This article investigates the potential of “meta”-modulatory hierarchy between neuromodulators nitric oxide (NO) and noradrenaline (NA) in Xenopus laevis tadpoles. (McLean, 2004)

Background

Intrinsic and extrinsic neuromodulation are both responsible for the flexibility of the neural circuits, that influence rhythmic behaviors, movements such as locomotion and mastication are generated by ensembles of interconnected neurons [central pattern generators (CPGs)] that control the timing and intensity of the discharges of motor neurons (Morgan et al., 2000). Intrinsic neuromodulation is exerted by neurons within a neural network and participate in information processing undertaken by that network, depends on past or ongoing network activity, and provides a ‘‘memory’’ of the network state. On the other hand, extrinsic neuromodulation is exerted by neurons that originate in independent networks and therefore provide information based on the activity of other neural network, depends on the activity of other networks, so extrinsic neuromodulation provides a context about the broader state of the animal. An example, Ach and NE neuromodulators are observed in experience-dependent plasticity (Yu & Dayan, 2005). However, metamodulation (the modulation of modulation), allows extrinsic neurons to exert global control over already existing state (Lizbinski et al., 2017), adenosine as an example is known as neuromodulator and metamodulator influencing synaptic plasticity (Sebastião & Ribeiro, 2015).

In this study, swimming of Xenopus laevis tadpoles gets interrupted by two ways, head contacts an obstacle and cement gland afferents trigger inhibitory GABA release from reticulospinal neurons onto spinal neurons, or locomotion gradually runs down because of adenosine accumulation. Neuromodulators plays a big role in adaptability of locomotor networks, changes the strength of synaptic connections and/or modify the integrative membrane properties of component neurons (Lizbinski et al.,2017). Speed and distance of tadpole swimming are two facets of locomotion that are major targets for neuromodulation, amines serotonin [5-hydroxytryptamine (5-HT)] and noradrenaline (NA) exert opposing modulatory influences over the amplitude of midcycle inhibition by decreasing or increasing, respectively, glycinergic inhibition from commissural interneurons onto motor neurons. NA and NO increases midcycle glycinergic inhibition while simultaneously increasing the occurrence of GABA IPSPs.

Methods

Extracellular recordings of ventral root impulses appropriate to drive swimming movements were made using glass suction electrodes fashioned from borosilicate nonfilamented glass placed over clefts, and intracellular recordings from motor neurons in the ventral quarter of the spinal cord. Pharmacological strategies used to investigate whether NO was facilitating NA release by increasing exogenous levels of NO using the NO donor SNAP and then blocked the targets of endogenous NA with the broad-spectrum alpha1 adrenoreceptor antagonist phentolamine. To investigate the possibility that NA may be facilitating NO production, experiments were conducted with exogenous NA and the NO scavenger PTIO. All drugs were added sequentially (McLean, 2004).

Results

Modulatory effects of on the fictive swimming rhythm in Xenopus tadpoles: NO: (1) increase in cycle periods and thus a slowing of swimming frequency, (2) decrease in the total amount of episode duration. Recordings from motor neurons suggest that NO achieves this by facilitating spinal glycinergic and GABAergic inhibition and by decreasing motor neuron membrane conductance, while NA: (1) increase cycle periods by increasing glycinergic inhibition from interneurons, (2) decrease in the total amount of episode duration Increase GABA, (3) decrease the longitudinal delay of motor bursts along the body by enhancing post inhibitory rebound in motor neurons. Since NA mediates three effects via the activation of aadrenoreceptors indicates possible hierarchical relationship between NO and NA. 

Significance

More information about neuromodulation influence does have many benefits, such as combining neuromodulation and a behavior of axon polarization resulting changes in action potential dynamics, can influence analog–digital information processing (Chakraborty et al., 2017). Combining neuromodulation and brain connectomics will increase the efficiency of transcranial direct current stimulation (tDCS), reducing the interindividual variability of the response. Personalization of the stimulation is adapted to fit the structural and functional features of individual subjects (Cancelli et al., 2015). Overall, personalizing neuromodulation is useful way to validate generalizable mechanisms, because some neuromodulation includes invasive methods such as stereotactic lesions and deep brain stimulation (DBS), other noninvasive methods such as transcranial magnetic neuromodulation can be reversible, as is the case with TMS or DBS, (Horn & Fox, 2020). Ideally, the distinction between statistically fitted models and mechanistic models should decrease as each type of model becomes more successful at predicting a system's outputs (Medaglia et al., 2020). Also, the fast-growing field of bioelectronic medicine aims to develop engineered systems that can relieve clinical conditions by stimulating the peripheral nervous system. This type of technology relies largely on electrical stimulation to provide neuromodulation of organ function or pain (Tyagi, 2019).

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