Bimanual coordination, fundamental to human motor control, typically involves the execution of different functions by the two limbs (e.g., opening a jar). Previous research has largely investigated bimanual control through simple coordination tasks in which the limbs perform similar movements (e.g., finger tapping); however, few studies have specifically examined coordination when the two limbs perform different yet complementary functions. In the current study, participants performed point-to-point movements of a rectangular cursor, where one limb controlled cursor trajectory and the other rotated a knob to match a target orientation. Participants ( N  = 116, 76 female, 1 nonbinary; 92% right-handed) were divided into four groups and completed the task with a visual feedback gain perturbation (an increase or decrease) applied either to the cursor trajectory or orientation. Our results showed rapid adaptation to perturbations of visual feedback of the movement trajectory, affecting both the perturbed limb ...

Fear extinction, the gradual reduction of conditioned fear in response to a previous threatening experience that no longer predicts danger, plays a crucial role in exposure-based therapies for anxiety and trauma-related disorders. Despite the efficacy of these therapies for many, a significant number of individuals encounter difficulties in extinguishing fear, resulting in treatment resistance. Understanding the mechanisms behind the variation in extinction success among individuals remains a central pursuit in neuroscience. Recent studies have identified dopamine (DA) neurons within the ventral tegmental area (VTA) to influence the extinction process. In addition to their well-established role in signaling reward prediction errors, specific populations of VTA DA neurons also respond to the unexpected omission of an aversive stimulus, producing a signal indicative of safety. In animals capable of successful extinction, this burst of activity associated with stimulus omission diminishes over time, signalin...

Speech in everyday life is often masked by background noise, making comprehension effortful. Characterizing brain activity patterns when individuals listen to masked speech can help clarify the mechanisms underlying such effort. In the current study, we used functional magnetic resonance imaging (fMRI) in humans of either sex to investigate how neural signatures of story listening change in the presence of masking noise. We show that, as speech masking increases, spatial and temporal activation patterns in auditory regions become more idiosyncratic to each listener. In contrast, spatial activity patterns in brain networks linked to effort (e.g., cingulo-opercular network) are more similar across listeners when speech is highly masked and less intelligible, suggesting shared neural processes. Moreover, at times during stories when one meaningful event ended and another began, neural activation increased in frontal, parietal, and medial cortices. This event-boundary response appeared little affected by backg...

Mirror invariance is the cognitive tendency to perceive mirror-image objects as identical. Mirrored letters, however, are distinct orthographic units and must be identified as different despite having the same shape. Consistent with this phenomenon, a small, localized region in the ventral visual stream, the Visual Word Form Area (VWFA), exhibits repetition suppression to both identical and mirror pairs of objects but only to identical, not mirror, pairs of letters ( [Pegado et al., 2011][1]), a phenomenon named mirror invariance “breaking”. The ability of congenitally blind individuals to “break” mirror invariance for pairs of mirrored Braille letters has been demonstrated behaviorally ( [de Heering et al., 2018][2], [Korczyk et al., 2024][3]). However, its neural underpinnings have not yet been investigated. Here, in an fMRI repetition suppression paradigm, congenitally blind individuals (8 males and 10 females) recognized pairs of everyday objects and Braille letters in identical (“p” and “p”), mirror (...

Repetitive mild traumatic brain injury (rmTBI) is a major contributor to long-term neurological dysfunction, yet many preclinical models lack precise control and quantification of biomechanical forces across impacts. We developed a reproducible, closed-skull mouse model of rmTBI using a custom-built weight–drop apparatus featuring a solenoid-based rebound arrest system, integrated high-speed videography, and accelerometry to track head kinematics during impact. Adult male and female mice received either a single impact or nine daily impacts. Linear and angular acceleration data were analyzed alongside behavioral and histological outcomes. Our apparatus delivered consistent impact and velocity forces with minimal intersubject variability. Additionally, the animals experienced consistent linear and angular acceleration as measured using high-speed video capture. These impacts did not cause skull fracture or acute vascular hemorrhage, but impacted animals had increased return of righting reflex time, consiste...

