Every so often, I conclude that life is not possible. It is not uncommon for me to walk out of a seminar about the pathways and dynamics of biochemical signaling or the structure of biological molecules to conclude that the complexities of life processes defy imagination. Our ability to maintain a sense of wonder about the mysteries of biological mechanisms is what drives us as scientists, as otherwise wresting new insights from the recalcitrant world of interacting pathways would be too frustrating. So all successful biologists must, paradoxically, see both the proverbial forest and their trees, and recognize both the elegant simplicity and the confounds characteristic of living organisms. That sense of mystery and wonder is somewhat at odds with our common sense. It is common sense that is now too often lost, as we grapple with new technologies and large datasets in our science. As scientists, today, we must balance our common sense with our growing reliance on big data to extract the new insights about...

The sensory system allows humans to not only explore the world but also to monitor their own bodies for injury and disease through the sensation of pain. After an injury, signals from the injured tissues travel along the nerves, entering the central nervous system through the spinal cord before going into the brain. In the acute stages, pain modulates behavior in ways that promote healing, including limiting mobility. In most cases, pain resolves as the injury heals, but, in some cases, pain persists and becomes chronic. Chronic pain is a massive issue, affecting up to 20% of Americans and leading to reduced quality of life for those affected. The factors leading to chronic pain are complex, and new approaches are needed to improve understanding of chronic pain and find effective treatments. In the current issue of eNeuro , Haroun et al. (2023) use a new approach to transiently silence sensory neurons in uninjured mice as well as mouse models of acute and chronic pain using a technique known as chemogenet...

Animals exhibit context-dependent behavioral decisions that are mediated by specific motor circuits. In social species these decisions are often influenced by social status. Although social status-dependent neural plasticity of motor circuits has been investigated in vertebrates, little is known of how cellular plasticity translates into differences in motor activity. Here, we used zebrafish ( Danio rerio ) as a model organism to examine how social dominance influences the activation of swimming and the Mauthner mediated startle escape behaviors. We show that the status-dependent shift in behavior patterns whereby dominants increase swimming and reduce sensitivity of startle escape while subordinates reduce their swimming and increase startle sensitivity is regulated by the synergistic interactions of dopaminergic, glycinergic and GABAergic inputs to shift the balance of activation of the underlying motor circuits. This shift is driven by socially induced differences in expression of dopaminergic receptor ...

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...

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.

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...

Psychotic drugs such as ketamine induce symptoms close to schizophrenia and stimulate the production of γ oscillations, as also seen in patients, but the underlying mechanisms are still unclear. Here, we have used computational models of cortical networks generating γ oscillations, and have integrated the action of drugs such as ketamine to partially block NMDA receptors (NMDARs). The model can reproduce the paradoxical increase of γ oscillations by NMDA receptor antagonists, assuming that antagonists affect NMDA receptors with higher affinity on inhibitory interneurons. We next used the model to compare the responsiveness of the network to external stimuli, and found that when NMDA channels are blocked, an increase of γ power is observed altogether with an increase of network responsiveness. However, this responsiveness increase applies not only to γ states, but also to asynchronous states with no apparent γ. We conclude that NMDA antagonists induce an increased excitability state, which may or may not pr...