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Mother-infant self- and interactive contingency at four months and infant cognition at one year: A view from microanalysis

Beebe, Beatrice; Abdurokhmonova, Gavkhar; Lee, Sang Han; Dougalis, Georgios; Champagne, Frances; Rauh, Virginia; Algermissen, Molly; Herbstman, Julie; Margolis, Amy E
Although a considerable literature documents associations between early mother-infant interaction and cognitive outcomes in the first years of life, few studies examine the contributions of contingently coordinated mother-infant interaction to infant cognitive development. This study examined associations between the temporal dynamics of the contingent coordination of mother-infant face-to-face interaction at 4 months and cognitive performance on the Bayley Scales of Infant Development at age one year in a sample of (N = 100) Latina mother-infant pairs. Split-screen videotaped interactions were coded on a one second time base for the communication modalities of infant and mother gaze and facial affect, infant vocal affect, and mother touch. Multi-level time-series models evaluated self- and interactive contingent processes in these modalities and revealed 4-month patterns of interaction associated with higher one-year cognitive performance, not identified in prior studies. Infant and mother self-contingency, the moment-to-moment probability that the individual's prior behavior predicts the individual's future behavior, was the most robust measure associated with infant cognitive performance. Self-contingency findings showed that more varying infant behavior was optimal for higher infant cognitive performance, namely, greater modulation of negative affect; more stable maternal behavior was optimal for higher infant cognitive performance, namely, greater likelihood of sustaining positive facial affect. Although interactive contingency findings were sparse, they showed that, when mothers looked away, or dampened their faces to interest or mild negative facial affect, infants with higher 12-month cognitive performance were less likely to show negative vocal affect. We suggest that infant ability to modulate negative affect, and maternal ability to sustain positive affect, may be mutually reinforcing, together creating a dyadic climate that is associated with more optimal infant cognitive development.
PMID: 38237345
ISSN: 1934-8800
CID: 5639722

Maternal choline supplementation protects against age-associated cholinergic and GABAergic basal forebrain neuron degeneration in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease

Gautier, Megan K; Kelley, Christy M; Lee, Sang Han; Alldred, Melissa J; McDaid, John; Mufson, Elliott J; Stutzmann, Grace E; Ginsberg, Stephen D
Down syndrome (DS) is a genetic disorder caused by triplication of human chromosome 21. In addition to intellectual disability, DS is defined by a premature aging phenotype and Alzheimer's disease (AD) neuropathology, including septohippocampal circuit vulnerability and degeneration of basal forebrain cholinergic neurons (BFCNs). The Ts65Dn mouse model recapitulates key aspects of DS/AD pathology, namely age-associated atrophy of BFCNs and cognitive decline in septohippocampal-dependent behavioral tasks. We investigated whether maternal choline supplementation (MCS), a well-tolerated treatment modality, protects vulnerable BFCNs from age- and genotype-associated degeneration in trisomic offspring. We also examined the effect of trisomy, and MCS, on GABAergic basal forebrain parvalbumin neurons (BFPNs), an unexplored neuronal population in this DS model. Unbiased stereological analyses of choline acetyltransferase (ChAT)-immunoreactive BFCNs and parvalbumin-immunoreactive BFPNs were conducted using confocal z-stacks of the medial septal nucleus and the vertical limb of the diagonal band (MSN/VDB) in Ts65Dn mice and disomic (2N) littermates at 3-4 and 10-12 months of age. MCS trisomic offspring displayed significant increases in ChAT-immunoreactive neuron number and density compared to unsupplemented counterparts, as well as increases in the area of the MSN/VDB occupied by ChAT-immunoreactive neuropil. MCS also rescued BFPN number and density in Ts65Dn offspring, a novel rescue of a non-cholinergic cell population. Furthermore, MCS prevented age-associated loss of BFCNs and MSN/VDB regional area in 2N offspring, indicating genotype-independent neuroprotective benefits. These findings demonstrate MCS provides neuroprotection of vulnerable BFCNs and non-cholinergic septohippocampal BFPNs, indicating this modality has translational value as an early life therapy for DS, as well as extending benefits to the aging population at large.
PMID: 37890559
ISSN: 1095-953x
CID: 5608002

