Activity-dependent Increases in Local Oxygen Consumption Correlate with Postsynaptic Currents in the Mouse Cerebellum<i>In Vivo</i>

Mathiesen, Claus; Caesar, K; Thomsen, Kristian; Hoogland, Tycho M.; Witgen, Brent M.; Brazhe, Alexey; Lauritzen, Martin

doi:10.1523/jneurosci.4526-11.2011

Cited by 40 publications

(46 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…41 Pharmacokinetic parameters after intravenous administration of 25 mg/kg Kaempferol in rats indicate concentrations of up to 30 mM in the plasma. 42 The in vivo drug effects on evoked electrical activity and hemodynamic response demonstrated by the results along with prior evidence of a similar decrease in the spatial extent of activation-induced CBF response in the somatosensory cortex during intracerebroventricular, intravenous, or topical modes of delivery 40,49 suggest that Ru360 and Kaempferol may impact neuronal function and hemodynamic response through an intracellular target. The resulting Ca 2 þ distribution in the different subcellular compartments during diminished mitochondrial Ca 2 þ uptake capacity ( Figures 1B and 1E), would not only reduce oxidative energy metabolism via diminished mitochondrial Ca 2 þ , 2,3 but additionally reduce neural activity through diminished Ca 2 þ influx into the cytoplasm.…”

Section: Ru360 Has Been Shown To Permeate Cells In Vitromentioning

confidence: 59%

Mitochondrial Calcium Uptake Capacity Modulates Neocortical Excitability

Sanganahalli

Hermán

Hyder

et al. 2013

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

Local calcium (Ca 2 þ ) changes regulate central nervous system metabolism and communication integrated by subcellular processes including mitochondrial Ca 2 þ uptake. Mitochondria take up Ca 2 þ through the calcium uniporter (mCU) aided by cytoplasmic microdomains of high Ca 2 þ . Known only in vitro, the in vivo impact of mCU activity may reveal Ca 2 þ -mediated roles of mitochondria in brain signaling and metabolism. From in vitro studies of mitochondrial Ca 2 þ sequestration and cycling in various cell types of the central nervous system, we evaluated ranges of spontaneous and activity-induced Ca 2 þ distributions in multiple subcellular compartments in vivo. We hypothesized that inhibiting (or enhancing) mCU activity would attenuate (or augment) cortical neuronal activity as well as activity-induced hemodynamic responses in an overall cytoplasmic and mitochondrial Ca 2 þ -dependent manner. Spontaneous and sensory-evoked cortical activities were measured by extracellular electrophysiology complemented with dynamic mapping of blood oxygen level dependence and cerebral blood flow. Calcium uniporter activity was inhibited and enhanced pharmacologically, and its impact on the multimodal measures were analyzed in an integrated manner. Ru360, an mCU inhibitor, reduced all stimulus-evoked responses, whereas Kaempferol, an mCU enhancer, augmented all evoked responses. Collectively, the results confirm aforementioned hypotheses and support the Ca 2 þ uptake-mediated integrative role of in vivo mitochondria on neocortical activity.

show abstract

Section: Ru360 Has Been Shown To Permeate Cells In Vitromentioning

confidence: 59%

Mitochondrial Calcium Uptake Capacity Modulates Neocortical Excitability

Sanganahalli

Hermán

Hyder

et al. 2013

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

show abstract

“…8A) and CBF responses ( Fig. 8B) (1,4,29,30). We regarded the minimum of our extracellular recorded LFPs as reflecting the fEPSPs.…”

Section: Significancementioning

confidence: 99%

Rapid stimulus-evoked astrocyte Ca ²⁺ elevations and hemodynamic responses in mouse somatosensory cortex in vivo

Lind

Brazhe

Jessen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

165

197

View full text Add to dashboard Cite

Increased neuron and astrocyte activity triggers increased brain blood flow, but controversy exists over whether stimulationinduced changes in astrocyte activity are rapid and widespread enough to contribute to brain blood flow control. Here, we provide evidence for stimulus-evoked Ca 2+ elevations with rapid onset and short duration in a large proportion of cortical astrocytes in the adult mouse somatosensory cortex. Our improved detection of the fast Ca 2+ signals is due to a signal-enhancing analysis of the Ca 2+ activity. The rapid stimulation-evoked Ca 2+ increases identified in astrocyte somas, processes, and end-feet preceded local vasodilatation. Fast Ca 2+ responses in both neurons and astrocytes correlated with synaptic activity, but only the astrocytic responses correlated with the hemodynamic shifts. These data establish that a large proportion of cortical astrocytes have brief Ca 2+ responses with a rapid onset in vivo, fast enough to initiate hemodynamic responses or influence synaptic activity. and associated astrocytes, which causes fluctuations in cerebral blood flow (CBF) (1-5). Astrocytes are ideally situated for controlling activity-dependent increases in CBF because they closely associate with synapses and contact blood vessels with their end-feet (1, 6). Whether or not astrocytic Ca 2+ responses develop often or rapidly enough to account for vascular signals in vivo is still controversial (7-10). Ca 2+ responses are of interest because intracellular Ca 2+ is a key messenger in astrocytic communication and because enzymes that synthesize the vasoactive substances responsible for neurovascular coupling are Ca 2+ -dependent (1, 4). Neuronal activity releases glutamate at synapses and activates metabotropic glutamate receptors on astrocytes, and this activation can be monitored by imaging cytosolic Ca 2+ changes (11). Astrocytic Ca 2+ responses are often reported to evolve on a slow (seconds) time scale, which is too slow to account for activity-dependent increases in CBF (8,10,12,13). Furthermore, uncaging of Ca 2+ in astrocytes triggers vascular responses in brain slices through specific Ca 2+ -dependent pathways with a protracted time course (14, 15). More recently, stimulation of single presynaptic neurons in hippocampal slices was shown to evoke fast, brief, local Ca 2+ elevations in astrocytic processes that were essential for local synaptic functioning in the adult brain (16,17). This work prompted us to reexamine the characteristics of fast, brief astrocytic Ca 2+ signals in vivo with special regard to neurovascular coupling, i.e., the association between local increases in neural activity and the concomitant rise in local blood flow, which constitutes the physiological basis for functional neuroimaging.Here, we describe how a previously undescribed method of analysis enabled us to provide evidence for fast Ca 2+ responses in a main fraction of astrocytes in mouse whisker barrel cortical layers II/III in response to somatosensory stimulation. The astrocytic Ca 2+ responses were brief en...

