Recently, the loss and dystrophy of hippocampal microglia induced by chronic unpredictable stress (CUS) has been reported to mediate the development of major depression in mice whose microglial cells were labeled with enhanced green fluorescent protein-conjuncted-CX3C receptor type 1. However, whether this happens in endogenous microglia with no genetic intervention remains unclear. Here, we addressed this issue in mice treated with different types of chronic stresses, including the CUS, chronic restraint stress (CRS) and chronic social defeat stress (CSDS). Results showed that the cellular numbers, process lengths, soma areas and activation markers of endogenous hippocampal but not cortical microglia, were markedly reduced by CUS, CRS and CSDS treatment. Administration of mice with two classical stimulators of microglia, lipopolysaccharide (LPS) or macrophage colony-stimulating factor (M-CSF), reversed the CUS-, CRS- and CSDS-induced reductions in endogenous hippocampal microglial numbers, and also improved the CUS-, CRS- or CSDS-induced behavioral abnormalities, including the increases in the immobile time in the forced swimming test and tail suspension test, the inhibition of sucrose preference, and the decrease in the time spent in the center of open field. Furthermore, inhibition of the initial activation of hippocampal microglia by minocycline pretreatment also reversed the reduction in hippocampal microglial numbers as well as the behavioral abnormalities induced by CUS, CRS and CSDS treatment. These results provide compelling evidences to show that different types of chronic stresses can trigger the loss of endogenous hippocampal microglia and restoration of microglial numbers may have therapeutic values in major depression.

The blood–brain barrier (BBB) limits therapeutic delivery in Alzheimer’s disease (AD) and other neurological disorders. Animal models have demonstrated safe BBB opening and reduction in β-amyloid plaque with focused ultrasound (FUS). We recently demonstrated the feasibility, safety, and reversibility of FUS-induced BBB opening in the hippocampus and entorhinal cortex in six participants with early AD. We now report the effect of BBB opening with FUS treatment on β-amyloid plaque. Six participants underwent 18 F-Florbetaben PET scan at baseline and 1 week after the completion of the third FUS treatment (60 days interval). PET analysis comparing the hippocampus and entorhinal cortex in the treated and untreated hemispheres revealed a decrease in the ratio of 18 F-Florbetaben ligand binding. The standard uptake value ratios (SUVr) reduction ranged from 2.7% to 10% with an average of 5.05% (±2.76) suggesting a decrease in β-amyloid plaque.

While preconditioning is induced before stroke onset, ischemic postconditioning (IPostC) is performed after reperfusion, which typically refers to a series of mechanical interruption of blood reperfusion after stroke. IPostC is known to reduce infarction in wild type animals. We investigated if IPostC protects against brain injury induced by focal ischemia in T-cell-deficient nude rats and to examine its effects on Akt and the mammalian target of rapamycin (mTOR) pathway. Although IPostC reduced infarct size at 2 days post-stroke in wild type rats, it did not attenuate infarction in nude rats. Despite the unaltered infarct size in nude rats, IPostC increased levels of phosphorylated Akt (p-Akt) and Akt isoforms (Akt1, Akt2, Akt3), and p-mTOR, p-S6K and p-4EBP1 in the mTOR pathway, as well as GAP-43, both in the peri-infarct area and core, 24 hours after stroke. IPostC improved neurological function in nude rats 1–30 days after stroke and reduced the extent of brain damage 30 days after stroke. The mTOR inhibitor rapamycin abolished the long-term protective effects of IPostC. We determined that IPostC did not inhibit acute infarction in nude rats but did provide long-term protection by enhancing Akt and mTOR activity during the acute post-stroke phase.

32Ever since the seminal findings of Ramon y Cajal, dendritic and axonal morphology has been 33 recognized as a defining feature of neuronal types and their connectivity. Yet our knowledge 34 about the diversity of neuronal morphology, in particular its distant axonal projections, is still 35 extremely limited. To systematically obtain single neuron full morphology on a brain-wide scale 36in mice, we established a pipeline that encompasses five major components: sparse labeling, 37whole-brain imaging, reconstruction, registration, and classification. We achieved sparse, robust 38and consistent fluorescent labeling of a wide range of neuronal types across the mouse brain in 39 an efficient way by combining transgenic or viral Cre delivery with novel transgenic reporter 40 lines, and generated a large set of high-resolution whole-brain fluorescent imaging datasets 41containing thousands of reconstructable neurons using the fluorescence micro-optical sectioning 42 tomography (fMOST) system. We developed a set of software tools based on the visualization 43 and analysis suite, Vaa3D, for large-volume image data processing and computation-assisted 44 morphological reconstruction. In a proof-of-principle case, we reconstructed full morphologies 45 of 96 neurons from the claustrum and cortex that belong to a single transcriptomically-defined 46 neuronal subclass. We developed a data-driven clustering approach to classify them into multiple 47 morphological and projection types, suggesting that these neurons work in a targeted and 48coordinated manner to process cortical information. Imaging data and the new computational 49 reconstruction tools are publicly available to enable community-based efforts towards large-scale 50 full morphology reconstruction of neurons throughout the entire mouse brain. 51 52 53