Rhythmogenic and Premotor Functions of Dbx1 Interneurons in the Pre-Bötzinger Complex and Reticular Formation: Modeling and Simulation Studies

Breathing in mammals depends on rhythms that originate from the preBötzinger complex (preBötC) of the ventral medulla and a network of brainstem and spinal premotor neurons. The rhythm-generating core of the preBötC, as well as some premotor circuits, consists of interneurons derived from Dbx1-expressing precursors but the structure and function of these networks remain incompletely understood. We previously developed a cell-specific detection and laser ablation system to interrogate respiratory network structure and function in a slice model of breathing that retains the preBötC, premotor circuits, and the respiratory related hypoglossal (XII) motor nucleus such that in spontaneously rhythmic slices, cumulative ablation of Dbx1 preBötC neurons decreased XII motor output by half after only a few cell deletions, and then decelerated and terminated rhythmic function altogether as the tally increased. In contrast, cumulatively deleting Dbx1 premotor neurons decreased XII motor output monotonically, but did not affect frequency nor stop functionality regardless of the ablation tally. This dissertation presents several network modeling and cellular modeling studies that would further our understanding of how respiratory rhythm is generated and transmitted to the XII motor nucleus. First, we propose that cumulative deletions of Dbx1 preBötC neurons preclude rhythm by diminishing the amount of excitatory inward current or disturbing the process of recurrent excitation rather than structurally breaking down the topological network. Second, we establish a feasible configuration for neural circuits including an Erdős-Rényi preBötC network and a small-world reticular premotor network with interconnections following an anti-preferential attachment rule, which is the only configuration that produces consistent outcomes with previous experimental benchmarks. Furthermore, since the performance of neuronal network simulations is, to some extent, affected by the nature of the cellular model, we aim to develop a more realistic cellular model based on the one we adopted in previous network studies, which would account for some recent experimental findings on rhythmogenic preBötC neurons

Mechanisms Leading to Rhythm Cessation in the Respiratory PreBotzinger Complex Due to Piecewise Cumulative Neuronal Deletions

The brainstem pre-Botzinger complex (preBotC) generates the rhythm underlying inspiratory breathing movements and its core interneurons are derived from Dbx-1 expressing precursors. Recurrent synaptic excitation is required to initiate inspiratory bursts, but whether excitatory synaptic mechanisms also contribute to inspiratory–expiratory phase transition is unknown. Here, we examined the role of short-term synaptic depression using a rhythmically active neonatal mouse brainstem slice preparation. We show that different axonal projections to Dbx-1 PreBotC neurons undergo activity-dependent depression and we identify a refractory period (approx. 2 s) after endogenous inspiratory bursts that precludes light-evoked bursts in channelrhodopsin-expressing Dbx1 Pre-BotC neurons. We demonstrate that the duration of the refractory period---but neither the cycle period nor the magnitude of endogenous inspiratory burst---is sensitive to changes in extracellular Ca^2+. Further, we show that postsynaptic factors are unlikely to explain the refractory period or its modulation by Ca^2+. Our findings are consistent with the hypothesis that short-term synaptic depression in Dbx-1 Pre-BotC neurons influences the inspiratory-expiratory phase transition during respiratory rhythmogenesis

Serum Oxytocin Levels and an Oxytocin Receptor Gene Polymorphism (rs2254298) Indicate Social Deficits in Children and Adolescents with Autism Spectrum Disorders

The neuropeptide oxytocin (OT) and its receptor (OXTR) have been predicted to be involved in the regulation of social functioning in autism spectrum disorders (ASD). Objective of the study was to investigate serum OT levels and the OXTR rs2254298 polymorphism in Chinese Han children and adolescents with ASD as well as to identify their social deficits relevant to the oxytocinergic system. We tested serum OT levels using ELISA in 55 ASD subjects and 110 typically developing (TD) controls as well as genotyped the OXTR rs2254298 polymorphism using PCR-RFLP in 100 ASD subjects and 232 TD controls. Autistic symptoms were assessed by the Autism Behavior Checklist (ABC) and the Childhood Autism Rating Scale (CARS). There were no significant associations between OXTR rs2254298 polymorphism and ASD, serum OT levels and age, as well as serum OT levels and intelligent quotient (IQ) in both ASD and TD groups. However, ASD subjects exhibited elevated serum OT levels compared to TD controls and positive correlations between serum OT levels and adaptation to change score in the CARS and CARS total scores. Moreover, in the ASD group, significant relationships were revealed between the single-nucleotide polymorphism (SNP) rs2254298 and serum OT levels, the category stereotypes and object use in the ABC and the category adaptation to change in the CARS. These findings indicated that individuals with ASD may exhibit a dysregulation in OT on the basis of changes in OXTR gene expression as well as environmentally induced alterations of the oxytocinergic system to determine their social deficits

