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Transient Suppression Of Dbx1 Prebotzinger Interneurons Disrupts Breathing In Adult Mice, Nikolas C. Vann, Francis D. Pham, John A. Hayes, Andrew Kottick, Christopher A. Del Negro
Transient Suppression Of Dbx1 Prebotzinger Interneurons Disrupts Breathing In Adult Mice, Nikolas C. Vann, Francis D. Pham, John A. Hayes, Andrew Kottick, Christopher A. Del Negro
Christopher Del Negro
Interneurons derived from Dbx1-expressing precursors located in the brainstem preBotzinger complex (preBotC) putatively form the core oscillator for inspiratory breathing movements. We tested this Dbx1 core hypothesis by expressing archaerhodopsin in Dbx1-derived interneurons and then transiently hyperpolarizing these neurons while measuring respiratory rhythm in vitro or breathing in vagus-intact adult mice. Transient illumination of the preBotC interrupted inspiratory rhythm in both slice preparations and sedated mice. In awake mice, light application reduced breathing frequency and prolonged the inspiratory duration. Support for the Dbx1 core hypothesis previously came from embryonic and perinatal mouse experiments, but these data suggest that Dbx1-derived preBotC …
Trpm4 Ion Channels In Pre-Bo¨Tzinger Complex Interneurons Are Essential For Breathing Motor Pattern But Not Rhythm, Marina Cristina D. Picardo, Yae K. Sugimura, Kaitlyn E. Dorst, Prajkta S. Kallurkar, Victoria T. Akins, Xingru Ma, Ryoichi Teruyama, Romaine Guinamard, Kaiwen Kam, Margaret Saha, Christopher A. Del Negro
Trpm4 Ion Channels In Pre-Bo¨Tzinger Complex Interneurons Are Essential For Breathing Motor Pattern But Not Rhythm, Marina Cristina D. Picardo, Yae K. Sugimura, Kaitlyn E. Dorst, Prajkta S. Kallurkar, Victoria T. Akins, Xingru Ma, Ryoichi Teruyama, Romaine Guinamard, Kaiwen Kam, Margaret Saha, Christopher A. Del Negro
Christopher Del Negro
Inspiratory breathing movements depend on pre-Bötzinger complex (preBötC) interneurons that express calcium (Ca2+)-activated nonselective cationic current (ICAN) to generate robust neural bursts. Hypothesized to be rhythmogenic, reducing ICAN is predicted to slow down or stop breathing; its contributions to motor pattern would be reflected in the magnitude of movements (output). We tested the role(s) of ICAN using reverse genetic techniques to diminish its putative ion channels Trpm4 or Trpc3 in preBötC neurons in vivo. Adult mice transduced with Trpm4-targeted short hairpin RNA (shRNA) progressively decreased the tidal volume of breaths yet surprisingly increased breathing frequency, often followed by gasping and …
Synaptic Depression Influences Inspiratory-Expiratory Phase Transition In Dbx1 Interneurons Of The Pre-Botzinger Complex In Neonatal Mice, Andrew Kottick, Christopher A. Del Negro
Synaptic Depression Influences Inspiratory-Expiratory Phase Transition In Dbx1 Interneurons Of The Pre-Botzinger Complex In Neonatal Mice, Andrew Kottick, Christopher A. Del Negro
Christopher Del Negro
The brainstem preBötzinger complex (preBötC) generates the rhythm underlying inspiratory breathing movements and its core interneurons are derived from Dbx1-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 afferent axonal projections to Dbx1 preBötC neurons undergo activity-dependent depression and we identify a refractory period (∼2 s) after endogenous inspiratory bursts that precludes light-evoked bursts in channelrhodopsin-expressing Dbx1 preBötC neurons. We demonstrate that the duration …
Outward Currents Contributing To Inspiratory Burst Termination In Prebotzinger Complex Neurons Of Neonatal Mice Studied In Vitro, Rebecca Kray, Adam M. Goodreau, Thomas B. Arnold, Christopher A. Del Negro
Outward Currents Contributing To Inspiratory Burst Termination In Prebotzinger Complex Neurons Of Neonatal Mice Studied In Vitro, Rebecca Kray, Adam M. Goodreau, Thomas B. Arnold, Christopher A. Del Negro
Christopher Del Negro
We studied pre-Botzinger(preBotC) inspiratory interneurons to determine the cellular mechanisms that influence burst termination in a mammalian central pattern generator. Neonatal mouse slice preparations that retain pre-BoTC neurons generate respiratory motor rhythms in vitro. Inspiratory-related bursts rely on inward currents that flux Na+, thus outward currents coupled to Na+ accumulation are logical candidates for assisting in, or causing, burst termination. We examined Na+/K+/ATPase electrogenic pump current (Ipump), Na+-dependent K+ current, and ATP-dependent K+ current (IK-ATP). The pharmacological blockade of IPUMP, IK-Na, or IK-ATP caused pathological depolarization akin to a burst that …
