Perinatal exposure to the organophosphorus insecticide chlorpyrifos (CPF) is associated with an increased incidence of neurodevelopmental disorders, such as autism spectrum disorder. While these behavioral detriments have been modeled in rodents, the underlying functional alterations in the developing brain are largely unknown. Previous reports using a rat model have identified alterations to both inhibitory synaptic transmission and serotonergic (5-HT) receptor binding in the cortex following developmental CPF exposure. Here, we use a rat model of gestational CPF exposure to investigate whether this altered inhibitory activity is driven by increased spontaneous firing of inhibitory interneurons and altered 5-HT receptor expression. Using cell-attached ex vivo electrophysiology in young rats of both sexes, we identified a significant increase in the number of spontaneously firing neurons in the somatosensory cortex of CPF-exposed offspring. Analysis of action potential metrics identified a subset of these ...

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 ...

Investigations into the neural basis of behavior frequently employ calcium imaging to measure neuronal activity. Across studies, however, seemingly reasonable but highly diverse methodological choices are typically made to assess the selectivity of individual neurons to task states. Here, we examine systematically the effect of parameter choices, along the pipeline from data acquisition through statistical testing, on the inferred encoding preferences of individual neurons. We use, as an experimental testbed, calcium imaging in the medial prefrontal cortex of freely behaving mice engaged in a classic exploration-avoidance task with animal-controlled state transitions, namely, navigation in the elevated zero maze. We report that most of the key parameters in the pipeline substantially impact the inferred selectivity of neurons and do so in distinct ways. Using novel accuracy and robustness metrics, we directly compare the quality of inference across combinations of parameter levels and discover an optimal c...

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...

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 ...

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...

Alpha peak frequency (APF) is defined as a prominent spectral peak within the 8–12 Hz frequency range. Typically, an individual's alpha frequency is regarded as a stable neurophysiological marker. A wealth of recent evidence, however, indicates that APF shifts within short timescales in relation to task demands and even spontaneously so. Further, brain stimulation studies often report shifts in APF both within and between experimental sessions, directly contradicting the idea of a stable APF. To characterize the nonstationarities in spectral parameters, we estimated APFs from 1 s epochs of resting-state magnetoencephalography (MEG) recordings from healthy adults of either sex. To enhance signal-to-noise ratio, without compromising on temporal resolution, we averaged power spectra within parcelled regions. Our findings indicate that variation in APFs exacerbates along the posterior-to-anterior cortical plane, i.e., from the occipital to the frontal cortices. Further, by comparisons with amplitude-matched si...

Autism spectrum disorder, schizophrenia, and bipolar disorder are neuropsychiatric conditions that manifest early in life with a wide range of phenotypes, including repetitive behavior, agitation, and anxiety ( [American Psychological Association, 2013][1]). While the etiology of these disorders is incompletely understood, recent data implicate a role for mitochondrial dysfunction ( [Norkett et al., 2017][2]; [Khaliulin et al., 2025][3]). Mitochondria translocate to intracellular compartments to support energetics and free-radical buffering; failure to achieve this localization results in cellular dysfunction ( [Picard et al., 2016][4]). Mitochondrial Rho-GTPase 1 ( Miro1 ) resides on the outer mitochondrial membrane and facilitates microtubule-mediated mitochondrial motility ( [Fransson et al., 2003][5]). The loss of MIRO1 is reported to contribute to the onset/progression of neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease ( [Kay et al., 20...

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...

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...