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. 2018 Sep 24;28(18):2998-3004.e3.
doi: 10.1016/j.cub.2018.07.020. Epub 2018 Aug 30.

Somatosensory Neurons Enter a State of Altered Excitability during Hibernation

Lydia J Hoffstaetter  1 , Marco Mastrotto  1 , Dana K Merriman  2 , Sulayman D Dib-Hajj  3 , Stephen G Waxman  3 , Sviatoslav N Bagriantsev  4 , Elena O Gracheva  5
Affiliations

Somatosensory Neurons Enter a State of Altered Excitability during Hibernation

Lydia J Hoffstaetter et al. Curr Biol. .

Abstract

Hibernation in mammals involves prolonged periods of inactivity, hypothermia, hypometabolism, and decreased somatosensation. Peripheral somatosensory neurons play an essential role in the detection and transmission of sensory information to CNS and in the generation of adaptive responses. During hibernation, when body temperature drops to as low as 2°C, animals dramatically reduce their sensitivity to physical cues [1, 2]. It is well established that, in non-hibernators, cold exposure suppresses energy production, leading to dissipation of the ionic and electrical gradients across the plasma membrane and, in the case of neurons, inhibiting the generation of action potentials [3]. Conceivably, such cold-induced elimination of electrogenesis could be part of a general mechanism that inhibits sensory abilities in hibernators. However, when hibernators become active, the bodily functions-including the ability to sense environmental cues-return to normal within hours, suggesting the existence of mechanisms supporting basal functionality of cells during torpor and rapid restoration of activity upon arousal. We tested this by comparing properties of somatosensory neurons from active and torpid thirteen-lined ground squirrels (Ictidomys tridecemlineatus). We found that torpid neurons can compensate for cold-induced functional deficits, resulting in unaltered resting potential, input resistance, and rheobase. Torpid neurons can generate action potentials but manifest markedly altered firing patterns, partially due to decreased activity of voltage-gated sodium channels. Our results provide insights into the mechanism that preserves somatosensory neurons in a semi-active state, enabling fast restoration of sensory function upon arousal. These findings contribute to the development of strategies enabling therapeutic hypothermia and hypometabolism.

Keywords: Na(v)1.7; Na(v)1.8; Na(v)1.9; action potential; dorsal root ganglia; ground squirrel; hibernation; sensory physiology; somatosensation; voltage-gated sodium cannel.

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Conflict of interest statement

DECLARATION OF INTERESTS

The authors declare no competing interests.

Figures

Figure 1.
Figure 1.. Somatosensory Neurons Retain Action Potential Electrogenesis during Hibernation
(A) Thirteen-lined ground squirrel in the active and torpid state (courtesy of the Gracheva lab). (B) Diameter of DRG neurons from active and torpid squirrels. NS, not significant; p > 0.05; Mann-Whitney U test. Data are shown as mean ± SEM; n ≥ 32 cells. (C–E) RMP (C), input resistance (D), and current threshold (E). NS, not significant; p > 0.05; unpaired t test (C) and Mann-Whitney U test (D and E). Data are shown as mean ± SEM; n ≥ 30 cells. (F) Action potential (AP) firing rate at increasing current injections from 0 to 100 pA. Ordinary two-way ANOVA with Bonferroni correction is shown; ****p 0.05; *p
Figure 2.
Figure 2.. Nav1.9 Properties Do Not Change during Torpor
(A) Exemplar traces of Nav1.9-mediated currents with representation of activation protocol in DRG neurons. (B) Current-voltage relationship of Nav1.9 from squirrel DRG. Ordinary two-way ANOVA with Bonferroni correction is shown; p < 0.0001 main effect between species. Data are shown as mean ± SEM; n ≥ 15 neurons. (C) Activation conductance and steady-state inactivation curves of Nav1.9. Data are shown as mean ± SEM fit with the Boltzmann function. Dashed line indicates average RMP. (D and E) V50 of activation (D) and steady-state inactivation (E), calculated from Boltzmann fit; unpaired t test. Data are shown as mean ± SEM; activation: n ≥ 10 neurons; inactivation: n ≥ 8 neurons.
Figure 3.
Figure 3.. TTX-S Current Density Is Reduced during Torpor
(A) Exemplar current traces and voltage protocols for activation (left) and steady-state inactivation (right) of TTX-S currents in DRG neurons. (B) Voltage dependence of TTX-S current. Ordinary two-way ANOVA with Bonferroni correction is shown; ****p 50 of activation (D) and steady-state inactivation (E), averaged from individual Boltzmann fits; Mann-Whitney U test. Data are shown as mean ± SEM; n ≥ 16 neurons. (F) Inactivation rate (tau of decay), calculated from a single-exponential curve fit to the decay of the current at each voltage. Only curves fit with an R2 > 0.95 were included. Ordinary two-way ANOVA with Bonferroni correction is shown; p < 0.0001 main effect between species. **p < 0.01; ***p < 0.001; ****p < 0.0001. Data are shown as mean ± SEM; n = 5–18 active; n = 2–17 torpid neurons. See also Figure S4.
Figure 4.
Figure 4.. Nav1.8 Current Activation Is Depolarized during Torpor
(A) Exemplar current traces and voltage protocols for activation (left) and steady-state inactivation (right) of Nav1.8 currents in DRG neurons. (B) Current-voltage relationship of Nav1.8. Ordinary two-way ANOVA with Bonferroni correction is shown; ****p < 0.0001 main effect between species. Data are shown as mean ± SEM; n ≥ 14 cells. (C) Activation conductance and steady-state inactivation of Nav1.8. Data are shown as mean ± SEM fit with Boltzmann functions. Dashed line indicates average RMP. (D and E) V50 of activation (D) and steady-state inactivation (E), averaged from individual Boltzmann fits; unpaired t test (D) and Mann-Whitney U test (E). Data are shown as mean ± SEM; n ≥ 12 neurons. (F) Inactivation rate (tau of decay), calculated from a single-exponential curve fit to the decay of the current at each voltage. Only curves fit with an R2 > 0.95 were included. Ordinary two-way ANOVA with Bonferroni correction is shown; p < 0.0001 main effect between species. **p < 0.01; ****p < 0.0001. Data are shown as mean ± SEM; n = 4–13 active; n = 2–15 torpid neurons. See also Figure S4.
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