The plasticity of glutamatergic transmission in the Ventral Tegmental Area (VTA) represents a fundamental mechanism in the modulation of dopamine neuron burst firing and the phasic dopamine release at VTA target regions. These processes encode basic behavioral responses, including locomotor activity, learning and motivated-behaviors. Here we describe a hitherto unidentified mechanism of long-lasting potentiation of glutamatergic synapses on DA neurons. We found that VTA astrocytes respond to dopamine neuron bursts with Ca 2+ elevations that require activation of endocannabinoid CB1 and dopamine D2 receptors colocalized at the same astrocytic process. Astrocytes, in turn, release glutamate that, through presynaptic metabotropic glutamate receptor activation coupled with neuronal nitric oxide production, induces long-lasting potentiation of excitatory synapses on adjacent dopamine neurons. Consistent with this finding, selective activation of VTA astrocytes increases dopamine neuron bursts in vivo and induces locomotor hyperactivity.Astrocytes play, therefore, a key role in the modulation of VTA dopamine neuron activity.

The brain is a highly energy demanding organ, which accounts in humans for the 20% of total energy consumption at resting state although comprising only 2% of the body mass. The necessary delivery of nutrients to brain parenchyma is ensured by the cerebral circulatory system, through the exchange of glucose and oxygen (O2) at the capillary level. Notably, a tight spatial and temporal correlation exists between local increases in neuronal activity and the subsequent changes in regional cerebral blood flow. The recognized concept of neurovascular coupling (NVC), also named functional hyperemia, expresses this close relationship and stands at the basis of the modern functional brain imaging techniques. Different cellular and molecular mechanisms have been proposed to mediate this tight coupling. In this context, astrocytes are ideally positioned to act as relay elements that sense neuronal activity through their perisynaptic processes and release vasodilator agents at their endfeet in contact with brain parenchymal vessels. Two decades after the astrocyte involvement in neurovascular coupling has been proposed, we here review the experimental evidence that contributed to unraveling the molecular and cellular mechanisms underlying cerebral blood flow regulation. While traveling through the different controversies that moved the research in this field, we keep a peculiar focus on those exploring the role of astrocytes in neurovascular coupling and conclude with two sections related to methodological aspects in neurovascular research and to some pathological conditions resulting in altered neurovascular coupling.

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