# Neuromodulation to the Rescue: Compensation of Temperature-Induced Breakdown of Rhythmic Motor Patterns via Extrinsic Neuromodulatory Input

## TL;DR

This study shows how neuromodulators help the nervous system compensate for temperature changes that disrupt rhythmic activity in neural circuits.

## Contribution

The paper reveals a novel mechanism where extrinsic neuromodulatory input counteracts temperature-induced changes in neural circuits.

## Key findings

- Temperature increases can stop rhythmic activity in isolated neural circuits due to increased leak currents.
- Extrinsic neuromodulatory input from projection neurons or CabTRP Ia rescues rhythmic activity by counteracting temperature effects.
- Computational modeling shows IMI can reduce leak-current influences and stabilize motor patterns over a wide temperature range.

## Abstract

Stable rhythmic neural activity depends on the well-coordinated interplay of synaptic and cell-intrinsic conductances. Since all biophysical processes are temperature dependent, this interplay is challenged during temperature fluctuations. How the nervous system remains functional during temperature perturbations remains mostly unknown. We present a hitherto unknown mechanism of how temperature-induced changes in neural networks are compensated by changing their neuromodulatory state: activation of neuromodulatory pathways establishes a dynamic coregulation of synaptic and intrinsic conductances with opposing effects on neuronal activity when temperature changes, hence rescuing neuronal activity. Using the well-studied gastric mill pattern generator of the crab, we show that modest temperature increase can abolish rhythmic activity in isolated neural circuits due to increased leak currents in rhythm-generating neurons. Dynamic clamp-mediated addition of leak currents was sufficient to stop neuronal oscillations at low temperatures, and subtraction of additional leak currents at elevated temperatures was sufficient to rescue the rhythm. Despite the apparent sensitivity of the isolated nervous system to temperature fluctuations, the rhythm could be stabilized by activating extrinsic neuromodulatory inputs from descending projection neurons, a strategy that we indeed found to be implemented in intact animals. In the isolated nervous system, temperature compensation was achieved by stronger extrinsic neuromodulatory input from projection neurons or by augmenting projection neuron influence via bath application of the peptide cotransmitter Cancer borealis tachykinin-related peptide Ia (CabTRP Ia). CabTRP Ia activates the modulator-induced current IMI (a nonlinear voltage-gated inward current) that effectively acted as a negative leak current and counterbalanced the temperature-induced leak to rescue neuronal oscillations. Computational modelling revealed the ability of IMI to reduce detrimental leak-current influences on neuronal networks over a broad conductance range and indicated that leak and IMI are closely coregulated in the biological system to enable stable motor patterns. In conclusion, these results show that temperature compensation does not need to be implemented within the network itself but can be conditionally provided by extrinsic neuromodulatory input that counterbalances temperature-induced modifications of circuit-intrinsic properties.

An electrophysiology and modelling study reveals how temperature can affect the balance of ionic conductances in neural circuits and how neuromodulators can compensate for detrimental temperature effects.

All physiological processes are influenced by temperature. This is a particular problem for the nervous system, as temperature changes can disrupt the well-balanced flow of ions across the cell membrane necessary for maintaining nerve cell function. Possessing compensatory mechanisms that counterbalance detrimental temperature effects and maintain vital behaviors is especially important for poikilothermic animals, because they do not actively maintain their body temperature and can experience substantial temperature fluctuations. In this study, we analyze the mechanisms that allow the nervous system to maintain rhythmic activity over a range of different temperatures. To do so, we use the well-characterized central pattern generator of the stomatogastric nervous system of the crab that controls the motion of the gut. In this system, when experimentally isolated from the rest of the nervous system, even a small temperature increase can lead to termination of rhythmic activity due to a change in the balance of ionic conductances at elevated temperatures. However, the intact animal can compensate for these detrimental temperature effects. We demonstrate that such compensation can be achieved by restoring the balance of ionic conductance via an increase in neuromodulator release from projection neurons that control the motor circuits. We conclude that temperature compensation via neuromodulation may be a widespread phenomenon since it allows quick and flexible compensation of temperature influences on the nervous system.