Replicability, the degree to which a previous scientific finding can be repeated in a distinct set of data, has been considered an integral component of institutionalized scientific practice since its inception several hundred years ago. In the past decade, large-scale replication studies have demonstrated that replicability is far from favorable, across multiple scientific fields. Here, I evaluate this literature and describe contributing factors including the prevalence of questionable research practices (QRPs), misunderstanding of p -values, and low statistical power. I subsequently discuss how these issues manifest specifically in preclinical neuroscience research. I conclude that these problems are multifaceted and difficult to solve, relying on the actions of early and late career researchers, funding sources, academic publishers, and others. I assert that any viable solution to the problem of substandard replicability must include changing academic incentives, with adoption of registered reports bei...

Two key features endow Drosophila Down syndrome cell adhesion molecule 1 (Dscam1) with the potential to provide a ubiquitous code for neuronal arbor self-avoidance. First, Dscam1 contains three large cassettes of alternative exons, so that stochastic alternative splicing yields 19,008 Dscam1 isoforms with different Ig ectodomains. Second, each neuron expresses a different subset of Dscam1 isoforms, and isoform-specific homophilic binding causes repulsion. This results in even spacing of self-arbors, while processes of other neurons can intermingle and share the same synaptic partners. In principle, this Dscam1 code could ensure arbor spacing of all neurons in Drosophila . This model is strongly supported by studies on dendrite spacing in the peripheral nervous system and studies on axonal branch segregation during brain development. However, the situation is less clear for central neuron dendrites, the major substrate for synaptic input in the CNS. We systematically tested the role of Dscam1 for dendrite g...

Forgetting is important for animals to manage acquired memories to enable adaptation to changing environments; however, the neural network in mechanisms of forgetting is not fully understood. To understand the mechanisms underlying forgetting, we examined olfactory adaptation, a form of associative learning, in Caenorhabditis elegans . The forgetting of diacetyl olfactory adaptation in C. elegans is regulated by secreted signals from AWC sensory neurons via the TIR-1/JNK-1 pathway. These signals cause a decline of the sensory memory trace in AWA neurons, where diacetyl is mainly sensed. To further understand the neural network that regulates this forgetting, we investigated the function of interneurons downstream of AWA and AWC neurons. We found that a pair of interneurons, AIA, is indispensable for the proper regulation of behavioral forgetting of diacetyl olfactory adaptation. Loss or inactivation of AIA caused the impairment of the chemotaxis recovery after adaptation without causing severe chemotaxis d...

Episodic memory is a recollection of past personal experiences associated with particular times and places. This kind of memory is commonly subject to loss of contextual information or “semantization,” which gradually decouples the encoded memory items from their associated contexts while transforming them into semantic or gist-like representations. Novel extensions to the classical Remember/Know (R/K) behavioral paradigm attribute the loss of episodicity to multiple exposures of an item in different contexts. Despite recent advancements explaining semantization at a behavioral level, the underlying neural mechanisms remain poorly understood. In this study, we suggest and evaluate a novel hypothesis proposing that Bayesian–Hebbian synaptic plasticity mechanisms might cause semantization of episodic memory. We implement a cortical spiking neural network model with a Bayesian–Hebbian learning rule called Bayesian Confidence Propagation Neural Network (BCPNN), which captures the semantization phenomenon and o...

Transcranial magnetic stimulation (TMS) is widely used for understanding brain function in neurologically intact subjects and for the treatment of various disorders. However, the precise neurophysiological effects of TMS at the site of stimulation remain poorly understood. The local effects of TMS can be studied using concurrent TMS-functional magnetic resonance imaging (fMRI), a technique where TMS is delivered during fMRI scanning. However, although concurrent TMS-fMRI was developed over 20 years ago and dozens of studies have used this technique, there is still no consensus on whether TMS increases blood oxygen level-dependent (BOLD) activity at the site of stimulation. To address this question, here we review all previous concurrent TMS-fMRI studies that reported analyses of BOLD activity at the target location. We find evidence that TMS increases local BOLD activity when stimulating the primary motor (M1) and visual (V1) cortices but that these effects are likely driven by the downstream consequences ...

