Voltage-gated CaV2.2 calcium channels are expressed in nociceptors at presynaptic terminals, soma, and axons. CaV2.2 channel inhibitors applied to the spinal cord relieve pain in humans and rodents, especially during pathologic pain, but a biological function of nociceptor CaV2.2 channels in processing of nociception, outside presynaptic terminals in the spinal cord, is underappreciated. Here, we demonstrate that functional CaV2.2 channels in peripheral axons innervating skin are required for capsaicin-induced heat hypersensitivity in male and female mice. We show that CaV2.2 channels in TRPV1-nociceptor endings are activated by capsaicin-induced depolarization and contribute to increased intracellular calcium. Capsaicin induces hypersensitivity of both thermal nociceptors and mechanoreceptors, but only heat hypersensitivity depends on peripheral CaV2.2 channel activity, and especially a cell-type-specific CaV2.2 splice isoform. CaV2.2 channels at peripheral nerve endings might be important therapeutic tar...

Alzheimer's disease is associated with poor sleep, but the impact of tau and β-amyloid (Aβ) pathology on sleep remains largely unknown. Here, we test the hypothesis that tau and Aβ predict unique impairments in objective and self-perceived human sleep under real-life, free-living conditions. Eighty-nine male and female cognitively healthy older adults received 18F-FTP-tau and 11C-PIB-Aβ PET imaging, 7 nights of sleep actigraphy and questionnaire measures, and neurocognitive assessment. Tau burden, but not Aβ, was associated with markedly worse objective sleep. In contrast, Aβ and tau were associated with worse self-reported sleep quality. Of clinical relevance, Aβ burden predicted a unique perceptual mismatch between objective and subject sleep evaluation, with individuals underestimating their sleep. The magnitude of this mismatch was further predicted by worse executive function. Thus, early-stage tau and Aβ deposition are linked with distinct phenotypes of real-world sleep impairment, one that includes ...

The ability to stop an already initiated action is paramount to adaptive behavior. Much scientific debate in the field of human action-stopping currently focuses on two interrelated questions. First: Which cognitive and neural processes uniquely underpin the implementation of inhibitory control when actions are stopped after explicit stop-signals, and which processes are instead commonly evoked by all salient signals, even those that do not require stopping? Second: Why do purported (neuro)physiological signatures of inhibition occur at two different latencies after stop-signals? Here, we address both questions via two pre-registered experiments that combined measurements of cortico-spinal excitability (CSE), electromyography (EMG), and whole-scalp electroencephalography (EEG). Adult human subjects performed a stop-signal task that also contained ‘ignore’ signals – equally salient signals that did not require stopping but rather completion of the Go response. We found that both stop- and ignore-signals pro...

Western-style diets cause disruptions in myelinating cells and astrocytes within the mouse central nervous system (CNS). CD38 shows increased expression in the cuprizone and experimental autoimmune encephalomyelitis models of demyelination; in addition, CD38 is the main nicotinamide adenine dinucleotide (NAD+)-depleting enzyme in the CNS. Altered NAD+ metabolism is linked to both high fat consumption and multiple sclerosis (MS). Here, we identify increased CD38 expression in the male mouse spinal cord following chronic high fat consumption, after focal toxin (lysolecithin[LL])-mediated demyelinating injury and in reactive astrocytes within active MS lesions. We demonstrate that CD38-catalytically inactive mice are substantially protected from high fat-induced NAD+ depletion, oligodendrocyte loss, oxidative damage, and astrogliosis. A CD38 inhibitor, 78c, increased NAD+ and attenuated neuroinflammatory changes induced by saturated fat applied to astrocyte cultures. Conditioned media from saturated fat-expos...

Intrinsic neuronal variability significantly limits information encoding in the primary visual cortex (V1). However, under certain conditions, neurons can respond reliably with highly precise responses to the same visual stimuli from trial to trial. This suggests that there exist intrinsic neural circuit mechanisms that dynamically modulate the inter-trial variability of visual cortical neurons. Here, we sought to elucidate the role of different inhibitory interneurons in reliable coding in mouse V1. To study the interactions between somatostatin-expressing (SST) and parvalbumin-expressing (PV) interneurons, we used a dual-color calcium imaging technique that allowed us to simultaneously monitor these two neural ensembles while awake mice, of both sexes, passively viewed natural movies. SST neurons were more active during epochs of reliable pyramidal neuron firing whereas PV neurons were more active during epochs of unreliable firing. SST neuron activity lagged that of PV neurons, consistent with a feedbac...

