Pacemaker Neuron and Network Oscillations Depend on a Neuromodulator-Regulated Linear Current

Linear leak currents have been implicated in the regulation of neuronal excitability, generation of neuronal and network oscillations, and network state transitions. Yet, few studies have directly tested the dependence of network oscillations on leak currents or explored the role of leak currents on network activity. In the oscillatory pyloric network of decapod crustaceans neuromodulatory inputs are necessary for pacemaker activity. A large subset of neuromodulators is known to activate a single voltage-gated inward current IMI, which has been shown to regulate the rhythmic activity of the network and its pacemaker neurons. Using the dynamic clamp technique, we show that the crucial component of IMI for the generation of oscillatory activity is only a close-to-linear portion of the current-voltage relationship. The nature of this conductance is such that the presence or the absence of neuromodulators effectively regulates the amount of leak current and the input resistance in the pacemaker neurons. When deprived of neuromodulatory inputs, pyloric oscillations are disrupted; yet, a linear reduction of the total conductance in a single neuron within the pacemaker group recovers not only the pacemaker activity in that neuron, but also leads to a recovery of oscillations in the entire pyloric network. The recovered activity produces proper frequency and phasing that is similar to that induced by neuromodulators. These results show that the passive properties of pacemaker neurons can significantly affect their capacity to generate and regulate the oscillatory activity of an entire network, and that this feature is exploited by neuromodulatory inputs

Neuromodulation of inhibitory feedback to pacemaker neurons and its consequent role in stabilizing the output of the neuronal network:

Stable oscillations can be important for the proper function of neuronal networks. Rhythmic movements, for example, often rely on stable input from central pattern generator (CPG) networks that generate the underlying oscillations. I used the crustacean pyloric motor network as a model oscillatory neural system. The primary goal is to characterize the effects of the neuropeptide proctolin on the LP to PD synapse and consequently to investigate functional role in shaping the network output. First, I characterized the effects of proctolin on both the spike-mediated and graded components of the LP to PD synapse. The results showed that both components of the LP to PD synapse were enhanced by bath-applied proctolin. The results also showed that proctolin caused facilitation of the LP to PD synapse with injection of low amplitude depolarization steps. This facilitation is associated with a slow inward Ca 2+ like current. Second, I investigated the function of the LP to PD synapse in the pyloric network. The results showed that the LP to PD synapse reduced the variability in the pyloric period. Also, analysis of the phase response curve (PRC) showed that the LP to PD synapse reduced the effect of perturbations. We used synaptic-PRC and its relationship with synaptic phase and synaptic duty cycle to explain how the LP to PD synapse counteracts the effect of perturbation. Third, I examined the role of proctolin in shaping the neural network output. It was found that in the presence of proctolin the variability of pyloric period was reduced. Furthermore, using PRC analysis, I demonstrated that proctolin reduced the effect of extrinsic perturbations on the pacemaker neurons in the presence of LP to PD synapse. The results suggest that proctolin, through its enhancement on the LP to PD synapse, plays an active role in stabilizing the pyloric network oscillation. Our findings suggest that modulations of the inhibitory feedback synapse can be a useful approach to regulate the stability of neuronal networks. Insights gained from this thesis could be applied to mammalian nervous system such as feedback or recurrent inhibitory circuits in cortex or oscillator-driven respiratory CPGs.Ph.D.Includes bibliographical references (p. 107-114)by Shunbing Zha