Still Excited, but Less Aroused-The Effects of Nutritional Ketosis on Epinephrine Response and Hypothalamic Orexin Neuron Activation Following Recurrent Hypoglycemia in Diabetic Rats.

Hypoglycemia-associated autonomic failure (HAAF) is a serious, life-threatening complication of intensive insulin therapy, particularly in people with type 1 diabetes. The ketogenic diet is reported to beneficially affect glycemic control in people with type 1 diabetes, however its effects on the neurohormonal counterregulatory response to recurrent hypoglycemia and HAAF development are understudied. In this study we used Sprague Dawley rats to establish a HAAF model under non-diabetic and streptozotocin (STZ)-induced diabetic conditions and determined how nutritional ketosis affected the neurohormonal counterregulation and the activity of energy-sensing orexin (OX) neurons.

Intermittent hypoxia enhances the expression of hypoxia inducible factor HIF1A through histone demethylation.

The cellular response to hypoxia is regulated through enzymatic oxygen sensors, including the prolyl hydroxylases, which control degradation of the well-known hypoxia inducible factors (HIFs). Other enzymatic oxygen sensors have been recently identified, including members of the KDM histone demethylase family. Little is known about how different oxygen-sensing pathways interact and if this varies depending on the form of hypoxia, such as chronic or intermittent.

Metabolite signatures of heart failure, sleep apnoea, their interaction, and outcomes in the community.

Aims: Sleep apnoea and congestive heart failure (CHF) commonly co-exist, but their interaction is unclear. Metabolomics may clarify their interaction and relationships to outcome.

Methods And Results: We assayed 372 circulating metabolites and lipids in 1919 and 1524 participants of the Framingham Heart Study (FHS) (mean age 54 ± 10 years, 53% women) and Women's Health Initiative (WHI) (mean age 67 ± 7 years), respectively.

Slow but Steady-The Responsiveness of Sympathoadrenal System to a Hypoglycemic Challenge in Ketogenic Diet-Fed Rats.

The sympathoadrenal counterregulatory response to hypoglycemia is critical for individuals with type 1 diabetes due to impaired ability to produce glucagon. Ketogenic diets (KD) are an increasingly popular diabetes management tool; however, the effects of KD on the sympathoadrenal response are largely unknown. Here, we determined the effects of KD-induced ketosis on the sympathoadrenal response to a single insulin-induced hypoglycemic challenge.

Pentobarbital Anesthesia Suppresses the Glucose Response to Acute Intermittent Hypoxia in Rat.

A key feature of sleep disordered breathing syndromes, such as obstructive sleep apnea is intermittent hypoxia. Intermittent hypoxia is well accepted to drive the sympathoexcitation that is frequently associated with hypertension and diabetes, with measurable effects after just 1 h. The aim of this study was to directly measure the glucose response to 1 h of acute intermittent hypoxia in pentobarbital anesthetized rats, compared to conscious rats.

PACAP-PAC1 Receptor Activation Is Necessary for the Sympathetic Response to Acute Intermittent Hypoxia.

Repetitive hypoxia is a key feature of obstructive sleep apnoea (OSA), a condition characterized by intermittent airways obstruction. Patients with OSA present with persistent increases in sympathetic activity and commonly develop hypertension. The objectives of this study were to determine if the persistent increases in sympathetic nerve activity, known to be induced by acute intermittent hypoxia (AIH), are mediated through activation of the pituitary adenylate cyclase activating polypeptide (PACAP) signaling system.

Microglia in the RVLM of SHR have reduced P2Y12R and CX3CR1 expression, shorter processes, and lower cell density.

The RVLM of spontaneously hypertensive rats (SHR) contains over-active C1 neurons, which model the pathology of essential hypertension. Hypertension involves chronic low-grade neuroinflammation. Inflammation in the brain is produced and maintained primarily by microglia.

Activation of µ-opioid receptors in the rostral ventrolateral medulla blocks the sympathetic counterregulatory response to glucoprivation.

Activation of neurons in the rostral ventrolateral medulla (RVLM) following glucoprivation initiates sympathoadrenal activation, adrenaline release, and increased glucose production. Here, we aimed to determine the role of RVLM µ-opioid receptors in the counterregulatory response to systemic glucoprivation. Experiments were performed in pentobarbital sodium anesthetized male Sprague-Dawley rats ( n = 30).

Activation of µ-opioid receptors in the rostral ventrolateral medulla blocks the sympathetic counterregulatory response to glucoprivation.

