Interactions between Arousal State and CO Determine the Activity of Central Chemoreceptor Neurons That Drive Breathing.

The homeostatic regulation of pulmonary ventilation, and ultimately arterial PCO, depends on interactions between respiratory chemoreflexes and arousal state. The ventilatory response to CO is triggered by neurons in the retrotrapezoid nucleus (RTN) that function as sensors of central pH, which can be identified in adulthood by the expression of Phox2b and neuromedin B. Here, we examine the dynamic response of genetically defined RTN neurons to hypercapnia and arousal state in freely behaving adult male and female mice using the calcium indicator jGCaMP7 and fiber photometry.

Molecular Organization of Autonomic, Respiratory, and Spinally-Projecting Neurons in the Mouse Ventrolateral Medulla.

The ventrolateral medulla (VLM) is a crucial region in the brain for visceral and somatic control, serving as a significant source of synaptic input to the spinal cord. Experimental studies have shown that gene expression in individual VLM neurons is predictive of their function. However, the molecular and cellular organization of the VLM has remained uncertain.

Molecular Disambiguation of Heart Rate Control by the Nucleus Ambiguus.

The nucleus ambiguus (nAmb) provides parasympathetic control of cardiorespiratory functions as well as motor control of the upper airways and striated esophagus. A subset of nAmb neurons innervates the heart through the vagus nerve to control cardiac function at rest and during key autonomic reflexes such as the mammalian diving reflex. These cardiovagal nAmb neurons may be molecularly and anatomically distinct, but how they differ from other nAmb neurons in the adult brain remains unclear.

The astrocytic Na -HCO cotransporter, NBCe1, is dispensable for respiratory chemosensitivity.

The interoceptive homeostatic mechanism that controls breathing, blood gases and acid-base balance in response to changes in CO /H is exquisitely sensitive, with convergent roles proposed for chemosensory brainstem neurons in the retrotrapezoid nucleus (RTN) and their supporting glial cells. For astrocytes, a central role for NBCe1, a Na -HCO cotransporter encoded by Slc4a4, has been envisaged in multiple mechanistic models (i.e.

Chemogenetic activation of noradrenergic A5 neurons increases blood pressure and visceral sympathetic activity in adult rats.

In mammals, the pontine noradrenergic system influences nearly every aspect of central nervous system function. A subpopulation of pontine noradrenergic neurons, called A5, are thought to be important in the cardiovascular response to physical stressors, yet their function is poorly defined. We hypothesized that activation of A5 neurons drives a sympathetically mediated increase in blood pressure (BP).

The arcuate nucleus: A site of synergism between Angiotensin II and leptin to increase sympathetic nerve activity and blood pressure in rats.

The action of leptin in brain to increase sympathetic nerve activity (SNA) and blood pressure depends upon functional Angiotensin II (AngII) type 1a receptors (AT1aR); however, the sites and mechanism of interaction are unknown. Here we identify one site, the hypothalamic arcuate nucleus (ArcN), since prior local blockade of AT1aR in the ArcN with losartan or candesartan in anesthetized male rats essentially eliminated the sympathoexcitatory and pressor responses to ArcN leptin nanoinjections. Unlike mice, in male and female rats, AT1aR and LepR rarely co-localized, suggesting that this interdependence occurs indirectly, via a local interneuron or network of neurons.

5-HT7 receptors expressed in the mouse parafacial region are not required for respiratory chemosensitivity.

A brainstem homeostatic system senses CO /H to regulate ventilation, blood gases and acid-base balance. Neurons of the retrotrapezoid nucleus (RTN) and medullary raphe are both implicated in this mechanism as respiratory chemosensors, but recent pharmacological work suggested that the CO /H sensitivity of RTN neurons is mediated indirectly, by raphe-derived serotonin acting on 5-HT7 receptors. To investigate this further, we characterized Htr7 transcript expression in phenotypically identified RTN neurons using multiplex single cell qRT-PCR and RNAscope.

Adrenergic C1 neurons monitor arterial blood pressure and determine the sympathetic response to hemorrhage.

Hemorrhage initially triggers a rise in sympathetic nerve activity (SNA) that maintains blood pressure (BP); however, SNA is suppressed following severe blood loss causing hypotension. We hypothesized that adrenergic C1 neurons in the rostral ventrolateral medulla (C1) drive the increase in SNA during compensated hemorrhage, and a reduction in C1 contributes to hypotension during decompensated hemorrhage. Using fiber photometry, we demonstrate that C1 activity increases during compensated hemorrhage and falls at the onset of decompensated hemorrhage.

Arcuate Angiotensin II Increases Arterial Pressure via Coordinated Increases in Sympathetic Nerve Activity and Vasopressin Secretion.

