Faculty Bibliography

The decisional reference point, the central mechanism underlying behavioral economics, conditions our evaluations of all reinforcers. Whether a given event is experienced as positive or negative depends on this reference point. A pathological elevation of the reference point would lead a person to experience once pleasurable activities as negative reinforcers. Thus, it has been hypothesized that a reference point pathology may play a critical role in the symptomology of major depressive disorder (MDD). Here, we test the hypothesis that the reference point is pathologically elevated and dynamically inflexible in patients suffering with MDD compared to healthy controls. We find that depression is associated with a significant elevation of the reference point, and the magnitude of this elevation correlates with disease severity. The ability of patients with MDD to dynamically adjust their reference point to the environment is also dysfunctional. Our findings link the previously demonstrated treatment of depression by deep brain stimulation to modulation of the reference point in the anterior cingulate cortex and identify pathology in the dynamics of reference point setting as a potential cognitive mechanism in the disorder. Finally, these results reveal that a three-minute video game-like task measuring the reference point strongly correlates with depression severity. After further testing for clinical validity, this rapid assay may serve as a potential tool for assessing and monitoring depression.

Episignatures are increasingly valuable for variant interpretation in rare neurodevelopmental disorders, especially when optimized to capture the impact of specific variant types and locations across a gene. Here, we generated a next-generation DNA methylation (DNAm) episignature for Kabuki syndrome type 1 (KS1) using the largest cohort studied to date, aiming to clarify the epigenomic and phenotypic effects of diverse KMT2D variant types and positions. Genome-wide DNAm profiles were obtained for 110 individuals with KMT2D variants and 854 controls using microarrays and long-read sequencing (LRS). Differentially methylated loci were enriched in genes involved in embryonic and nervous system development and were leveraged to construct a support-vector machine classifier for detecting pathogenic KMT2D variants. The classifier achieved 97% sensitivity and 100% specificity in validation cohorts and outperformed in silico tools, demonstrating stronger concordance with clinical presentation. Missense variants in the C-terminal region (exon 48) of KMT2D and the N-terminal plant homeodomain (PHD)-type zinc fingers were predominantly classified as pathogenic, highlighting regions enriched for pathogenic variants. Missense variants in the central region (exons 31-39) were more often predicted benign for KS1, consistent with potential association with a different syndrome, highlighting the classifier's specificity for KS1. Test performance was consistent across array and LRS platforms, and classifier scores reflected levels of mosaicism detected by LRS. The KS1 episignature also positively classified pathogenic KDM6A variants associated with KS2. These findings represent a significant advance in the evolution of episignature development, demonstrating diagnostic and interpretive value of a KS1 signature in resolving uncertain or complex cases.

Protease-activated receptor 2 (PAR₂) mediates oral cancer pain. Patients with metastatic (N + ) cancers report greater pain. PAR₂ is activated by N-terminal proteolytic cleavage. Here we show that proteases encoded by genes overexpressed in N+ cancers from patients with pain (matrix metallopeptidase 1, MMP1 and serine protease 23, PRSS23) elicit protease-specific receptor redistribution (trafficking) and signaling that differs from that promoted by proteases encoded by genes not differentially expressed (transmembrane serine protease matriptase, ST14 and cathepsin S, CTSS). Mixtures of the proteases prepared to model the oral cancer microenvironment revealed that ST14-mediated PAR₂ activation predominated at low protease concentrations. At high concentrations, MMP1 and PRSS23 prevailed over the greater potency of ST14. We propose that PAR₂ activation in oral N+ cancers from patients with pain is driven by high levels of MMP1 and PRSS23. Our study informs design of signaling and location-specific antagonists to provide more efficacious analgesia.

