Biomedical subjects

Andrew K Tryba

Publications and source records attributed to Andrew K Tryba.

8 recordsLinked to original sources

PubMed2006

Gasping activity in vitro: a rhythm dependent on 5-HT2A receptors.

Many rhythmic behaviors are continuously modulated by endogenous peptides and amines, but whether neuromodulation is critical to the expression of a rhythmic behavior often remains unknown, particularly in mammals. Here, we address this issue in the respiratory network that was isolated in spontaneously rhythmic medullary slice preparations from mice. Under control conditions, the respiratory network generates fictive eupneic activity. We hypothesized previously that this activity depends on two types of pacemaker neurons. The bursting properties of one pacemaker rely on the persistent sodium current (INa(p)) and are insensitive to blockade of calcium channels with cadmium (CI-pacemakers), whereas bursting mechanisms of a second pacemaker are sensitive to cadmium (CS-pacemakers) and the calcium-dependent nonspecific cation current blocker flufenamic acid. During hypoxia, fictive eupneic activity is supplanted by the neural correlate of gasping, which is proposed to depend only on CI-pacemakers. Because CI-pacemakers require endogenous activation of 5-HT2A receptors, we tested the hypothesis that 5-HT2A receptor activation is critical for gasping. Here, we demonstrate that fictive gasping and CI-pacemaker bursting were selectively eliminated by the 5-HT2A receptor antagonist piperidine or ketanserin. Neither 5-HT2A antagonist eliminated bursting by CS-pacemakers and ventral respiratory group (VRG) population activity. However, this VRG activity was very different from eupneic activity. In the presence of 5-HT2A antagonists, VRG activity was eliminated by flufenamic acid and could not be reliably restored by adding substance P. These data support the hypothesis that two types of pacemaker bursting mechanisms underlie fictive eupnea, whereas only one burst mechanism is critical for gasping.

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PubMed2005

Mecp2 deficiency disrupts norepinephrine and respiratory systems in mice.

Rett syndrome is a severe X-linked neurological disorder in which most patients have mutations in the methyl-CpG binding protein 2 (MECP2) gene and suffer from bioaminergic deficiencies and life-threatening breathing disturbances. We used in vivo plethysmography, in vitro electrophysiology, neuropharmacology, immunohistochemistry, and biochemistry to characterize the consequences of the MECP2 mutation on breathing in wild-type (wt) and Mecp2-deficient (Mecp2-/y) mice. At birth, Mecp2-/y mice showed normal breathing and a normal number of medullary neurons that express tyrosine hydroxylase (TH neurons). At approximately 1 month of age, most Mecp2-/y mice showed respiratory cycles of variable duration; meanwhile, their medulla contained a significantly reduced number of TH neurons and norepinephrine (NE) content, even in Mecp2-/y mice that showed a normal breathing pattern. Between 1 and 2 months of age, all unanesthetized Mecp2-/y mice showed breathing disturbances that worsened until fatal respiratory arrest at approximately 2 months of age. During their last week of life, Mecp2-/y mice had a slow and erratic breathing pattern with a highly variable cycle period and frequent apneas. In addition, their medulla had a drastically reduced number of TH neurons, NE content, and serotonin (5-HT) content. In vitro experiments using transverse brainstem slices of mice between 2 and 3 weeks of age revealed that the rhythm produced by the isolated respiratory network was irregular in Mecp2-/y mice but could be stabilized with exogenous NE. We hypothesize that breathing disturbances in Mecp2-/y mice, and probably Rett patients, originate in part from a deficiency in noradrenergic and serotonergic modulation of the medullary respiratory network.

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PubMed2004

Background sodium current stabilizes bursting in respiratory pacemaker neurons.

