding task, the variability makes the behavior unsuccessful. We propose that the behavior is variable nevertheless because the variability serves a higher-order functional purpose.

Identification of a new neuropeptide precursor reveals a novel source of extrinsic modulation in the feeding system of Aplysia.

The Aplysia feeding system is advantageous for investigating the role of neuropeptides in behavioral plasticity. One family of Aplysia neuropeptides is the myomodulins (MMs), originally purified from one of the feeding muscles, the accessory radula closer (ARC). However, two MMs, MMc and MMe, are not encoded on the only known MM gene.

Variability of swallowing performance in intact, freely feeding aplysia.

Variability in nervous systems is often taken to be merely "noise." Yet in some cases it may play a positive, active role in the production of behavior. The central pattern generator (CPG) that drives the consummatory feeding behaviors of Aplysia generates large, quasi-random variability in the parameters of the feeding motor programs from one cycle to the next; the variability then propagates through the firing patterns of the motor neurons to the contractions of the feeding muscles.

Temperature compensation of neuromuscular modulation in aplysia.

Physiological systems that must operate over a range of temperatures often incorporate temperature-compensatory mechanisms to maintain their output within a relatively narrow, functional range of values. We analyze here an example in the accessory radula closer (ARC) neuromuscular system, a representative part of the feeding neuromusculature of the sea slug Aplysia. The ARC muscle's two motor neurons, B15 and B16, release, in addition to ACh that contracts the muscle, modulatory peptide cotransmitters that, through a complex network of effects in the muscle, shape the ACh-induced contractions.

Tight or loose coupling between components of the feeding neuromusculature of Aplysia?

Like other complex behaviors, the cyclical, rhythmic consummatory feeding behaviors of Aplysia-biting, swallowing, and rejection of unsuitable food-are produced by a complex neuromuscular system: the animal's buccal mass, with numerous pairs of antagonistic muscles, controlled by the firing of numerous motor neurons, all driven by the motor programs of a central pattern generator (CPG) in the buccal ganglia. In such a complex neuromuscular system, it has always been assumed that the activities of the various components must necessarily be tightly coupled and coordinated if successful functional behavior is to be produced. However, we have recently found that the CPG generates extremely variable motor programs from one cycle to the next, and so very variable motor neuron firing patterns and contractions of individual muscles.

Changes of internal state are expressed in coherent shifts of neuromuscular activity in Aplysia feeding behavior.

The multitasking central pattern generator (CPG) that drives consummatory feeding behaviors of Aplysia can produce ingestive, egestive, and intermediate motor programs. External stimuli trigger the programs but, remarkably, do not directly specify which type of program is produced. Rather, recent work has proposed, the type of program is determined by the internal network state of the CPG that has developed in response to the previous history of the stimulation.

Modeling neuromuscular modulation in Aplysia. III. Interaction of central motor commands and peripheral modulatory state for optimal behavior.

Recent work in computational neuroethology has emphasized that "the brain has a body": successful adaptive behavior is not simply commanded by the nervous system, but emerges from interactions of nervous system, body, and environment. Here we continue our study of these issues in the accessory radula closer (ARC) neuromuscular system of Aplysia. The ARC muscle participates in the animal's feeding behaviors, a set of cyclical, rhythmic behaviors driven by a central pattern generator (CPG).

Modulation of an integrated central pattern generator-effector system: dopaminergic regulation of cardiac activity in the blue crab Callinectes sapidus.

Theoretical studies have suggested that the output of a central pattern generator (CPG) must be matched to the properties of its peripheral effector system to ensure production of functional behavior. One way that such matching could be achieved is through coordinated central and peripheral modulation. In this study, morphological and physiological methods were used to examine the sources and actions of dopaminergic modulation in the cardiac system of the blue crab, Callinectes sapidus.

Dynamical basis of intentions and expectations in a simple neuronal network.

Selection of behavioral responses to external stimuli is strongly influenced by internal states, such as intentions and expectations. These internal states are often attributed to higher-order brain functions. Yet here we show that even in the simple feeding network of Aplysia, external stimuli do not directly specify which motor output is expressed; instead, the motor output is specified by the state of the network at the moment of stimulation.

A specific synaptic pathway activates a conditional plateau potential underlying protraction phase in the Aplysia feeding central pattern generator.

A common feature in the architecture of neuronal networks is a high degree of seemingly redundant synaptic connectivity. In many cases, the synaptic inputs converging on any particular neuron all use the same neurotransmitter and appear to be fundamentally equivalent. Here, we analyze a striking counterexample in which such inputs are not equivalent and, as a result, play very different roles in the generation of the pattern of activity produced by the network.