Summary The precise regulation of cerebral blood flow is critical for normal brain function and its disruption underlies many neuropathologies. The extent to which smooth muscle-covered arterioles or pericyte-covered capillaries control vasomotion during neurovascular coupling remains controversial. We found that capillary pericytes in mice and humans do not express smooth muscle actin and are morphologically and functionally distinct from adjacent precapillary smooth muscle cells (SMCs). Using optical imaging we investigated blood flow regulation at various sites on the vascular tree in living mice. Optogenetic, whisker stimulation or cortical spreading depolarization caused microvascular diameter or flow changes in SMC but not pericyte-covered microvessels. During early stages of brain ischemia, transient SMC but not pericyte constrictions were a major cause of hypoperfusion leading to thrombosis and distal microvascular occlusions. Thus, capillary pericytes are not contractile and regulation of cerebral blood flow in physiological and pathological conditions is mediated by arteriolar smooth muscle cells.

Pericytes and smooth muscle cells are integral components of the brain microvasculature. However, no techniques exist to unambiguously identify these cell types, greatly limiting their investigation in vivo. Here we show that a fluorescent Nissl dye (NeuroTrace 500/525) labels brain pericytes with exquisite specificity allowing high-resolution optical imaging in the live mouse. We demonstrate that capillary pericytes are a population of mural cells with distinct morphological, molecular, and functional features that do not overlap with pre-capillary or arteriolar smooth-muscle actin-expressing cells. The remarkable specificity for dye uptake suggests that pericytes have molecular transport mechanisms not present in other brain cells. We demonstrate feasibility for longitudinal pericyte imaging during microvascular development and aging and in models of brain ischemia and Alzheimer’s disease. The ability to easily label pericytes in any mouse model opens the possibility of a broad range of investigations of mural cells in vascular development, neurovascular coupling and neuropathology.

The precise mechanisms that lead to cognitive decline in Alzheimer’s disease are unknown. Here we identify amyloid-plaque-associated axonal spheroids as prominent contributors to neural network dysfunction. Using intravital calcium and voltage imaging, we show that a mouse model of Alzheimer’s disease demonstrates severe disruption in long-range axonal connectivity. This disruption is caused by action-potential conduction blockades due to enlarging spheroids acting as electric current sinks in a size-dependent manner. Spheroid growth was associated with an age-dependent accumulation of large endolysosomal vesicles and was mechanistically linked with Pld3—a potential Alzheimer’s-disease-associated risk gene1 that encodes a lysosomal protein2,3 that is highly enriched in axonal spheroids. Neuronal overexpression of Pld3 led to endolysosomal vesicle accumulation and spheroid enlargement, which worsened axonal conduction blockades. By contrast, Pld3 deletion reduced endolysosomal vesicle and spheroid size, leading to improved electrical conduction and neural network function. Thus, targeted modulation of endolysosomal biogenesis in neurons could potentially reverse axonal spheroid-induced neural circuit abnormalities in Alzheimer’s disease, independent of amyloid removal.

No abstract

No abstract

No abstract

Logic Circuits Are 2D semiconductors ready for next‐generation IC application? In article number 2202472, Yufeng Xie, Lifeng Bian, Wenzhong Bao, and co‐workers present a wafer‐scale demonstration by circuit‐level fabrication on a 4‐inch MoS2 wafer. While pass‐transistor configuration is more like an expedient to build logic circuits based on n‐type MoS2, future development should add complementary p‐type 2D semiconductors to realize more complex ICs.

AbstractOptogenetics at single-cell resolution can be achieved by two-photon stimulation; however, this requires intense or holographic illumination. We markedly improve stimulation efficiency by positioning fluorophores with high two-photon cross-sections adjacent to opsins. The two-photon-excited fluorescence matches the opsin absorbance and can stimulate opsins in a highly localized manner through efficient single-photon absorption. This indirect fluorescence transfer illumination allows experiments difficult to implement in the live brain such as all-optical neural interrogation and control of regional cerebral blood flow.