Activation of neurons in the rostral ventrolateral medulla (RVLM) following glucoprivation initiates sympathoadrenal activation, adrenaline release, and increased glucose production. Here, we aimed to determine the role of RVLM µ-opioid receptors in the counterregulatory response to systemic glucoprivation. Experiments were performed in pentobarbital sodium anesthetized male Sprague-Dawley rats ( n = 30).

Integration of hindbrain and carotid body mechanisms that control the autonomic response to cardiorespiratory and glucoprivic insults.

Autonomic reflex responses are critical in restoring changes to circulatory factors reduced beyond the domain of homeostasis. Intermittent hypoxia triggers repeated activation of chemoreflexes, resulting in baroreflex dysfunction and widespread changes in cellular and neuronal activity regulated by sensory/motor pathways. Hypoglycaemia initiates a rapid neurally-mediated counter-regulatory response.

Glia and central cardiorespiratory pathology.

Respiration and blood pressure are primarily controlled by somatic and autonomic motor neurones, respectively. Central cardiorespiratory control is critical in moment-to-moment survival, but it also has a role in the development and maintenance of chronic pathological conditions such as hypertension. The glial cells of the brain are non-neuronal cells with metabolic, immune, and developmental functions.

PACAP-(6-38) or kynurenate microinjections in the RVLM prevent the development of sympathetic long-term facilitation after acute intermittent hypoxia.

Intermittent hypoxia causes a persistent increase in sympathetic activity that progresses to hypertension in chronic conditions such as obstructive sleep apnea. Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neurotransmitter that causes long-lasting sympathetic excitation. We aimed to determine if intermittent activation of the rostral ventrolateral medulla (RVLM) causes PACAP-mediated elevation of sympathetic nerve activity, termed sympathetic long-term facilitation (sLTF).

Acute intermittent hypoxia with concurrent hypercapnia evokes P2X and TRPV1 receptor-dependent sensory long-term facilitation in naïve carotid bodies.

Key Points: Activity-dependent plasticity can be induced in carotid body (CB) chemosensory afferents without chronic intermittent hypoxia (CIH) preconditioning by acute intermittent hypoxia coincident with bouts of hypercapnia (AIH-Hc). Several properties of this acute plasticity are shared with CIH-dependent sensory long-term facilitation (LTF) in that induction is dependent on 5-HT, angiotensin II, protein kinase C and reactive oxygen species. Several properties differ from CIH-dependent sensory LTF; H O appears to play no part in induction, whereas maintenance requires purinergic P2X2/3 receptor activation and is dependent on transient receptor potential vanilloid type 1 (TRPV1) receptor sensitization.

Inhibition of microglial activation with minocycline at the intrathecal level attenuates sympathoexcitatory and proarrhythmogenic changes in rats with chronic temporal lobe epilepsy.

The incidence of sudden unexpected death in epilepsy (SUDEP) is highest in people with chronic and drug-resistant epilepsy. Chronic spontaneous recurrent seizures cause cardiorespiratory autonomic dysfunctions. Pituitary adenylate cyclase-activating polypeptide (PACAP) is neuroprotective, whereas microglia produce both pro- and anti-inflammatory effects in the CNS.

Intrathecal Intermittent Orexin-A Causes Sympathetic Long-Term Facilitation and Sensitizes the Peripheral Chemoreceptor Response to Hypoxia in Rats.

Intermittent hypoxia causes a persistent increase in sympathetic nerve activity (SNA), which progresses to hypertension in conditions such as obstructive sleep apnea. Orexins (A and B) are hypothalamic neurotransmitters with arousal-promoting and sympathoexcitatory effects. We investigated whether the sustained elevation of SNA, termed sympathetic long-term facilitation, after acute intermittent hypoxia (AIH) is caused by endogenous orexin acting on spinal sympathetic preganglionic neurons.

Microglial number is related to the number of tyrosine hydroxylase neurons in SHR and normotensive rats.

Microglia are ubiquitously distributed throughout the central nervous system (CNS) and play a critical role in the maintenance of neuronal homeostasis. Recent advances have shown that microglia, never resting cells of the CNS, continuously monitor and influence neuronal/synaptic activity levels, by communicating with neurons with the aid of their dynamic processes. The brainstem contains many catecholaminergic nuclei that are key to many aspects of brain function.

Dynamic changes in the relationship of microglia to cardiovascular neurons in response to increases and decreases in blood pressure.

Microglia are present throughout the central nervous system (CNS) and express receptors for every known neurotransmitter. During inflammation, microglia change into a state that either promotes removal of debris (M1), or into a state that promotes soothing (M2). Caudal- and rostral- ventrolateral medullary regions (CVLM and RVLM, respectively) of the brainstem are key nuclei involved in all aspects of the cardiovascular system.

