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Noninvasive deep brain stimulation is an important goal in neuroscience and neuroengineering. Optogenetics normally requires the use of a blue laser inserted into the brain. Chen et al. used specialized nanoparticles that can upconvert near-infrared light from outside the brain into the local emission of blue light (see the Perspective by Feliu et al. ). They injected these nanoparticles into the ventral tegmental area of the mouse brain and activated channelrhodopsin expressed in dopaminergic neurons with near-infrared light generated outside the skull at a distance of several millimeters. This technique allowed distant near-infrared light to evoke fast increases in dopamine release. The method was also used successfully to evoke fear memories in the dentate gyrus during fear conditioning. Science , this issue p. 679 ; see also p. 633 Optogenetic experiments can be performed inside the mouse brain by using near-infrared light applied outside the skull. Optogenetics has revolutionized the experimental interrogation of neural circuits and holds promise for the treatment of neurological disorders. It is limited, however, because visible light cannot penetrate deep inside brain tissue. Upconversion nanoparticles (UCNPs) absorb tissue-penetrating near-infrared (NIR) light and emit wavelength-specific visible light. Here, we demonstrate that molecularly tailored UCNPs can serve as optogenetic actuators of transcranial NIR light to stimulate deep brain neurons. Transcranial NIR UCNP-mediated optogenetics evoked dopamine release from genetically tagged neurons in the ventral tegmental area, induced brain oscillations through activation of inhibitory neurons in the medial septum, silenced seizure by inhibition of hippocampal excitatory cells, and triggered memory recall. UCNP technology will enable less-invasive optical neuronal activity manipulation with the potential for remote therapy.

Electron microscopy (EM)-based synaptology is a fundamental discipline for achieving a complex wiring diagram of the brain. A quantitative understanding of synaptic ultrastructure also serves as a basis to estimate the relative magnitude of synaptic transmission across individual circuits in the brain. Although conventional light microscopic techniques have substantially contributed to our ever-increasing understanding of the morphological characteristics of the putative synaptic junctions, EM is the gold standard for systematic visualization of the synaptic morphology. Furthermore, a complete three-dimensional reconstruction of an individual synaptic profile is required for the precise quantitation of different parameters that shape synaptic transmission. While volumetric imaging of synapses can be routinely obtained from the transmission EM (TEM) imaging of ultrathin sections, it requires an unimaginable amount of effort and time to reconstruct very long segments of dendrites and their spines from the serial section TEM images. The challenges of low throughput EM imaging have been addressed to an appreciable degree by the development of automated EM imaging tools that allow imaging and reconstruction of dendritic segments in a realistic time frame. Here, we review studies that have been instrumental in determining the three-dimensional ultrastructure of synapses. With a particular focus on dendritic spine synapses in the rodent brain, we discuss various key studies that have highlighted the structural diversity of spines, the principles of their organization in the dendrites, their presynaptic wiring patterns, and their activity-dependent structural remodeling.

Recent studies have identified intercellular networks for material exchange by bridge-like nanotubular structures, yet their existence in neurons remains unexplored within the brain. Here, we identified long, thin dendritic filopodia that establish direct dendrite-to-dendrite contacts, forming dendritic nanotubes (DNTs) in mammalian brains. Using super-resolution microscopy, we characterized their unique molecular composition and dynamics in dissociated neurons, enabling Ca propagation over distances. Utilizing imaging and machine-learning-based analysis, we confirmed the presence of DNTs connecting dendrites to other dendrites whose anatomical features are distinguished from synaptic dendritic spines. DNTs mediate the active transport of small molecules or human amyloid-beta (Aβ), implicating the role of DNT network in AD pathology. Notably, DNT levels increased prior to the onset of amyloid plaque deposits in the mPFC of APP/PS1 mice. Computational simulations predicted the progression of amyloidosis, providing insight into the mechanisms underlying neurodegeneration through these DNTs. This study unveils a previously unrecognized nanotubular network, highlighting another dimension of neuronal connectivity beyond synapses.