Robust tests for scatter separability beyond Gaussianity

Kim, Seungkyu; Park, Seongoh; Lim, Johan; Lee, Sang Han
Separability (a Kronecker product) of a scatter matrix is one of favorable structures when multivariate heavy-tailed data are collected in a matrix form, due to its parsimonious representation. However, little attempt has been made to test separability beyond Gaussianity. In this paper, we present nonparametric separability tests that can be applied to a larger class of multivariate distributions not only including elliptical distributions but also generalized elliptical distributions and transelliptical distributions. The proposed test statistic exploits robustness of Tyler's M (or Kendall's tau) estimator and a likelihood function of a scaled variable. Since its distribution is hard to specify, we approximate the p-value using a permutation procedure, whose unbiasedness is obtained from the permutation invariance of multivariate paired data. Our simulation study demonstrates the efficacy of our method against other alternatives, and we apply it to rhesus monkey data and corpus callosum data.
ISSN: 0167-9473
CID: 5350452

Correction to: Profiling Basal Forebrain Cholinergic Neurons Reveals a Molecular Basis for Vulnerability Within the Ts65Dn Model of Down Syndrome and Alzheimer's Disease

Alldred, Melissa J; Penikalapati, Sai C; Lee, Sang Han; Heguy, Adriana; Roussos, Panos; Ginsberg, Stephen D
PMID: 34837629
ISSN: 1559-1182
CID: 5063972

Profiling Basal Forebrain Cholinergic Neurons Reveals a Molecular Basis for Vulnerability Within the Ts65Dn Model of Down Syndrome and Alzheimer's Disease

Alldred, Melissa J; Penikalapati, Sai C; Lee, Sang Han; Heguy, Adriana; Roussos, Panos; Ginsberg, Stephen D
Basal forebrain cholinergic neuron (BFCN) degeneration is a hallmark of Down syndrome (DS) and Alzheimer's disease (AD). Current therapeutics have been unsuccessful in slowing disease progression, likely due to complex pathological interactions and dysregulated pathways that are poorly understood. The Ts65Dn trisomic mouse model recapitulates both cognitive and morphological deficits of DS and AD, including BFCN degeneration. We utilized Ts65Dn mice to understand mechanisms underlying BFCN degeneration to identify novel targets for therapeutic intervention. We performed high-throughput, single population RNA sequencing (RNA-seq) to interrogate transcriptomic changes within medial septal nucleus (MSN) BFCNs, using laser capture microdissection to individually isolate ~500 choline acetyltransferase-immunopositive neurons in Ts65Dn and normal disomic (2N) mice at 6 months of age (MO). Ts65Dn mice had unique MSN BFCN transcriptomic profiles at ~6 MO clearly differentiating them from 2N mice. Leveraging Ingenuity Pathway Analysis and KEGG analysis, we linked differentially expressed gene (DEG) changes within MSN BFCNs to several canonical pathways and aberrant physiological functions. The dysregulated transcriptomic profile of trisomic BFCNs provides key information underscoring selective vulnerability within the septohippocampal circuit. We propose both expected and novel therapeutic targets for DS and AD, including specific DEGs within cholinergic, glutamatergic, GABAergic, and neurotrophin pathways, as well as select targets for repairing oxidative phosphorylation status in neurons. We demonstrate and validate this interrogative quantitative bioinformatic analysis of a key dysregulated neuronal population linking single population transcript changes to an established pathological hallmark associated with cognitive decline for therapeutic development in human DS and AD.
PMID: 34263425
ISSN: 1559-1182
CID: 4937542

Adiponectin Modulation by Genotype and Maternal Choline Supplementation in a Mouse Model of Down Syndrome and Alzheimer's Disease

