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.

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.DOI: http://dx.doi.org/10.7554/eLife.12024.001

, S.M. The psychostimulant modafinil facilitates water maze performance and augments synaptic potentiation in dentate gyrus, Neuropharmacology (2010Neuropharmacology ( ), doi: 10.1016Neuropharmacology ( /j.neuropharm.2010 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPTThe psychostimulant modafinil facilitates water maze performance and augments synaptic potentiation in dentate gyrus. M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT AbstractModafinil is a psychostimulant drug used widely for the treatment of narcolepsy, which also has additional positive effects on cognition. Here, we investigate the effects of modafinil on behavioral performance and synaptic plasticity in rats.Improved acquisition of water maze task was observed for animals that underwent chronic treatment with modafinil. We found that the distance travelled and escape latency were reduced after the first day in chronically-treated rats, compared to controls. Importantly, the swim velocity was similar for both groups, excluding pharmacological effects on motor skills. We also found that modafinil increases synaptic plasticity in the dentate gyrus of urethane-anaesthetized rats; modafinil induced a robust augmentation of the population spike, evident after application of 2 bursts of 200Hz, high-frequency stimulation. Furthermore, the modafinil-dependent enhancement of postsynaptic potentials correlated selectively with theta rhythm augmentation. We propose that modafinil may facilitate spatial orientation via increased theta-related hippocampal plasticity.

Research over the last 20 years has firmly established the existence of sleep states across the animal kingdom. Work in non-mammalian animal models such as nematodes, fruit flies, and zebrafish has now uncovered many evolutionarily conserved aspects of sleep physiology and regulation, including shared circuit architecture, homeostatic and circadian control elements, and principles linking sleep physiology to function. Non-mammalian sleep research is now shedding light on fundamental aspects of the genetic and neuronal circuit regulation of sleep, with direct implications for the understanding of how sleep is regulated in mammals. Introduction:Sleep is an evolutionarily ancient behavior observed in every animal species that has been extensively studied [1], even those that lack a centralized nervous system, such as jellyfish [2]. In these diverse taxa, sleep is defined as a rapidly reversible period of quiescence that is characterized by a decreased sensitivity to sensory stimuli. Other core features of sleep that are usually observed across species include species-specific ManuscriptClick here to view linked References

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. During stimulant drug treatment, dampening noradrenergic tone with the α2-adrenoceptor agonist clonidine unexpectedly enhanced subsequent rebound sleep, whereas enhancing noradrenergic signalling with a cocktail of α1- and β-adrenoceptor agonists did not enhance rebound 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 correlated strongly with the amount of induced rebound sleep, but was inversely related to the strength of noradrenergic modulatory tone. 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.

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 thedopamine 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-fosexpression 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 ofc-fosinduction, drive a sleep pressure signal that promotes rebound sleep independently of noradrenergic tone.

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