Astrocytes provide neurons with essential metabolic and structural support, modulate neuronal circuit activity and may also function as versatile surveyors of brain milieu, tuned to sense conditions ...of potential metabolic insufficiency. Here we show that astrocytes detect falling cerebral perfusion pressure and activate CNS autonomic sympathetic control circuits to increase systemic arterial blood pressure and heart rate with the purpose of maintaining brain blood flow and oxygen delivery. Studies conducted in experimental animals (laboratory rats) show that astrocytes respond to acute decreases in brain perfusion with elevations in intracellular Ca
. Blockade of Ca
-dependent signaling mechanisms in populations of astrocytes that reside alongside CNS sympathetic control circuits prevents compensatory increases in sympathetic nerve activity, heart rate and arterial blood pressure induced by reductions in cerebral perfusion. These data suggest that astrocytes function as intracranial baroreceptors and play an important role in homeostatic control of arterial blood pressure and brain blood flow.
Many stressors cause an increase in ventilation in humans. This is predominantly reported as an increase in minute ventilation (V̇E). But, the same V̇E can be achieved by a wide variety of changes in ...the depth (tidal volume, VT) and number of breaths (respiratory frequency, ƒR). This review investigates the impact of stressors including: cold, heat, hypoxia, pain and panic on the contributions of ƒR and VT to V̇E to see if they differ with different stressors. Where possible we also consider the potential mechanisms that underpin the responses identified, and propose mechanisms by which differences in ƒR and VT are mediated. Our aim being to consider if there is an overall differential control of ƒR and VT that applies in a wide range of conditions. We consider moderating factors, including exercise, sex, intensity and duration of stimuli. For the stressors reviewed, as the stress becomes extreme V̇E generally becomes increased more by ƒR than VT. We also present some tentative evidence that the pattern of ƒR and VT could provide some useful diagnostic information for a variety of clinical conditions. In The Physiological Society's year of ‘Making Sense of Stress’, this review has wide‐ranging implications that are not limited to one discipline, but are integrative and relevant for physiology, psychophysiology, neuroscience and pathophysiology.
Schematic of the tidal volume and breathing (respiratory) frequency responses to a range of stressors.
Arginine vasopressin (AVP) is synthesised in magnocellular neurons (MCNs) of supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus. In response to the hyperosmotic stressors ...of dehydration (complete fluid deprivation, DH) or salt loading (drinking 2% salt solution, SL), AVP synthesis increases in MCNs, which over-burdens the protein folding machinery in the endoplasmic reticulum (ER). ER stress and the unfolded protein response (UPR) are signaling pathways that improve ER function in response to the accumulation of misfold/unfold protein. We asked whether an ER stress response was activated in the SON and PVN of DH and SL rats. We observed increased mRNA expression for the immunoglobulin heavy chain binding protein (BiP), activating transcription factor 4 (Atf4), C/EBP-homologous protein (Chop), and cAMP responsive element binding protein 3 like 1 (Creb3l1) in both SON and PVN of DH and SL rats. Although we found no changes in the splicing pattern of X box-binding protein 1 (Xbp1), an increase in the level of the unspliced form of Xbp1 (Xbp1U) was observed in DH and SL rats. CREB3L1, a novel ER stress inducer, has been shown to be activated by ER stress to regulate the expression of target genes. We have previously shown that CREB3L1 is a transcriptional regulator of the AVP gene; however, a role for CREB3L1 in the response to ER stress has yet to be investigated in MCNs. Here, we used lentiviral vectors to introduce a dominant negative form of CREB3L1 (CREB3L1DN) in the rat SON. Expression of CREB3L1DN in the SON decreased Chop and Xbp1U mRNA levels, but not BiP and Atf4 transcript expression. CREB3L1 is thus implicated as a transcriptional mediator of the ER stress response in the osmotically stimulated SON.
The dysfunction of ion channels is a causative factor in a variety of neurological diseases, thereby defining the implicated channels as key drug targets. The detection of functional changes in ...multiple specific ionic currents currently presents a challenge, particularly when the neurological causes are either a priori unknown, or are unexpected. Traditional patch clamp electrophysiology is a powerful tool in this regard but is low throughput. Here, we introduce a single-shot method for detecting alterations amongst a range of ion channel types from subtle changes in membrane voltage in response to a short chaotically driven current clamp protocol. We used data assimilation to estimate the parameters of individual ion channels and from these we reconstructed ionic currents which exhibit significantly lower error than the parameter estimates. Such reconstructed currents thereby become sensitive predictors of functional alterations in biological ion channels. The technique correctly predicted which ionic current was altered, and by approximately how much, following pharmacological blockade of BK, SK, A-type K
and HCN channels in hippocampal CA1 neurons. We anticipate this assay technique could aid in the detection of functional changes in specific ionic currents during drug screening, as well as in research targeting ion channel dysfunction.
