Ventral tegmental area astrocytes orchestrate avoidance and approach behavior

Abstract

The ventral tegmental area (VTA) is a heterogeneous midbrain structure, containing neurons and astrocytes, that coordinates approach and avoidance behaviors by integrating activity from numerous afferents. Within neuron-astrocyte networks, astrocytes control signals from distinct afferents in a circuit-specific manner, but whether this capacity scales up to drive motivated behavior has been undetermined. Using genetic and optical dissection strategies in vitro and during behavior we report that VTA astrocytes tune glutamatergic signaling selectively on local inhibitory neurons to drive a functional circuit for learned avoidance. In this circuit, VTA astrocytes facilitate excitation of local GABA neurons to increase inhibition of dopamine neurons. The increased inhibition of dopamine neurons elicits real-time and learned avoidance behavior that is sufficient to impede expression of learned preference for reward. Despite the large number of functions performed by astrocytes, loss of one glutamate transporter (GLT-1) from VTA astrocytes selectively blocks these avoidance behaviors and spares preference for reward. Thus, VTA astrocytes selectively regulate excitation of local GABA neurons to drive a distinct learned avoidance circuit that opposes learned approach behavior.

In vivo microstimulation with cathodic and anodic asymmetric waveforms modulates spatiotemporal calcium dynamics in cortical neuropil and pyramidal neurons of male mice

“…While the size of the imaging plane may influence the ability to observe this effect (407 µm vs. 3 mm), mesoscale imaging averages the neuronal activity of several layers, and a reduction in direct or indirect layer I neuronal activity without a reduction in layer II/III activity could still result in a decreased activation area. Furthermore, since astrocytes are key regulators of neurotransmitter clearance, and astrocytic voltage changes can influence the efficiency of this regulation (Gomez et al., 2019) they could also influence the entrainment of somas. Investigation into these effects may be even more important in the context of temporal patterned stimulation (Brocker et al., 2017), in which different neuronal subtypes can differentially entrain during the pulse bursts likely modulating the excitatory inhibitory balance during the inter‐pulse intervals.…”

Astroglia-specific contributions to the regulation of synapses, cognition and behaviour

“…Optogenetic stimulation of astrocytes expressing channel rhodopsin 2, which triggers an increase in cytoplasmic Na + thus modulating glutamate neurotransmission, induced real-time avoidance in mice as assessed by a real-time place preference test. This astroglia-driven pathway ultimately relied upon expression of glutamate transporter GLT-1 (Gomez et al, 2019). These experiments demonstrate that astrocytes can trigger complex behavioural paradigm using astroglia-specific homeostatic mechanisms.…”

Optogenetic manipulation of astrocytes from synapses to neuronal networks: A potential therapeutic strategy for neurodegenerative diseases

“…Moreover, astrocytes can decode interneuron activity and transform inhibitory into excitatory signals, contributing to the novel network properties led by the interneuron‐astrocyte interplay (Perea et al, ). Gomez et al reported that astrocytes in ventral tegmental area tune glutamatergic signaling selectively on local inhibitory neurons to drive a functional circuit for learning and memory using optogenetic strategy (Gomez et al, ). In this section, we focus on reviewing the astrocyte‐involved inhibitory neural network, and discussing potential therapeutic strategies of NDs via optogenetics.…”