Neuroscience and Neurobiology Commons^™

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

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

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

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 (I_pump), Na+-dependent K+ current, and ATP-dependent K+ current (I_K-ATP). The pharmacological blockade of I_PUMP, I_K-Na, or I_K-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

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

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

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

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

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

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

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

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

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

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

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

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, …

Fishes Are Gaining Academic Respect, Jonathan Balcombe

Jonathan Balcombe, PhD

I respond to five commentaries on my 2016 book What a Fish Knows. The commentaries express more harmony than dissent about my interpretation of fishes as cognitive, aware individuals deserving better treatment by humankind.

Chicken Of The Sea, Jonathan Balcombe

Jonathan Balcombe, PhD

Marino summarizes research showing that chickens perform cognitively and emotionally at a higher level than previously assumed. Here, I describe capacities of teleost fishes that parallel those of chickens, including the ability to recognize human faces, perspective-taking, and referential communication. Research on chickens and on fishes reveals an emerging trend in cognitive ethology: abilities once thought limited to a scant few highly intelligent non-humans may actually occur broadly across taxa.

What Sets Us Apart Could Be Our Salvation, Anne Fawcett, Paul Mcgreevy

Paul McGreevy, PhD

We agree with Chapman & Huffman that human capacities are often assumed to be unique — or attempts are made to demonstrate uniqueness scientifically — in order to justify the exploitation of animals and ecosystems. To extend the argument that human exceptionalism is against our interests, we recommend adopting the One Welfare framework, according to which animal welfare, environmental sustainability and human wellbeing are inseparably linked. Let us distinguish ourselves from other animals by resisting our short- and mid-term Darwinian inclinations, consuming less, reproducing less, and striving for a much longer-term biological fitness for us all.

Farm Animals Are Not Humans In Sheep Clothing, Lorenz Gygax, Christian Nawroth

Christian Nawroth, PhD

Research on the mental lives of farm animals is crucial to assess not only their physical but also their psychological wellbeing. Their current housing and handling practices are highly unlikely to meet their cognitive needs and demands, but our knowledge of their mental capacities is still limited. Although folk wisdom often refers to farm animals as dull and inflexible, recent studies show they have a rich interpretation of their environment and can solve complex problems. Yet an uncritical and anthropomorphic assessment of farm animal cognition and behaviour may lead to the attribution of an exaggerated amount of cognitive flexibility. Contrary …

Microarray Gene Expression Profiles Of Fasting Induced Changes In Liver And Adipose Tissues Of Pigs Expressing The Melanocortin-4 Receptor D298n Variant, Sender Lkhagvadorj, Long Qu, Weiguo Cai, Oliver P. Coutoure, C. Richard Barb, Gary J. Hausman, Dan Nettleton, Lloyd L. Anderson, Jack C. M. Dekkers, Christopher K. Tuggle

Dan Nettleton

Transcriptional profiling coupled with blood metabolite analyses were used to identify porcine genes and pathways that respond to a fasting treatment or to a D298N missense mutation in the melanocortin-4 receptor (MC4R) gene. Gilts (12 homozygous for D298 and 12 homozygous for N298) were either fed ad libitum or fasted for 3 days. Fasting decreased body weight, backfat, and serum urea concentration and increased serum nonesterified fatty acid. In response to fasting, 7,029 genes in fat and 1,831 genes in liver were differentially expressed (DE). MC4R genotype did not significantly affect gene expression, body weight, backfat depth, or any measured …

Relationship Of Maternal And Infant Cortisol Matrices With Later Infant Behavior And Temperament, Anastasia Perris

Anastasia Perris

Gene Therapy For Amyotrophic Lateral Sclerosis: An Aav Mediated Rnai Approach For Autosomal Dominant C9orf72 Associated Als, Gabriela Toro

Gabriela Toro

The Neural Correlates Of Third-Party Punishment, Owen D. Jones, Joshua Buckholtz, Christopher L. Asplund, Paul E. Dux, David H. Zald, John C. Gore, Rene Marois

Owen Jones

This article reports the discovery, from the first full-scale law and neuroscience experiment, of the brain activity underlying punishment decisions.

We used functional magnetic resonance imaging (fMRI) to measure brain activity of subjects as they read hypothetical scenarios about harm-causing protagonists and then decided whether to punish and, if so, how much.