We studied the role of movement and outcome information in forming metacognitive representations of agency. Human participants ( N  = 40; 25 female, 15 male, 0 diverse) completed a goal-oriented task: a semivirtual version of a ball-throwing game. In two conditions, we manipulated either the visual representation of the throwing movement or its proximal outcome (the resulting ball trajectory). We measured participants’ accuracy in a discrimination agency task, as well as confidence in their responses and tested for differences in the electrophysiological (EEG) signal using mass linear mixed-effect modeling. We found no mean differences between participants’ metacognitive efficiency between conditions. However, through exploratory analyses, we found that metacognitive sensitivity did not correlate between the two conditions and that the EEG signal differed between the two conditions during the agency discrimination task. We cautiously interpret these results as suggesting that although both movement and out...

The growing therapeutic promise of repeated, low-dose ketamine treatment across various psychopathologies—including depression and drug addiction—warrants clarity on its potential addictive properties and their associated mechanisms in both sexes. Accordingly, the present work examined the effects of intermittent low-dose ketamine in male and female rats on behavioral sensitization to the locomotor-activating effects of ketamine, as well as associated molecular profiles in dopamine D1- and D2-receptor-expressing medium spiny neurons (D1- and D2-MSNs) of the nucleus accumbens (NAc). Following intra-NAc infusion of a Cre-inducible RiboTag virus, locomotor activity was measured in adult Drd1a-iCre and Drd2-iCre male and female rats in either diestrus or proestrus following repeated administration of ketamine (0, 10, or 20 mg/kg, i.p.) to evaluate the development of locomotor sensitization. Female—but not male—rats developed sensitization to the locomotor-activating effects of ketamine, occurring more rapidly ...

Alcohol use disorder (AUD) is one of the top behavioral causes of global disease burden in the United States. Repeated cycles of alcohol intoxication and abstinence induce neuroplastic alterations which induce excessive drinking and cognitive impairments. A system deeply dysregulated by chronic drinking is norepinephrine (NE). At moderate levels, NE has beneficial effects on cognition and behavior, mediated by the α2 adrenergic receptor (AR) subtype. Whether α2 AR activation blunts alcohol consumption in models of heavy drinking has not been determined, and whether α2 AR activation improves cognitive performance following chronic alcohol consumption is unknown. Here, we show that the α2 AR agonist clonidine worsens ethanol-induced hypothermia and sedation in male mice, while the more selective α2 AR agonist guanfacine is devoid of these effects. We also observed that, in male and female mice, while both clonidine and guanfacine reduce heavy alcohol drinking, guanfacine does so with higher potency. Furtherm...

The nigrostriatal and mesoaccumbal dopamine systems are thought to contribute to changes in behavior and learning during adolescence, yet it is unclear how the rise in gonadal hormones at puberty impacts the function of these systems. We studied the impact of prepubertal gonadectomy (GDX) on later evoked dopamine release in male Mus spicilegus , a mouse whose adolescent life history has been carefully characterized in the wild and laboratory. To examine how puberty impacts dopamine neuron function in M. spicilegus males, we removed the gonads prepubertally at postnatal day (P)25 and then examined evoked dopamine release in the dorsomedial, dorsolateral (DLS), and nucleus accumbens core regions of striatal slices at P60–70 (late adolescence/early adulthood). To measure dopamine release, we used near-infrared catecholamine nanosensors which enable study of spatial distribution of dopamine release. We found that prepubertal GDX led to a significantly reduced density of dopamine release sites and reduced dopam...

Sulf1 is an extracellular sulfatase that regulates cell signaling by removing 6- O -sulfates from heparan sulfate. Although the roles of Sulf1 in neural development have been studied extensively, its functions in the adult brain remain largely unknown. Here, we report the effects of Sulf1 disruption on the neuronal properties of the medium spiny neurons (MSNs) in the nucleus accumbens (NAc) shell, one of the regions highly expressing Sulf1 . We separately labeled MSNs expressing dopamine D1 receptors (D1-MSNs) or D2 receptors (D2-MSNs) by injecting adult male Drd1-Cre and Drd2-Cre mice with a Cre-dependent AAV vector expressing a red fluorescent protein, mCherry, and examined their electrophysiological properties by means of whole-cell patch–clamp recording. In the D2-MSNs, Sulf1 disruption led to drastic changes in neural firing responses to depolarizing current injections: in the Sulf1 knock-out mice, the rheobase was smaller than in the wild-type mice, but the number of action potentials elicited by dep...