A social hierarchy is an ordered ranking of individuals that arises through their interactions and governs relative access to resources and social influence. This form of social organization is pervasive across animal species and has a crucial role in shaping survival and reproductive outcomes. Across species, the routes to high status vary widely. As social groups become more complex, the basis of hierarchy shifts from simple residency rules to fighting-based dominance and finally to alliance-based systems. In this Review, we first examine the neuroendocrine and subcortical mechanisms that support status transitions in residency-based hierarchies. We then discuss plasticity within hypothalamic and mesolimbic circuits that underlie fighting-outcome-based social learning, through which fighting-based hierarchies emerge. Finally, we explore alliance-based hierarchies in cognitively complex species, in which individuals attain status through coalition formation, cooperation and reputation. We review evidence that cortical regions encode information about the strengths, emotions, experiences and intentions of other individuals and use this to navigate complex social interactions and attain status. As social hierarchies have shifted from primarily fighting-based to increasingly alliance-based strategies over evolutionary time, neural control of status has, thus, transitioned from subcortical social behaviour circuits to a more elaborated cortical network in humans.

The capacity of hippocampal circuits to transform inputs into downstream outputs is fundamental to navigation and memory, yet the circuit-level mechanisms that enable this flexibility in adapting to experience remain unclear. Here we approach this problem by performing large-scale (up to 1,024 channel) recordings across the hippocampal-retrosplenial cortex (RSC) circuit in behaving mice, enabling simultaneous access to spiking activity in dentate gyrus (DG), CA3, CA2, CA1 and RSC. On the basis of a linear dimensionality-reduction technique known as partial canonical correlation analysis, we identify low-dimensional communication subspaces¹ between two regions while accounting for influences from a third area. These subspaces captured distinct input-output transformations in the CA1 region, linking upstream hippocampal activity (DG, CA3 and CA2) to downstream cortical targets (RSC). Intrinsic firing properties and anatomical location constrained subspace memberships-members were mapped to deep sublayers of the CA3-CA1-RSC axis during both spatial and non-spatial tasks. These subspaces could recombine overlapping neuronal pools to support distinct interareal interactions across changing experiences and brain states. Reactivation patterns of CA1-CA3 subspaces, but not those of CA1-RSC, during post-experience sleep correlated with replay, reflecting a plasticity-stability balance in the input-output transformation along the hippocampal-retrosplenial axis. Our findings suggest a model in which hippocampal-neocortical communication reconfigures predetermined circuit motifs to flexibly encode experiences.

Neuronal axons have traditionally been considered to be the primary mediators of functional connectivity among brain regions. However, the role of astrocyte-mediated communication has been largely underappreciated. Astrocytes communicate with one another through gap junctions, but the extent and specificity of this communication remain poorly understood. Astrocyte gap junctions are necessary for memory formation^1,2, synaptic plasticity^3-5, coordination of neuronal signalling⁶, and closing the visual and motor critical periods^7,8. These findings indicate that this form of communication is essential for proper central nervous system development and function. Despite the importance of astrocyte gap junctional networks, studying them has been challenging. Current methods such as slice electrophysiology disrupt network connectivity and introduce artefacts due to tissue damage. Here, we developed a vector-based approach that labels molecules as they are fluxed by astrocyte gap junctions in awake, behaving animals to overcome these limitations. We then used whole-brain tissue clearing^9,10 to image these intact, three-dimensional astrocyte networks. We show that multiple astrocyte networks traverse the mouse brain. These networks selectively connect specific regions, rather than diffusing indiscriminately, and vary in size and organization. We observe local networks that are confined to single brain regions and long-range networks that robustly interconnect multiple regions across hemispheres, often exhibiting patterns distinct from known neuronal networks. We also demonstrate that astrocyte networks undergo structural reorganization in the adult brain after sensory deprivation. These findings reveal a mode of communication between distant brain regions that is mediated by plastic networks of gap junction-coupled astrocytes.

