Dissociation Between Neuronal and Astrocytic Calcium Activity in Response to Locomotion in Mice

Abstract

Orchestrated activity of different cell types and their interactions within the brain active milieu provide the cellular basis for brain functions. Locomotion triggers a coordinated response of both neurons and astrocytes in various brain regions. Here we performed calcium (Ca2+) imaging of these two cell types in the somatosensory cortex in head-fixed mice moving on the airlifted platform. Ca2+ activity in astrocytes significantly increased during locomotion from a low baseline level during animal quiescence. Ca2+ signals first appeared in the distal processes and then propagated to astrocytic somata. In somata, Ca2+ concentration ([Ca2+]i) elevations became significantly larger and exhibited oscillatory behaviour. Hence, astrocytic soma operates as both integrator and amplifier of Ca2+ signal. In contrast to astrocytes, pronounced Ca2+ activity was detected in neurons in quiescent periods, and it further increased during locomotion. Neuronal [Ca2+]i rose almost immediately following the onset of locomotion, whereas astrocytic Ca2+ signals lagged by several seconds. Such a long lag suggests that astrocytic [Ca2+]i elevations are unlikely to be triggered by the activity of synapses among local neurons. Next, we compared Ca2+ responses to pairs of consecutive episodes of locomotion (paired-run ratio). Neurons reliably responded to each episode, whereas [Ca2+]i elevations in astrocytes were significantly diminished in response to the second locomotion. This refractory period in astrocytes may arise from distinct mechanisms underlying Ca2+ signal generation. In neurons, the bulk of Ca2+ enters through the Ca2+ channels in the plasma membrane allowing for steady-level Ca2+ elevations in repetitive runs. Astrocytic Ca2+ responses originate from the intracellular stores, the depletion of which affects subsequent Ca2+ signals. Functionally, neuronal Ca2+ response is primary and reflects sensory input processed by neurons. Astrocytic Ca2+ dynamics is secondary and likely to participate in regulation of metabolic and homeostatic support of intercellular communication and plasticity within the brain active milieu.

Functional activation of dorsal striatum astrocytes improves movement deficits in hemi-parkinsonian mice

“…2g and 2h). These results are consistent with previous studies comparing the time course of astrocyte and neuronal calcium activity at single cell resolution 24 and suggest that these cell types may regulate behavioral processes at different timescales. One interpretation is that astrocyte activity signals a locomotion behavioral state for the striatal circuit and promotes continued coordination of incoming cortical and thalamic sensorimotor information 24,37,46 with dopaminergic neuromodulation and local neuronal processing 47 .…”

“…These results are consistent with previous studies comparing the time course of astrocyte and neuronal calcium activity at single cell resolution 24 and suggest that these cell types may regulate behavioral processes at different timescales. One interpretation is that astrocyte activity signals a locomotion behavioral state for the striatal circuit and promotes continued coordination of incoming cortical and thalamic sensorimotor information 24,37,46 with dopaminergic neuromodulation and local neuronal processing 47 . Reduction of astrocyte calcium activity with dopamine loss would disrupt this process, which in parallel with the well-documented effects of dopamine loss on neuronal intrinsic properties and synaptic structure and function 3 would result in motor dysfunction.…”

Bringing astrocytes into the spotlight of electrical brain stimulation

“…The large response of astrocytes may prevent them from fully restoring calcium levels for the next event, leading to a decline in response to electrical stimulation. A similar refractory period was observed in vivo, where astrocytes had a significantly diminished response to a second event [18] and ex-vivo where a decrease in average calcium amplitude was observed after stimulation of astrocytes with baclofen [19]. The astrocytic response exhibits/displays electrical signals even in the absence of a calcium signal.…”

“…This might be associated with a refractory period of calcium signalling in astrocytes that may become evident after the massive calcium release observed after stimulation. Fedotova and colleagues recently proposed an astrocytic refractory period that arises due to the depletion of intracellular calcium stores in astrocytes, which affects consecutive calcium signals [18]. This excludes the use of calcium imaging data to clarify the mechanisms behind its dynamics as the response is inherently different when comparing the first stimuli (baseline) with the response obtained after pharmacological manipulation.…”

Centripetal integration of past events in hippocampal astrocytes regulated by locus coeruleus

“…9 ). Interestingly, a recent study has observed centripetal propagation in cortical brain regions 44 ; hence, it is likely that this phenomenon is not restricted to hippocampus.…”