Organotypic Slice Cultures Containing The Prebotzinger Complex Generate Respiratory-Like Rhythms, Wiktor S. Phillips, Mikkel Herly, Jens C. Rekling, Christopher A. Del Negro
Organotypic Slice Cultures Containing The Prebotzinger Complex Generate Respiratory-Like Rhythms, Wiktor S. Phillips, Mikkel Herly, Jens C. Rekling, Christopher A. Del Negro
Christopher Del Negro
Study of acute brain stem slice preparations in vitro has advanced our understanding of the cellular and synaptic mechanisms of respiratory rhythm generation, but their inherent limitations preclude long-term manipulation and recording experiments. In the current study, we have developed an organotypic slice culture preparation containing the preBotzinger complex (preBotC), the core inspiratory rhythm generator of the ventrolateral brain stem. We measured bilateral synchronous network oscillations, using calcium-sensitive fluorescent dyes, in both ventrolateral (presumably the preBotC) and dorsomedial regions of slice cultures at 7-43 days in vitro. These calcium oscillations appear to be driven by periodic bursts of inspiratory neuronal …
Mechanisms Leading To Rhythm Cessation In The Respiratory Prebotzinger Complex Due To Piecewise Cumulative Neuronal Deletions, Hanbing Song, John A. Hayes, Nicolas A. Vann, M. Drew Lamar, Christopher A. Del Negro
Mechanisms Leading To Rhythm Cessation In The Respiratory Prebotzinger Complex Due To Piecewise Cumulative Neuronal Deletions, Hanbing Song, John A. Hayes, Nicolas A. Vann, M. Drew Lamar, Christopher A. Del Negro
Christopher Del Negro
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 …
Laser Ablation Of Dbx1 Neurons In The Pre-Botzinger Complex Stops Inspiratory Rhythm And Impairs Output In Neonatal Mice, Xueying Wang, John A. Hayes, Hanbing Song, Andrew Kottick, Nikolas C. Vann, Maria Cristina D. Picardo, Victoria T. Akins, Christopher A. Del Negro, Ann L. Revill, Gregory D. Funk, M. Drew Lamar
Laser Ablation Of Dbx1 Neurons In The Pre-Botzinger Complex Stops Inspiratory Rhythm And Impairs Output In Neonatal Mice, Xueying Wang, John A. Hayes, Hanbing Song, Andrew Kottick, Nikolas C. Vann, Maria Cristina D. Picardo, Victoria T. Akins, Christopher A. Del Negro, Ann L. Revill, Gregory D. Funk, M. Drew Lamar
Christopher Del Negro
To understand the neural origins of rhythmic behavior one must characterize the central pattern generator circuit and quantify the population size needed to sustain functionality. Breathing-related interneurons of the brainstem pre-Botzinger complex (preBotC) that putatively comprise the core respiratory rhythm generator in mammals are derived from Dbx1-expressing precursors. Here, we show that selective photonic destruction of Dbx1 preBotC neurons in neonatal mouse slices impairs respiratory rhythm but surprisingly also the magnitude of motor output; respiratory hypoglossal nerve discharge decreased and its frequency steadily diminished until rhythm stopped irreversibly after 85 +/- 20 (mean +/- SEM) cellular ablations, which corresponds to …
Functional Interactions Between Mammalian Respiratory Rhythmogenic And Premotor Circuitry, Hanbing Song, John A. Hayes, Nikolas C. Vann, Xueying Wang, Christopher A. Del Negro, M. Drew Lamar
Functional Interactions Between Mammalian Respiratory Rhythmogenic And Premotor Circuitry, Hanbing Song, John A. Hayes, Nikolas C. Vann, Xueying Wang, Christopher A. Del Negro, M. Drew Lamar
Christopher Del Negro
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 …
Developmental Origin Of Prebotzinger Complex Respiratory Neurons, Paul A. Gray, John A. Hayes, Guang Y. Ling, Isabel Llona, Srinivasan Tupal, Marina Cristina D. Picardo, Sarah E. Ross, Tsutomu Hirata, Joshua G. Corbin, Jaime Eugenin, Christopher A. Del Negro
Developmental Origin Of Prebotzinger Complex Respiratory Neurons, Paul A. Gray, John A. Hayes, Guang Y. Ling, Isabel Llona, Srinivasan Tupal, Marina Cristina D. Picardo, Sarah E. Ross, Tsutomu Hirata, Joshua G. Corbin, Jaime Eugenin, Christopher A. Del Negro
Christopher Del Negro
