The Role of Ca and BK Channels of Locus Coeruleus (LC) Neurons as a Brake to the CO Chemosensitivity Response of Rats.

The cellular mechanisms by which LC neurons respond to hypercapnia are usually attributed to an "accelerator" whereby hypercapnic acidosis causes an inhibition of K channels or activation of Na and Ca channels to depolarize CO-sensitive neurons. Nevertheless, it is still unknown if this "accelerator" mechanism could be controlled by a brake phenomenon. Whole-cell patch clamping, fluorescence imaging microscopy and plethysmography were used to study the chemosensitive response of the LC neurons.

Ventilatory and chemoreceptor responses to hypercapnia in neonatal rats chronically exposed to moderate hyperoxia.

Rats reared in hyperoxia hypoventilate in normoxia and exhibit progressive blunting of the hypoxic ventilatory response, changes which are at least partially attributed to abnormal carotid body development. Since the carotid body also responds to changes in arterial CO/pH, we tested the hypothesis that developmental hyperoxia would attenuate the hypercapnic ventilatory response (HCVR) of neonatal rats by blunting peripheral and/or central chemoreceptor responses to hypercapnic challenges. Rats were reared in 21% O (Control) or 60% O (Hyperoxia) until studied at 4, 6-7, or 13-14days of age.

Microglial Acid Sensing Regulates Carbon Dioxide-Evoked Fear.

Background: Carbon dioxide (CO2) inhalation, a biological challenge and pathologic marker in panic disorder, evokes intense fear and panic attacks in susceptible individuals. The molecular identity and anatomic location of CO2-sensing systems that translate CO2-evoked fear remain unclear. We investigated contributions of microglial acid sensor T cell death-associated gene-8 (TDAG8) and microglial proinflammatory responses in CO2-evoked behavioral and physiological responses.

A HCO(3)(-)-dependent mechanism involving soluble adenylyl cyclase for the activation of Ca²⁺ currents in locus coeruleus neurons.

Hypercapnic acidosis activates Ca²⁺ channels and increases intracellular Ca²⁺ levels in neurons of the locus coeruleus, a known chemosensitive region involved in respiratory control. We have also shown that large conductance Ca²⁺-activated K⁺ channels, in conjunction with this pathway, limits the hypercapnic-induced increase in firing rate in locus coeruleus neurons. Here, we present evidence that the Ca²⁺ current is activated by a HCO(3)(-)-sensitive pathway.

Substance P differentially modulates firing rate of solitary complex (SC) neurons from control and chronic hypoxia-adapted adult rats.

NK1 receptors, which bind substance P, are present in the majority of brainstem regions that contain CO2/H(+)-sensitive neurons that play a role in central chemosensitivity. However, the effect of substance P on the chemosensitive response of neurons from these regions has not been studied. Hypoxia increases substance P release from peripheral afferents that terminate in the caudal nucleus tractus solitarius (NTS).

Temperature influences neuronal activity and CO2/pH sensitivity of locus coeruleus neurons in the bullfrog, Lithobates catesbeianus.

The locus coeruleus (LC) is a chemoreceptive brain stem region in anuran amphibians and contains neurons sensitive to physiological changes in CO2/pH. The ventilatory and central sensitivity to CO2/pH is proportional to the temperature in amphibians, i.e.

Cardiorespiratory effects of gap junction blockade in the locus coeruleus in unanesthetized adult rats.

The locus coeruleus (LC) plays an important role in central chemoreception. In young rats (P9 or younger), 85% of LC neurons increase firing rate in response to hypercapnia vs. only about 45% of neurons from rats P10 or older.

Transient outwardly rectifying A currents are involved in the firing rate response to altered CO2 in chemosensitive locus coeruleus neurons from neonatal rats.

The effect of hypercapnia on outwardly rectifying currents was examined in locus coeruleus (LC) neurons in slices from neonatal rats [postnatal day 3 (P3)-P15]. Two outwardly rectifying currents [4-aminopyridine (4-AP)-sensitive transient current and tetraethyl ammonium (TEA)-sensitive sustained current] were found in LC neurons. 4-AP induced a membrane depolarization of 3.

Postnatal development and activation of L-type Ca2+ currents in locus ceruleus neurons: implications for a role for Ca2+ in central chemosensitivity.

Little is known about the role of Ca(2+) in central chemosensitive signaling. We use electrophysiology to examine the chemosensitive responses of tetrodotoxin (TTX)-insensitive oscillations and spikes in neurons of the locus ceruleus (LC), a chemosensitive region involved in respiratory control. We show that both TTX-insensitive spikes and oscillations in LC neurons are sensitive to L-type Ca(2+) channel inhibition and are activated by increased CO(2)/H(+).

The caudal solitary complex is a site of central CO(2) chemoreception and integration of multiple systems that regulate expired CO(2).

The solitary complex is comprised of the nucleus tractus solitarius (NTS, sensory) and dorsal motor nucleus of the vagus (DMV, motor), which functions as an integrative center for neural control of multiple systems including the respiratory, cardiovascular and gastroesophageal systems. The caudal NTS-DMV is one of the several sites of central CO(2) chemoreception in the brain stem. CO(2) chemosensitive neurons are fully responsive to CO(2) at birth and their responsiveness seems to depend on pH-sensitive K(+) channels.

Hyperbaric hyperoxia and normobaric reoxygenation increase excitability and activate oxygen-induced potentiation in CA1 hippocampal neurons.

Breathing hyperbaric oxygen (HBO) is common practice in hyperbaric and diving medicine. The benefits of breathing HBO, however, are limited by the risk of central nervous system O2 toxicity, which presents as seizures. We tested the hypothesis that excitability increases in CA1 neurons of the rat hippocampal slice (400 microm) over a continuum of hyperoxia that spans normobaric and hyperbaric pressures.

