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Central sympathetic neural circuits continuously generate efferent commands to sustain rhythmic operations of their peripheral effectors. However, beyond the firing rates, in what configuration an effective visceral command is formatted by the spiking activities was largely unknown. This study used an in vitro splanchnic nerve–spinal cord preparation of the neonatal rats as an experimental model and recorded spontaneous efferent activities from single sympathetic fibers. The patterns of the fiber activities were quantitatively evaluated by a metric, the so-called local variation (Lv). Lv was derived from calculating the relative differences between adjacent interspike intervals (ISIs), and thus, described the spiking patterns from a regular spiking with Lv = 0 to that spiking in bursts with Lv >1. Along the time course, the dynamic components of Lv (dLv) displayed quasiperiodic oscillations. Continuous wavelet analysis showed that dLv oscillations registered a dominant power rhythm at ∼7 mHz. This slow rhythmicity was heterogeneously altered by application of various antagonists that interrupted endogenous neurotransmitter activities mediated by ionotropic glutamate receptors or GABAA receptors in the spinal cord. Thus, the oscillation of dLv manifested itself as a feature of neural network operation. On the assumption that the total power of the dLv oscillations reflects an activity status of neural network operation, the antagonist-induced change of the power fits well with a concomitant ISI change in a negative sigmoid relationship, which explains the heterogeneity of the antagonist-induced firing responses. In conclusion, dLv oscillations reflect a dynamic status of neural network operation. The slow rhythms embedded in the dLv oscillations are likely acting as an information coder and convey effective central visceral commands that can be followed by their downstream effectors.Author summaryIn what format the information is encoded by the neural activity is relatively unknown. This is especially true for autonomic regulation of visceral functions. We seek to determine the format of the central sympathetic commands, by which it can generate an effective driving force to regulate the operation of their peripheral target organs. Because most visceral organs operate with certain rhythms, we anticipate that the central visceral commands are also formatted in rhythms. Two aspects of techniques were employed. One was the in vitro electrophysiological and pharmacological techniques to acquire and to manipulate the neural signals recorded from sympathetic single-fibers. The other was the computational techniques to extract the information embedded in the timing of the spiking behaviors and to examine how these features were altered by pharmacological manipulations. We found a spontaneous change of sympathetic spiking patterns displaying rhythms with a frequency that could match the rhythmic operation of many visceral organs. Thus, the meaningful information carried by the sympathetic neural circuits for the visceral controls is likely to be encoded in the dynamics of their spiking patterns. In summary, a dynamic change of neural spiking patterns could be used as a simple scheme for neural information coding.

The central adrenergic and noradrenergic neurotransmitter systems diffusively affect the operation of the spinal neural network and dynamically gauge central sympathetic outflow. Using in vitro splanchnic nerve-thoracic spinal cord preparations as an experimental model, this study examined the intraspinal α

Cytoplasmic polyadenylation element binding protein 2 (CPEB2) is an RNA-binding protein and translational regulator. To understand the physiological function of CPEB2, we generated CPEB2 knock-out (KO) mice and found that most died within 3 d after birth. CPEB2 is highly expressed in the brainstem, which controls vital functions, such as breathing. Whole-body plethysmography revealed that KO neonates had aberrant respiration with frequent apnea. Nevertheless, the morphology and function of the respiratory rhythm generator and diaphragm neuromuscular junctions appeared normal. We found that upregulated translation of choline acetyltransferase in the CPEB2 KO dorsal motor nucleus of vagus resulted in hyperactivation of parasympathetic signaling-induced bronchoconstriction, as evidenced by increased pulmonary acetylcholine and phosphorylated myosin light chain 2 in bronchial smooth muscles. Specific deletion of CPEB2 in cholinergic neurons sufficiently caused increased apnea in neonatal pups and airway hyper-reactivity in adult mice. Moreover, inhalation of an anticholinergic bronchodilator reduced apnea episodes in global and cholinergic CPEB2-KO mice. Together, the elevated airway constriction induced by cholinergic transmission in KO neonates may account for the respiratory defect and mortality.SIGNIFICANCE STATEMENTThis study first generated and characterizedcpeb2gene-deficient mice. CPEB2-knock-out (KO) mice are born alive but most die within 3 d after birth showing no overt defects in anatomy. We found that the KO neonates showed severe apnea and altered respiratory pattern. Such respiratory defects could be recapitulated in mice with pan-neuron-specific or cholinergic neuron-specific ablation of thecpeb2gene. Further investigation revealed that cholinergic transmission in the KO dorsal motor nucleus of vagus was overactivated because KO mice lack CPEB2-suppressed translation of the rate-limiting enzyme in the production of acetylcholine (i.e., choline acetyltransferase). Consequently, increased parasympathetic signaling leads to hyperactivated bronchoconstriction and abnormal respiration in the KO neonates.