The key variables were: a) presence or absence of excusing, justifying, or otherwise mitigating factors (such as acting under duress); and b) harm severity (which ranged from a stolen CD to a rape/murder/torture combination).

Findings include:

(1) Analytic and emotional brain circuitries are jointly involved, yet quite separately …

Neuroscientists In Court, Owen D. Jones, Anthony D. Wagner, David L. Faigman, Marcus E. Raichle

Owen Jones

Neuroscientific evidence is increasingly being offered in court cases. Consequently, the legal system needs neuroscientists to act as expert witnesses who can explain the limitations and interpretations of neuroscientific findings so that judges and jurors can make informed and appropriate inferences. The growing role of neuroscientists in court means that neuroscientists should be aware of important differences between the scientific and legal fields, and, especially, how scientific facts can be easily misunderstood by non-scientists,including judges and jurors.

This article describes similarities, as well as key differences, of legal and scientific cultures. And it explains six key principles about neuroscience that …

Parsing The Behavioral And Brain Mechanisms Of Third-Party Punishment, Owen D. Jones, Matthew Ginther, Richard J. Bonnie, Morris B. Hoffman, Francis X. Shen, Kenneth W. Simons, Rene Marois

Owen Jones

The evolved capacity for third-party punishment is considered crucial to the emergence and maintenance of elaborate human social organization and is central to the modern provision of fairness and justice within society. Although it is well established that the mental state of the offender and the severity of the harm he caused are the two primary predictors of punishment decisions, the precise cognitive and brain mechanisms by which these distinct components are evaluated and integrated into a punishment decision are poorly understood.

Using a brain-scanning technique known as functional magnetic resonance imaging (fMRI), we implemented a novel experimental design to …

Law And The Biology Of Rape: Reflections On Transitions, Owen D. Jones

Owen Jones

This Article serves is a sequel to a previous Article: Sex, Culture, and the Biology of Rape: Toward Explanation and Prevention, 87 Cal. L. Rev. 827 (1999). Part I briefly considers the threshold question: why consider the behavioral biology of sexual aggression at all? Part II proposes that the first step in transitioning to a more accurate and more useful model of rape behavior is to avoid a number of common definitional ambiguities that plague most rape discussions. Because those ambiguities are particularly likely to foster misunderstandings about biobehavioral perspectives, Part II also clarifies the scope of what biobehavioral theories …

Law, Responsibility, And The Brain, Owen D. Jones, Dean Mobbs, Hakwan C. Lau, Christopher D. Frith

Owen Jones

This article addresses new developments in neuroscience, and their implications for law. It explores, for example, the relationships between brain injury and violence, as well as the connections between mental disorders and criminal behaviors. It discusses a variety of issues surrounding brain fingerprinting, the use of brain scans for lie detection, and concerns about free will. It considers the possible uses for, and legal implications of, brain-imaging technology. And it also identifies six essential limits on the use of brain imaging in courtroom procedures.

Evolution And The Expression Of Biases: Situational Value Changes The Endowment Effect In Chimpanzees, Owen D. Jones, Sarah F. Brosnan, Molly Gardner, Susan P. Lambeth, Steven J. Schapiro

Owen Jones

Cognitive and behavioral biases, which are widespread among humans, have recently been demonstrated in other primates, suggesting a common origin. Here we examine whether the expression of one shared bias, the endowment effect, varies as a function of context. We tested whether objects lacking inherent value elicited a stronger endowment effect (or preference for keeping the object) in a context in which the objects had immediate instrumental value for obtaining valuable resources (food). Chimpanzee subjects had opportunities to trade tools when food was not present, visible but unobtainable, and obtainable using the tools. We found that the endowment effect for …

Law And Biology: Toward An Integrated Model Of Human Behavior, Owen D. Jones

Owen Jones

As first year law students unhappily discover, the meaning of "law" is frustratingly protean, shifting by usage and user. Depending on whom you ask, law is a system of rules, a body of precedents, a legislative enactment, a collection of norms, a process by which social goals are pursued, or some dynamic mixture of these. Law's principal purpose is to define and protect individual rights, to ensure public order, to resolve disputes, to redistribute wealth, to dispense justice, to prevent or compensate for injury, to optimize economic efficiency, or perhaps to do something else. And yet one thing is irreducibly …