Alldred, Melissa J; Lee, Sang Han; Ginsberg, Stephen D
Down syndrome (DS) is a genetic disorder caused by the triplication of human chromosome 21, which results in neurological and physiological pathologies. These deficits increase during aging and are exacerbated by cognitive decline and increase of Alzheimer's disease (AD) neuropathology. A nontoxic, noninvasive treatment, maternal choline supplementation (MCS) attenuates cognitive decline in mouse models of DS and AD. To evaluate potential underlying mechanisms, laser capture microdissection of individual neuronal populations of MCS offspring was performed, followed by RNA sequencing and bioinformatic inquiry. Results at ~6 months of age (MO) revealed DS mice (the well-established Ts65Dn model) have significant dysregulation of select genes within the Type 2 Diabetes Mellitus (T2DM) signaling pathway relative to normal disomic (2N) littermates. Accordingly, we interrogated key T2DM protein hormones by ELISA assay in addition to gene and encoded protein levels in the brain. We found dysregulation of adiponectin (APN) protein levels in the frontal cortex of ~6 MO trisomic mice, which was attenuated by MCS. APN receptors also displayed expression level changes in response to MCS. APN is a potential biomarker for AD pathology and may be relevant in DS. We posit that changes in APN signaling may be an early marker of cognitive decline and neurodegeneration.
PMID: 34279477
ISSN: 2077-0383
CID: 4947912

Oxidative Phosphorylation Is Dysregulated Within the Basocortical Circuit in a 6-month old Mouse Model of Down Syndrome and Alzheimer's Disease

Alldred, Melissa J; Lee, Sang Han; Stutzmann, Grace E; Ginsberg, Stephen D
Down syndrome (DS) is the primary genetic cause of intellectual disability (ID), which is due to the triplication of human chromosome 21 (HSA21). In addition to ID, HSA21 trisomy results in a number of neurological and physiological pathologies in individuals with DS, including progressive cognitive dysfunction and learning and memory deficits which worsen with age. Further exacerbating neurological dysfunction associated with DS is the concomitant basal forebrain cholinergic neuron (BFCN) degeneration and onset of Alzheimer's disease (AD) pathology in early mid-life. Recent single population RNA sequencing (RNA-seq) analysis in the Ts65Dn mouse model of DS, specifically the medial septal cholinergic neurons of the basal forebrain (BF), revealed the mitochondrial oxidative phosphorylation pathway was significantly impacted, with a large subset of genes within this pathway being downregulated. We further queried oxidative phosphorylation pathway dysregulation in Ts65Dn mice by examining genes and encoded proteins within brain regions comprising the basocortical system at the start of BFCN degeneration (6 months of age). In select Ts65Dn mice we demonstrate significant deficits in gene and/or encoded protein levels of Complex I-V of the mitochondrial oxidative phosphorylation pathway in the BF. In the frontal cortex (Fr Ctx) these complexes had concomitant alterations in select gene expression but not of the proteins queried from Complex I-V, suggesting that defects at this time point in the BF are more severe and occur prior to cortical dysfunction within the basocortical circuit. We propose dysregulation within mitochondrial oxidative phosphorylation complexes is an early marker of cognitive decline onset and specifically linked to BFCN degeneration that may propagate pathology throughout cortical memory and executive function circuits in DS and AD.
PMID: 34489678
ISSN: 1663-4365
CID: 5067122

Expression profiling of precuneus layer III cathepsin D-immunopositive pyramidal neurons in mild cognitive impairment and Alzheimer's disease: Evidence for neuronal signaling vulnerability

