Point-scanning two-photon microscopy enables high-resolution imaging within scattering specimens such as the mammalian brain, but sequential acquisition of voxels fundamentally limits imaging speed. We developed a two-photon imaging technique that scans lines of excitation across a focal plane at multiple angles and uses prior information to recover high-resolution images at over 1.4 billion voxels per second. Using a structural image as a prior for recording neural activity, we imaged visually-evoked and spontaneous glutamate release across hundreds of dendritic spines in mice at depths over 250 µm and frame-rates over 1 kHz. Dendritic glutamate transients in anaesthetized mice are synchronized within spatially-contiguous domains spanning tens of microns at frequencies ranging from 1-100 Hz. We demonstrate high-speed recording of acetylcholine and calcium sensors, 3D single-particle tracking, and imaging in densely-labeled cortex. Our method surpasses limits on the speed of raster-scanned imaging imposed by fluorescence lifetime.The study of brain function relies on measurement tools that achieve high spatial resolution over large volumes at high rates 1 . Fluorescent sensors enable imaging of activity in large numbers of individual neurons or synapses on scales ranging from micrometers to millimeters 2-7 . However, the intact mammalian brain is opaque, and obtaining high-resolution images deeper than approximately 50 µm below its surface requires specialized techniques that are insensitive to light absorption and scattering. Two-photon imaging uses nonlinear absorption to confine fluorescence excitation to the highintensity focus of a laser, reducing excitation by scattered light. Since fluorescence is generated only at the focus, scattered emission light can be collected without forming an optical image. Instead, images are computationally assembled by scanning the focus in space. However, this serial approach creates a tradeoff between achievable frame-rates and pixels per frame. Common fluorophores have fluorescence lifetimes of approximately 3 ns, requiring approximately 10 ns between consecutive measurements to avoid crosstalk 8,9 . The maximum achievable frame-rate for a 1-megapixel rasterscanned fluorescence image is therefore approximately 100 Hz, and is further limited in practice by factors such as photodamage and scanner bandwidth 1 . Biophysical events underlying neuronal communication, such as action potentials and neurotransmitter release 3,10,11 , occur on millisecond timescales. Kilohertz megapixel in vivo imaging would enable monitoring of these signals at speeds commensurate with signaling in the brain.The pixel rate bottleneck can be avoided by efficient sampling 1,4 . When recording activity, raster images are usually reduced to a lower-dimensional space after acquisition, e.g. by selecting regions of interest 12,13 . Random-Access Microscopy 14-16 samples that space more directly by only scanning targeted sets of pixels, with an access time cost to move between targets. When targets are suf...