Non-invasive observation of spatiotemporal activity of large neural populations distributed over entire brains is a longstanding goal of neuroscience. We developed a volumetric multispectral optoacoustic tomography platform for imaging neural activation deep in scattering brains. It can record 100 volumetric frames per second across scalable fields of view ranging between 50 and 1000 mm3 with respective spatial resolution of 35–200 μm. Experiments performed in immobilized and freely swimming larvae and in adult zebrafish brains expressing the genetically encoded calcium indicator GCaMP5G demonstrate, for the first time, the fundamental ability to directly track neural dynamics using optoacoustics while overcoming the longstanding penetration barrier of optical imaging in scattering brains. The newly developed platform thus offers unprecedented capabilities for functional whole-brain observations of fast calcium dynamics; in combination with optoacoustics' well-established capacity for resolving vascular hemodynamics, it could open new vistas in the study of neural activity and neurovascular coupling in health and disease.

A critical link exists between pathological changes of cerebral vasculature and diseases affecting brain function. Microscopic techniques have played an indispensable role in the study of neurovascular anatomy and functions. Yet, investigations are often hindered by suboptimal trade-offs between the spatiotemporal resolution, field-of-view (FOV) and type of contrast offered by the existing optical microscopy techniques. We present a hybrid dual-wavelength optoacoustic (OA) biomicroscope capable of rapid transcranial visualization of large-scale cerebral vascular networks. The system offers 3-dimensional views of the morphology and oxygenation status of the cerebral vasculature with single capillary resolution and a FOV exceeding 6 × 8 mm , thus covering the entire cortical vasculature in mice. The large-scale OA imaging capacity is complemented by simultaneously acquired pulse-echo ultrasound (US) biomicroscopy scans of the mouse skull. The new approach holds great potential to provide better insights into cerebrovascular function and facilitate efficient studies into neurological and vascular abnormalities of the brain.

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Genetically-encoded calcium indicators (GECIs) have revolutionized neuroimaging by enabling mapping of the activity of entire neuronal populations in vivo. Visualization of these powerful activity sensors has to date been limited to depth-restricted microscopic studies due to intense light scattering in the brain. We demonstrate, for the first time, in vivo real-time volumetric optoacoustic monitoring of calcium transients in adult transgenic zebrafish expressing the GCaMP5G calcium indicator. Fast changes in optoacoustic traces associated with GCaMP5G activity were detectable in the presence of other strongly absorbing endogenous chromophores, such as hemoglobin. The new functional optoacoustic neuroimaging method can visualize neural activity at penetration depths and spatio-temporal resolution scales not covered with the existing neuroimaging techniques.

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The heart accommodates to rapid changes in demands. This review elucidates the adaptive control of cardiac function by loading conditions, and integrates the sarcomeric control of contraction (SCC) with isolated trabeculae and in vivo whole-heart studies. The SCC includes two feedback mechanisms: (1) cooperativity that regulates cross-bridge (XB) recruitment and the force-length relationship, and (2) mechanical feedback, whereby the filament-sliding velocity determines the XB-weakening rate and the force-velocity relationship. An isolated rat trabeculae study tested the suggested mechanisms during sarcomeric lengthening. The observations indicate that lengthening decreases the XB-weakening rate in a velocity-dependent manner, congruent with the suggested hypothesis and in contrast to alternative theories. A whole-heart level study in sheep reveals the existence of a preload-independent linear relationship between the external work (EW) and pressure-time integral during transient vena cava occlusions, for any given afterload, and not just at isovolumic contractions. The slope of this relationship decreases as the afterload increases. These findings highlight the mechanisms underlying the pressure (Frank's phenomenon) and EW (Starling's phenomenon) generation and the roles that the preload and afterload play. The theoretical, isolated fibers and whole-heart studies provide complementary information that strengthens our understanding of cardiac function from the top-down and bottom-up.

This chapter explores the adaptive control of cardiac function by the loading conditions and relates the observed phenomena to our theory of the sarcomeric control of contraction. Our theory includes two feedback mechanisms: cooperativity-regulated cross-bridge recruitment and energy consumption, and mechanical feedback that determines the interplay between the external work and the force-time integral. The latter also suggests that cardiac efficiency is load independent. This paper explores the regulation of cardiac function by loading conditions, and the role of afterload in adult sheep in situ (n=8). Different afterloads were imposed by partial aortic occlusions. Transient inferior vena cava occlusions (IVCOs) were pre-formed at each steady afterload. A novel, highly linear relationship was found between the external work and pressure-time integral during each transient IVCO at constant afterload. Of interest, the slope of this relationship was afterload-dependent also during fast transient changes in the afterload. These observations are congruent with the suggested adaptive sarcomeric control of contraction, and may provide a powerful tool for quantifying cardiac function.

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