Early childhood neglect can impact brain development across the lifespan. Using voxel-based approaches we recently reported that severe and time-limited institutional deprivation in early childhood was linked to substantial reductions in total brain volume in adulthood, >20 years later. Here, we extend this analysis to explore deprivation-related regional white matter volume and microstructural organization using diffusion-based techniques. A combination of tensor-based morphometry (TBM) analysis and tractography was conducted on diffusion-weighted imaging (DWI) data from 59 young adults who spent between 3 and 41 months in the severely depriving Romanian institutions of the 1980s before being adopted into United Kingdom families, and 20 nondeprived age-matched United Kingdom controls. Independent of total volume, institutional deprivation was associated with smaller volumes in localized regions across a range of white matter tracts including (1) long-ranging association fibers such as bilateral inferior l...

Certain structural brain connections have been confirmed to influence sleep duration in children. However, the causal relationships between all brain regions and children's sleep duration remain unclear. A two-sample Mendelian randomization analysis was conducted using data from genome-wide association studies (GWAS) to examine the relationships between 206 structural connections and sleep duration in children. Sensitivity analyses were employed to validate the findings and assess the robustness of the causal inferences. Stronger connectivity from the left hemisphere (LH) control network to the accumbens ( β  = −0.15; 95% CI = [−0.30, −2.88 × 10−3]; p  = 0.05) and from the LH somatomotor network to the LH default network ( β  = −0.18; 95% CI = [−0.34, −0.03]; p  = 0.02) in white-matter structural connectivity (SC) were associated with shorter sleep durations. Conversely, increased white-matter SC from the LH dorsal attention network to the thalamus ( β  = 0.14; 95% CI = [8.45 × 10−4, 0.27]; p  = 0.05), fro...

Prior experiences have the ability to alter the nature of and capacity for future learning. Therefore, identifying the mechanisms that allow prior experience to affect future learning is important in understanding how memories are formed. We have previo...

The relative contributions of glutamate and dopamine within the nucleus accumbens to cocaine-induced reinstatement of drug-seeking behavior were assessed. When extinguished cocaine self-administration behavior was reinstated by a cocaine-priming injection, extracellular levels of both dopamine and glutamate were elevated in the nucleus accumbens. However, when yoked cocaine or saline control subjects were administered a cocaine prime, only dopamine levels were elevated. Thus, glutamate increased only when animals reinstated lever pressing, whereas dopamine increased regardless of behavior. The increase in glutamate was not accounted for simply by the act of lever pressing itself, because the cocaine self-administration group still demonstrated elevated glutamate when the levers were withdrawn from the operant chamber. Moreover, reinstatement of lever pressing for food did not elevate extracellular glutamate, indicating that increased glutamate initiated responding selectively for a drug reinforcement. The ...

Social status and dominance are critical factors influencing well-being and survival across multiple species. However, dominance behaviors vary widely across species, from elaborate feather displays in birds to aggression in chimps. To effectively study dominance, it is essential to clearly define and reliably measure dominance behaviors. In laboratory settings, C57BL/6 mice are commonly used to study dominance due to their stable and linear social hierarchies. However, other mouse strains are also used for laboratory research. Despite substantial evidence for strain effects on behavioral repertoires, the impact of strain on dominance in mice remains largely unstudied. To address this gap, we compared dominance behaviors between CD1 and C57BL/6 male mice across four assays: observation of agonistic behaviors, urine marking, tube test, and a reward competition. We found that CD1 mice demonstrate increased fighting, increased territorial marking through urination, and increased pushing and resisting in the t...

Withdrawal from repeated cocaine dysregulates Gi-protein signaling. The recently discovered G-protein dissociation inhibitor, AGS3, is selectively upregulated in the rat prefrontal cortex and accumbens core following extended withdrawal (3 wks) from repeated cocaine (7 daily injections). AGS3 can bind to and stabilize up to 4 Giαs, independent of the βγ complex, preferentially in the GDP bound conformation. Aggregating Giα in its inactive conformation may therefore potentiate signaling via βγ-mediated effectors. Interestingly, preventing the withdrawal-induced rise in prefrontal cortex AGS3 expression with antisense oligonucleotides also prevents both the expression of behavioral sensitization to cocaine and the reinstatement of drug seeking following administration of a cocaine prime (10 mg/kg; ip). Furthermore, the sensitized behavioral response returns following oligonucleotide washout. AGS3 may represent a novel mode of action for Gi coupled receptors in the rat prefrontal cortex following extended wit...

Pattern separation is a computational process whereby potentially similar memory representations are made as dissimilar as possible at the time of encoding. The complementary process, pattern completion, is the process whereby memory representations are...

People are extremely efficient at detecting relevant objects in complex natural scenes. In three experiments, we used functional magnetic resonance imaging-guided transcranial magnetic stimulation (TMS) to investigate the role of the extrastriate body area (EBA) in the detection of people in scenes. In Experiment 1, participants reported, in different blocks, whether people or cars were present in a briefly presented scene. Detection (d-prime) of people, but not of cars, was impaired after TMS over right EBA (rEBA; five pulses at −200, −100, 0, 100, 200 ms) compared with sham stimulation. In Experiment 2, we applied TMS either before (−200, −100 ms) or after (+100, +200) the scene onset. Poststimulus EBA stimulation impaired people detection relative to prestimulus EBA stimulation, while timing had no effect during sham stimulation. In Experiment 3, we examined anatomical specificity by comparing TMS over EBA with TMS over scene-selective transverse occipital sulcus (TOS). Two scenes were presented side by...

Normal pressure hydrocephalus (NPH) is marked by enlarged cerebral ventricles with normal intracranial pressure, plus three stereotypical symptoms: gait impairment, cognitive dysfunction, and urinary frequency with urge incontinence. The neural circuit dysfunction responsible for each of these symptoms remains unknown, and an adult mouse model would expand opportunities to explore these mechanisms in preclinical experiments. Here, we describe the first mouse model of chronic, communicating hydrocephalus with normal intracranial pressure. Hydrocephalic male and female mice had unsteady gait and reduced maximum velocity. Despite performing well on a variety of behavioral tests, they exhibited subtle learning impairments. Hydrocephalic mice also developed urinary frequency, and many became incontinent. This mouse model, with symptoms resembling human NPH, can be combined with molecular-genetic tools in any mouse strain to explore the neural circuit mechanisms of these symptoms. Preclinical work using this hyd...

Presynaptic reuptake, mediated by the dopamine (DA) transporter (DAT), terminates DAergic neurotransmission and constrains extracellular DA levels. Addictive and therapeutic psychostimulants inhibit DA reuptake and multiple DAT coding variants have been reported in patients with neuropsychiatric disorders. These findings underscore that DAT is critical for DA neurotransmission and homeostasis. DAT surface availability is regulated acutely by endocytic trafficking, and considerable effort has been directed toward understanding mechanisms that govern DAT's plasma membrane expression and postendocytic fate. Multiple studies have demonstrated DAT endocytic recycling and enhanced surface delivery in response to various stimuli. Paradoxically, imaging studies have not detected DAT targeting to classic recycling endosomes, suggesting that internalized DAT targets to either degradation or an undefined recycling compartment. Here, we leveraged PRIME (PRobe Incorporation Mediated by Enzyme) labeling to couple surfac...