Theoretical perspectives on central chemosensitivity: CO2/H+-sensitive neurons in the locus coeruleus

Figures

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  Fig 1. Comparison of experimental and model-generated data. LC neuron (black) and model-generated action potential waveforms (blue) were recorded during normal spontaneous activity. The model is capable of reproducing a similar pattern of AHP existent throughout the entire interspike interval observed in LC neurons.

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  Fig 2. Spike frequency adaptation response to applied depolarizing current. A. Applied 0.1 nA depolarizing pulse. B. Simulated membrane potential during the pulse. C. M-type potassium current dynamics showing an increase in response to initial depolarization followed by a new, elevated steady state during stimulation. D. Intracellular calcium concentration [Ca2+]i. E. Calcium-activated SK-type potassium current. [Ca2+]i and SK-type potassium current are both involved in the change in firing rate during depolarizing stimuli. F. Firing frequency.

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  Fig 3. Spike frequency adaptation response to excitatory chemical stimulus. A. Simulated application of normocapnic (5% CO2) and hypercapnic acidotic (15% CO2) stimuli. B. Corresponding simulated membrane potential. C. Dynamic response of calcium-activated SK-type potassium current. D. Dynamic response of intracellular calcium concentration ([Ca2+]i). E. Firing frequency during CO2 level change.

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  Fig 4. Postinhibitory rebound and post-stimulation recovery. Response to a hyperpolarizing pulse of −0.5 nA followed by a depolarizing pulse of 0.6 nA. A. Simulated membrane potential during current application. B. Postinhibitory rebound, involving an increase in A-type potassium and T-type calcium currents and an increase in intracellular calcium ([Ca2+]i). C. Post-stimulation recovery after postinhibitory rebound. This behavior was associated with accumulation of [Ca2+]i and increased M-type and SK potassium currents.

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  Fig 5. Comparison of simulated chemosensitive behavior and intracellular recordings. Effect of hypocapnia and hypercapnia on the spontaneous firing rate in locus coeruleus (LC) neurons from rats. A. Hypocapnic alkalosis (2.5% CO2, pHo = 7.55, pHi = 7.3). B. Normocapnia (5% CO2, pHo = 7.45, pHi = 7.23); C. Hypercapnia (10% CO2, pHo = 7.15, pHi = 7.4); D. Hypercapnic acidosis (15%CO2, pHo = 7, pHi = 6.96). Traces of membrane potential (Vm) vs. time showing action potential frequency from experimental data (black) and model-generated data (colored) for different conditions. Experimental traces were redrawn from data from Li and Putnam (2013) [45].

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  Fig 6. Neuronal response to hypocapnic and hypercapnic stimulation. A. Application of simulated normocapnia (5% CO2), hypocapnic alkalosis (2.5% CO2), and hypercapnic acidosis (15% CO2). B. Corresponding membrane potential. C. Firing frequency during changing chemical conditions.

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  Fig 7. Effect of electrical and chemical signals on firing rate. A. Firing frequencies at different extracellular and intracellular pH levels, B. Firing frequency for different levels of CO2. C. Firing frequency for different external stimulus current values (negative values for depolarizing current. D. Contribution of each signal to the firing-rate response measured as the percentage change from control firing rate upon exposure to each signal.

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  Fig 8. Firing frequency response to different electrical and chemical stimuli. A. Simulated membrane potential for different chemical stimuli: control (normocapnic: 5% CO2, pHo = 7.45, pHi = 7.25), isohydric hypercapnia (IH: 15% CO2, pHo = 7.45, pHi = 7.25), isocapnic acidosis (IA: 5% CO2, pHo = 7.1, pHi = 7.0), and hypercapnic acidosis (HA: 15% CO2, pHo = 7.1, pHi = 7.0). B. Firing rate under normocapnia (grey bar) and the same chemical stimuli as in A (blue bars) at different values of external applied current: excitatory stimulus current, Is < 0; spontaneously firing neuron, Is = 0; and inhibitory stimulus current, Is > 0. C. Sensitivity for each chemical stimulus was calculated as the percentage increase from control firing rate.