Breathing movements in mammals are driven by rhythmic neural activity generated within spatially and functionally organized brainstem neural circuits comprising the respiratory central pattern ...generator (CPG). This rhythmic activity provides homeostatic regulation of gases in blood and tissues and integrates breathing with other motor acts. We review new insights into the spatial–functional organization of key neural microcircuits of this CPG from recent multidisciplinary experimental and computational studies. The emerging view is that the microcircuit organization within the CPG allows the generation of multiple rhythmic breathing patterns and adaptive switching between them, depending on physiological or pathophysiological conditions. These insights open the possibility for site- and mechanism-specific interventions to treat various disorders of the neural control of breathing.
Key points
Peripheral chemoreflex sensitivity is enhanced in hypertension yet the role of these receptors in the development and maintenance of high blood pressure remains unknown.
Carotid ...chemoreceptors were denervated in both young and adult spontaneously hypertensive rats (SHRs) by sectioning the carotid sinus nerves bilaterally while recording arterial blood pressure chronically using radio telemetry.
Carotid sinus denervation (CSD) in the young animals prevented arterial pressure from reaching the hypertensive levels observed in sham‐operated animals whereas in adult SHRs arterial pressure fell by ∼20 mmHg.
After CSD there was a decrease in sympathetic activity, measured indirectly using power spectral analysis and hexamethonium, and an improvement in baroreceptor reflex gain.
Carotid bodies are active in the SHR and contribute to both the development and maintenance of hypertension; whether carotid body ablation is a useful anti‐hypertensive intervention in drug‐resistant hypertensive patients remains to be resolved.
The peripheral chemoreflex is known to be enhanced in individuals with hypertension. In pre‐hypertensive (PH) and adult spontaneously hypertensive rats (SHRs) carotid body type I (glomus) cells exhibit hypersensitivity to chemosensory stimuli and elevated sympathoexcitatory responses to peripheral chemoreceptor stimulation. Herein, we eliminated carotid body inputs in both PH‐SHRs and SHRs to test the hypothesis that heightened peripheral chemoreceptor activity contributes to both the development and maintenance of hypertension. The carotid sinus nerves were surgically denervated under general anaesthesia in 4‐ and 12‐week‐old SHRs. Control groups comprised sham‐operated SHRs and aged‐matched sham‐operated and carotid sinus nerve denervated Wistar rats. Arterial blood pressure was recorded chronically in conscious, freely moving animals. Successful carotid sinus nerve denervation (CSD) was confirmed by testing respiratory responses to hypoxia (10% O2) or cardiovascular responses to i.v. injection of sodium cyanide. In the SHR, CSD reduced both the development of hypertension and its maintenance (P < 0.05) and was associated with a reduction in sympathetic vasomotor tone (as revealed by frequency domain analysis and reduced arterial pressure responses to administration of hexamethonium; P < 0.05 vs. sham‐operated SHR) and an improvement in baroreflex sensitivity. No effect on blood pressure was observed in sham‐operated SHRs or Wistar rats. In conclusion, carotid sinus nerve inputs from the carotid body are, in part, responsible for elevated sympathetic tone and critical for the genesis of hypertension in the developing SHR and its maintenance in later life.
Key points
Five years after bilateral carotid body resection (bCBR) performed in four patients, the absence of the hypoxic ventilatory response persisted, suggesting no compensatory regrowth.
...Breathing hypoxic gas mixtures (15% and 12%) results in a lower (by ∼10%) minimal blood oxygen saturation (SpO2) in bCBR patients compared to heart failure subjects (CHF) with intact peripheral chemoreceptors.
After bCBR, patients were characterized by a greater short‐term variability in SpO2 during mild hypoxia in comparison to the CHF group.
The ventilatory response to hypercapnia was preserved following bCBR and was sufficient to maintain minimal SpO2 at levels comparable to controls when combined with hypoxia.
Bilateral CBR – a novel treatment modality for sympathetically mediated diseases – should be used with caution due to the risk of significant desaturation even during mild hypoxia equivalent to that experienced during long‐haul air travel and high altitude.
