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EDITORIAL FOCUS
) provides the network with the ability to reconfigure itself dynamically, with the extent of the modification dependent on the firing patterns of the neuromodulator-containing neuron(s). Understanding the role of intrinsic neuromodulation is most straightforward in small circuits where the individual neurons and synaptic connections can be identified and characterized. Not surprisingly, much of the progress in this field has been made by studying invertebrate systems (Katz 1995; Katz and Frost 1996; Marder and Calabrese 1996). How temperature and neuromodulation interact in these circuits is a topic that has not yet been given much attention. The body temperature of most poikilotherms tracks that of their surroundings; all physiological processes, including neuromodulatory release, ultimately are constructed from basic temperature-dependent biochemical reactions. In this issue of the Journal of Neurophysiology (p. 3259–3277), Zhurov and Brezina (2005) contribute to the understanding on how a small neural system can continue to produce a stable output despite a dramatic temperature-dependent reduction in intrinsic neuromodulatory release.
The network studied by the authors, the accessory radula closer (ARC) neuromuscular system in the sea slug Aplysia californica, consists of a muscle used for biting and the two motor neurons that innervate it. When one or the other neuron is stimulated at high frequency, it releases peptide cotransmitters that, among other actions, modify the amplitude and time-course of contractions generated by either neuron (Cropper et al. 1987). A complete dynamical model of the system has been constructed that allows contractions to be predicted and analyzed in response to realistic firing patterns (Brezina et al. 2003a,b). Several years ago, Vilim et al. (1996) reported that neuromodulatory peptide release in the ARC system dropped by a factor of 
4 when the temperature was increased from 15 to 19°C. It would thus seem that neuromodulatory actions should be insignificant toward the high end of the water temperature range (<15–25°C) that A. californica encounters in its natural habitat (Kupfermann and Carew 1974). Zhurov and Brezina (2005) show this not be to be the case. They identify and analyze two qualitatively different compensation mechanisms that act to largely maintain the strength of neuromodulatory effects on muscle contraction between 15 and 25°C.
Temperature compensation in poikilotherms has been studied for >50 years (Fry 1958) and will continue to be a topic of interest, although probably with a shift from studies of enzymatic activity (Hazel and Prosser 1974; Somero and Hochachka 1969) to gene expression (Podrabsky and Somero 2004; Tsuchiya et al. 2003). The effect of temperature on the output of a motor network clearly is related to the temperature dependences of its constituent parts. Temperature insensitivity in a network can come about in two different ways. First, the intrinsic temperature dependences of the processes that contribute to the system output can simply balance each other. Temperature compensation, as such, occurs because reaction rates have been "chosen properly." Alternatively, the structure of the network itself can stabilize its output. Zhurov and Brezina find evidence of each of the two compensation schemes in the ARC system. First, in experiments involving exogenous peptide application, they show that the modulatory effect on the relaxation rate of contraction is inherently three times stronger at 25°C than at 15°C. (This parameter of contraction was the primary focus of the study because its modulation is thought to be a unitary process and activated identically by the neuropeptides released by each motor neuron.) That neuropeptide efficacy increases at higher temperature is not surprising; one would expect temperature to have some effect of one sign or the other. However, the modest increase in the inherent strength of neuromodulator action is too small to explain how the magnitude of the modulation of the relaxation rate actually increases in response to a calculated 20-fold decrease in neuropeptide release at the higher temperature. The second compensation mechanism identified is simpler and of greater general interest. Using their model, the authors construct an intrinsic dose–response relationship relating the magnitude of the effect on relaxation rate to the concentration of released neuropeptide. For peptide release at 15 and 25°C, this magnitude differs not by a factor of 20, but by less than a factor of 2 because, between the two concentrations, the dose–response curve saturates (flattens) as the maximal neuromodulatory effect is approached.
The identification of a dose–response relationship as a means to generate stable network behavior is intriguing for several reasons. First, in the ARC system, this mechanism should compensate not just for changes in temperature, but in any parameter that influences the release of neuropeptide. In particular, the magnitude of the modulatory effect on the relaxation rate should not depend sensitively on the motor neuron firing pattern, as long as it is of sufficient frequency and duration to access the nearly flat part of the dose–response curve. Taken to the extreme, these results suggest that, although release of neuromodulator is a graded function of a neuron’s activity, the resulting neuromodulatory effect may be binary in nature. If the relevant portion of the dose–response curve is sufficiently flat, there will only be two states of the system: unmodulated and modulated. To produce more than two or a continuum of states would require multiple neuromodulatory effects or a differently shaped dose–response relationship. It will be interesting to discover whether the simple structural mechanism identified by Zhurov and Brezina acts to stabilize other aspects of motor output in the ARC or other systems and if this might lead to a deeper understanding of the function of intrinsic neuromodulation in small neural circuits.
Department of Physics, Santa Clara University, Santa Clara, California
Address for reprint requests and other correspondence: J. T. Birmingham, Dept. of Physics, Santa Clara Univ., Santa Clara, CA 95053. (E-mail: jbirmingham{at}scu.edu)
REFERENCES
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Brezina V, Orekhova IV, and Weiss KR. Neuromuscular modulation in Aplysia. II. Modulation of the neuromuscular transform in behavior. J Neurophysiol 90: 2613–2628, 2003b.
Cropper EC, Lloyd PE, Reed W, Tenenbaum R, Kupfermann I, and Weiss KR. Multiple neuropeptides in cholinergic motor neurons of Aplysia: evidence for modulation intrinsic to the motor circuit. Proc Natl Acad Sci USA 84: 3486–3490, 1987.
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Hazel JR and Prosser CL. Molecular mechanisms of temperature compensation in poikilotherms. Physiol Rev 54: 620–677, 1974.
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Kupfermann I and Carew TJ. Behavior patterns of Aplysia californica in its natural environment. Behav Biol 12: 317–337, 1974.[CrossRef][ISI][Medline]
Marder E and Calabrese RL. Principles of rhythmic motor pattern generation. Physiol Rev 76: 687–717, 1996.
Podrabsky JE and Somero GN. Changes in gene expression associated with acclimation to constant temperatures and fluctuating daily temperatures in an annual killifish Austrofundulus limnaeus. J Exp Biol 207: 2237–2254, 2004.
Somero GN and Hochachka PW. Isoenzymes and short-term temperature compensation in poikilotherms: activation of lactate dehydrogenase isoenzymes by temperature decreases. Nature 223: 194–195, 1969.[CrossRef][Medline]
Tsuchiya Y, Akashi M, and Nishida E. Temperature compensation and temperature resetting of circadian rhythms in mammalian cultured fibroblasts. Genes Cells 8: 713–720, 2003.[Abstract]
Vilim FS, Cropper EC, Price DA, Kupfermann I, and Weiss KR. Release of peptide cotransmitters in Aplysia: regulation and functional implications. J Neurosci 16: 8105–8114, 1996.
Zhurov Y and Brezina V. Temperature compensation of neuromuscular modulation in Aplysia. J Neurophysiol 94: 3259–3277, 2005.
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