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SUMMARYShort-term memory (STM) maintains information during a short delay period. How long-range and local connections interact to support STM encoding remains elusive. Here we tackled the problem focusing on long-range projections from medial prefrontal cortex (mPFC) to anterior agranular insular cortex (aAIC) in head-fixed mice performing an olfactory delayed-response task. Optogenetic and electrophysiological experiments revealed behavioral importance of the two regions in encoding STM information. Spike-correlogram analysis revealed strong local and cross-region functional coupling (FC) between memory neurons encoding the same information. Optogenetic suppression of mPFC-aAIC projections during the delay period reduced behavioral performance, the proportion of memory neurons and memory-specific FC within aAIC, whereas optogenetic excitation enhanced all of them. MPFC-to-aAIC projections also bidirectionally modulated efficacy of STM-information transfer, measured by contribution of FC spiking pairs to coding ability of following neurons. Thus, prefrontal projections modulate functional connectivity and coding ability of insular neurons to support short-term memory.

Background Brain innate immunity is vital for maintaining normal brain functions. Immune homeostatic imbalances play pivotal roles in the pathogenesis of neurological diseases including Parkinson’s disease (PD). However, the molecular and cellular mechanisms underlying the regulation of brain innate immunity and their significance in PD pathogenesis are still largely unknown. Methods Cre-inducible diphtheria toxin receptor (iDTR) and diphtheria toxin-mediated cell ablation was performed to investigate the impact of neuron-glial antigen 2 (NG2) glia on the brain innate immunity. RNA sequencing analysis was carried out to identify differentially expressed genes in mouse brain with ablated NG2 glia and lipopolysaccharide (LPS) challenge. Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice were used to evaluate neuroinflammatory response in the presence or absence of NG2 glia. The survival of dopaminergic neurons or glial cell activation was evaluated by immunohistochemistry. Co-cultures of NG2 glia and microglia were used to examine the influence of NG2 glia to microglial activation. Results We show that NG2 glia are required for the maintenance of immune homeostasis in the brain via transforming growth factor-β2 (TGF-β2)-TGF-β type II receptor (TGFBR2)-CX3C chemokine receptor 1 (CX3CR1) signaling, which suppresses the activation of microglia. We demonstrate that mice with ablated NG2 glia display a profound downregulation of the expression of microglia-specific signature genes and remarkable inflammatory response in the brain following exposure to endotoxin lipopolysaccharides. Gain- or loss-of-function studies show that NG2 glia-derived TGF-β2 and its receptor TGFBR2 in microglia are key regulators of the CX3CR1-modulated immune response. Furthermore, deficiency of NG2 glia contributes to neuroinflammation and nigral dopaminergic neuron loss in MPTP-induced mouse PD model. Conclusions These findings suggest that NG2 glia play a critical role in modulation of neuroinflammation and provide a compelling rationale for the development of new therapeutics for neurological disorders.

et al., Dopamine (DA) homeostasis is essential for a variety of brain activities. Dopamine transporter (DAT)-mediated DA reuptake is one of the most critical mechanisms for normal DA homeostasis. However, the molecular mechanisms underlying the regulation of DAT activity in the brain remain poorly understood. Here we show that the Rho-family guanine nucleotide exchange factor protein Vav2 is required for DAT cell surface expression and transporter activity modulated by glial cell line-derived neurotrophic factor (GDNF) and its cognate receptor Ret. Mice deficient in either Vav2 or Ret displayed elevated DAT activity, which was accompanied by an increase in intracellular DA selectively in the nucleus accumbens. Vav2 â'/â' mice exposed to cocaine showed reduced DAT activity and diminished behavioral cocaine response. Our data demonstrate that Vav2 is a determinant of DAT trafficking in vivo and contributes to the maintenance of DA homeostasis in limbic DA neuron terminals., This work was supported by grants from the National Key Basic Research Program of China (2015CB553500, 2011CB504102), Natural Science Foundation of China (31123002, 31321091 and 30621130075), Beijing Institute for Brain Disorders (BIBD-PXM2013_014226_07_000084) and Strategic Priority Research Program (B) of the Chinese Academy of Sciences (XDB01020300). X.R.B.'s work has been funded by the Spanish Ministry of Economy and Competitiveness (SAF2009-07172, SAF2012-3171, RD06/0020/0001 and RD12/0036/0002), the Castilla-León Autonomous Government (CSI101U13) and Spanish Association of Science Communication.

Geniposide, an iridoid glycoside isolated from Gardenia, has neuroprotective activities against oxidative stress and inflammation. The present study investigated the in vivo protective effect of geniposide on ischemia/reperfusion-injured rats by middle cerebral artery occlusion (MCAO), and the inhibitory effects of geniposide and mechanisms against activation of microglial cells by oxygen-glucose deprivation (OGD) in vitro. Male SD rats were subjected to treatment with geniposide at 15, 30 and 60 mg/kg immediately after MCAO. Cerebral infarct volume and microglial cell activation were assessed following 24 h reperfusion. Cultured primary rat microglial cells were exposed to geniposide at the concentrations of 12.5, 25 and 50 μg/mL during 4 h of OGD. The effects of geniposide were evaluated in terms of (1) cell viability; (2) secretion of TNF-α, IL-1β, IL-6, IL-8 and IL-10 into culture media; (3) TLR4 mRNA expression; (4) protein expression of TLR4, p-ERK1/2, p-IκB, p-p38, nuclear and cytoplasmic fraction NF-κB p65; and (5) nuclear transfer of NF-κB p65. Geniposide reduced the infarct volume and inhibited the activation of microglial cells in ischemic penumbra in vivo. OGD increased cell viability and release of TNF-α, IL-1β, IL-6, IL-8 and IL-10, these effects were suppressed by geniposide. Geniposide also attenuated the increases in the OGD-induced TLR4 mRNA and protein levels. In addition, geniposide at 25 and 50 μg/mL downregulated the phosphorylation of ERK, IκB and p38, as well as inhibited nuclear transcriptional activity triggered via NF-κB p65 in microglial cells by OGD. In conclusion, geniposide displays a neuroprotective effect on ischemia/reperfusion-injured rats in vivo and inhibits OGD-induced activation of microglial cells by attenuating inflammatory factors and NF-κB activation in vitro.