He, Bin; Perez, Sylvia E; Lee, Sang Han; Ginsberg, Stephen D; Malek-Ahmadi, Michael; Mufson, Elliott J
The precuneus (PreC; Brodmann area 7), a key hub within the default mode network (DMN) displays amyloid and tau-containing neurofibrillary tangle (NFT) pathology during the onset of Alzheimer's disease (AD). PreC layer III projection neurons contain lysosomal hydrolase cathepsin D (CatD), 14)a marker of neurons vulnerable to NFT pathology. Here we applied single population laser capture microdissection coupled with custom-designed microarray profiling to determine the genetic signature of PreC CatD-positive-layer III neurons accrued from postmortem tissue obtained from the Rush Religious Orders Study (RROS) cases with a premortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI) and AD. Expression profiling revealed significant differential expression of key transcripts in MCI and AD compared to NCI that underlie signaling defects, including dysregulation of genes within the endosomal-lysosomal and autophagy pathways, cytoskeletal elements, AD-related genes, ionotropic and metabotropic glutamate receptors, cholinergic enzyme and receptors, markers of monoamine neurotransmission as well as steroid-related transcripts. Pervasive defects in both MCI and AD were found in select transcripts within these key gene ontology categories, underscoring the vulnerability of these corticocortical neurons during the onset and progression of dementia. Select PreC dysregulated genes detected via custom-designed microarray analysis were validated using qPCR. In summary, expression profiling of CatD positive PreC layer III neurons revealed significant dysregulation of a mosaic of genes in MCI and AD that were not previously appreciated in terms of their indication of systems-wide signaling defects in a key hub of the DMN. This article is protected by copyright. All rights reserved.
PMID: 32323319
ISSN: 1096-9861
CID: 4402282

Urgent engagement in 9/11 pregnant widows and their infants: Transmission of trauma

Beebe, Beatrice; Hoven, Christina W; Kaitz, Marsha; Steele, Miriam; Musa, George; Margolis, Amy; Ewing, Julie; Sossin, K Mark; Lee, Sang Han
The potential effects of maternal trauma on mother-infant interaction remain insufficiently studied empirically. This study examined the effects of the September 11, 2001, trauma on mother-infant interaction in mothers who were pregnant and widowed on 9/11, and their infants aged 4-6 months. Split-screen videotaped interaction was coded on a one-second basis for infant gaze, facial affect, and vocal affect; and mother gaze, facial affect, and touch. We examined the temporal dynamics of communication: self-contingency and interactive contingency of behavior by time-series methods. We documented heightened maternal and infant efforts at engagement in the 9/11 (vs. control) dyads. Both partners had difficulty tolerating moments of looking away as well as moments of negative behavior patterns. Heightened efforts to maintain a positive visual engagement may be adaptive and a potential source of resilience, but these patterns may also carry risk: working too hard to make it work. A vigilant, hyper-contingent, high-arousal engagement was the central mode of the interpersonal transmission of the trauma to these infants, with implications for intervention.
PMID: 32749044
ISSN: 1532-7078
CID: 4553852

Grant Report on Social Reward Learning in Schizophrenia †

Butler, Pamela D; Hoptman, Matthew J; Smith, David V; Ermel, Julia A; Calderone, Daniel J; Lee, Sang Han; Barch, Deanna M
We report on the ongoing R21 project "Social Reward Learning in Schizophrenia". Impairments in social cognition are a hallmark of schizophrenia. However, little work has been done on social reward learning deficits in schizophrenia. The overall goal of the project is to assess social reward learning in schizophrenia. A probabilistic reward learning (PRL) task is being used in the MRI scanner to evaluate reward learning to negative and positive social feedback. Monetary reward learning is used as a comparison to assess specificity. Behavioral outcomes and brain areas, included those involved in reward, are assessed in patients with schizophrenia or schizoaffective disorder and controls. It is also critical to determine whether decreased expected value (EV) of social stimuli and/or reward prediction error (RPE) learning underlie social reward learning deficits to inform potential treatment pathways. Our central hypothesis is that the pattern of social learning deficits is an extension of a more general reward learning impairment in schizophrenia and that social reward learning deficits critically contribute to deficits in social motivation and pleasure. We hypothesize that people with schizophrenia will show impaired behavioral social reward learning compared to controls, as well as decreased ventromedial prefrontal cortex (vmPFC) EV signaling at time of choice and decreased striatal RPE signaling at time of outcome, with potentially greater impairment to positive than negative feedback. The grant is in its second year. It is hoped that this innovative approach may lead to novel and more targeted treatment approaches for social cognitive impairments, using cognitive remediation and/or brain stimulation.
PMID: 32206729
ISSN: 2398-385x
CID: 4357732