Down Syndrome is the most common genetic cause for intellectual disability, yet the pathophysiology of cognitive impairment in Down Syndrome is unknown. We compared fMRI scans of 15 individuals with Down Syndrome to 14 typically developing control subjects while they viewed 50 min of cartoon video clips. There was widespread increased synchrony between brain regions, with only a small subset of strong, distant connections showing underconnectivity in Down Syndrome. Brain regions showing negative correlations were less anticorrelated and were among the most strongly affected connections in the brain. Increased correlation was observed between all of the distributed brain networks studied, with the strongest internetwork correlation in subjects with the lowest performance IQ. A functional parcellation of the brain showed simplified network structure in Down Syndrome organized by local connectivity. Despite increased interregional synchrony, intersubject correlation to the cartoon stimuli was lower in Down Syndrome, indicating that increased synchrony had a temporal pattern that was not in response to environmental stimuli, but idiosyncratic to each Down Syndrome subject. Short-range, increased synchrony was not observed in a comparison sample of 447 autism vs. 517 control subjects from the Autism Brain Imaging Exchange (ABIDE) collection of resting state fMRI data, and increased internetwork synchrony was only observed between the default mode and attentional networks in autism. These findings suggest immature development of connectivity in Down Syndrome with impaired ability to integrate information from distant brain regions into coherent distributed networks.

Summary Background Lactation is thought to buffer stress reactivity via oxytocin (OT). Dysregulation of the HPA axis has been reported in women with postpartum depression (PPD). The co-occurrence of PPD and lactation failure suggests that abnormalities in OT signaling may play a role in PPD. We hypothesized that abnormal OT signaling is implicated in dysregulated HPA axis reactivity among postpartum women with mood symptoms. In a prospective perinatal cohort, we tested associations between OT levels during breastfeeding and stress reactivity. Methods We recruited 52 pregnant women who intended to breastfeed, among whom 47 underwent a standardized stressor, the Trier Social Stress Test (TSST), at 8 weeks postpartum. 39 were breastfeeding at time of TSST. We assessed mood symptoms using validated instruments and defined as symptomatic women with EPDS ≥ 10 and/or Spielberger ≥ 34. Following IV placement for blood draws, women breastfed their infants and then underwent the TSST. Mothers’ hormone responses were quantified. Results Among symptomatic breastfeeding women (N=11; asymptomatic N=28), we found lower OT levels during breastfeeding (p<0.05) and higher CORT levels (p<0.05) both during breastfeeding and the TSST, as compared to asymptomatic breastfeeding women. In a mixed effects model examining CORT reactivity by symptom group and OT AUC, we observed a paradoxical response in symptomatic breastfeeding women during the TSST (group × time × OT AUC p< 0.05); higher OT AUC was associated with higher CORT. Conclusions In all breastfeeding women, the surge of OT during feeding appears to buffer subsequent stress-induced CORT secretion. However, in symptomatic breastfeeding women, we found a positive correlation between OT AUC and CORT, instead of the expected negative correlation, which we found among asymptomatic women.

Application of the treatment cascade model suggests multiple opportunities for improving perinatal depression management, informing optimal allocation of resources, and providing adequate treatment to this underrecognized and undertreated population..

The purpose of this article is to describe the development of translational methods by which spectrum analysis of human infant crying and rat pup ultrasonic vocalizations (USVs) can be used to assess potentially adverse effects of various prenatal conditions on early neurobehavioral development. The study of human infant crying has resulted in a rich set of measures that has long been used to assess early neurobehavioral insult due to non-optimal prenatal environments, even among seemingly healthy newborn and young infants. In another domain of study, the analysis of rat put USVs has been conducted via paradigms that allow for better experimental control over correlated prenatal conditions that may confound findings and conclusions regarding the effects of specific prenatal experiences. The development of translational methods by which cry vocalizations of both species can be analyzed may provide the opportunity for findings from the two approaches of inquiry to inform one another through their respective strengths. To this end, we present an enhanced taxonomy of a novel set of common measures of cry vocalizations of both human infants and rat pups based on a conceptual framework that emphasizes infant crying as a graded and dynamic acoustic signal. This set includes latency to vocalization onset, duration and repetition rate of expiratory components, duration of inter-vocalization-intervals and spectral features of the sound, including the frequency and amplitude of the fundamental and dominant frequencies. We also present a new set of classifications of rat pup USV waveforms that include qualitative shifts in fundamental frequency, similar to the presence of qualitative shifts in fundamental frequency that have previously been related to insults to neurobehavioral integrity in human infants. Challenges to the development of translational analyses, including the use of different terminologies, methods of recording, and spectral analyses are discussed, as well as descriptions of automated processes, software solutions, and pitfalls.