The arcuate nucleus (ArcN) is an integrative hub for the regulation of energy balance, reproduction, and arterial pressure (AP), all of which are influenced by Angiotensin II (AngII); however, the cellular mechanisms and downstream neurocircuitry are unclear. Here, we show that ArcN AngII increases AP in female rats via two phases, both of which are mediated via activation of AngII type 1 receptors (AT1aRs): initial vasopressin-induced vasoconstriction, followed by slowly developing increases in sympathetic nerve activity (SNA) and heart rate (HR). In male rats, ArcN AngII evoked a similarly slow increase in SNA, but the initial pressor response was variable.

Vagus nerve stimulation activates two distinct neuroimmune circuits converging in the spleen to protect mice from kidney injury.

Acute kidney injury is highly prevalent and associated with high morbidity and mortality, and there are no approved drugs for its prevention and treatment. Vagus nerve stimulation (VNS) alleviates inflammatory diseases including kidney disease; however, neural circuits involved in VNS-induced tissue protection remain poorly understood. The vagus nerve, a heterogeneous group of neural fibers, innervates numerous organs.

A brainstem peptide system activated at birth protects postnatal breathing.

Among numerous challenges encountered at the beginning of extrauterine life, the most celebrated is the first breath that initiates a life-sustaining motor activity. The neural systems that regulate breathing are fragile early in development, and it is not clear how they adjust to support breathing at birth. Here we identify a neuropeptide system that becomes activated immediately after birth and supports breathing.

Differential Contribution of the Retrotrapezoid Nucleus and C1 Neurons to Active Expiration and Arousal in Rats.

Collectively, the retrotrapezoid nucleus (RTN) and adjacent C1 neurons regulate breathing, circulation and the state of vigilance, but previous methods to manipulate the activity of these neurons have been insufficiently selective to parse out their relative roles. We hypothesize that RTN and C1 neurons regulate distinct aspects of breathing (e.g.

Contribution of the Retrotrapezoid Nucleus and Carotid Bodies to Hypercapnia- and Hypoxia-induced Arousal from Sleep.

The combination of hypoxia and hypercapnia during sleep produces arousal, which helps restore breathing and normalizes blood gases. Hypercapnia and hypoxia produce arousal in mammals by activating central (pH-sensitive) and peripheral (primarily O-sensitive) chemoreceptors. The relevant chemoreceptors and the neuronal circuits responsible for arousal are largely unknown.

Breathing regulation and blood gas homeostasis after near complete lesions of the retrotrapezoid nucleus in adult rats.

Key Points: The retrotrapezoid nucleus (RTN) drives breathing proportionally to brain PCO2 but its role during various states of vigilance needs clarification. Under normoxia, RTN lesions increased the arterial PCO2 set-point, lowered the PO2 set-point and reduced alveolar ventilation relative to CO production. Tidal volume was reduced and breathing frequency increased to a comparable degree during wake, slow-wave sleep and REM sleep.

Neuromedin B Expression Defines the Mouse Retrotrapezoid Nucleus.

The retrotrapezoid nucleus (RTN) consists, by definition, of Phox2b-expressing, glutamatergic, non-catecholaminergic, noncholinergic neurons located in the parafacial region of the medulla oblongata. An unknown proportion of RTN neurons are central respiratory chemoreceptors and there is mounting evidence for biochemical diversity among these cells. Here, we used multiplexed hybridization and single-cell RNA-Seq in male and female mice to provide a more comprehensive view of the phenotypic diversity of RTN neurons.

Blood Pressure Regulation by the Rostral Ventrolateral Medulla in Conscious Rats: Effects of Hypoxia, Hypercapnia, Baroreceptor Denervation, and Anesthesia.

Current understanding of the contribution of C1 neurons to blood pressure (BP) regulation derives predominantly from experiments performed in anesthetized animals or reduced preparations. Here, we use ArchaerhodopsinT3.0 (ArchT) loss-of-function optogenetics to explore BP regulation by C1 neurons in intact, unanesthetized rats.

Hypoxia silences retrotrapezoid nucleus respiratory chemoreceptors via alkalosis.

In conscious mammals, hypoxia or hypercapnia stimulates breathing while theoretically exerting opposite effects on central respiratory chemoreceptors (CRCs). We tested this theory by examining how hypoxia and hypercapnia change the activity of the retrotrapezoid nucleus (RTN), a putative CRC and chemoreflex integrator. Archaerhodopsin-(Arch)-transduced RTN neurons were reversibly silenced by light in anesthetized rats.

[The therapy of equine sarcoid with a non-specific immunostimulator--the epidemiology and spontaneous regression of sarcoids].

20 sarcoid-affected horses from a practice in the northern Jura were used in this experiment. The mean age of the 20 horses was 3.9 years at the time of the first observation of sarcoid tumors.