Animal studies consistently demonstrate that testosterone is protective against pain in multiple models, including an animal model of activity-induced muscle pain . In this model, females develop widespread muscle hyperalgesia, and reducing testosterone levels in males results in widespread muscle hyperalgesia. Widespread pain is believed to be mediated by changes in the central nervous system, including the rostral ventromedial medulla (RVM). The enzyme that converts testosterone to estradiol, aromatase, is highly expressed in the RVM. Therefore, we hypothesized that testosterone is converted by aromatase to estradiol locally in the RVM to prevent development of widespread muscle hyperalgesia in male mice. This was tested through pharmacological inhibition of estrogen receptors (ER), aromatase, or ER-α in the RVM which resulted in contralateral hyperalgesia in male mice (C57BL/6J). ER inhibition in the RVM had no effect on hyperalgesia in female mice. As prior studies show modulation of estradiol signalin...

ATP1A3 is a Na,K-ATPase gene expressed specifically in neurons in the brain. Human mutations are dominant and produce an unusually wide spectrum of neurological phenotypes, most notably rapid-onset dystonia- parkinsonism (RDP) and alternating hemiplegia childhood (AHC). Here we compared heterozygotes of two mouse lines, a line with little or no expression ( Atp1a 3tm1Ling/+) and a knock-in expressing p.Asp801Tyr (D801Y, Atp1a3 +/D801Y). Both mouse lines had normal lifespans, but Atp1a3 +/D801Y had mild perinatal mortality contrasting with D801N mice ( Atp1a3 +/D801N), which had high mortality. The phenotypes of Atp1a 3tm1Ling/+ and Atp1a3 +/D801Y were different, and testing of each strain was tailored to its symptom range. Atp1a 3tm1Ling/+ mice displayed little at baseline, but repeated ethanol intoxication produced hyperkinetic motor abnormalities not seen in littermate controls. Atp1a3 +/D801Y mice displayed robust phenotypes: hyperactivity, diminished posture consistent with hypotonia, and deficiencies ...

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Adults heard recordings of two spatially separated speakers reading newspaper and magazine articles. They were asked to listen to one of them and ignore the other, and EEG was recorded to assess their neural processing. Machine learning extracted neural sources that tracked the target and distractor speakers at three levels: the acoustic envelope of speech (delta- and theta-band modulations), lexical frequency for individual words, and the contextual predictability of individual words estimated by GPT-4 and earlier lexical models. To provide a broader view of speech perception, half of the subjects completed a simultaneous visual task, and the listeners included both native and non-native English speakers. Distinct neural components were extracted for these levels of auditory and lexical processing, demonstrating that native English speakers had greater target-distractor separation compared to non-native English speakers on most measures, and that lexical processing was reduced by the visual task. Moreover...

Recent advances in extracellular electrophysiology now facilitate the recording of spikes from hundreds or thousands of neurons simultaneously. This has necessitated both the development of new computational methods for spike sorting and better methods to determine spike sorting accuracy. One longstanding method of assessing the false discovery rate (FDR) of spike sorting – the rate at which spikes are assigned to the wrong cluster – has been the rate of inter-spike-interval (ISI) violations. Despite their near ubiquitous usage in spike sorting, our understanding of how exactly ISI violations relate to FDR, as well as best practices for using ISI violations as a quality metric, remain limited. Here, we describe an analytical solution that can be used to predict FDR from ISI violation rate. We test this model in silico through Monte Carlo simulation, and apply it to publicly available spike-sorted electrophysiology datasets. We find that the relationship between ISI violation rate and FDR is highly nonlinea...

