Implementing novel instructions is a complex and uniquely human cognitive ability, which requires the rapid and flexible conversion of symbolic content into a format that enables the execution of the instructed behavior. Preparing to implement novel instructions, as opposed to their mere maintenance, involves the activation of the instructed motor plans, and the binding of the action information to the specific context in which this should be executed. Recent evidence and prominent computational models suggest that this efficient configuration of the system might involve a central role of frontal theta oscillations in establishing top-down long-range synchronization between distant and task-relevant brain areas. In the present EEG study (human subjects, 30 females, 4 males), we demonstrate that proactively preparing for the implementation of novels instructions, as opposed to their maintenance, involves a strengthened degree of connectivity in the theta frequency range between medial prefrontal and motor/v...

Neurofilaments are abundant space-filling cytoskeletal polymers that are transported into and along axons. During postnatal development, these polymers accumulate in myelinated axons causing an expansion of axon caliber, which is necessary for rapid electrical transmission. Studies on cultured nerve cells have shown that axonal neurofilaments move rapidly and intermittently along microtubule tracks in both anterograde and retrograde directions. However, it is unclear whether neurofilament transport is also bidirectional in vivo . Here, we describe a pulse-spread fluorescence photoactivation method to address this in peripheral nerves dissected from hThy1-paGFP-NFM transgenic mice, which express a photoactivatable fluorescent neurofilament protein. Neurofilaments were photoactivated in short segments of myelinated axons in tibial nerves at 2, 4, 8, and 16 weeks of age. The proximal and distal spread of the fluorescence due to the movement of the fluorescent neurofilaments was measured over time. We show tha...

Seizures cause retrograde amnesia. We have previously demonstrated that seizures erode recently formed memories through shared ensembles and mechanisms in the CA1 region of the hippocampus. Here, we tested whether seizure circuits overlap spatial memory circuits outside of the CA. Spatial memory is consolidated by the hippocampal-cortical coupling that are connected via multiple pathways. We tested whether a seizure invades structures involved in memory consolidation by using the activity reporter TRAP2 mice. T-maze alternation learning activated neurons in the dentate gyrus (DG), mediodorsal thalamus (MD), retrosplenial cortex (RSC), and medial prefrontal cortex (mPFC). This spatial memory relies on the plasticity of the AMPA receptor GluA1 subunit. GluA1 knock-out (KO)/TRAP2 mice did not learn to alternate, and structures interposed between the hippocampus and the cortex were not active. A seizure prevented the recall of alternation memory and activated memory-labeled structures. There was a widespread o...

There are currently no Food and Drug Administration (FDA)-approved δ-opioid receptor (DOR)-selective agonists, despite having fewer side effects in rodents and nonhuman primates compared with traditional μ-opioid receptor (MOR) therapeutics ([Vanderah, 2010][1]). Targeting peripheral receptors is an attractive strategy to reduce abuse potential. However, peripheral opioid receptors do not readily respond to agonists unless primed by inflammation, which would limit their efficacy in noninflammatory pain patients ([Stein et al., 1989][2]). It was recently identified that G-protein-coupled receptor kinase 2 (GRK2) maintains DOR incompetence in noninflamed nociceptors ([Brackley et al., 2016][3], [2017][4]). Here, we report that paroxetine, a selective serotonin reuptake inhibitor (SSRI) and potent GRK2 inhibitor ([Thal et al., 2012][5]), reduces chronic GRK2 association with membrane DOR, thereby enhancing peripheral DOR-mediated analgesic competence in the absence of inflammation. Interestingly, paroxetine’s...

Altered lipoprotein metabolism is considered a pathogenic component of amyotrophic lateral sclerosis (ALS). Apolipoprotein A1 (ApoA1), a major high-density lipoprotein (HDL) protein, is associated with prevention of vascular damage. However, ApoA1’s effects on damaged endothelium in ALS are unknown. This study aimed to determine therapeutic potential of ApoA1 for endothelial cell (EC) repair under a pathologic condition reminiscent of ALS. We performed in vitro studies using mouse brain ECs (mBECs) exposed to plasma from symptomatic G93A SOD1 mice. Dosage effects of ApoA1, including inhibition of the phosphoinoside 3-kinase (PI3K)/Akt signaling pathway and integration of ApoA1 into mBECs were examined. Also, human bone marrow-derived endothelial progenitor cells (hBM-EPCs) and mBECs were co-cultured without cell contact to establish therapeutic mechanism of hBM-EPC transplantation. Results showed that ApoA1 significantly reduced mBEC death via the PI3K/Akt downstream signaling pathway. Also, ApoA1 was inco...

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that results in intellectual disability and, in ∼50% of patients, autism spectrum disorder. The protein products that are altered in TSC (TSC1 and TSC2) form a complex to inhibit the mammalian target of rapamycin [mTOR; mTOR complex 1 (mTORC1)] pathway. This pathway has been shown to affect the process of mRNA translation through its action on ribosomal protein S6 and 4-elongation binding protein 1. It is thought that mutations in the TSC proteins lead to upregulation of the mTORC1 pathway and consequently an increase in protein synthesis. Unexpectedly, our previous study of a mouse model of TSC ( Tsc2Djk +/−) demonstrated decreased in vivo rates of protein synthesis throughout the brain. In the present study, we confirm those results in another Tsc2 +/− mouse model, one with a different mutation locus and on a mixed background ( Tsc2Mjg +/−). We also examine mTORC1 signaling and possible effects of prior isoflurane anesthesia. Because meas...

We mourn the loss of Hirsh Cohen who died on December 20, 2020, at the age of 95. Many of us benefitted from Hirsh’s humor and wisdom, as he fostered the early growth and well being of the field of computational neuroscience. When we first met Hirsh, he was just starting his second full career, as a grant officer at the Sloan Foundation. (In his first career, Hirsh was an applied mathematician in academia and at the IBM Research Laboratory). In 1994, the field of computational neuroscience was small, and …

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...

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...

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...