Carotid body resection has been proposed as a novel treatment for sympathetically mediated diseases but the safety of bilateral carotid body resection (bCBR) for blood oxygenation during hypoxic stress (long‐haul flights or high altitude) remains uncertain. Also unknown is whether central ventilatory drive is sufficient to maintain adequate oxygen saturation when exposed to hypercapnia with concomitant hypoxia. Thus, we administered: 15% O2, 12% O2, 5% CO2/12% O2 and 5% CO2/95% O2 to a group of four patients with congestive heart failure (65 ± 2.9 years) in whom bCBR was performed 5 years earlier. Ventilatory, haemodynamic and blood oxygen saturation (SpO2) responses were recorded non‐invasively and compared to control groups with intact peripheral chemoreceptors (both healthy and heart failure patients). First, we confirmed that the ventilatory response to hypoxia was eliminated in patients with bCBR, although the increase in cardiac output was preserved. Second, administration of hypoxic gas mixtures resulted in a larger decrease in SpO2 and greater short‐term variability of the SpO2 leading to a lower minimal SpO2 for both hypoxia levels in the bCBR group compared to heart failure controls (82.5 ± 1.2% vs. 91.6 ± 2.3% for 15% O2 and 73.8 ± 4.0% vs. 83.7 ± 3.1% for 12% O2). Third, in bCBR patients the ventilatory response to hypercapnia was present and sufficient to maintain a minimal SpO2 at a level comparable to heart failure controls following administration of 5% CO2/12% O2 (88.7 ± 4.2% vs. 91.1 ± 2.8%). We conclude that bCBR carries a risk of significant oxygen desaturation even during mild hypoxia. Despite preservation of central chemosensitivity, future studies should focus on unilateral CBR or on pharmacological modulation of peripheral chemosensitivity.
Key points
Five years after bilateral carotid body resection (bCBR) performed in four patients, the absence of the hypoxic ventilatory response persisted, suggesting no compensatory regrowth.
Breathing hypoxic gas mixtures (15% and 12%) results in a lower (by ∼10%) minimal blood oxygen saturation (SpO2) in bCBR patients compared to heart failure subjects (CHF) with intact peripheral chemoreceptors.
After bCBR, patients were characterized by a greater short‐term variability in SpO2 during mild hypoxia in comparison to the CHF group.
The ventilatory response to hypercapnia was preserved following bCBR and was sufficient to maintain minimal SpO2 at levels comparable to controls when combined with hypoxia.
Bilateral CBR – a novel treatment modality for sympathetically mediated diseases – should be used with caution due to the risk of significant desaturation even during mild hypoxia equivalent to that experienced during long‐haul air travel and high altitude.
Key points
In addition to reductions in respiratory rate, opioids also cause aspiration and difficulty swallowing, indicating impairment of the upper airways. The Kölliker–Fuse (KF) maintains upper ...airway patency and a normal respiratory pattern.
In this study, activation of μ opioid receptors in the KF reduced respiratory frequency and tidal volume in anaesthetized rats.
Nerve recordings in an in situ preparation showed that activation of μ opioid receptors in the KF eliminated the post‐inspiration phase of the respiratory cycle.
In brain slices, μ opioid agonists hyperpolarized a distinct population (61%) of KF neurons by activation of an inwardly rectifying potassium conductance.
These results suggest that KF neurons that are hyperpolarized by opioids could contribute to opioid‐induced respiratory disturbances, particularly the impairment of upper airways.
Opioid‐induced respiratory effects include aspiration and difficulty swallowing, suggesting impairment of the upper airways. The pontine Kölliker–Fuse nucleus (KF) controls upper airway patency and regulates respiration, in particular the inspiratory/expiratory phase transition. Given the importance of the KF in coordinating respiratory pattern, the mechanisms of μ opioid receptor activation in this nucleus were investigated at the systems and cellular level. In anaesthetized, vagi‐intact rats, injection of opioid agonists DAMGO or Met5enkephalin (ME) into the KF reduced respiratory frequency and amplitude. The μ opioid agonist DAMGO applied directly into the KF of the in situ arterially perfused working heart–brainstem preparation of rat resulted in robust apneusis (lengthened low amplitude inspiration due to loss of post‐inspiratory drive) that was rapidly reversed by the opioid antagonist naloxone. In brain slice preparations, activation of μ opioid receptors on KF neurons hyperpolarized a distinct population (61%) of neurons. As expected, the opioid‐induced hyperpolarization reduced the excitability of the neuron in response to either current injection or local application of glutamate. In voltage‐clamp recordings the outward current produced by the opioid agonist ME was concentration dependent, reversed at the potassium equilibrium potential and was blocked by BaCl2, characteristics of a G protein‐coupled inwardly rectifying potassium (GIRK) conductance. The clinically used drug morphine produced an outward current in KF neurons with similar potency to morphine‐mediated currents in locus coeruleus brain slice preparations. Thus, the population of KF neurons that are hyperpolarized by μ opioid agonists are likely mediators of the opioid‐induced loss of post‐inspiration and induction of apneusis.
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