The primary sensory modality for probing spatial orientation can vary among psychophysical tasks. In the subjective visual vertical (SVV) task, a visual stimulus is used to measure perceived vertical orientation, while a haptic stimulus is used in the subjective haptic vertical (SHV) task. Here we examined disparity in SHV and SVV task results and asked whether it could be related to biases in probing different spatial estimates by each task. Forty-two healthy volunteers (mean ± SD age, 25 ± 10 years; 19 females; 21 left handed) were recruited. The effect of a task to measure spatial orientation was calculated as the difference between SHV and SVV values, and with the head upright and tilted 20° laterally. There was a task bias regardless of head position related to hand use in the haptic task but not handedness (mean head upright ± SEM: left hand, −3.7 ± 1.1°; right hand, 7.9 ± 1.0°). When this task bias was subtracted out, there was a similar spatial bias using each hand in the SHV task that was also com...

Estrogen plays fundamental roles in nervous system development and function. Traditional studies examining the effect of estrogen in the brain have focused on the nuclear estrogen receptors (ERs), ERα and ERβ. Studies related to the extranuclear, membrane-bound G-protein-coupled ER (GPER/GPR30) have revealed a neuroprotective role for GPER in mature neurons. In this study, we investigated the differential effects of GPER activation in primary rat embryonic day 18 (E18) hippocampal and cortical neurons. Microscopy imaging, multielectrode array (MEA), and Ca2+ imaging experiments revealed that GPER activation with selective agonist, G-1, and nonselective agonist, 17β-estradiol (E2), increased neural growth, neural firing activity, and intracellular Ca2+ more profoundly in hippocampal neurons than in cortical neurons. The GPER-mediated Ca2+ rise in hippocampal neurons involves internal Ca2+ store release via activation of phospholipase C (PLC) and extracellular entry via Ca2+ channels. Immunocytochemistry res...

X-linked dystonia-parkinsonism (XDP) is an inherited, X-linked, adult-onset movement disorder characterized by degeneration in the neostriatum. No therapeutics alter disease progression. The mechanisms underlying regional differences in degeneration and adult onset are unknown. Developing therapeutics requires a deeper understanding of how XDP-relevant features vary in health and disease. XDP is possibly due, in part, to a partial loss of TAF1 function. A disease-specific SINE-VNTR-Alu (SVA) retrotransposon insertion occurs within intron 32 of TAF1 , a subunit of TFIID involved in transcription initiation. While all XDP males are usually clinically affected, females are heterozygous carriers generally not manifesting the full syndrome. As a resource for disease modeling, we characterized eight iPSC lines from three XDP female carrier individuals for X chromosome inactivation (XCI) status and identified clonal lines that express either the wild-type X or XDP haplotype. Furthermore, we characterized XDP-rele...

Model selection is often implicit: when performing an ANOVA, one assumes that the normal distribution is a good model of the data; fitting a tuning curve implies that an additive and a multiplicative scaler describes the behavior of the neuron; even calculating an average implicitly assumes that the data were sampled from a distribution that has a finite first statistical moment: the mean. Model selection may be explicit, when the aim is to test whether one model provides a better description of the data than a competing one. As a special case, clustering algorithms identify groups with similar properties within the data. They are widely used from spike sorting to cell type identification to gene expression analysis. We discuss model selection and clustering techniques from a statistician’s point of view, revealing the assumptions behind, and the logic that governs the various approaches. We also showcase important neuroscience applications and provide suggestions how neuroscientists could put model select...

The levels of voltage-gated and synaptic currents in the same neuron type can vary substantially across individuals. Yet, the phase relationships between neurons in oscillatory circuits are often maintained, even in the face of varying oscillation frequencies. We examined whether synaptic and intrinsic currents are matched to maintain constant activity phases across preparations, using the lateral pyloric (LP) neuron of the stomatogastric ganglion (STG) of the crab, Cancer borealis . LP produces stable oscillatory bursts on release from inhibition, with an onset phase that is independent of oscillation frequency. We quantified the parameters that define the shape of the synaptic current inputs across preparations and found no linear correlations with voltage-gated currents. However, several synaptic parameters were correlated with oscillation period and burst onset phase, suggesting they may play a role in phase maintenance. We used dynamic clamp to apply artificial synaptic inputs and found that those syn...