Comorbid chronic neuropathic pain and anxiety is a common disease that represents a major clinical challenge. The underlying mechanisms of chronic neuropathic pain and anxiety are not entirely understood, which limits the exploration of effective treatment methods. Glutamatergic neurons in the ventrolateral periaqueductal gray (vlPAG) have been implicated in regulating pain, but the potential roles of the vlPAG in neuropathic pain-induced anxiety have not been investigated. Herein, whole-cell recording and immunofluorescence showed that the excitability of CamkIIα neurons in the vlPAG (vlPAGCamkIIα+ neurons) was decreased in mice with spared nerve injury (SNI), while electroacupuncture (EA) activated these neurons. We also showed that chemogenetic inhibition of vlPAGCamkIIα+ neurons resulted in allodynia and anxiety-like behaviors in naive mice. Furthermore, chemogenetic activation of vlPAGCamkIIα+ neurons reduced anxiety-like behaviors and allodynia in mice with SNI, and EA had a similar effect in allevia...

The integration of spatial information in the mammalian dentate gyrus (DG) is critical to navigation. Indeed, DG granule cells (DGCs) rely upon finely balanced inhibitory neurotransmission in order to respond appropriately to specific spatial inputs. This inhibition arises from a heterogeneous population of local GABAergic interneurons (INs) that activate both fast, ionotropic GABAA receptors (GABAAR) and slow, metabotropic GABAB receptors (GABABR), respectively. GABABRs in turn inhibit pre- and postsynaptic neuronal compartments via temporally long-lasting G-protein-dependent mechanisms. The relative contribution of each IN subtype to network level GABABR signal setting remains unknown. However, within the DG, the somatostatin (SSt) expressing IN subtype is considered crucial in coordinating appropriate feedback inhibition on to DGCs. Therefore, we virally delivered channelrhodopsin 2 to the DG in order to obtain control of this specific SSt IN subpopulation in male and female adult mice. Using a combinat...

Adaptive behavior relies on efficient cognitive control. The anterior cingulate cortex (ACC) is a key node within the executive prefrontal network. The reciprocal connectivity between the locus ceruleus (LC) and ACC is thought to support behavioral reorganization triggered by the detection of an unexpected change. We transduced LC neurons with either excitatory or inhibitory chemogenetic receptors in adult male rats and trained rats on a spatial task. Subsequently, we altered LC activity and confronted rats with an unexpected change of reward locations. In a new spatial context, rats with decreased noradrenaline (NA) in the ACC entered unbaited maze arms more persistently which was indicative of perseveration. In contrast, the suppression of the global NA transmission reduced perseveration. Neither chemogenetic manipulation nor inactivation of the ACC by muscimol affected the rate of learning, possibly due to partial virus transduction of the LC neurons and/or the compensatory engagement of other prefronta...

Hunger and thirst drive animals’ consumption behavior and regulate their decision-making concerning rewards. We previously assessed the thirst states of monkeys by measuring blood osmolality under controlled water access and examined how these thirst states influenced their risk-taking behavior in decisions involving fluid rewards. However, hunger assessment in monkeys remains poorly performed. Moreover, the lack of precise measures for hunger states leads to another issue regarding how hunger and thirst states interact with each other in each individual. Thus, when controlling food access to motivate performance, it remains unclear how these two physiological needs are satisfied in captive monkeys. Here, we measured blood ghrelin and osmolality levels to respectively assess hunger and thirst in four captive macaques. Using an enzyme-linked immunosorbent assay, we identified that the levels of blood ghrelin, a widely measured hunger-related peptide hormone in humans, were high after 20 h of no food access ...

The electrophysiological response to rewards recorded during laboratory tasks has been well documented, yet little is known about the neural response patterns in a more naturalistic setting. Here, we combined a mobile-EEG system with an augmented reality headset to record event-related brain potentials (ERPs) while participants engaged in a naturalistic operant task to find rewards. Twenty-five participants were asked to navigate toward a west or east goal location marked by floating orbs, and once participants reached the goal location, the orb would then signify a reward (5 cents) or no-reward (0 cents) outcome. Following the outcome, participants returned to a start location marked by floating purple rings, and once standing in the middle, a 3 s counter signaled the next trial, for a total of 200 trials. Consistent with previous research, reward feedback evoked the reward positivity, an ERP component believed to index the sensitivity of the anterior cingulate cortex to reward prediction error signals. T...