Intermittent hypoxia-induced cardiorespiratory long-term facilitation: A new role for microglia.

Intermittent hypoxia induces plasticity in neural networks controlling breathing and cardiovascular function. Studies demonstrate that mechanisms causing cardiorespiratory plasticity rely on intracellular signalling pathways that are activated by specific neurotransmitters. Peptides such as serotonin, PACAP and orexin are well-known for their physiological significance in regulating the cardiorespiratory system.

Microglia PACAP and glutamate: Friends or foes in seizure-induced autonomic dysfunction and SUDEP?

Seizure-induced cardiorespiratory autonomic dysfunction is a major cause of sudden unexpected death in epilepsy (SUDEP), and the underlying mechanism is unclear. Seizures lead to increased synthesis, and release of glutamate, pituitary adenylate cyclase activating polypeptide (PACAP), and other neurotransmitters, and cause extensive activation of microglia at multiple regions in the brain including central autonomic cardiorespiratory brainstem nuclei. Glutamate contributes to neurodegeneration, and inflammation in epilepsy.

Seizure-Induced Sympathoexcitation Is Caused by Activation of Glutamatergic Receptors in RVLM That Also Causes Proarrhythmogenic Changes Mediated by PACAP and Microglia in Rats.

Unlabelled: Cardiovascular autonomic dysfunction in seizure is a major cause of sudden unexpected death in epilepsy. The catecholaminergic neurons in the rostral ventrolateral medulla (RVLM) maintain sympathetic vasomotor tone and blood pressure through their direct excitatory projections to the intermediolateral (IML) cell column. Glutamate, the principal excitatory neurotransmitter in brain, is increased in seizures.

Alerted microglia and the sympathetic nervous system: A novel form of microglia in the development of hypertension.

Microglia, commonly known as the tissue resident macrophages of the central nervous system (CNS), are ubiquitously expressed in the CNS. Microglia, in their resting, or surveilling, stage, play a critical role in the maintenance of normal neuronal physiology and homeostasis. On activation, microglia can acquire either a neurotoxic (M1) or a neuroprotective (M2) phenotype.

Gene Interference with Morpholinos in a Gold Nanoparticle-Based Delivery Platform in Rat PC12 Cells.

For the first time the efficiency of gene knockdown of the pituitary adenylate cyclase-activating polypeptide (PACAP) receptor 1 (PAC1R) is demonstrated by employing gold nanocomplexes. This gene knockdown subsequently affects the action of PACAP on neurite outgrowth in PC12 cells. These nanocomplexes comprise cholera toxin B (CTB)-gold nanoparticle conjugates loaded with double-stranded morpholinos (MOs) (photo MO and antisense MO).

Surgical preparation of mice for recording cardiorespiratory parameters in vivo.

Background: The explosion in the use of genetically modified mouse strains to investigate function in biology has an enormous potential to expand on pharmacological studies traditionally conducted in rats. A key limitation to date is the inability to record from multiple nerves in an anaesthetised mouse for long periods.

New Method: Here we describe an in vivo preparation that maintains mice in a suitable physiological state, under anaesthesia, for at least 6 hr and also enables multiple cardiorespiratory recordings over that time.

The effect of losartan on differential reflex control of sympathetic nerve activity in chronic kidney disease.

Background: The effect of angiotensin II type I receptor (AT1R) inhibition on the pattern of reflex sympathetic nerve activity (SNA) to multiple target organs in the Lewis polycystic kidney (LPK) rat model of chronic kidney disease was determined.

Methods: Mean arterial pressure (MAP), splanchnic SNA (sSNA), renal SNA (rSNA) and lumbar SNA (lSNA) were recorded in urethane-anaesthetized LPK and Lewis controls (total n = 39). Baroreflex, peripheral and central chemoreflex, and somatosensory reflex control of SNA (evoked by phenylephrine/sodium nitroprusside infusion, 10% O2 in N2 or 100% N2 ventilation, 5% CO2 ventilation and sciatic nerve stimulation, respectively) were determined before and after administration of losartan (AT1R antagonist 3 mg/kg, intravenous).

Antagonism of PACAP or microglia function worsens the cardiovascular consequences of kainic-acid-induced seizures in rats.

Seizures are accompanied by cardiovascular changes that are a major cause of sudden unexpected death in epilepsy (SUDEP). Seizures activate inflammatory responses in the cardiovascular nuclei of the medulla oblongata and increase neuronal excitability. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with autocrine and paracrine neuroprotective properties.