Commenting about science has risks. Being critical sometimes raises strong opposing reactions. People work so hard and leaders do not like to see their strategies under fire. Critics do not usually provide easy solutions to the problems they raise, and the questions, even if they are right on target, remain largely unanswered. When the stakes are high and massive funds wait to be delivered, the train (or ship), once launched, ought not to derail (nor sink). It must go on, as planned, keeping the initial thrust alive. In terms of management efficacy, a typical reason why the project’s leadership does not answer critiques is to “keep the monkey(s) on the critics’ shoulders” (Oncken and Wass, 1974; Cover, 1999). Being proactive may be a better way to get rid of the monkeys and open a constructive dialogue. The issue then becomes: what could have been done instead, for a better science? This is typically the question that I am asked at the end of my neuro-epistemological talks, or in comments received followi...

Electroacupuncture (EA) is widely applied in clinical therapy for spinal cord injury (SCI). However, the associated molecular mechanism has yet to be elucidated. The current study aimed to investigate the underlying mechanism of EA in neurologic repair after SCI. First, we investigated the role of EA in the neurologic repair of the SCI rat model. The expression levels of human antigen R (HuR) and Krüppel-like factor 9 (KLF9) in spinal cord tissues were quantified after treatment. Second, we conducted bioinformatics analysis, RNA pull-down assays, RNA immunoprecipitation, and luciferase reporter gene assay to verify the binding of HuR and KLF9 mRNA for mRNA stability. Last, HuR inhibitor CMLD-2 was used to verify the enhanced effect of EA on neurologic repair after SCI via the HuR/KLF9 axis. Our data provided convincing evidence that EA facilitated the recovery of neuronal function in SCI rats by reducing apoptosis and inflammation of neurons. We found that EA significantly diminished the SCI-mediated upreg...

Human startle disease is associated with mutations in distinct genes encoding glycine receptors, transporters or interacting proteins at glycinergic synapses in spinal cord and brainstem. However, a significant number of diagnosed patients does not carry a mutation in the common genes GLRA1 , GLRB , and SLC6A5 . Recently, studies on solute carrier 7 subfamily 10 ( SLC7A10 ; Asc-1, alanine-serine-cysteine transporter) knock-out (KO) mice displaying a startle disease-like phenotype hypothesized that this transporter might represent a novel candidate for human startle disease. Here, we screened 51 patients from our patient cohort negative for the common genes and found three exonic (one missense, two synonymous), seven intronic, and single nucleotide changes in the 5′ and 3′ untranslated regions (UTRs) in Asc-1. The identified missense mutation Asc-1G307R from a patient with startle disease and developmental delay was investigated in functional studies. At the molecular level, the mutation Asc-1G307R did not ...

Plaque formation, microglial activation, and synaptic loss are pathologic hallmarks of Alzheimer’s disease; however, removing plaques has had little clinical benefit. Here, we show that neuregulin-1, a glial growth factor, induces inflammatory cytokines and promotes phagocytic activity in vitro and augments microglial activation and plaque formation in 5XFAD Alzheimer’s mice. Brain-specific targeting of neuregulin-1 by intraventricular delivery of a novel neuregulin-1 fusion protein antagonist, GlyB4, significantly alters microglial morphology and function to a nonpathogenic morphology in early-stage 5XFAD mice and prevents plaques from forming. Once plaques have already formed, GlyB4 reduces new plaque formation and prevents synaptic loss. Selective, targeted disruption of neuregulin-1 signaling on brain microglia with GlyB4 could be a novel “upstream” approach to slow or stop disease progression in Alzheimer’s disease.

Spatial cognition research requires behavioral paradigms that can distinguish between different navigational elements, such as allocentric (map-like) navigation and egocentric (e.g., body centered) navigation. To fill this need, we developed a flexible experimental platform that can be quickly modified without the need for significant changes to software and hardware. In this paper, we present this inexpensive and flexible behavioral platform paired with software which we are making freely available. Our behavioral platform serves as the foundation for a range of experiments, and although developed for assessing spatial cognition, it also has applications in the nonspatial domain of behavioral testing. There are two components of the software platform, “Maze” and “Stim Trigger.” While intended as a general platform, presently both programs can work in conjunction with Neuralynx and Open Ephys electrophysiology acquisition systems, allowing for precise time stamping of neural events. The Maze program includ...