Hyperoxic stimulation of synchronous orthodromic activity and induction of neural plasticity does not require changes in excitatory synaptic transmission.

The first study, described in the companion article, reports that acute exposure of rat hippocampal slices to either hyperbaric oxygen (HBO: 2.84 and 4.54 atmospheres absolute, ATA) or normobaric reoxygenation (NBOreox; i.

The locus coeruleus and central chemosensitivity.

The locus coeruleus (LC) lies in the dorsal pons and supplies noradrenergic (NA) input to many regions of the brain, including respiratory control areas. The LC may provide tonic input for basal respiratory drive and is involved in central chemosensitivity since focal acidosis of the region stimulates ventilation and ablation reduces CO(2)-induced increased ventilation. The output of LC is modulated by both serotonergic and glutamatergic inputs.

CO2 chemoreception in cardiorespiratory control.

Considerable progress has been made elucidating the cellular signals and ion channel targets involved in the response to increased CO2/H+ of brain stem neurons from chemosensitive regions. Intracellular pH (pHi) does not exhibit recovery from an acid load when extracellular pH (pHo) is also acid. This lack of pHi recovery is an essential but not unique feature of all chemosensitive neurons.

pH regulating transporters in neurons from various chemosensitive brainstem regions in neonatal rats.

We studied the membrane transporters that mediate intracellular pH (pH(i)) recovery from acidification in brainstem neurons from chemosensitive regions of neonatal rats. Individual neurons within brainstem slices from the retrotrapezoid nucleus (RTN), the nucleus tractus solitarii (NTS), and the locus coeruleus (LC) were studied using a pH-sensitive fluorescent dye and fluorescence imaging microscopy. The rate of pH(i) recovery from an NH(4)Cl-induced acidification was measured, and the effects of inhibitors of various pH-regulating transporters determined.

Chronic hypoxia suppresses the CO2 response of solitary complex (SC) neurons from rats.

We studied the effect of chronic hypobaric hypoxia (CHx; 10-11% O(2)) on the response to hypercapnia (15% CO(2)) of individual solitary complex (SC) neurons from adult rats. We simultaneously measured the intracellular pH and firing rate responses to hypercapnia of SC neurons in superfused medullary slices from control and CHx-adapted adult rats using the blind whole cell patch clamp technique and fluorescence imaging microscopy. We found that CHx caused the percentage of SC neurons inhibited by hypercapnia to significantly increase from about 10% up to about 30%, but did not significantly alter the percentage of SC neurons activated by hypercapnia (50% in control vs.

Chemosensory responses to CO2 in multiple brain stem nuclei determined using a voltage-sensitive dye in brain slices from rats.

We used epifluorescence microscopy and a voltage-sensitive dye, di-8-ANEPPS, to study changes in membrane potential during hypercapnia with or without synaptic blockade in chemosensory brain stem nuclei: the locus coeruleus (LC), the nucleus of the solitary tract, lateral paragigantocellularis nucleus, raphé pallidus, and raphé obscurus and, in putative nonchemosensitive nuclei, the gigantocellularis reticular nucleus and the spinotrigeminal nucleus. We studied the response to hypercapnia in LC cells to evaluate the performance characteristics of the voltage-sensitive dye. Hypercapnia depolarized many LC cells and the voltage responses to hypercapnia were diminished, but not eradicated, by synaptic blockade (there were intrinsically CO2-sensitive cells in the LC).

Characterization of the chemosensitive response of individual solitary complex neurons from adult rats.

We studied the CO(2)/H(+)-chemosensitive responses of individual solitary complex (SC) neurons from adult rats by simultaneously measuring the intracellular pH (pH(i)) and electrical responses to hypercapnic acidosis (HA). SC neurons were recorded using the blind whole cell patch-clamp technique and loading the soma with the pH-sensitive dye pyranine through the patch pipette. We found that SC neurons from adult rats have a lower steady-state pH(i) than SC neurons from neonatal rats.

Development of chemosensitivity in neurons from the nucleus tractus solitarii (NTS) of neonatal rats.

We studied the development of chemosensitivity during the neonatal period in rat nucleus tractus solitarii (NTS) neurons. We determined the percentage of neurons activated by hypercapnia (15% CO(2)) and assessed the magnitude of the response by calculating the chemosensitivity index (CI). There were no differences in the percentage of neurons that were inhibited (9%) or activated (44.

Intrinsic chemosensitivity of individual nucleus tractus solitarius (NTS) and locus coeruleus (LC) neurons from neonatal rats.

Chemosensitive (CS) neurons are found in discrete brainstem regions, but whether the CS response of these neurons is due to intrinsic chemosensitivity of individual neurons or is mediated by changes in chemical and/or electrical synaptic input is largely unknown. We studied the effect of synaptic blockade (11.4 mM Mg2+/0.

The chemosensitive response of neurons from the locus coeruleus (LC) to hypercapnic acidosis with clamped intracellular pH.

Currently, a change in pH(i) is believed to be the major signal in the chemosensitive (CS) response of brainstem neurons to hypercapnia; however, multiple factors (e.g., Ca2+, CO2, pH(i), and pHo) have been suggested to contribute to this increase in firing rate.

Glial modulation of CO2 chemosensory excitability in the retrotrapezoid nucleus of rodents.

We investigated the possibility that astrocytes modify the extracellular milieu and thereby modify the activity of central CO2 chemosensory neurons. The ability of astrocytes to modify the extracellular milieu is heterogeneously distributed among chemosensory sites that have, at least nominally, the same function. The differences in astrocytic activity may make some central chemosensory sites better attuned to the local brain tissue environment and other chemosensory sites better suited to integrate chemosensory activity from multiple sites within and outside the central nervous system.