Endogenous pacemaker properties have been proposed to generate rhythmic activity underlying many behaviors including respiration. For pacemakers to generate regenerative bursting, background currents maintain their membrane potential (Vm) within a range where bi-stable properties are expressed, thereby stabilizing rhythmogenesis. We previously found that the baseline Vm of respiratory pacemakers is stabilized against hyperpolarizing shifts in their Vm. In response to prolonged hyperpolarizing current injection synaptically isolated respiratory pacemakers steadily depolarize and resume bursting, suggesting a stabilizing background current is involved. What is the ionic basis of this background current in respiratory pacemakers? Here we demonstrate that in low-[Na(+)](o) ACSF, synaptically isolated respiratory pacemakers hyperpolarized and remained outside the bursting window, but could burst upon depolarizing current injection. These data suggest that pacemakers possess a background sodium current that is necessary to bring their Vm into a bursting range. Low-[Na(+)](o) ACSF also abolished the depolarizing shift evoked during prolonged hyperpolarizing current injection, and bursting did not resume. This depolarizing shift persisted in the presence of I(h)-current blockers, but was abolished in tetrodotoxin. Although, under control conditions, the Vm of synaptically isolated respiratory pacemaker neurons was not significantly affected when [K(+)](o) was changed from 3 to 8 mM, the Vm is altered when [K(+)](o) was raised in low-[Na(+)](o) ACSF. Thus, current-clamp studies suggest that respiratory pacemaker neurons possess a background sodium current that maintains their membrane potential within a range where they express bursting, thereby stabilizing rhythmogenesis.

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PubMed2004

Differential contribution of pacemaker properties to the generation of respiratory rhythms during normoxia and hypoxia.

Pacemaker neurons have been described in most neural networks. However, whether such neurons are essential for generating an activity pattern in a given preparation remains mostly unknown. Here, we show that in the mammalian respiratory network two types of pacemaker neurons exist. Differential blockade of these neurons indicates that their relative contribution to respiratory rhythm generation changes during the transition from normoxia to hypoxia. During hypoxia, blockade of neurons with sodium-dependent bursting properties abolishes respiratory rhythm generation, while in normoxia respiratory rhythm generation only ceases upon pharmacological blockade of neurons with heterogeneous bursting properties. We propose that respiratory rhythm generation in normoxia depends on a heterogeneous population of pacemaker neurons, while during hypoxia the respiratory rhythm is driven by only one type of pacemaker.

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PubMed2004

Hyperthermia modulates respiratory pacemaker bursting properties.

Most mammals modulate respiratory frequency (RF) to dissipate heat (e.g., panting) and avoid heat stroke during hyperthermic conditions. Respiratory neural network activity recorded in an isolated brain stem-slice preparation of mice exhibits a similar RF modulation in response to hyperthermia; fictive eupneic frequency increases while inspiratory network activity amplitude and duration are significantly reduced. Here, we study the effects of hyperthermia on the activity of synaptically isolated respiratory pacemakers to examine the possibility that these changes may account for the hyperthermic RF modulation of the respiratory network. During heating, modulation of the bursting frequency of synaptically isolated pacemakers paralleled that of population bursting recorded from the intact network, whereas nonpacemaker neurons were unaffected, suggesting that pacemaker bursting may account for the temperature-enhanced RF observed at the network level. Some respiratory neurons that were tonically active at hypothermic conditions exhibited pacemaker properties at approximately the normal body temperature of eutherian mammals (36.81 +/- 1.17 degrees C; mean +/- SD) and continued to burst at 40 degrees C. At elevated temperatures (40 degrees C), there was an enhancement of the depolarizing drive potential in synaptically isolated pacemakers, while the amplitude of integrated population activity declined. Isolated pacemaker bursting ceased at 41-42 degrees C (n = 5), which corresponds to temperatures at which hyperthermic-apnea typically occurs in vivo. We conclude that pacemaker properties may play an important role in the hyperthermic frequency modulation and apnea, while network effects may play important roles in generating other aspects of the hyperthermic response, such as the decreased amplitude of ventral respiratory group activity during hyperthermia.

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PubMed2004

Pacemaker neurons and neuronal networks: an integrative view.

