Neuroscientists endeavor to unravel the mysteries of brain functions and dysfunctions. A common research strategy involves measuring specific parameters across various conditions. These measurements are then typically repeated, averaged, and used to infer general patterns or rules. The act of averaging data is an ancient practice; for instance, early astronomers in Babylonian, Chinese, and Indian cultures implicitly averaged observations of celestial phenomena to predict significant periods, such as those crucial for agriculture. Averaging is a sound approach when the process being studied follows to a mathematical function, represented as y = f(x), where f is a very general function. This is true even if the exact function is not known at the outset of the experiments. Implicit in this method is the assumption that any variations in measurements arise from imperfections in the recording process since a consistent mathematical rule suggests that identical inputs should always yield the same output. In ess...

Real science is not only about “the data” but also about theoretical, sociological, economic, and political matters. Reflecting on the struggles of the ongoing adversarial collaboration to test theories of consciousness, here I suggest to “ask not what neuroscience can do for consciousness but what consciousness can do for neuroscience.” “Big fish: Aren’t these waters fascinating and treacherous? Small fish: What waters?” – Anonymous Richard Feynman is notorious for his witty quotes, including that “philosophy of science is about as useful to scientists as ornithology is to birds.” Indeed, some neuroscientists would look perplexed in front of analytic accounts of their own practices, methods, and foundations. Starlings fly by flapping their feathered wings and yet, regardless of their individual skills and collective choreographies, they may be ignorant about how and why they do it. A tweet-long crash course in philosophy of science could suffice to realize that binary thinking (“Is it true or not?”) co...

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...

Highlighted Research Paper: [[T. Moldwin, M. Kalmenson, and I. Segev, “Asymmetric voltage attenuation in dendrites can enable hierarchical heterosynaptic plasticity.” eNeuro (2023).][2]][2] []: /lookup/doi/10.1523/ENEURO.0014-23.2023

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 ...

Working memory can maintain sequential and concurrent information, and the load enhances the gamma-band oscillation during the delay period. To provide a unified account for these phenomena in working memory, we investigated a continuous network model consisting of pyramidal cells, high-threshold fast-spiking interneurons (FS), and low-threshold non-fast-spiking interneurons (nFS) for working memory of sequential and concurrent directional cues. Our model exhibits the gamma (30-100Hz) and beta (10-30Hz) band oscillation during the retention of both concurrent cues and sequential cues. We found that the beta oscillation results from the interaction between pyramidal cells and nFS, whereas the gamma oscillation emerges from the interaction between pyramidal cells and FS due to the strong excitation elicited by cue presentation, shedding light on the mechanism underlying the enhancement of gamma power in many cognitive executions. Significance Statement We constructed a spiking network to perform working m...

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 SLC7A10 (Asc-1 alanine-serine-cysteine transporter) knockout 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. 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 interfere with cell-surface expression, but disrupted gl...

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...

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), we examined neural correlates of evidence accumulation across brain areas. We demonstrated that the neurons with Drift-Diffusion-Model-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 integration t...