A subset of preBötzinger Complex (preBötC) neurokinin 1 receptor (NK1R) and somatostatin peptide (SST)-expressing neurons are necessary for breathing in adult rats, in vivo. Their developmental origins and relationship to other preBötC glutamatergic neurons are unknown. Here we show, in mice, that the “core” of preBötC SST+/NK1R+/SST 2a receptor+ (SST2aR) neurons, are derived from Dbx1-expressing progenitors. We also show that Dbx1-derived neurons heterogeneously coexpress NK1R and SST2aR within and beyond the borders of preBötC. More striking, we find that nearly all non-catecholaminergic glutamatergic neurons of the ventrolateral medulla (VLM) are also Dbx1 derived. PreBötC SST+ neurons are born between E9.5 …
Fate Mapping Neurons And Glia Derived From Dbx1-Expressing Progenitors In Mouse Prebotzinger Complex, Andrew Kottick, Caroline A. Martin, Christopher A. Del Negro
Fate Mapping Neurons And Glia Derived From Dbx1-Expressing Progenitors In Mouse Prebotzinger Complex, Andrew Kottick, Caroline A. Martin, Christopher A. Del Negro
Christopher Del Negro
The brainstem preBotzinger complex (preBotC) generates the inspiratory breathing rhythm, and its core rhythmogenic interneurons are derived from Dbx1-expressing progenitors. To study the neural bases of breathing, tamoxifen-inducible Cre-driver mice and Cre-dependent reporters are used to identify, record, and perturb Dbx1 preBotC neurons. However, the relationship between tamoxifen administration and reporter protein expression in preBotC neurons and glia has not been quantified. To address this problem, we crossed mice that express tamoxifen-inducible Cre recombinase under the control of the Dbx1 gene (Dbx1(CreERT2)) with Cre-dependent fluorescent reporter mice (Rosa26(tdTomato)), administered tamoxifen at different times during development, and analyzed tdTomato expression in …
Dendritic A-Current In Rhythmically Active Prebo¨Tzinger Complex Neurons In Organotypic Cultures From Newborn Mice, Wiktor S. Phillips, Christopher A. Del Negro, Jens K. Rekling
Dendritic A-Current In Rhythmically Active Prebo¨Tzinger Complex Neurons In Organotypic Cultures From Newborn Mice, Wiktor S. Phillips, Christopher A. Del Negro, Jens K. Rekling
Christopher Del Negro
Brainstem neurons in the preBo¨tC generate the oscillatory activity that underlies breathing. PreBo¨tC neurons express voltagedependent currents that can influence inspiratory activity, among which is a transient potassium current (IA) previously identified in a rhythmogenic excitatory subset of type-1 preBo¨tC neurons. We sought to determine whether IA is expressed in the dendrites of preBo¨tC. We found that dendrites of type-1 preBo¨tC neurons indeed express IA, which may aid in shunting sparse non-summating synaptic inputs, while enabling strong summating excitatory inputs to readily pass and thus influence somatic membrane potential trajectory. The subcellular distribution of IA in rhythmically active neurons of …
Dbx1 Precursor Cells Are A Source Of Inspiratory Xii Premotoneurons., Ann L. Revill, Nicolas C. Vann, Victoria T. Akins, Andrew Kottick, Paul A. Gray, Christopher A. Del Negro, Gregory D. Funk
Dbx1 Precursor Cells Are A Source Of Inspiratory Xii Premotoneurons., Ann L. Revill, Nicolas C. Vann, Victoria T. Akins, Andrew Kottick, Paul A. Gray, Christopher A. Del Negro, Gregory D. Funk
Christopher Del Negro
All behaviors require coordinated activation of motoneurons from central command and premotor networks. The genetic identities of premotoneurons providing behaviorally relevant excitation to any pool of respiratory motoneurons remain unknown. Recently, we established in vitro that Dbx1-derived pre-Bo¨ tzinger complex neurons are critical for rhythm generation and that a subpopulation serves a premotor function (Wang et al., 2014). Here, we further show that a subpopulation of Dbx1-derived intermediate reticular (IRt) neurons are rhythmically active during inspiration and project to the hypoglossal (XII) nucleus that contains motoneurons important for maintaining airway patency. Laser ablation of Dbx1 IRt neurons, 57% of which …
Axon Targeting Of The Alpha 7 Nicotinic Receptor In Developing Hippocampal Neurons By Gprin 1 Regulates Growth, Jacob C. Nordman, Nathan Kodama, Sarah G. Clark, Wiktor S. Phillips, Christopher A. Del Negro
