Faculty Bibliography

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.

BACKGROUND:The striatal-pallidal pathway plays an important role in cognitive control and modulation of behaviors. Globus pallidus interna (GPi), as a primary output structure, is crucial in modulating excitation and inhibition. Studies of GPi in psychiatric illnesses are lacking given the technical challenges of examining this small and functionally diverse subcortical structure. METHODS:71 medication-naïve first episode schizophrenia (FES) participants and 73 healthy controls (HC) were recruited at the Shanghai Mental Health Center. Clinical symptoms and imaging data were collected at baseline and, in a subset of patients, 8 weeks after initiating treatment. Resting-state functional connectivity of sub-regions of the GP were assessed using a novel mask that combines two atlases to create 8 ROIs in the GP. RESULTS: = 0.486, p < 0.001). CONCLUSIONS:Our results implicate striatal-pallidal-thalamic pathways in antipsychotic efficacy. If replicated, these findings may reflect failure of neurodevelopmental processes in adolescence and early adulthood that decrease functional connectivity as an index of failure of the limbic/associative GPi to appropriately inhibit irrelevant signals in psychosis.

OBJECTIVES/OBJECTIVE:Heightened irritability in adolescence is an impairing symptom that can lead to negative outcomes in adulthood, but effective screening tools are lacking. This study aimed to derive clinically-optimized cutoff scores using the Multidimensional Assessment Profile Scales-Temper Loss (MAPS-TL) to pragmatically identify adolescents with impairing irritability. METHODS:A diverse sample of 79 adolescents and their parents completed the MAPS-TL-Youth version. Stepwise logistic regression analyses were used to determine the items associated with impairment, and receiver operator characteristic (ROC) analyses were conducted to derive optimal cutoff scores. RESULTS:Three parent-report items (become frustrated easily, angry/irritable/grouchy throughout the day, difficulty calming down when angry) and two youth-report items (hit/shove/kick when lost temper, difficulty calming down when angry) were strongly associated with impairment. Optimal cutoff scores garnered very good sensitivity (91%, 73%) and specificity (77%, 75%) for the parent- and youth-report versions respectively. Scores above these cutoffs were associated with increased internalizing and externalizing problems and lower overall quality of life. CONCLUSIONS:The MAPS-TL clinically optimized irritability scores show preliminary validity for implementation in practical settings to efficiently identify adolescents who need additional evaluation and/or intervention. Further research is important to validate these cutoff scores with larger population-based samples and real-world settings.

When children first meet a stranger, there is great variation in how much they will approach and engage with the stranger. While individual differences in this type of behavior-called social wariness-are well-documented in temperament research, surprisingly little attention has been paid to the social groups (such as race) of the stranger and how these characteristics might influence children's social wariness. In contrast, research on children's social bias and interracial friendships rarely examines individual differences in temperament and how temperament might influence cross-group interactions. The current study bridges the gap across these different fields of research by examining whether the racial group of an unfamiliar peer or adult moderates the association between temperament and the social wariness that children display. Utilizing a longitudinal dataset that collected multiple measurements of children's temperament and behaviors (including parent-reported shyness and social wariness toward unfamiliar adults and peers) across early childhood, we found that 2- to 7-year-old children with high parent-reported shyness showed greater social wariness toward a different-race stranger compared to a same-race stranger, whereas children with low parent-reported shyness did not. These results point to the importance of considering racial group membership in temperament research and the potential role that temperament might play in children's cross-race interactions. RESEARCH HIGHLIGHTS: Previous research on temperament has not considered how the race of strangers could influence children's social wariness. We find evidence that 2- to 7-year-old children with high parent-reported shyness show greater social wariness toward a different-race stranger compared to a same-race stranger. These results point to the importance of considering racial group membership in temperament research. Our findings also suggest temperament may play a role in children's cross-race interactions.

Interferon ɛ (IFNɛ) is a unique type I IFN that has been implicated in host defense against sexually transmitted infections. Zika virus (ZIKV), an emerging pathogen, can infect the female reproductive tract (FRT) and cause devastating diseases, particularly in pregnant women. How IFNɛ contributes to protection against ZIKV infection in vivo is unknown. In this study, we show that IFNɛ plays a critical role in host protection against vaginal ZIKV infection in mice. We found that IFNɛ was expressed not only by epithelial cells in the FRT but also by immune and stromal cells at baseline or after exposure to viruses or specific Toll-like receptor (TLR) agonists. IFNɛ-deficient mice exhibited abnormalities in the epithelial border and underlying tissue in the cervicovaginal tract, and these defects were associated with increased susceptibility to vaginal but not subcutaneous ZIKV infection. IFNɛ deficiency resulted in an increase in magnitude, duration, and depth of ZIKV infection in the FRT. Critically, intravaginal administration of recombinant IFNɛ protected Ifnɛ^-/-