Functional Interactions between Mammalian Respiratory Rhythmogenic and Premotor Circuitry

Breathing in mammals depends on rhythms that originate from the preBotzinger complex (preBotC) of the ventral medulla and a network of brainstem and spinal premotor neurons. The rhythm-generating core of the preBotC, as well as some premotor circuits, consist of interneurons derived from Dbx1-expressing precursors (Dbx1 neurons), but the structure and function of these networks remain incompletely understood. We previously developed a cell-specific detection and laser ablation system to interrogate respiratory network structure and function in a slice model of breathing that retains the preBotC, the respiratory-related hypoglossal (XII) motor nucleus and XII premotor circuits. In spontaneously rhythmic slices, cumulative ablation of Dbx1 preBotC neurons decreased XII motor output by similar to 50% after similar to 15 cell deletions, and then decelerated and terminated rhythmic function altogether as the tally increased to similar to 85 neurons. In contrast, cumulatively deleting Dbx1 XII premotor neurons decreased motor output monotonically but did not affect frequency nor stop XII output regardless of the ablation tally. Here, we couple an existing preBotC model with a premotor population in several topological configurations to investigate which one may replicate the laser ablation experiments best. If the XII premotor population is a small-world network (rich in local connections with sparse long-range connections among constituent premotor neurons) and connected with the preBotC such that the total number of incoming synapses remains fixed, then the in silico system successfully replicates the in vitro laser ablation experiments. This study proposes a feasible configuration for circuits consisting of Dbx1-derived interneurons that generate inspiratory rhythm and motor pattern

Avian Influenza (H5N1) Virus in Waterfowl and Chickens, Central China

In 2004, 3 and 4 strains of avian influenza virus (subtype H5N1) were isolated from waterfowl and chickens, respectively, in central People’s Republic of China. Viral replication and pathogenicity were evaluated in chickens, quails, pigeons, and mice. We analyzed the sequences of the hemagglutinin and neuraminidase genes of the isolates and found broad diversity among them

Disruption of LRRK2 Does Not Cause Specific Loss of Dopaminergic Neurons in Zebrafish

Mutations in LRRK2 are genetically linked to Parkinson's disease (PD) but its normal biological function is largely unknown. Sheng et al. recently reported that deletion of the WD40 domain of LRRK2 in zebrafish specifically causes PD-like loss of neurons and behavior defect. However, our similar early study and recent confirming experiments using the same reagents reported by Sheng et al. failed to reproduce the phenotype of the loss of dopaminergic neurons, although the mRNA of LRRK2 was molecularly disrupted. Our study suggests that function of LRRK2 and its usefulness to generate zebrafish PD model needs further evaluation

26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15–20 July 2017

This work was produced as part of the activities of FAPESP Research,\ud Disseminations and Innovation Center for Neuromathematics (grant\ud 2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud supported by a CNPq fellowship (grant 306251/2014-0)

A Hybrid Martian VTOL UAV: Design, Dynamics and Control.

Mars is always an intriguing planet for exploration due to its similarity to Earth and hospitability compared with other planets in the Solar System. So far, Mars exploration has occurred in three stages: flyby, Orbiter, Lander/Rover. For the next stage of Mars exploration, a novel unmanned aerial vehicle (UAV or Aerobot) is required to guarantee regional coverage of the Martian surface with high resolution sensing for precise investigations of geology and life processes. Based on the knowledge of existing Mars Aerobot/Aeroplane/etc concepts, the combination of fixed wing and VTOL (vertical take-off and landing) capability is chosen for further investigation, with the ambition of regional coverage and multiple flights over the mission target region. A mission profile to investigate the Isidis Planitia region of Mars has been proposed based on the knowledge of the planet’s geophysical characteristics, its atmosphere and terrain. A novel aircraft design based on a combination of helicopter and flying wing dynamics has been presented with commercial-off-the-shelf sensors and instruments. A six-degree-of-freedom flight simulator has been created to support the Martian UAV design process by providing performance evaluations. The results demonstrate that this Martian UAV is flyable and feasible in both forward and VTOL mode. The controller loops and gains for both longitudinal modes and lateral/directional modes are also designed and verified by implementing different control command respectively. The results proved that this Martian UAV is controllable within a reasonable time in both longitudinal and lateral/directional modes