Individual neurons in sensory cortices exhibit specific receptive fields based on their dendritic patterns. These dendritic morphologies are established and refined during the neonatal period through activity-dependent plasticity. This process can be visualized using two-photon in vivo time-lapse imaging, but sufficient spatiotemporal resolution is essential. We previously examined dendritic patterning from spiny stellate (SS) neurons, the major type of layer 4 (L4) neurons, in the mouse primary somatosensory cortex (barrel cortex), where mature dendrites display a strong orientation bias toward the barrel center. Longitudinal imaging at 8 h intervals revealed the long-term dynamics by which SS neurons acquire this unique dendritic pattern. However, the spatiotemporal resolution was insufficient to detect the more rapid changes in SS neuron dendrite morphology during the critical neonatal period. In the current study, we imaged neonatal L4 neurons hourly for 8 h and improved the spatial resolution by unifo...

It has been suggested that stochasticity acts in the formation of topographically ordered maps in the visual system through the opposing chemoaffinity and neural activity forces acting on the innervating nerve fibers being held in an unstable equilibrium. Evidence comes from the Islet2-EphA3 knock-in mouse, in which ∼50% of the retinal ganglion cells, distributed across the retina, acquire the EphA3 receptor, thus having an enhanced density of EphA which specifies retinotopic order along the rostrocaudal (RC) axis of the colliculus. Sampling EphA3 knock-in maps in heterozygotes at different positions along the mediolateral (ML) extent of the colliculus had found single 1D maps [as in wild types (WTs)], double maps (as in homozygous knock-ins) or both single and double maps. We constructed full 2D maps from the same mouse dataset. We found either single maps or maps where the visual field projects rostrally, with a part-projection more caudally to form a double map, the extent and location of this duplicati...

The gradual accumulation of noisy evidence for or against options is the main step in the perceptual decision-making process. Using brain-wide electrophysiological recording in mice ([Steinmetz et al., 2019][1]), we examined neural correlates of evidence accumulation across brain areas. We demonstrated that the neurons with drift-diffusion model (DDM)-like firing rate activity (i.e., evidence-sensitive ramping firing rate) were distributed across the brain. Exploring the underlying neural mechanism of evidence accumulation for the DDM-like neurons revealed different accumulation mechanisms (i.e., single and race) both within and across the brain areas. Our findings support the hypothesis that evidence accumulation is happening through multiple integration mechanisms in the brain. We further explored the timescale of the integration process in the single and race accumulator models. The results demonstrated that the accumulator microcircuits within each brain area had distinct properties in terms of their i...

Plaque formation, microglial activation, and synaptic loss are pathological hallmarks of Alzheimer's disease, however, removing plaques have had little clinical benefit. Here, we show that neuregulin-1, a glial growth factor, induces inflammatory cytokines and promotes phagocytic activity in vitro and augments microglial activation and plaque formation in 5XFAD Alzheimer’s mice. Brain-specific targeting of neuregulin-1 by intraventricular delivery of a novel neuregulin-1 fusion protein antagonist GlyB4 significantly alters microglial morphology and function to a non-pathogenic morphology in early-stage 5XFAD mice and prevents plaques from forming. Once plaques have already formed, GlyB4 reduces new plaque formation and prevents synaptic loss. Selective, targeted disruption of neuregulin-1 signaling on brain microglia with GlyB4 could be a novel ‘upstream’ approach to slow or stop disease progression in Alzheimer’s disease. Significance Statement Microglia-associated neuroinflammation is a major hallmark...

During early development, neurons in the brain often form excess synaptic connections. Later, they strengthen some connections while eliminating others to build functional neuronal circuits. In the olfactory bulb, a mitral cell initially extends multiple dendrites to multiple glomeruli but eventually forms a single primary dendrite through the activity-dependent dendrite pruning process. Recent studies have reported that microglia facilitate synapse pruning during the circuit remodeling in some systems. It has remained unclear whether microglia are involved in the activity-dependent dendrite pruning in the developing brains. Here, we examined whether microglia are required for the developmental dendrite pruning of mitral cells in mice. To deplete microglia in the fetal brain, we treated mice with a CSF1R inhibitor, PLX5622, from pregnancy. Microglia were reduced by >90% in mice treated with PLX5622. However, dendrite pruning of mitral cells was not significantly affected. Moreover, we found no significant ...