Inhibition of Rac1-dependent forgetting alleviates memory deficits in animal models of Alzheimer's disease

Accelerated forgetting has been identified as a feature of Alzheimer's disease(AD),but the therapeutic efficacy of the manipulation of biological mechanisms of forgetting has not been assessed in AD animal models.Ras-re-lated C3 botulinum toxin substrate 1(Rac1),a small GTPase,has been shown to regulate active forgetting in Drosophila and mice?Here,we showed that Rac1 activity is aberrantly elevated in the hippocampal tissues of AD patients and AD animal models.Moreover,amyloid-beta 42 could induce Rac1 activation in cultured cells.The elevation of Rac1 activity not only accelerated 6-hour spatial memory decay in 3-month-old APP/PS1 mice,but also significantly contributed to severe memory loss in aged APP/PS1 mice.A similar age-dependent Rac1 activity-based memory loss was also observed in an AD fly model.Moreover,inhibition of Rac1 activity could ameliorate cognitive defects and synaptic plasticity in AD animal models.Finally,two novel compounds,identified through behavioral screening of a randomly selected pool of brain permeable small molecules for their positive effect in rescuing memory loss in both fly and mouse models,were found to be capable of inhibiting Rac1 activity.Thus,multiple lines of evidence corroborate in supporting the idea that inhibition of Rac1 activity is effective for treating AD-related memory loss.

Sarm1-mediated neurodegeneration within the enteric nervous system protects against local inflammation of the colon

Axonal degeneration is one of the key features of neu-rodegenerative disorders.In the canonical view,axonal degeneration destructs neural connections and promotes detrimental disease defects.Here,we assessed the enteric nervous system(ENS)of the mouse,nonhuman primate,and human by advanced 3D imaging.We observed the profound neurodegeneration of catecholaminergic axons in human colons with ulcerative colitis,and similarly,in mouse colons during acute dextran sulfate sodium-induced colitis.However,we unexpectedly revealed that blockage of such axonal degeneration by the Sarml deletion in mice exacerbated the colitis condition.In contrast,pharmacologic ablation or chemogenetic inhibition of catecholaminergic axons suppressed the colon inflammation.We further showed that the catecholaminergic neurotransmitter norepinephrine exerted a pro-inflammatory function by enhancing the expression of IL-17 cytokines.Together,this study demonstrated that Sarm1-mediated neurodegeneration within the ENS mitigated local inflammation of the colon,uncovering a previously-unrecognized beneficial role of axonal degeneration in this disease context.

NONO Regulates Cortical Neuronal Migration and Postnatal Neuronal Maturation

Dear Editor,The mammalian cerebral cortex,responsible for all higherorder brain functions,is organized into six layers of neurons that form distinct projections and connections within and outside the cortex.During cortical development,neural progenitor cells(NPCs)in the proliferative ventricular zone(VZ)and subventricular zone(SVZ)of the dorsal telencephalon produce projection neurons that migrate toward the pial surface to form the cortical plate(CP).

Topography of Visual Features in the Human Ventral Visual Pathway

Visual object recognition in humans and nonhuman primates is achieved by the ventral visual pathway(ventral occipital-temporal cortex,VOTC),which shows a well-documented object domain structure.An on-going question is what type of information is processed in the higher-order VOTC that underlies such observations,with recent evidence suggesting effects of certain visual features.Combining computational vision models,fMRI experiment using a parametric-modulation approach,and natural image statistics of common objects,we depicted the neural distribution of a comprehensive set of visual features in the VOTC,identifying voxel sensitivities with specific feature sets across geometry/shape,Fourier power,and color.The visual feature combination pattern in the VOTC is significantly explained by their relationships to different types of response-action computation(fight-or-flight,navigation,and manipulation),as derived from behavioral ratings and natural image statistics.These results offer a comprehensive visual feature map in the VOTC and a plausible theoretical explanation as a mapping onto different types of downstream response-action systems.

Integrative analysis of in vivo recording with single-cell RNA-seq data reveals molecular properties of light-sensitive neurons in mouse V1

Vision formation is classically based on projections from retinal ganglion cells(RGC)to the lateral geniculate nucleus(LGN)and the primary visual cortex(V1).Neurons in the mouse V1 are tuned to light stimuli.Although the cellular information of the retina and the LGN has been widely studied,the transcriptome profiles of single light-stimulated neuron in V1 remain unknown.In our study,in vivo calcium imaging and whole-cell electrophysiological patch-clamp recording were utilized to identify 53 individual cells from layer 2/3 of V1 as lightsensitive(LS)or non-light-sensitive(NS)by single-cell light-evoked calcium evaluation and action potential spiking.The contents of each cell after functional tests were aspirated in vivo through a patch-clamp pipette for mRNA sequencing.Moreover,the three-dimensional(3-D)morphological characterizations of the neurons were reconstructed in a live mouse after the whole-cell recordings.Our sequencing results indicated that V1 neurons with a high expression of genes related to transmission regulation,such as Rtn4r and Rgs7,and genes involved in membrane transport,such as Na+/K+ATPase and NMDA-type glutamatergic receptors,preferentially responded to light stimulation.Furthermore,an antagonist that blocks Rtn4r signals could inactivate the neuronal responses to light stimulation in live mice.In conclusion,our findings of the vivo-seq analysis indicate the key role of the strength of synaptic transmission possesses neurons in V1 of light sensory.

Preferential distribution of nuclear MAPK signal in α/β core neurons during long-term memory consolidation in Drosophila

Neuronal signal relay from synapse to nucleus, which is evoked by behavioral training, plays a vital part in consolidation of protein synthesis-dependent long-term memory （LTM） from invertebrates to vertebrates （Kandel et al., 2014）.