Faculty Bibliography

Human brain function undergoes complex transformations across the lifespan. We employed resting-state functional MRI and graph-theory approaches to systematically chart the lifespan trajectory of the topological organization of human whole-brain functional networks in 126 healthy individuals ranging in age from 7 to 85 years. Brain networks were constructed by computing Pearson's correlations in blood-oxygenation-level-dependent temporal fluctuations among 1024 parcellation units followed by graph-based network analyses. We observed that the human brain functional connectome exhibited highly preserved non-random modular and rich club organization over the entire age range studied. Further quantitative analyses revealed linear decreases in modularity and inverted-U shaped trajectories of local efficiency and rich club architecture. Regionally heterogeneous age effects were mainly located in several hubs (e.g., default network, dorsal attention regions). Finally, we observed inverse trajectories of long- and short-distance functional connections, indicating that the reorganization of connectivity concentrates and distributes the brain's functional networks. Our results demonstrate topological changes in the whole-brain functional connectome across nearly the entire human lifespan, providing insights into the neural substrates underlying individual variations in behavior and cognition. These results have important implications for disease connectomics because they provide a baseline for evaluating network impairments in age-related neuropsychiatric disorders.

Sulfur is required for the biosynthesis of cysteine, methionine and numerous other metabolites, and thus is critical for cellular metabolism and various growth and developmental processes. Plants are able to sense their physiological state with respect to sulfur availability, but the sensor remains to be identified. Here we report the isolation and characterization of two novel allelic mutants of Arabidopsis thaliana, sel1-15 and sel1-16, which show increased expression of a sulfur deficiency-activated gene beta-glucosidase 28 (BGLU28). The mutants, which represent two different missense alleles of SULTR1;2, which encodes a high-affinity sulfate transporter, are defective in sulfate transport and as a result have a lower cellular sulfate level. However, when treated with a very high dose of sulfate, sel1-15 and sel1-16 accumulated similar amounts of internal sulfate and its metabolite glutathione (GSH) to wild-type, but showed higher expression of BGLU28 and other sulfur deficiency-activated genes than wild-type. Reduced sensitivity to inhibition of gene expression was also observed in the sel1 mutants when fed with the sulfate metabolites Cys and GSH. In addition, a SULTR1;2 knockout allele also exhibits reduced inhibition in response to sulfate, Cys and GSH, consistent with the phenotype of sel1-15 and sel1-16. Taken together, the genetic evidence suggests that, in addition to its known function as a high-affinity sulfate transporter, SULTR1;2 may have a regulatory role in response to sulfur nutrient status. The possibility that SULTR1;2 may function as a sensor of sulfur status or a component of a sulfur sensory mechanism is discussed.

Pavlovian conditioning is the reference paradigm for the study of associative learning based on the programmed relation of two stimuli, the conditioned stimulus (CS) and the unconditioned stimulus (US). Some authors believe that learning the CS-US interval is a co-requisite of or a pre-requisite to learning the CS-US association. There is a substantial literature showing that the amygdala is a critical player in Pavlovian conditioning, with both aversive and appetitive USs. We review a sparse but growing body of literature suggesting that the amygdala may also participate in processing the timing of the CS-US interval. We discuss whether the amygdala, in particular its central, basal and lateral nuclei, in concert with the network it belongs to, may play a role in learning the CS-US interval. We also suggest new and dedicated strategies that would result in better knowledge of the neural mechanisms underlying the learning of the CS-US time interval in isolation from the CS-US association.

Relapse vulnerability in cocaine dependence is rooted in genetic and environmental determinants, and propelled by both impulsivity and the responsivity to cocaine-linked cues ('cue reactivity'). The serotonin (5-hydroxytryptamine, 5-HT) 5-HT2C receptor (5-HT2CR) within the medial prefrontal cortex (mPFC) is uniquely poised to serve as a strategic nexus to mechanistically control these behaviors. The 5-HT2CR functional capacity is regulated by a number of factors including availability of active membrane receptor pools, the composition of the 5-HT2CR macromolecular protein complex, and editing of the 5-HT2CR pre-mRNA. The one-choice serial reaction time (1-CSRT) task was used to identify impulsive action phenotypes in an outbred rat population before cocaine self-administration and assessment of cue reactivity in the form of lever presses reinforced by the cocaine-associated discrete cue complex during forced abstinence. The 1-CSRT task reliably and reproducibly identified high impulsive (HI) and low impulsive (LI) action phenotypes; HI action predicted high cue reactivity. Lower cortical 5-HT2CR membrane protein levels concomitant with higher levels of 5-HT2CR:postsynaptic density 95 complex distinguished HI rats from LI rats. The frequency of edited 5-HT2CR mRNA variants was elevated with the prediction that the protein population in HI rats favors those isoforms linked to reduced signaling capacity. Genetic loss of the mPFC 5-HT2CR induced aggregate impulsive action/cue reactivity, suggesting that depressed cortical 5-HT2CR tone confers vulnerability to these interlocked behaviors. Thus, impulsive action and cue reactivity appear to neuromechanistically overlap in rodents, with the 5-HT2CR functional status acting as a neural rheostat to regulate, in part, the intersection between these vulnerability behaviors.

Perceiving possibilities for action-affordances-requires sensitivity, accuracy, and consistency. In the current study, we tested children of different ages (16-month-olds to 7-year-olds) and adults to examine the development of affordance perception for reaching through openings of various sizes. Using a psychophysical procedure, we estimated individual affordance functions to characterize participants' actual ability to fit their hand through openings and individual decision functions to characterize attempts to reach. Decisions were less accurate in younger children (16-month-olds to 5-year-olds); they were more likely to attempt impossible openings and to touch openings prior to refusing, suggesting a slow developmental trend in learning to perceive affordances for fitting through openings. However, analyses of multiple outcome measures revealed that the youngest participants were equally consistent in their decision making as the oldest ones and that every age group showed sensitivity to changes in the environment by scaling their attempts to opening size.

Quality indicators for programs integrating parent-delivered family support services for children's mental health have not been systematically developed. Increasing emphasis on accountability under the Affordable Care Act highlights the importance of quality-benchmarking efforts. Using a modified Delphi approach, quality indicators were developed for both program level and family support specialist level practices. These indicators were pilot tested with 21 community-based mental health programs. Psychometric properties of these indicators are reported; variations in program and family support specialist performance suggest the utility of these indicators as tools to guide policies and practices in organizations that integrate parent-delivered family support service components.

This study describes services provided by family support specialists (FSS), peer advocates in programs for children with serious psychiatric conditions, to delineate differences between recommended components of FSS services and services actually provided. An analysis of qualitative interview and observational data and quantitative survey data from 63 staff at 21 mental health programs in New York identified that FSS and other staff have generally similar ideas about FSS services, and that these perceptions of activities are generally congruent with what FSS actually did. Implications of findings are discussed in the context of developing competencies and quality indicators for FSS.