Axon Targeting Of The Alpha 7 Nicotinic Receptor In Developing Hippocampal Neurons By Gprin 1 Regulates Growth, Jacob C. Nordman, Nathan Kodama, Sarah G. Clark, Wiktor S. Phillips, Christopher A. Del Negro
Christopher Del Negro
Stages in the development of CA3 neurons illustrate how the 7 nicotinic receptor (nAChR) can contribute to axon growth. Protein expression of 7 and G protein-regulated inducer of neurite outgrowth 1 (Gprin1) peaks between E18 and P10 in rodents. This time period is characterized by significant changes in synaptic structure and circuit development in the hippocampus. 7-mediated elevations in intracellular calcium within the growth cone (GC) are proposed to serve as stop' signal for axon growth, thereby possibly contributing to synaptic pruning. Interaction with Gprin1 ensures localization of 7 at the GC, and mediates coupling to a G(o), GAP-43, and …
Atoh1-Dependent Rhombic Lip Neurons Are Required For Temporal Delay Between Independent Respiratory Oscillators In Embryonic Mice, Srinivasan Tupal, Guang-Yi Ling, Paul A. Gray, Maria Cristina D. Picardo, Christopher A. Del Negro
Atoh1-Dependent Rhombic Lip Neurons Are Required For Temporal Delay Between Independent Respiratory Oscillators In Embryonic Mice, Srinivasan Tupal, Guang-Yi Ling, Paul A. Gray, Maria Cristina D. Picardo, Christopher A. Del Negro
Christopher Del Negro
All motor behaviors require precise temporal coordination of different muscle groups. Breathing, for example, involves the sequential activation of numerous muscles hypothesized to be driven by a primary respiratory oscillator, the preBotzinger Complex, and at least one other as-yet unidentified rhythmogenic population. We tested the roles of Atoh1-, Phox2b-, and Dbx1-derived neurons (three groups that have known roles in respiration) in the generation and coordination of respiratory output in embryonic mice. We found that Dbx1-derived neurons are necessary for all respiratory behaviors, whereas independent but coupled respiratory rhythms persist from at least three different motor pools after eliminating or silencing …
Cumulative Lesioning Of Respiratory Interneurons Disrupts And Precludes Motor Rhythms In Vitro, Xueying Wang, John A. Hayes, Christopher A. Del Negro
Cumulative Lesioning Of Respiratory Interneurons Disrupts And Precludes Motor Rhythms In Vitro, Xueying Wang, John A. Hayes, Christopher A. Del Negro
Christopher Del Negro
How brain functions degenerate in the face of progressive cell loss is an important issue that pertains to neurodegenerative diseases and basic properties of neural networks. We developed an automated system that uses two-photon microscopy to detect rhythmic neurons from calcium activity, and then individually laser ablates the targets while monitoring network function in real time. We applied this system to the mammalian respiratory oscillator located in the pre-Bötzinger Complex (preBötC) of the ventral medulla, which spontaneously generates breathing-related motor activity in vitro. Here, we show that cumulatively deleting preBötC neurons progressively decreases respiratory frequency and the amplitude of motor …
Dbx1 Pre-Bötzinger Complex Interneurons Comprise The Core Inspiratory Oscillator For Breathing In Unanesthetized Adult Mice, Christopher A. Del Negro, Francis Pham
Dbx1 Pre-Bötzinger Complex Interneurons Comprise The Core Inspiratory Oscillator For Breathing In Unanesthetized Adult Mice, Christopher A. Del Negro, Francis Pham
Christopher Del Negro
The brainstem pre-Bötzinger complex (preBötC) generates inspiratory breathing rhythms, but which neurons comprise its rhythmogenic core? Dbx1-derived neurons may play the preeminent role in rhythm generation, an idea well founded at perinatal stages of development but incompletely evaluated in adulthood. We expressed archaerhodopsin or channelrhodopsin in Dbx1 preBötC neurons in intact adult mice to interrogate their function. Prolonged photoinhibition slowed down or stopped breathing, whereas prolonged photostimulation sped up breathing. Brief inspiratory-phase photoinhibition evoked the next breath earlier than expected, whereas brief expiratory-phase photoinhibition delayed the subsequent breath. Conversely, brief inspiratory-phase photostimulation increased inspiratory duration and delayed the subsequent breath, …