Individuals using cocaine, particularly those with Cocaine Use Disorder, experience long-lasting neurobiological alterations that contribute to high rates of relapse and increased morbidity and mortality. Rodent models suggest that neuronal activation, as represented by Fos expression, in the nucleus accumbens (NAc) is crucial for cocaine-related behaviors. However, the role of biological sex in NAc activation in these behaviors remains unclear. Therefore, the present study examined the impact of sex on cocaine-induced locomotor activity (LMA), cocaine self-administration, cocaine seeking, and associated NAc Fos expression. We hypothesized that, relative to males, female rats would display heightened behavioral responses in the tested models and greater numbers of Fos+ cells in the NAc, and that Fos expression would correlate with the outcome measures of the assessed behaviors (i.e., locomotor activity and cocaine seeking). In this study, females displayed greater cocaine-induced locomotor activity, cocaine self-administration, and cocaine seeking than males. However, neither sex nor cocaine treatment impacted NAc Fos expression in the LMA study, and NAc Fos levels did not correlate with LMA in either sex. Following cocaine seeking, NAc Fos expression was not sex-dependent, though it correlated with cocaine seeking in males, but not in females. Taken together, these results suggest that the number of Fos+ cells in the NAc do not underlie sex differences in cocaine use or relapse-like behaviors. Future work should characterize the proteomic or electrophysiologic profiles in specific cell types of Fos+ cells in the NAc following cocaine use to determine how these behaviors differ by sex.

Longitudinal subcortical volume changes and their correlations with multiple PET and fluid biomarkers in dominantly inherited Alzheimer's disease.

Incubation of oxycodone craving is associated with CP-AMPAR upregulation in D1 and A2a receptor-expressing medium spiny neurons in nucleus accumbens core and shell.

Curiosity scaffolds children's exploration and learning. Yet, the neural mechanisms of curiosity-modulated learning in children remain unclear. Here, we designed an fMRI task to test how curiosity, as defined by children's self-reported excitement about learning information, modulates memory and neural activity in 5- to 8-year-olds (n = 60 with behavioral data, n = 51 with fMRI). We observed greater learning when children reported more curiosity. In whole-brain analyses, high-curiosity was associated with greater activation in inferior frontal gyrus, lateral occipital cortex, the thalamus, and the putamen. Curiosity did not modulate activation in preregistered regions of interest (dorsal attention network, hippocampus, nucleus accumbens) but did modulate activation in an exploratory region of interest, the amygdala. Multivariate searchlight decoding revealed local activity patterns that reliably distinguished reported curiosity levels in dorsolateral prefrontal cortex, fusiform gyrus, angular gyrus, precuneus, and cerebellum. Together, these findings are consistent with prior work on curiosity-related activation during information receipt in adults, suggesting that neural systems that support curiosity-driven learning are already engaged in early childhood.

Cocaine Use Disorder (CUD) has been associated with differences in gray matter (GM) measures, but prior meta-analyses have yielded inconsistent results due to methodological variability, publication bias, and selective reporting. To address these gaps, this study integrates multilevel frequentist, Bayesian, and coordinate-based approaches to provide a comprehensive, anatomically resolved synthesis of structural neuroimaging findings in CUD. Following PRISMA guidelines (PROSPERO: CRD42024585260), 47 studies were included that compared GM indices between individuals with CUD and healthy controls. Multilevel random-effects meta-analyses were conducted to quantify cortical and subcortical group differences while accounting for clinically relevant moderators. Bayesian hierarchical models were used to conduct sensitivity analyses addressing potential reporting bias, and a coordinate-based Activation Likelihood Estimation (ALE) analysis evaluated spatial convergence across voxel-based morphometry studies. The analyses indicated that CUD showed lower GM measures in prefrontal and temporal cortical regions, particularly the ITG and the rostral middle frontal gyrus. Subcortical analyses showed lower GM volume in the amygdala, hippocampus, thalamus, pallidum, nucleus accumbens, brainstem, and cerebellum. Longer duration of cocaine use and greater clinical severity were associated with larger negative effect-size estimates for cortical measures. Bayesian regularization yielded consistent cortical effect-size estimates across sensitivity analyses, whereas the coordinate-based ALE analysis identified no clusters surviving family-wise error correction. Together, results from this meta-analysis identify consistent patterns of GM differences across cortico-subcortical regions in individuals with CUD. These findings provide an integrated neuroanatomical reference framework that may inform future longitudinal studies and the evaluation of candidate neuroimaging biomarkers.

