The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease

Astrocytes are neural cells of ectodermal, neuroepithelial origin that provide for homeostasis and defense of the central nervous system (CNS). Astrocytes are highly heterogeneous in morphological appearance; they express a multitude of receptors, channels, and membrane transporters. This complement underlies their remarkable adaptive plasticity that defines the functional maintenance of the CNS in development and aging. Astrocytes are tightly integrated into neural networks and act within the context of neural tissue; astrocytes control homeostasis of the CNS at all levels of organization from molecular to the whole organ.

Physiology of astroglia

Cerebral blood flow (CBF) regulation is essential for normal brain function The mammalian brain has evolved a unique mechanism for CBF control known as neurovascular coupling This mechanism ensures a rapid increase in the rate of CBF and oxygen delivery to activated brain structures The neurovascular unit is composed of astrocytes, mural vascular smooth muscle cells and pericytes, and endothelia, and regulates neurovascular coupling This Review article examines the cellular and molecular mechanisms within the neurovascular unit that contribute to CBF control, and neurovascular dysfunction in neurodegenerative disorders such as Alzheimer disease

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Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease

The discovery that transient elevations of calcium concentration occur in astrocytes, and release 'gliotransmitters' which act on neurons and vascular smooth muscle, led to the idea that astrocytes are powerful regulators of neuronal spiking, synaptic plasticity and brain blood flow. These findings were challenged by a second wave of reports that astrocyte calcium transients did not mediate functions attributed to gliotransmitters and were too slow to generate blood flow increases. Remarkably, the tide has now turned again: the most important calcium transients occur in fine astrocyte processes not resolved in earlier studies, and new mechanisms have been discovered by which astrocyte [Ca(2+)]i is raised and exerts its effects. Here we review how this third wave of discoveries has changed our understanding of astrocyte calcium signaling and its consequences for neuronal function.

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Astrocyte Calcium Signaling: The Third Wave

Pathogenesis of depression: Insights from human and rodent studies

Enhanced neuronal activity in the brain triggers a local increase in blood flow, termed functional hyperemia, via several mechanisms, including calcium (Ca2+) signaling in astrocytes. However, recent in vivo studies have questioned the role of astrocytes in functional hyperemia because of the slow and sparse dynamics of their somatic Ca2+ signals and the absence of glutamate metabotropic receptor 5 in adults. Here, we reexamined their role in neurovascular coupling by selectively expressing a genetically encoded Ca2+ sensor in astrocytes of the olfactory bulb. We show that in anesthetized mice, the physiological activation of olfactory sensory neuron (OSN) terminals reliably triggers Ca2+ increases in astrocyte processes but not in somata. These Ca2+ increases systematically precede the onset of functional hyperemia by 1-2 s, reestablishing astrocytes as potential regulators of neurovascular coupling.

Calcium dynamics in astrocyte processes during neurovascular coupling

Sleep is a nearly universal behaviour with unclear functions 

Sleep pressure modulates single-neuron synapse number in zebrafish

Sleep pressure builds during wakefulness, but the mechanisms underlying this homeostatic process are poorly understood. One zebrafish model suggests that sleep pressure increases as a function of global neuronal activity, such as during sleep deprivation or acute exposure to drugs that induce widespread brain activation. Given that the arousal-promoting noradrenergic system is important for maintaining heightened neuronal activity during wakefulness, we hypothesised that genetic and pharmacological reduction of noradrenergic tone during drug-induced neuronal activation would dampen subsequent rebound sleep in zebrafish larvae. Unexpectedly, dampening noradrenergic tone with the α2-adrenoceptor agonist clonidine during acute caffeine or pentylenetetrazol treatment enhanced subsequent rebound sleep, while stimulating noradrenergic signalling during caffeine exposure with a cocktail of α1- and β-adrenoceptor agonists did not enhance sleep. Similarly, CRISPR/Cas9-mediated elimination of the dopamine β-hydroxylase (dbh) gene, which encodes an enzyme required for noradrenalin synthesis, enhanced baseline sleep in larvae but did not prevent additional rebound sleep following acute induction of neuronal activity. Across all drug conditions, c-fos expression immediately after drug exposure varied inversely with noradrenergic tone and correlated strongly with the amount of induced rebound sleep. These results are consistent with a model in which increases in neuronal activity, as reflected by brain-wide levels of c-fos induction, drive a sleep pressure signal that promotes rebound sleep independently of noradrenergic tone.

/pdf/noradrenergic-tone-is-not-required-for-neuronal-activity-3fbyvw20.pdf

Noradrenergic Tone is Not Required for Neuronal Activity-Induced Rebound Sleep in Zebrafish

Although critical for brain function, the physiological values of cerebral oxygen concentration have remained elusive because high-resolution measurements have only been performed during anesthesia, which affects two major parameters modulating tissue oxygenation: neuronal activity and blood flow. Using measurements of capillary erythrocyte-associated transients, fluctuations of oxygen partial pressure (Po2) associated with individual erythrocytes, to infer Po2 in the nearby neuropil, we report the first non-invasive micron-scale mapping of cerebral Po2 in awake, resting mice. Interstitial Po2 has similar values in the olfactory bulb glomerular layer and the somatosensory cortex, whereas there are large capillary hematocrit and erythrocyte flux differences. Awake tissue Po2 is about half that under isoflurane anesthesia, and within the cortex, vascular and interstitial Po2 values display layer-specific differences which dramatically contrast with those recorded under anesthesia. Our findings emphasize the importance of measuring energy parameters non-invasively in physiological conditions to precisely quantify and model brain metabolism.

/pdf/mapping-oxygen-concentration-in-the-awake-mouse-brain-4mzuuckkfi.pdf

Mapping oxygen concentration in the awake mouse brain

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Papers

Calcium dynamics in astrocyte processes during neurovascular coupling

Sleep pressure modulates single-neuron synapse number in zebrafish

Noradrenergic Tone is Not Required for Neuronal Activity-Induced Rebound Sleep in Zebrafish

Mapping oxygen concentration in the awake mouse brain