Neural cell adhesion molecule (NCAM) is a membrane-bound cell recognition molecule that exerts important functions in normal neurodevelopment including cell migration, neurite outgrowth, axon fasciculation, and synaptic plasticity. Alternative splicing of NCAM mRNA generates three main protein isoforms: NCAM-180, -140, and -120. Ectodomain shedding of NCAM isoforms can produce an extracellular 105-115 kDa soluble NCAM fragment (NCAM-EC) and a smaller intracellular cytoplasmic fragment (NCAM-IC). NCAM also undergoes a unique post-translational modification in brain by the addition of polysialic acid (PSA)-NCAM. Interestingly, both PSA-NCAM and NCAM-EC have been implicated in the pathophysiology of schizophrenia. The developmental expression patterns of the main NCAM isoforms and PSA-NCAM have been described in rodent brain, but no studies have examined NCAM expression across human cortical development. Western blotting was used to quantify NCAM in human postmortem prefrontal cortex in 42 individuals ranging in age from mid-gestation to early adulthood. Each NCAM isoform , post-translational modification (PSA-NCAM) and cleavage fragment (NCAM-EC and NCAM-IC) demonstrated developmental regulation in frontal cortex. , as well as PSA-NCAM, and NCAM-IC all showed strong developmental regulation during fetal and early postnatal ages, consistent with their identified roles in axon growth and plasticity. NCAM-EC demonstrated a more gradual increase from the early postnatal period to reach a plateau by early adolescence, potentially implicating involvement in later developmental processes. In summary, this study implicates the major NCAM isoforms, PSA-NCAM and proteolytically cleaved NCAM in Address correspondence to: L. Fredrik Jarskog, M.D., NYSPI/Columbia University, 1051 Riverside Dr. -Unit 42, New York, NY 10032, Tel: (212) Fax: (212) 543-1350.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2010 August 4. Published in final edited form as:Neuroscience. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript pre-and postnatal development of the human prefrontal cortex. These data provide new insights on human cortical development and also provide a basis for how altered NCAM signaling during specific developmental intervals could affect synaptic connectivity and circuit formation, and thereby contribute to neurodevelopmental disorders. KeywordsNCAM; adhesion molecules; synaptic plasticity; neurite outgrowth; adolescence; schizophrenia Neural cell adhesion m...

Alcohol consumption and smoking during pregnancy is common, despite the known adverse effects of these drugs on fetal development. Though studies on the effects of each drug separately are published, little is known about the effect of concurrent use of alcohol and nicotine in humans or in preclinical models. In this report, we examined the impact of continuous gestational exposure to both ethanol via liquid diet and nicotine via an osmotic minipump on maternal behavior, offspring ethanol intake, and oxytocin levels in a rat model. Dams were tested for the onset of maternal behavior with litters of unexposed surrogate pups and then killed to examine oxytocin levels within specific brain regions. Drug-exposed offspring reared by surrogate dams were tested for ethanol intake at either adolescence or adulthood, and oxytocin levels were measured in relevant brain regions after behavioral tests. Dams exhibited minor deficits in maternal care, which were associated with lower oxytocin levels in both the ventral tegmental and medial preoptic areas compared to control dams. Prenatal exposure altered sex-specific ethanol intake, with differential effects at adolescence and adulthood. Oxytocin system changes were also apparent in the ventral tegmental and medial preoptic regions of drug-exposed adolescent and adult offspring. These results suggest that dam treatment with ethanol and nicotine can somewhat negatively affect the early rearing environment, and that prenatal exposure to both of these drugs results in drinking behavior differing from what would be expected from either drug alone. Oxytocin's possible involvement in the mediation of these effects is highlighted.

Rationale-Little is known about mechanisms underlying female rodent aggression during the late postpartum period with no pups present. Studies of aggression, dominance, and oxytocin (OT) response in cocaine-treated females are sparse.Objectives-This study was designed to examine dominance (drinking success) and aggression in a limited-access drinking model of water competition. Acute OT level measures were made on postpartum day (PPD) 36 in several brain regions of interest. Chronic and intermittent cocaine- NIH Public AccessAuthor Manuscript Psychopharmacology (Berl). Author manuscript; available in PMC 2011 August 1. and saline-treated and untreated rats 10 days post-weaning were tested (without pups) over PPDs 31-35 following cessation of cocaine treatment 10-30 days before testing.Methods-Subjects were water-deprived overnight, and triads consisting of an untreated control (UN), a chronic continuous saline-treated (CS), and chronic continuous cocaine-treated (CC; 30 mg/kg/day throughout gestation) or a UN, an intermittent saline-treated (IS), and an intermittent cocaine-treated (IC; 30 mg/kg two consecutive days every 4 days throughout gestation until PPD 20) female were tested for aggression and drinking behavior during 5 min sessions on five consecutive days. The amygdala, medial preoptic area (MPOA), and ventral tegmental area were assayed for OT levels.Results-CC and IC females were more aggressive than controls, but only IC females drank more often than controls. OT levels were lower in the MPOA of IC and CC females than in controls.Conclusions-Findings demonstrate that long after cessation of treatment, CC-and IC-treated non-lactating females (no pups present) had higher rates of aggression, altered drinking behavior, and acutely lower MPOA OT levels.

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