The opioid epidemic led to an increase in the number of Neonatal Opioid Withdrawal Syndrome ( NOWS ) cases in infants born to opioid-dependent mothers. Hallmark features of NOWS include weight loss, severe irritability, respiratory problems, and sleep fragmentation. Mouse models provide an opportunity to identify brain mechanisms that contribute to NOWS. Neonatal outbred Swiss Webster Cartworth Farms White (CFW) mice were administered morphine (15mg/kg, s.c.) twice daily for postnatal days (P) 1-14, an approximate of the third trimester of human gestation. Female and male mice underwent behavioral testing on P7 and P14 to determine the impact of opioid exposure on anxiety and pain sensitivity. Ultrasonic vocalizations (USVs) and daily body weights were also recorded. Brainstems containing pons and medulla were collected during morphine withdrawal on P14 for RNA-sequencing. Morphine induced weight loss from P2-14, which persisted during adolescence (P21) and adulthood (P50). USVs markedly increased at P7 in...

Convincing evidence of blood-spinal cord barrier (BSCB) alterations has been demonstrated in amyotrophic lateral sclerosis (ALS) and barrier repair is imperative to prevent motor neuron dysfunction. We showed benefits of human bone marrow-derived CD34+ cells (hBM34+) and endothelial progenitor cells (hBM-EPCs) intravenous transplantation into symptomatic G93A SOD1 mutant mice on barrier reparative processes. These gains likely occurred by replacement of damaged endothelial cells, prolonging motor neuron survival. However, additional investigations are needed to confirm the effects of administered cells on integrity of the microvascular endothelium. The aim of this study was to determine tight junction protein levels, capillary pericyte coverage, microvascular basement membrane, and endothelial F-actin status in spinal cord capillaries of G93A SOD1 mutant mice treated with human bone marrow-derived stem cells. Tight junction proteins were detected in the spinal cords of cell-treated vs. non-treated mice via...

Many daily choices are based on one’s own knowledge. However, when predicting other people’s behavior, we need to consider the differences between our knowledge and other people’s presumed knowledge. Social agents need a mechanism to use privileged information for their own behavior but exclude it from predictions of others. Using fMRI, we investigated the neural implementation of such social and personal predictions predictions in healthy human volunteers of both sexes by manipulating privileged and shared information. The medial frontal cortex appeared to have an important role in flexibly making decisions using privileged information for oneself or predicting others behavior. Specifically, we show that ventromedial prefrontal cortex tracked the state of the world independent of the type of decision (personal, social), whereas dorsomedial regions adjusted their frame of reference to the use of privileged or shared information. Sampling privileged evidence not available to the confederate also relied on s...

Apolipoprotein E (APOE), one of the primary lipoproteins in the brain has three isoforms in humans – APOE2, APOE3, and APOE4. APOE4 is the most well-established risk factor increasing the pre-disposition for Alzheimer's disease. The presence of the APOE4 allele alone is shown to cause synaptic defects in neurons and recent studies have identified multiple pathways directly influenced by APOE4. However, the mechanisms underlying APOE4 induced synaptic dysfunction remain elusive. Here, we report that the acute exposure of primary cortical neurons or synaptoneurosomes to APOE4 leads to a significant decrease in global protein synthesis. Primary cortical neurons were derived from male and female embryos of Sprague-Dawley rats or C57BL/6J mice. Synaptoneurosomes were prepared from P30 male Sprague-Dawley rats. APOE4 treatment also abrogates the NMDA mediated translation response indicating an alteration of synaptic signaling. Importantly, we demonstrate that both APOE3 and APOE4 generate a distinct translation ...

Mutations in the voltage-gated sodium channel gene SCN1A are associated with human epilepsy disorders, but how most of these mutations alter channel properties and result in seizures is unknown. This study focuses on two different mutations occurring at one position within SCN1A . R1648C is associated with the severe disorder Dravet Syndrome, and R1648H, with the milder disorder GEFS+. To explore how these different mutations contribute to distinct seizure disorders, Drosophila lines with the R-C or R-H mutation, or R-R control substitution in the fly sodium channel gene para were generated by CRISPR-Cas9 gene editing. The R-C and R-H mutations are homozygous lethal. Animals heterozygous for R-C or R-H mutations displayed reduced lifespans and spontaneous and temperature-induced seizures not observed in R-R controls. Electrophysiological recordings from adult GABAergic neurons in R-C and R-H mutants revealed appearance of sustained neuronal depolarizations and altered firing frequency that were exacerbated...