Early effects of oral naltrexone on craving, resting state and cue-induced brain activation in opioid use disorder: a prospective fMRI study.

Foreign language modulates neural responses to instructed fear: a neuroimaging study in bilinguals.

Persistent neuropathic pain selectively impairs hedonic and motivational aspects of eating: Insights from a mouse model.

Autism spectrum disorder (ASD) is characterized by social impairments and stereotyped behavior, with some individuals exhibiting heightened aggression in response to stress. This stress induced aggression (SIA) can severely impact quality of life, yet its underlying neural mechanisms remain poorly understood. Here, we investigated the behavioral phenotypes and neural activity that result as a consequence of stress in Cntnap2-/-:TRAP2+/-:Ai14+/- mice. Deletion of the CNTNAP2 gene leads to a highly penetrant syndromic form of ASD, and the targeted recombination in active populations (TRAP) system allows for permanent access to neuronal populations activated during a specific experience, such as stress and aggression. We implemented a behavioral paradigm consisting of a baseline resident intruder assay, with either a single day or four consecutive days of restraint stress, followed by a posttest resident intruder assay in Cntnap2-/-:TRAP2+/-:Ai14+/- and control mice. While a single day of restraint stress failed to induce changes in aggressive behavior in either genotype, 4 days of restraint stress significantly escalated aggression and reduced latency to attack selectively in Cntnap2-/- mice. Using TRAP-based labeling, we observed increased neuronal activity in the lateral septum, lateral habenula, lateral hypothalamus, nucleus accumbens, and prelimbic cortex of Cntnap2-/- mice. Interestingly, time aggressive and aggressive events were positively correlated with activity in the lateral septum, lateral habenula, and infralimbic cortex. These findings suggest that repeated stress engages specific fronto-striatal and limbic regions in Cntnap2-/- mice and provide insight into the neural substrates of maladaptive SIA, offering a foundation for targeted therapeutic strategies.

Increased responsivity to pharmacological manipulations of dopamine D1 receptors in binge eating prone rats.

Despite the impact of depression in multiple sclerosis (MS), the neurobiological mechanisms underlying its pathogenesis are still poorly understood. Disrupted functional connectivity (FC) within the reward circuit has been observed in major depressive disorder (MDD), highlighting its essential role in the neurobiology of depression. Here, we hypothesised that an analogous dysconnectivity may underpin depression in MS. The present study aimed to investigate FC of key nodes of the reward circuit (nucleus accumbens, NAcc and ventral tegmental area, VTA) in MS patients with depression (MS-D; n=30, 22 females), characterising differences with MS patients without depression (MS-nD; n=30, 17 females) and MDD patients without MS (n=30, 23 females). Furthermore, dynamic causal modelling (DCM) was applied to resting-state functional magnetic resonance imaging (fMRI) data to characterise effective connectivity (EC), which refers to the causal influences of brain regions involved in the circuit. MS-D group showed reduced FC compared with both MS-nD and MDD, suggesting that the association of depression with MS may reflect dysfunction of the reward circuit. The DCM analysis showed inhibitory self-connections, a negative modulation of VTA in MS-D>MS-nD, a negative modulation between VTA, NAcc and the right amygdala as an effect of having depression and no EC differences for MS-D>MDD. The present connectivity study revealed promising results for understanding the pathophysiology of depression in MS. A combined FC-EC investigation of the reward circuit may represent a potential non-invasive in vivo MRI biomarker for understanding the onset of core depressive symptoms, supporting the development of effective and personalised therapies.

The continual emergence of novel synthetic cathinones poses significant public health concerns due to their unpredictable pharmacological profiles and potential for abuse. Among these, 4-F-3-Me-α-PVP-a newly identified analogue of α-PVP-has recently surfaced on the illicit drug market, yet its biological effects remain uncharacterized. To provide the first comprehensive pharmacological evaluation of 4-F-3-Me-α-PVP. In vitro transporter inhibition was assessed using HEK293 cells expressing human dopamine (DA), norepinephrine, and serotonin transporter (DAT, NET, or SERT). In male rodents, locomotor activity was measured after i.p. (mice) or s.c. (rats) administration. In vivo microdialysis in rats quantified extracellular DA in the nucleus accumbens. Rewarding and reinforcing effects were evaluated using conditioned place preference (CPP) in mice and intravenous self-administration (IVSA) in rats under fixed-ratio and progressive-ratio schedules. In vitro assays revealed that 4-F-3-Me-α-PVP acts as a potent DAT and NET inhibitor, with additional, though weaker, activity at SERT. In vivo, 4-F-3-Me-α-PVP significantly increased locomotor activity in male rodents (10 and 30 mg/kg in mice; 3 mg/kg in rats). Importantly, 4-F-3-Me-α-PVP also increased extracellular DA levels in the rat nucleus accumbens (3 mg/kg, s.c.), pointing to its potential for abuse. Behavioral assays further demonstrated rewarding and reinforcing effects in rodents, with significant CPP in mice at all doses tested and dose-dependent IVSA in rats observed under both fixed-ratio and progressive-ratio schedules. Collectively, these findings indicate that 4-F-3-Me-α-PVP possesses substantial psychostimulant and abuse-related effects in rodents, underscoring the need for regulatory vigilance and continued investigation into emerging synthetic cathinones.