Nitric oxide (NO) is a diffusible gas and has multifarious effects on both pre- and postsynaptic events. As a consequence of complex excitatory and inhibitory integrations, NO effects on neuronal activities are heterogeneous. Using in vitro preparations of neonatal rats that retain the splanchnic sympathetic nerves and the thoracic spinal cord as an experimental model, we report here that either enhancement or attenuation of NO production in the neonatal rat spinal cords could increase, decrease, or not change the spontaneous firing behaviors recorded from splanchnic sympathetic single fibers. To elucidate the mathematical features of NO-mediated heterogeneous responses, the ratios of changes in firing were plotted against their original firing rates. In log-log plots, a linear data distribution demonstrated that NO-mediated heterogeneity in sympathetic firing responses was well described by a power function. Selective antagonists were applied to test if glycinergic, GABAergic, glutamatergic, and cholinergic neurotransmission in the spinal cord are involved in NO-mediated power-law firing modulations (plFM). NO-mediated plFM diminished in the presence of mecamylamine (an open-channel blocker of nicotinic cholinergic receptors), indicating that endogenous nicotinic receptor activities were essential for plFM. Applications of strychnine (a glycine receptor blocker), gabazine (a GABAA receptor blocker), or kynurenate (a broad-spectrum ionotropic glutamate receptor blocker) also caused plFM. However, strychnine- or kynurenate-induced plFM was diminished by L-NAME (an NO synthase inhibitor) pretreatments, indicating that the involvements of glycine or ionotropic glutamate receptor activities in plFM were secondary to NO signaling. To recapitulate the arithmetic natures of the plFM, the plFM were simulated by firing changes in two components: a step increment and a fractional reduction of their basal firing activities. Ionotropic glutamate receptor activities were found to participate in plFM by both components. In contrast, GABAA receptor activities are involved in the component of fractional reduction only. These findings suggest that NO orchestrates a repertoire of excitatory and inhibitory neurotransmissions, incurs a shunting effect on postsynaptic membrane properties, and thus, alters sympathetic firing in a manner of plFM. We propose that the plFM mediated by NO forms a basic scheme of differential controls for heterogeneous sympathetic regulation of visceral functions.

Delivering effective commands in the nervous systems require a temporal integration of neural activities such as synchronous firing. Although sympathetic nerve discharges are characterized by synchronous firing, its temporal structures and how it is modulated are largely unknown. This study used a collagenase-dissociated splanchnic sympathetic nerve-thoracic spinal cord preparation of neonatal rats in vitro as an experimental model. Several single-fiber activities were recorded simultaneously and verified by rigorous computational algorithms. Among 3763 fiber pairs that had spontaneous fiber activities, 382 fiber pairs had firing positively correlated. Their temporal relationship was quantitatively evaluated by cross-correlogram. On average, correlated firing in a fiber pair occurred in scales of ∼40ms lasting for ∼11ms. The relative frequency distribution curves of correlogram parametrical values pertinent to the temporal features were best described by trimodal Gaussians, suggesting a correlated firing originated from three or less sources. Applications of bicuculline or gabazine (noncompetitive or competitive GABA(A) receptor antagonist) and/or strychnine (noncompetitive glycine receptor antagonist) increased, decreased, or did not change individual fiber activities. Antagonist-induced enhancement and attenuation of correlated firing were demonstrated by a respective increase and decrease of the peak probability of the cross-correlograms. Heterogeneity in antagonistic responses suggests that the inhibitory neurotransmission mediated by GABA(A) and glycine receptors is not essential for but can serve as a neural substrate to modulate synchronous firing behaviors. Plausible neural mechanisms were proposed to explain the temporal structures of correlated firing between sympathetic fibers.