Developmental Switch in Neurovascular Coupling in the Immature Rodent Barrel Cortex

Abstract

Neurovascular coupling (NVC) in the adult central nervous system (CNS) is a mechanism that provides regions of the brain with more oxygen and glucose upon increased levels of neural activation. Hemodynamic changes that go along with neural activation evoke a blood oxygen level-dependent (BOLD) signal in functional magnetic resonance imaging (fMRI) that can be used to study brain activity non-invasively. A correct correlation of the BOLD signal to neural activity is pivotal to understand this signal in neuronal development, health and disease. However, the function of NVC during development is largely unknown. The rodent whisker-to-barrel cortex is an experimentally well established model to study neurovascular interdependences. Using extracellular multi-electrode recordings and laser-Doppler-flowmetry (LDF) we show in the murine barrel cortex of postnatal day 7 (P7) and P30 mice in vivo that NVC undergoes a physiological shift during the first month of life. In the mature CNS it is well accepted that cortical sensory processing results in a rise in regional cerebral blood flow (rCBF). We show in P7 animals that rCBF decreases during prolonged multi-whisker stimulation and goes along with multi unit activity (MUA) fatigue. In contrast at P30, MUA remains stable during repetitive stimulation and is associated with an increase in rCBF. Further we characterize in both age groups the responses in NVC to single sensory stimuli. We suggest that the observed shift in NVC is an important process in cortical development that may be of high relevance for the correct interpretation of brain activity e.g. in fMRI studies of the immature central nervous system (CNS).

Rapid Postnatal Expansion of Neural Networks Occurs in an Environment of Altered Neurovascular and Neurometabolic Coupling

“…8 A, B), supporting previous reports that FAD fluorescence increases reflect primarily neural oxygen consumption (Shibuki et al, 2003;Reinert et al, 2011). A notable difference, however, is that the area under the curve of the GCaMP response remains constant while the FAD response increases significantly with age (Fig.…”

“…Green and red reflectance data were temporally lowpass filtered at 3 Hz, and divided by respective prestimulus reflectance values. Based on the different absorption spectra of HbO and HbR at visible wavelengths, these data were then converted to movies of ⌬ [HbO] and ⌬[HbR] using the modified Beer-Lambert law with wavelengthdependent path length factors derived from Monte Carlo modeling (Hillman et al, 2007;Sakaguchi et al, 2007;Bouchard et al, 2009). The resulting images represent a superficially weighted sum of signal from the cortex, extending 300 -500 m below the surface.…”

“…FAD is more fluorescent than FADH 2 and stimulus-evoked localized increases in cortical autofluorescence at 470 nm excitation have been rigorously demonstrated to correspond to an increased rate of oxidation of FAD, and thus an increase in oxidative metabolism (Shibuki et al, 2003). Here, FAD data were acquired in postnatal wild-type mice using identical preparation and stimulation paradigms as for GCaMP imaging (although weaker FAD fluorescence required 5ϫ longer exposure times than for GCaMP3 recordings).…”

“…The light phase of FAD responses (increased fluorescence) is generally attributed to an increased rate of oxidative phosphorylation. The dark phase has been explained as an indication that FAD is being reduced to FADH 2 by the TCA cycle at a faster rate than the oxidation of FADH 2 to FAD by the electron transport chain (Reinert et al, 2011), a state that could occur due to a lack of available oxygen (Turner et al, 2007). The presence of a localized FAD dark phase immediately following the short-duration light phase in the younger age groups suggests a period of local oxygen depletion (Fig.…”

Interpreting BOLD: towards a dialogue between cognitive and cellular neuroscience

“…There also appear to be regional differences in the involvement of metabotropic glutamate receptor (mGluR) subtypes, as the mGluR5 antagonist MPEP decreases stimulation-evoked BOLD responses more in rat subcortical regions than in the neocortex [75]. Furthermore, many enzymes involved in neurovascular coupling are developmentally regulated [9], and neuronal activity elicits vascular constriction, and CBF decreases [76][77][78] corresponding to negative BOLD responses in infants [79,80]. The mechanisms underlying neurovascular coupling in a given situation will vary depending on expression patterns of key enzymes and receptors across different brain areas, as well as the local and global circuit dynamics engaged by a given task.…”