BackgroundThe cellular mechanisms that promote the maintenance of cognitive abilities in very old people designated as successful agers remain under-investigated. Here, we report an episodic memory performance-based criteria that differentiates superior cognitive function from normative cognitive function in adults aged 80 and older.ObjectiveUsing this new criteria, we demonstrate how neuropathological and neurobiological underpinnings of superior cognitive performance can be investigated.MethodsThe most recent verbal episodic memory WMS-R Logical Memory Delayed Recall (LM-DR) score was derived from 144 participants with no cognitive impairment (NCI) 80 years or older participants from the Rush Religious Orders Study classified with Superior Cognitive Performance (SCP, LM-DR ≥ 14) or Normal Cognitive Performance (NCP, LM-DR 13 ≥ 7). Both groups were compared on neuropathological measures for neuritic plaque (NP), diffuse plaque (DP), and neurofibrillary tangle (NFT) load.ResultsNP (p = 0.44), DP (p = 0.27), and NFT (p = 0.28) burden did not differ between SCP and NCP cases. LM-DR scores did not correlate with NP (r = -0.08, p = 0.32), DP (r = -0.14, p = 0.07), or NFT (r = -0.12, p = 0.13) load. Biochemical analysis revealed significantly higher levels of heat-shock protein HSPB6 in SCP compared to NCP (p < 0.001).ConclusionsHeat shock protein differences were observed between NCP and SCP groups. This suggests that our proposed criteria for SCP can help identify neurobiological mechanisms of successful cognitive aging. Our SCP criteria are also concordant with the SuperAger criteria which supports the generalizability of the SCP criteria to other datasets.

BACKGROUND/UNASSIGNED:The aging and caregiving population is becoming increasingly diverse in the United States, leading to a growing need for culturally adapted interventions to address the unique needs of underrepresented groups, such as Asian Americans. However, interventions targeting Asian Americans and exploring cultural adaptation strategies remain limited in dementia caregiving research. OBJECTIVE/UNASSIGNED:This study aimed to describe the cultural adaptation process of an evidence-based intervention for Chinese and Korean American dementia caregivers, called the New York University Caregiver Intervention-Enhanced Support. METHODS/UNASSIGNED:We conducted a deductive content analysis and categorized our adaptation strategies into 5 elements: content, context, relationship fidelity and core elements, engagement, and cultural competence. Timing and types of responses to each adaptation strategy were also observed. Two authors conducted the initial analysis, and additional team members finalized the synthesis through discussion. The Template for Intervention Description and Replication (TIDieR) checklist was used to guide the methodological rigor. RESULTS/UNASSIGNED:Twenty-four major adaptations were identified and categorized. For content, we translated materials, used culturally relevant terms, incorporated ethnic-specific surveys and resources, created social media support groups on platforms widely used by the targeted population, and extended the time allocated to complete the 6 counseling sessions. Context adaptation included expanding the range of individuals eligible for family counseling sessions to include fictive kin, using online and social media apps for communication, cultural matching and training of staff, and partnerships with relevant community organizations. Relationship fidelity and core elements involved consulting with community experts, conducting focus group interviews with caregivers, having regular meetings with the developer of the original intervention and an experienced New York University Caregiver Intervention-Enhanced Support clinician as well as experts in Chinese and Korean culture, and continuing regular counseling supervision. To enhance engagement, we provided clear explanations of the study procedure, which emphasized the benefits in participants' native languages and matched participants with social workers who shared the same cultural backgrounds. We also used a step-by-step contact approach and prolonged communication, explained staff roles to build rapport, and offered participant compensation. Finally, cultural competence was reflected in tailoring counseling techniques with respect for cultural beliefs, the use of euphemistic language for taboo subjects, and culturally appropriate refreshments to show respect and build interpersonal relationships. CONCLUSIONS/UNASSIGNED:We systematically adjusted a counseling-based intervention, an approach less familiar among Asian Americans, to fit the cultural characteristics of the target population. A contribution of this study is using an integrated, theory-driven approach that combines 2 cultural adaptation frameworks while also capturing real-time adaptations informed by external feedback and self-reflection. This work provides a practical model for adapting evidence-based interventions to serve Chinese and Korean American dementia caregivers and may inform future adaptations for other East Asian populations.

MR imaging is increasingly used in evaluation of patients with known or suspected hypertrophic cardiomyopathy (HCM), as it provides useful information on cardiac structure, function, and tissue characterization that is complementary to echocardiography. While the adverse effect of left ventricle (LV) outflow tract obstruction on blood flow patterns is well characterized by the midsystolic drop in LV ejection velocities and flow, flow patterns in HCM with mid-LV obstruction, with or without apical aneurysm, are less well characterized. MR imaging can provide additional information on alterations of blood flow patterns in these HCM phenotypes and "paradoxic" flows associated with apical aneurysms.