A touch-guided neural circuit regulates motivated gnawing to maintain dental alignment.

Behavioural rigidity, the tendency to persist with inflexible patterns of thoughts or actions, is increasingly recognised as a transdiagnostic symptom across psychiatric, neurodevelopmental, and neurodegenerative disorders. Empirical studies exploring the prevalence and underlying neural mechanisms of behavioural rigidity in dementia, however, are lacking. This cross-sectional study sought to delineate the structural and functional neural correlates of behavioural rigidity using a transdiagnostic approach looking across the frontotemporal lobar degeneration (FTLD) spectrum and Alzheimer's disease. A total of 204 participants were recruited, including 110 frontotemporal dementia (FTD), 53 Alzheimer's disease (AD), and 41 healthy older control participants. Within the FTD group, 66 cases were diagnosed with clinically probable behavioural variant FTD (bvFTD), 26 presented with semantic dementia (SD), and 18 cases had progressive non-fluent aphasia (PNFA). Behavioural rigidity was assessed using the Stereotypical and Motor Behaviour subscale of the Cambridge Behavioural Inventory-Revised. Voxel-based morphometry (VBM) was performed to identify grey matter regions associated with behavioural rigidity transdiagnostically, the results of which informed subsequent seed-based voxel-wise functional connectivity analyses. All imaging analyses were adjusted for relevant demographic and technical covariates. Statistical thresholds were set at voxel-level p < 0.001 (uncorrected) and cluster-level p < 0.05 (FDR-corrected). Our main finding was that behavioural rigidity is pervasive across dementia subtypes, ranging from most pronounced in bvFTD to milder/relatively absent in PNFA, relative to Controls. Whole-brain VBM across the entire patient sample revealed a significant negative association between behavioural rigidity and grey matter intensity exclusively in the bilateral nucleus accumbens. Using the bilateral nucleus accumbens as seeds, resting-state functional connectivity analysis showed that higher levels of behavioural rigidity were associated with stronger connectivity between the left nucleus accumbens and the left supplementary motor area, paracentral lobule, and precuneus. This is the first study, to our knowledge, to examine the neural substrates of behavioural rigidity across FTLD syndromes transdiagnostically using structural and functional neuroimaging approaches. Our findings reveal a gradation of rigid and repetitive behaviours, most apparent in bvFTD, which in turn reflects pathological disruption of the nucleus accumbens. Taken together, our findings highlight the need to consider repetitive and rigid behaviours as a transdiagnostic feature in neurodegenerative disorders, and one which indexes underlying nucleus accumbens pathology. More broadly, this study underscores the importance of screening for rigid and repetitive behaviours in the clinic and identifies the nucleus accumbens as a promising neural target to ameliorate these symptoms.

Brain oxygen levels fluctuate with changes in neural activity and systemic physiology, yet it remains unclear whether oxygen responses to salient stimuli are structure-specific or reflect generalized brain activation. Using oxygen sensors coupled with high-speed amperometry in freely moving rats, we compared oxygen dynamics in three structures with markedly different neuronal firing properties: nucleus accumbens, medial thalamus, and substantia nigra pars reticulata, along with simultaneous measurements in the subcutaneous space. Natural arousing stimuli produced rapid oxygen increases in all brain sites coupled with robust subcutaneous oxygen decreases, though there are minor differences in magnitude. In contrast, intravenous fentanyl (30 µg/kg) induced uniform hypoxic responses in all brain sites, consisting of a rapid and strong decrease followed by a weaker post-hypoxic rebound, with low between-site variability. These findings show that physiological oxygen increases during arousal are largely generalized and likely dominated by systemic mechanisms such as peripheral vasoconstriction, cerebral vasodilation, and global increases in cerebral blood flow, whereas fentanyl-induced hypoxia reflects purely systemic effect induced by respiratory depression. Overall, these results indicate that brain oxygen dynamics are shaped predominantly by systemic physiology rather than local neuronal firing properties, highlighting important constraints on interpreting oxygen-based signals as markers of neuronal activity.