show abstract

“…However, in the cerebellum, CMRO 2 changes during climbing fiber stimulation remained unchanged when stimulus-induced increases in intracellular calcium were pharmacologically reduced. 102 The complex interplay of processes involved in the regulation of oxidative phosphorylation remains incompletely understood. Nevertheless, it seems likely that factors other than oxygen availability are involved in the control of CMRO 2 and may adjust ATP supply rapidly and independently of CBF within the limits set by oxygen delivery.…”

Section: Regulation Of Oxidative Phosphorylation and Nonzero Mitochonmentioning

confidence: 99%

The Oxygen Paradox of Neurovascular Coupling

Leithner

Royl

2013

J Cereb Blood Flow Metab

116

110

View full text Add to dashboard Cite

The coupling of cerebral blood flow (CBF) to neuronal activity is well preserved during evolution. Upon changes in the neuronal activity, an incompletely understood coupling mechanism regulates diameter changes of supplying blood vessels, which adjust CBF within seconds. The physiologic brain tissue oxygen content would sustain unimpeded brain function for only 1 second if continuous oxygen supply would suddenly stop. This suggests that the CBF response has evolved to balance oxygen supply and demand. Surprisingly, CBF increases surpass the accompanying increases of cerebral metabolic rate of oxygen (CMRO 2 ). However, a disproportionate CBF increase may be required to increase the concentration gradient from capillary to tissue that drives oxygen delivery. However, the brain tissue oxygen content is not zero, and tissue pO 2 decreases could serve to increase oxygen delivery without a CBF increase. Experimental evidence suggests that CMRO 2 can increase with constant CBF within limits and decreases of baseline CBF were observed with constant CMRO 2 . This conflicting evidence may be viewed as an oxygen paradox of neurovascular coupling. As a possible solution for this paradox, we hypothesize that the CBF response has evolved to safeguard brain function in situations of moderate pathophysiological interference with oxygen supply. Keywords: brain; CMRO 2 ; functional hyperemia; neurovascular coupling; oxygen A quick glance at basic numbers of oxygen and glucose delivery to the brain and cerebral energy metabolism suggests that the most delicate function of cerebral blood flow (CBF) is the delivery of sufficient amounts of oxygen to the tissue where the oxygen reserve is so low that ATP production declines almost immediately once blood flow ceases. Therefore, the intuitive explanation for the rapid and large CBF response to neuronal activation is the supply of the additional oxygen needed. Experimental observations of large CBF responses accompanying small increases of cerebral metabolic rate of oxygen (CMRO 2 ), however, have cast doubt on this intuitive assumption. A number of alternative hypotheses may reconcile the seemingly conflicting findings: (1) A small increase of CMRO 2 may only be possible with a large increase in CBF due to physical limitations of oxygen delivery. Journal of Cerebral Blood(2) The large CBF response may be necessary to ensure oxygen delivery to the areas most distant from blood supply. (3) The large CBF response may not be necessary in its full extent but may have evolved as a safety mechanism ensuring sufficient oxygen supply in situations where oxygen delivery to the brain is impaired. (4) The large CBF response may be necessary for reasons other than oxygen delivery.In this opinion paper, we discuss studies on brain energy metabolism and neurovascular coupling. Based on the available evidence, we hypothesize that the surprisingly large CBF response to neuronal activation has evolved as a safety mechanism for oxygen delivery. To support this hypothesis, we first review basic facts on ...

show abstract

Activity-dependent Increases in Local Oxygen Consumption Correlate with Postsynaptic Currents in the Mouse CerebellumIn Vivo

Cited by 40 publications

References 46 publications

Mitochondrial Calcium Uptake Capacity Modulates Neocortical Excitability

Mitochondrial Calcium Uptake Capacity Modulates Neocortical Excitability

Rapid stimulus-evoked astrocyte Ca ²⁺ elevations and hemodynamic responses in mouse somatosensory cortex in vivo

The Oxygen Paradox of Neurovascular Coupling

Contact Info

Product

Resources

About

Activity-dependent Increases in Local Oxygen Consumption Correlate with Postsynaptic Currents in the Mouse CerebellumIn Vivo

Cited by 40 publications

References 46 publications

Mitochondrial Calcium Uptake Capacity Modulates Neocortical Excitability

Mitochondrial Calcium Uptake Capacity Modulates Neocortical Excitability

Rapid stimulus-evoked astrocyte Ca 2+ elevations and hemodynamic responses in mouse somatosensory cortex in vivo

The Oxygen Paradox of Neurovascular Coupling

Contact Info

Product

Resources

About

Rapid stimulus-evoked astrocyte Ca ²⁺ elevations and hemodynamic responses in mouse somatosensory cortex in vivo