Focused ultrasound (US) is an emerging neuromodulation technology that has gained much attention due to its ability to modulate, noninvasively, neuronal activity in a variety of animals, including humans. However, there has been considerable debate about exactly which types of neurons can be influenced and what underlying mechanisms are in play. Are US-evoked motor changes driven indirectly by activated mechanosensory inputs, or more directly via central interneurons or motoneurons? Although it has been shown that US can mechanically depolarize mechanosensory neurons, there are no studies that have yet tested how identified motoneurons respond directly to US and what the underlying mechanism might be. Here, we examined the effects of US on a single, identified motoneuron within a well-studied and tractable invertebrate preparation, the medicinal leech, Hirudo verbana . Our approach aimed to clarify single neuronal responses to US, which may be obscured in other studies whereby US is applied across a divers...

The insula contributes to behavioral control and is disrupted by substance abuse, yet we know little about the neural signals underlying these functions or how they are disrupted after chronic drug self-administration. Here, male and female rats self-administered either cocaine (experimental group) or sucrose (control) for twelve consecutive days. After a one-month withdrawal period, we recorded from insula while rats performed a previously learned reward-guided decision-making task. Cocaine-exposed rats were more sensitive to value manipulations and were faster to respond. These behavioral changes were accompanied by elevated counts of neurons in the insula that increased firing to reward. These neurons also fired more strongly at the start of long delay trials, when a more immediate reward would be expected, and fired less strongly in anticipation of the actual delivery of delayed rewards. Although reward-related firing to immediate reward was enhanced after cocaine self-administration, reward-predicting...

Reactive oxygen species (ROS) produced by NADPH oxidases (Nox) contribute to the development of different types of sensorineural hearing loss (SNHL), a common impairment in humans with no established treatment. Although the essential role of Nox3 in otoconia biosynthesis and its possible involvement in hearing have been reported in rodents, immunohistological methods targeted at detecting Nox3 expression in inner ear cells reveal ambiguous results. Therefore, the mechanism underlying Nox3 -dependent SNHL remains unclear and warrants further investigation. We generated Nox3-Cre knock-in mice, in which Nox3 was replaced with Cre recombinase ( Cre ). Using Nox3-Cre;tdTomato mice of either sex, in which tdTomato is expressed under the control of the Nox3 promoter, we determined Nox3-expressing regions and cell types in the inner ear. Nox3 -expressing cells in the cochlea included various types of supporting cells (SC), outer hair cells (OHC), inner hair cells (IHC), and spiral ganglion neurons (SGN). Nox3 expr...

A central challenge in the study of conscious perception lies in dissociating the neural correlates of perceptual awareness from those reflecting its precursors and consequences. No-report paradigms have been instrumental in this endeavour, demonstrating that the event-related potential P300, recorded from the human scalp, reflects reports rather than awareness. However, these paradigms cannot probe the degree to which stimuli are consciously processed from trial to trial and thus, leave open the possibility that the P300 is a genuine correlate of conscious access enabling reports. Here, instead of removing report requirements we took the opposite approach and equated post-perceptual task demands across conscious and unconscious trials by orthogonalising target detection and overt reports in a somatosensory detection task. We used Bayesian model selection to track the transformation from physical to perceptual processing stages in the EEG data of 24 male and female participants and show that the early P50 ...

Theoretical and modeling studies demonstrate that heterosynaptic plasticity - changes at synapses inactive during induction - facilitates fine-grained discriminative learning in Hebbian-type systems, and helps to achieve a robust ability for repetitive learning. A dearth of tools for selective manipulation has hindered experimental analysis of the proposed role of heterosynaptic plasticity in behavior. Here we circumvent this obstacle by testing specific predictions about behavioral consequences of the impairment of heterosynaptic plasticity by experimental manipulations to adenosine A1 receptors (A1R). Our prior work demonstrated that blockade of adenosine A1 receptors impairs heterosynaptic plasticity in brain slices, and, when implemented in computer models, selectively impairs repetitive learning on sequential tasks. Based on this work we predict that A1 receptor knockout (A1R KO) mice will express (i) impairment of heterosynaptic plasticity, and (ii) behavioral deficits in learning on sequential tasks...

