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SummaryRecent progress in understanding the diversity of midbrain dopamine neurons has highlighted the importance—and the challenges—of defining mammalian neuronal cell types. Although neurons may be best categorized using inclusive criteria spanning biophysical properties, wiring of inputs, wiring of outputs, and activity during behavior, linking all of these measurements to cell types within the intact brains of living mammals has been difficult. Here, using an array of intact-brain circuit interrogation tools, including CLARITY, COLM, optogenetics, viral tracing, and fiber photometry, we explore the diversity of dopamine neurons within the substantia nigra pars compacta (SNc). We identify two parallel nigrostriatal dopamine neuron subpopulations differing in biophysical properties, input wiring, output wiring to dorsomedial striatum (DMS) versus dorsolateral striatum (DLS), and natural activity patterns during free behavior. Our results reveal independently operating nigrostriatal information streams, with implications for understanding the logic of dopaminergic feedback circuits and the diversity of mammalian neuronal cell types.

Summary The goal of understanding living nervous systems has driven interest in high-speed and large field-of-view volumetric imaging at cellular resolution. Light sheet microscopy approaches have emerged for cellular-resolution functional brain imaging in small organisms such as larval zebrafish, but remain fundamentally limited in speed. Here, we have developed SPED light sheet microscopy, which combines large volumetric field-of-view via an extended depth of field with the optical sectioning of light sheet microscopy, thereby eliminating the need to physically scan detection objectives for volumetric imaging. SPED enables scanning of thousands of volumes-per-second, limited only by camera acquisition rate, through the harnessing of optical mechanisms that normally result in unwanted spherical aberrations. We demonstrate capabilities of SPED microscopy by performing fast sub-cellular resolution imaging of CLARITY mouse brains and cellular-resolution volumetric Ca 2+ imaging of entire zebrafish nervous systems. Together, SPED light sheet methods enable high-speed cellular-resolution volumetric mapping of biological system structure and function.

SummaryThe evolution of the highest-order human brain center, the “pallium” or “cortex,” remains enigmatic. To elucidate its origins, we set out to identify related brain parts in phylogenetically distant animals, to then unravel common aspects in cellular composition and molecular architecture. Here, we compare vertebrate pallium development to that of the mushroom bodies, sensory-associative brain centers, in an annelid. Using a newly developed protocol for cellular profiling by image registration (PrImR), we obtain a high-resolution gene expression map for the developing annelid brain. Comparison to the vertebrate pallium reveals that the annelid mushroom bodies develop from similar molecular coordinates within a conserved overall molecular brain topology and that their development involves conserved patterning mechanisms and produces conserved neuron types that existed already in the protostome-deuterostome ancestors. These data indicate deep homology of pallium and mushroom bodies and date back the origin of higher brain centers to prebilaterian times.