The unique effects of chronic exposure to ambient fine particulate matter and indoor radon on subcortical brain morphology in youth.

Ventral hippocampus (vHPC) CA1 pyramidal neurons send glutamatergic projections to nucleus accumbens (NAc), and this vHPC-NAc circuit mediates cocaine seeking and reward, but it is unclear whether vHPC-NAc neuron properties are modulated by cocaine exposure to drive subsequent behavior. The immediate early gene transcription factor FosB/ΔFosB is induced throughout the brain by cocaine and is critical for cocaine seeking, but its function in vHPC-NAc neurons is not understood. We now show that circuit-specific knockout of FosB/ΔFosB in vHPC-NAc neurons impaired cocaine reward expression and forced abstinence-induced seeking. We also found that vHPC-NAc excitability was decreased by experimenter-administered repeated cocaine and cocaine self-administration, and this cocaine-induced excitability decrease was mediated by ΔFosB expression. To uncover the mechanism of this change in circuit function, we used circuit-specific translating ribosome affinity purification to assess cocaine-induced, FosB/ΔFosB-dependent changes in gene expression in vHPC-NAc. We found that cocaine causes a FosB/ΔFosB-dependent increase in the expression of calreticulin, an endoplasmic reticulum-resident calcium-buffering protein. Calreticulin expression mediated vHPC-NAc excitability and was necessary for cocaine reward. These findings uncover a noncanonical mechanism by which cocaine increases calreticulin in vHPC leading to decreased vHPC-NAc excitability and drives cocaine seeking and reward.

Dose- and sex-related effects of the MAGL inhibitor MCH11 on binge-like ethanol consumption in mice.

Apocynin-tandospirone derivatives (ATDs) have recently been shown to ameliorate methamphetamine (MAP)-induced behavioral abnormalities when administered chronically, presumably through antioxidant and interneuron-related mechanisms. However, their acute behavioral profile remains unclear. In this study, we examined whether acute ATD administration exerts antipsychotic-like effects in rats. Rats received acute treatment with ATDs (A-2, A-3, A-4), atypical antipsychotics, or saline, followed by assessments of spontaneous locomotor activity and MAP-induced hyperlocomotion. Prepulse inhibition (PPI), dopamine (DA) concentrations in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAC) were also measured. Acute ATD administration did not reduce spontaneous activity and failed to suppress MAP-induced hyperlocomotion. Instead, all three ATDs significantly enhanced MAP-induced locomotor responses, with A-3 showing dose-dependent potentiation. ATDs did not improve MAP-induced PPI deficits, except for a modest effect of high-dose A-3. Consistent with these behavioral outcomes, DA levels in the NAC were unchanged, and only small increases in mPFC DA were observed with A-2 and high-dose A-3. The results demonstrate that acute ATD administration neither suppressed MAP-induced behavioral abnormalities nor produced marked neurochemical changes, but instead enhanced MAP-induced locomotor activity, indicating a clear dissociation from their previously reported chronic effects.

Humans and animals can sense the negative states of other individuals and respond with prosocial behaviour to improve their conditions1,2. Although prosocial behaviour is hypothesized to have an evolutionary root in caring for vulnerable newborn offspring1,3, whether the neural substrates underlying parenting may contribute to adult-directed prosocial behaviours remains largely unclear. We show that mice with higher levels of parenting exhibit more prosocial allogrooming toward stressed adults. The medial preoptic area (MPOA), a brain area involved in parenting behaviour, bidirectionally regulates allogrooming toward stressed conspecifics. Allogrooming and parenting behaviours recruit a partially overlapping neuronal ensemble in the MPOA, are both controlled by an MPOA-to-VTA pathway and are associated with dopamine release in the nucleus accumbens. Using activity-dependent labeling, we demonstrate that MPOA neuronal ensembles engaged during parenting behaviours are functionally required for allogrooming. Conversely, MPOA neurons activated during prosocial behaviour are functionally required for pup grooming. Collectively, these findings uncover a neural circuit mechanism of prosocial behaviour and reveal partially shared neural substrates between parenting and prosocial behaviours, suggesting that the neural systems evolved for offspring care may have provided a scaffold for the emergence of broader prosocial support between adults.