Complex regional pain syndrome (CRPS) is a chronic pain disorder with a clear acute-to-chronic transition. Preclinical studies demonstrate that toll-like receptor 4 (TLR4), expressed by myeloid-lineage cells, astrocytes, and neurons, mediates a sex-dependent transition to chronic pain; however, evidence is lacking on which exact TLR4-expressing cells are responsible. We used complementary pharmacologic and transgenic approaches in mice to more specifically manipulate myeloid-lineage TLR4 and outline its contribution to the transition from acute-to-chronic CRPS based on three key variables: location (peripheral vs. central), timing (prevention vs. treatment), and sex (male vs. female). We demonstrate that systemic TLR4 antagonism is more effective at improving chronic allodynia trajectory when administered at the time of injury (early) in the tibial fracture model of CRPS in both sexes. In order to clarify the contribution of myeloid-lineage cells peripherally (macrophages) or centrally (microglia), we rigo...

Ca2+-dependent activator protein for secretion 2 (CAPS2) regulates dense-core vesicle (DCV) exocytosis to facilitate peptidergic and catecholaminergic transmitter release. CAPS2 deficiency in mice has mild neuronal effects but markedly impairs social behavior. Rare de novo Caps2 alterations also occur in autism spectrum disorder, although whether CAPS2-mediated release influences social behavior remains unclear. Here, we demonstrate that CAPS2 is associated with DCV exocytosis-mediated release of the social interaction modulatory peptide oxytocin (OXT). CAPS2 is expressed in hypothalamic OXT neurons and localizes to OXT nerve projection and OXT release sites, such as the pituitary. Caps2 KO mice exhibited reduced plasma albeit increased hypothalamic and pituitary OXT levels, indicating insufficient release. OXT neuron-specific Caps2 conditional KO supported CAPS2 function in pituitary OXT release, also affording impaired social interaction and recognition behavior that could be ameliorated by exogenous OXT...

Binge-eating is a distressing, transdiagnostic eating disorder symptom associated with impulsivity, particularly in negative mood states. Neuroimaging studies of bulimia nervosa (BN) report reduced activity in fronto-striatal regions implicated in self-regulatory control, and an influential theory posits that binge-eating results from self-regulation failures under stress. However, there is no direct evidence that psychological stress impairs self-regulation in binge-eating disorders, or that any such self-regulatory deficits generalize to binge-eating in underweight individuals (i.e., the anorexia nervosa bingeing/purging subtype; AN-BP). We therefore determined the effect of acute stress on inhibitory control in 85 women (33 BN, 22 AN-BP, 30 controls). Participants underwent repeated functional MRI scanning, during performance of the stop-signal anticipation task, a validated measure of proactive (i.e., anticipation of stopping) and reactive (outright stopping) inhibition. Neural and behavioral responses...

The neuropeptides CGRP and PACAP have emerged as mediators of migraine, yet the potential overlap of their mechanisms remains unknown. Infusion of PACAP, like CGRP, can cause migraine in people, and both peptides share similar vasodilatory and nociceptive functions. In this study, we have used light aversion in mice as a surrogate for migraine-like photophobia to compare CGRP and PACAP and ask whether CGRP or PACAP actions were dependent on each other. Similar to CGRP, PACAP induced light aversion in outbred CD-1 mice. The light aversion was accompanied by increased resting in the dark, but not anxiety in a light-independent open field assay. Unexpectedly, about a third of the CD-1 mice did not respond to PACAP, which was not seen with CGRP. The responder and nonresponder phenotypes were stable, inheritable, and not sex-linked, although there was a trend for greater responses among male mice. RNA-seq analysis of trigeminal ganglia yielded hieriechial clustering of responder and nonresponder mice and reveal...

Multivariate analyses of hemodynamic signals serve to identify the storage of specific stimulus contents in working memory. Representations of visual stimuli have been demonstrated both in sensory regions and in higher cortical areas. While previous research has typically focused on the working memory maintenance of a single content feature, it remains unclear whether two separate features of a single object can be decoded concurrently. Also, much less evidence exists for representations of auditory compared with visual stimulus features. To address these issues, human participants had to memorize both pitch and perceived location of one of two sample sounds. After a delay phase, they were asked to reproduce either pitch or location. At recall, both features showed comparable levels of discriminability. Region-of-interest-based decoding of functional magnetic resonance imaging data during the delay phase revealed feature-selective activity for both pitch and location of a memorized sound in auditory cortex...