Santin JM, Watters KC, Putnam RW, Hartzler LK. Temperature influences neuronal activity and CO 2/pH sensitivity of locus coeruleus neurons in the bullfrog, Lithobates catesbeianus. Am J Physiol Regul Integr Comp Physiol 305: R1451-R1464, 2013. First published October 9, 2013 doi:10.1152/ajpregu.00348.2013.-The locus coeruleus (LC) is a chemoreceptive brain stem region in anuran amphibians and contains neurons sensitive to physiological changes in CO 2/pH. The ventilatory and central sensitivity to CO2/pH is proportional to the temperature in amphibians, i.e., sensitivity increases with increasing temperature. We hypothesized that LC neurons from bullfrogs, Lithobates catesbeianus, would increase CO 2/pH sensitivity with increasing temperature and decrease CO 2/pH sensitivity with decreasing temperature. Further, we hypothesized that cooling would decrease, while warming would increase, normocapnic firing rates of LC neurons. To test these hypotheses, we used whole cell patch-clamp electrophysiology to measure firing rate, membrane potential (Vm), and input resistance (Rin) in LC neurons in brain stem slices from adult bullfrogs over a physiological range of temperatures during normocapnia and hypercapnia. We found that cooling reduced chemosensitive responses of LC neurons as temperature decreased until elimination of CO 2/pH sensitivity at 10°C. Chemosensitive responses increased at elevated temperatures. Surprisingly, chemosensitive LC neurons increased normocapnic firing rate and underwent membrane depolarization when cooled and decreased normocapnic firing rate and underwent membrane hyperpolarization when warmed. These responses to temperature were not observed in nonchemosensitive LC neurons or neurons in a brain stem slice 500 m rostral to the LC. Our results indicate that modulation of cellular chemosensitivity within the LC during temperature changes may influence temperature-dependent respiratory drive during acid-base disturbances in amphibians. Additionally, cold-activated/warm-inhibited LC neurons introduce paradoxical temperature sensitivity in respiratory control neurons of amphibians. chemosensitivity; temperature sensitivity; bullfrog; locus coeruleus; respiratory control THE BULLFROG, LITHOBATES CATESBEIANUS (formerly Rana catesbiena), inhabits much of North America and experiences a broad range of daily and seasonal changes in temperature. Activity during high and low temperatures can cause substantial disturbances to acid-base status in amphibians (1, 52). Unlike the endothermic mammals and birds, which regulate constant arterial pH (pH a ), amphibians and other ectothermic vertebrates preserve acid-base balance by maintaining temperature-dependent pH a . This acid-base regulatory strategy is achieved by allowing pH a to vary inversely with body temperature (T b ; for recent review, see Ref. 11). Although extensive work has attempted to illuminate the precise physiological role of an inverse pH-temperature relationship, it is still unclear as to which intracellular or extracellular variable...
Mechanisms that determine neuronal excitability under variable temperatures are unclear. In bullfrogs, cooling increases action potential (AP) firing in locus coeruleus (LC) neurons. We used whole‐cell patch clamp electrophysiology in brainstem slices to test whether inhibition of a hyperpolarization‐activated current (Ih) promotes increases in LC neuron excitability during cooling from 20°C to 10°C. Cooling reduced maximum Ih amplitude from ‐211.5±55.0pA to ‐69.5±7.8pA (P<0.05) and shifted the voltage at half maximal activation (V50) from ‐69.9±11.4mV to ‐92.9±5.8mV (P<0.05). Application of 2mM CsCl inhibited Ih (‐142.8±53.3pA vs. ‐3.3±14.3pA; P<0.05), and may potentiate AP firing increases induced by cooling (increase in AP firing; control: 0.9±0.5Hz vs. Cs+: 2.2±1.6Hz; P=0.2; n=3). Elevating intracellular cyclic AMP to 100μM increased the proportion of activated Ih near resting membrane potential (Vm ) at 20°C and 10°C (V50 =‐63.7±9.5mV and ‐71.3±10.2mV); yet, activation of Ih suppressed the firing increase elicited by cooling (0.2±0.7Hz decrease vs. increased firing in controls; P=0.06; n=5). Our data suggest inhibition of Ih enhances LC excitability during cooling and implicate Ih as a temperature‐sensitive mechanism that modulates neuronal excitability during changes in brain temperature. Given extensive involvement of LC neurons in physiological functions, understanding the regulation of LC neuron excitability during temperature changes has broad ramifications. Grant Funding Source: Supported by NSF IOS 1257338
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