The perception of time is critical to adaptive behavior. While prefrontal cortex and basal ganglia have been implicated in interval timing in the seconds to minutes range, little is known about the role of the mediodorsal thalamus (MD), which is a key component of the limbic cortico–basal ganglia–thalamocortical loop. In this study, we tested the role of the MD in timing, using an operant temporal production task in male mice. In this task, that the expected timing of available rewards is indicated by lever pressing. Inactivation of the MD with muscimol produced rightward shifts in peak pressing on probe trials as well as increases in peak spread, thus significantly altering both temporal accuracy and precision. Optogenetic inhibition of glutamatergic projection neurons in the MD also resulted in similar changes in timing. The observed effects were found to be independent of significant changes in movement. Our findings suggest that the MD is a critical component of the neural circuit for interval timing, ...

Kaylynn E. Coates, Steven A. Calle-Schuler, Levi M. Helmick, Victoria L. Knotts, Brennah N. Martik, et al. (see pages [6309–6327][1]) Neuromodulators have widespread effects in the brain, but they are produced by a relatively small number of neurons. These neurons can project to multiple brain

The legalization of cannabis and shifting cultural attitudes have driven an increase in cannabis use and the proliferation of vapor delivery devices. The DSM-V recognizes “cannabis use disorder” under the umbrella of substance use disorders, but its neural mechanisms require greater clarity ([

Structural and functional plasticity induced by neuronal competition is a common feature of developing nervous systems. However, the rules governing how postsynaptic cells differentiate between presynaptic inputs are unclear. In this study, we characterized synaptic interactions following manipulations of tonic Ib or phasic Is glutamatergic motoneurons that coinnervate postsynaptic muscles of male or female Drosophila melanogaster larvae. After identifying drivers for each neuronal subtype, we performed ablation or genetic manipulations to alter neuronal activity and examined the effects on synaptic innervation and function at neuromuscular junctions. Ablation of either Ib or Is resulted in decreased muscle response, with some functional compensation occurring in the Ib input when Is was missing. In contrast, the Is terminal failed to show functional or structural changes following loss of the coinnervating Ib input. Decreasing the activity of the Ib or Is neuron with tetanus toxin light chain resulted in ...

Synaptic transmission has been studied for decades to understand the fundamental properties underlying neural communication, yet some basic questions about synaptic transmission remain unanswered. Historically, ribbon synapses have been a particularly important model because of the massive amounts

Previous studies demonstrate that activation of pancreatic ER kinase (PERK) protects oligodendrocytes against inflammation in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Interestingly, data indicate that the cytoprotective effects of PERK activation on oligodendrocytes during EAE are not mediated by activating transcription factor 4 (ATF4) but are accompanied by activation of nuclear factor κB (NF-κB). NF-κB plays a critical role in MS and EAE; however, the effects of NF-κB activation on oligodendrocytes in these diseases remain elusive. Herein, we generated a mouse model that allow for activation of NF-κB specifically in oligodendrocytes and found that enhanced NF-κB activation in oligodendrocytes had a minimal effect on their viability and function under normal conditions (both male and female mice). Interestingly, we found that enhanced NF-κB activation in oligodendrocytes attenuated EAE disease severity and ameliorated EAE-induced oligodendrocyte loss, demyelin...

Communication signal diversification is a driving force in the evolution of sensory and motor systems. However, little is known about the evolution of sensorimotor integration. Mormyrid fishes generate stereotyped electric pulses (electric organ discharge [EOD]) for communication and active sensing. The EOD has diversified extensively, especially in duration, which varies across species from 0.1 to >10 ms. In the electrosensory hindbrain, a corollary discharge that signals the timing of EOD production provides brief, precisely timed inhibition that effectively blocks responses to self-generated EODs. However, corollary discharge inhibition has only been studied in a few species, all with short-duration EODs. Here, we asked how corollary discharge inhibition has coevolved with the diversification of EOD duration. We addressed this question by comparing 7 mormyrid species (both sexes) having varied EOD duration. For each individual fish, we measured EOD duration and then measured corollary discharge inhibiti...

A corollary discharge (CD) is a copy of a neuronal command for movement sent to other brain regions to inform them of the impending movement. In monkeys, a circuit from superior colliculus (SC) through medial-dorsal nucleus of the thalamus (MD) to frontal eye field (FEF) carries such a CD for saccadic eye movements. This circuit provides the clearest example of such internal monitoring reaching cerebral cortex. In this report we first investigated the functional organization of the critical MD relay by systematically recording neurons within a grid of penetrations. In two male rhesus macaque monkeys ( Macaca mulatta ), we found that lateral MD neurons carrying CD signals discharged before saccades to ipsilateral as well as contralateral visual fields instead of just contralateral fields, often had activity over large movement fields, and had activity from both central and peripheral visual fields. Each of these characteristics has been found in FEF, but these findings indicate that these characteristics ar...

In “This Week in the Journal,” which appeared on page [5343][1] of the July 8, 2020 issue, the title of the section How Relaxin-3 Inhibits Eating appeared incorrectly. The section title should instead read: How Relaxin-3 Increases Eating . The online version has been corrected. [1]: /lookup/

In murine experimental glioma models, TLR3 or TLR9 activation of microglial/macrophages has been shown to impair glioma growth, which could, however, not been verified in recent clinical trials. We therefore tested whether combined TLR3 and TLR9 activation of microglia/macrophages would have a synergistic effect. Indeed, combined TLR3/TLR9 activation augmented the suppression of glioma growth in organotypic brain slices from male mice in a microglia-dependent fashion, and this synergistic suppression depended on interferon β release and phagocytic tumor clearance. Combined TLR3/TLR9 stimulation also augmented several functional features of microglia, such as the release of proinflammatory factors, motility, and phagocytosis activity. TLR3/TLR9 stimulation combined with CD47 blockade further augmented glioma clearance. Finally, we confirmed that the coactivation of TLR3/TLR9 also augments the impairment of glioma growth in vivo . Our results show that combined activation of TLR3/TLR9 in microglia/macrophage...