Rhythmically active neuronal networks give rise to rhythmic motor activities but also to seemingly non-rhythmic behaviors such as sleep, arousal, addiction, memory and cognition. Many of these networks contain pacemaker neurons. The ability of these neurons to generate bursts of activity intrinsically lies in voltage- and time-dependent ion fluxes resulting from a dynamic interplay among ion channels, second messenger pathways and intracellular Ca2+ concentrations, and is influenced by neuromodulators and synaptic inputs. This complex intrinsic and extrinsic modulation of pacemaker activity exerts a dynamic effect on network activity. The nonlinearity of bursting activity might enable pacemaker neurons to facilitate the onset of excitatory states or to synchronize neuronal ensembles--an interactive process that is intimately regulated by synaptic and modulatory processes.

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PubMed2003

Stabilization of bursting in respiratory pacemaker neurons.

Synaptic and endogenous pacemaker properties have been hypothesized as principal cellular mechanisms for respiratory rhythm generation. This rhythmic activity is thought to originate in the pre-Bötzinger complex, an area that can generate fictive respiration when isolated in brainstem slice preparations of mice. In slice preparations, external potassium concentration ([K+]o) is typically elevated from 3 to 8 mm to induce rhythmic population activity. However, elevated [K+](o) may not simply depolarize respiratory neurons but also change rhythm-generating mechanisms by inducing or altering pacemaker properties. To test this, we examined the membrane potential (V(m)) of nonpacemaker neurons and endogenous bursting properties of pacemaker neurons before and after blockade of excitatory and inhibitory synaptic input in 3 mm [K+]o artificial CSF (aCSF). Most pacemaker neurons (82%) ceased to burst in 3 mm [K+]o aCSF after blockade of glutamatergic transmission. In all of these, endogenous bursting was restored on additional blockade of glycinergic and GABAergic inhibition. Thus, bursting properties are suppressed by endogenous synaptic inhibition, the level of which may determine whether network rhythmicity is generated in 3 mm (n = 12) or 8 mm (n = 40) [K+]o aCSF. In 3 mm [K+]o aCSF, synaptically isolated pacemaker neurons (n = 22) continued to burst over a wide range of imposed V(m). Furthermore, the V(m) of synaptically isolated pacemaker neurons was not significantly affected (p = 0.1; n = 10) when [K+]o was changed from 8 to 3 mm, whereas isolated nonpacemakers hyperpolarized (p < 0.001; n = 14). We conclude that respiratory pacemaker neurons possess membrane properties that stabilize their bursting against changes in [K+]o and imposed changes in V(m).

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PubMed2003

Response of the respiratory network of mice to hyperthermia.

Most mammals modulate respiratory frequency (RF) to dissipate heat (i.e., panting) and avoid heat stroke during hyperthermic conditions. During hyperthermia, the RF of intact mammals increases and then declines or ceases (apnea). It has been proposed that this RF modulation depends on the presence of higher brain structures such as the hypothalamus. However, the direct effects of hyperthermia on the respiratory neural network have not been examined. To address this issue, the respiratory neural network [i.e., ventral respiratory group (VRG)] was isolated in a brain stem preparation taken from the medulla of mice (P0 -P6). Integrated population activity, predominated by inspiratory neurons, was recorded extracellularly from VRG neurons. The bath temperature was then heated from 30 to 40 degrees C, resulting in a biphasic frequency response in VRG activity. Following an initial six- to sevenfold increase and subsequent decline, fictive RF was maintained at a frequency that was higher than baseline frequency; at 40 degrees C, the RF was maintained at about two to four times that at 30 degrees C. The inspiratory burst amplitude and duration were significantly reduced during hyperthermic conditions. An increase in RF and decrease in VRG burst amplitude and duration also occurred when heating from 37 to 40 degrees C. Fictive apnea typically occurred during cooling to the control temperature. Furthermore, changes in hypoglossal motor nucleus activity paralleled those of the VRG, suggesting that temperature modulation of the VRG is likely to have a behaviorally relevant impact on respiration. We conclude that the VRG activity itself is modulated during hyperthermia and the respiratory network is particularly sensitive to temperature changes.

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