Faculty Bibliography

Tau protein truncated at Asp 421 is a characteristic feature of Alzheimer's disease and other tauopathies. Here, we show that a monoclonal antibody against Asp421, 5G2, cleared insoluble tau in the brains of JNPL3 mice, decreased tau levels in brain interstitial fluid in awake JNPL3 mice, improved in vivo neuronal function, and reduced microglial Iba-1 expression in PS19 mice, in which neuronal tau aggregation and dysfunction occurred earlier than microglial activation. For mechanistic insight using culture models, 5G2 prevented tau-mediated toxicity, cleared extra- and intracellular tau, and prevented microgliosis. TRIM21 knockdown reduced neuronal retention of tau antibodies and their acute but not longer-term efficacy. Inhibition of the endosomal/lysosomal pathway but not the proteasomal pathway blocked 5G2-mediated neuroprotection and tau clearance. These findings support targeting the Asp421 truncated tau protein to treat tauopathies, indicate that tau-associated neuronal dysfunction precedes microglial activation, and that intraneuronal antibody-mediated tau clearance is mostly via the lysosomes.

Ischemic heart disease is the leading cause of heart failure with reduced ejection fraction in the developed world. An evolution of background medical therapy over the past decade has spurred improvement in symptoms and a reduction in morbidity and mortality with ischemic cardiomyopathy. However, there is still ongoing debate about the role and impact of revascularization. Much of the societal guidance regarding revascularization with coronary artery bypass grafting in ischemic cardiomyopathy comes from the STICH trial (Surgical Treatment for Ischemic Heart Failure) which predates improvements in medical therapy. More recently, the REVIVED-BCIS2 trial (Revascularization for Ischemic Ventricular Dysfunction-British Cardiovascular Intervention Society) failed to show a benefit of percutaneous coronary intervention on heart failure hospitalization and mortality in ischemic cardiomyopathy over contemporary medical therapy alone. Yet, there are outstanding questions regarding the role and modality of revascularization required to improve outcomes. We review current data and future directions in the management of ischemic cardiomyopathy and the potential role of revascularization.

Becoming a parent involves extraordinary changes that allow caregivers to attend to and nurture infants. Neural circuits must adapt to the demands of caregiving to orchestrate various complex nurturing behaviors. These changes occur between two opposing circuits: a circuit primed for the expression of parenting to execute caregiving, and a circuit that suppresses this behavioral expression when the timing is not appropriate. In this review, we provide an overview of the neural circuits supporting the positive and negative control of parental behaviors and discuss mechanisms by which these opposing circuits are altered to facilitate the onset of parental care.

Identifying the computational roles of different neuron families is crucial for understanding neural networks. Most neural diversity is embodied in various types of γ-aminobutyric acid-mediated (GABAergic) interneurons, grouped into four major families. We collected datasets of opto-tagged neurons from all four families, along with excitatory neurons, from both the neocortex and hippocampus. The physiological features of these neurons were used to train a machine learning classifier, which subsequently inferred specific interneuron families in large-scale recordings. This combined approach enabled the reconstruction of synaptic connectivity motifs across interneuron family members. We further showed that these motifs differentially control the place field features of pyramidal neurons. Our findings attribute a prominent role to interneurons in the formation of a flexible cognitive map.

Fish actively control posture in the pitch axis (nose-up/nose-down) to counter instability and regulate their elevation in the water column. To test the hypothesis that environmental cues shape strategies fish use to control posture, we leveraged a serendipitous finding: larval zebrafish (Danio rerio) lose swim bladder volume and sink mildly after acute loss of lateral line hair cells. Using long-term (48 h) recordings of unrestrained swimming, we discovered that sinking larvae compensated differently depending on light conditions. In the dark, they swim more frequently with an increased nose-up posture. In contrast, larvae in the light do not swim more frequently, but do climb more often. Finally, after lateral line regeneration, larvae returned to normal buoyancy and swam comparably to control siblings. We conclude that larvae can switch postural control strategies depending on the availability of visual information. Our findings complement and extend morphological and kinematic analyses of locomotion. More broadly, by quantifying the variation in strategies our work speaks to the evolutionary substrate for different balance behaviors.

Decreased brain levels of coenzyme Q₁₀ (CoQ₁₀), an endogenously synthesized lipophilic antioxidant^1,2, underpin encephalopathy in primary CoQ₁₀ deficiencies^3,4 and are associated with common neurodegenerative diseases and the ageing process^5,6. CoQ₁₀ supplementation does not increase CoQ₁₀ pools in the brain or in other tissues. The recent discovery of the mammalian CoQ₁₀ headgroup synthesis pathway, in which 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL) makes 4-hydroxymandelate (4-HMA) to synthesize the CoQ₁₀ headgroup precursor 4-hydroxybenzoate (4-HB)⁷, offers an opportunity to pharmacologically restore CoQ₁₀ synthesis and mechanistically treat CoQ₁₀ deficiencies. To test whether 4-HMA or 4-HB supplementation promotes CoQ₁₀ headgroup synthesis in vivo, here we administered 4-HMA and 4-HB to Hpdl^-/- mice, which model an ultra-rare, lethal mitochondrial encephalopathy in humans. Both 4-HMA and 4-HB were incorporated into CoQ₉ and CoQ₁₀ in the brains of Hpdl^-/- mice. Oral treatment of Hpdl^-/- pups with 4-HMA or 4-HB enabled 90-100% of Hpdl^-/- mice to live to adulthood. Furthermore, 4-HB treatment stabilized and improved the neurological symptoms of a patient with progressive spasticity due to biallelic HPDL variants. Our work shows that 4-HMA and 4-HB can modify the course of mitochondrial encephalopathy driven by HPDL variants and demonstrates that CoQ₁₀ headgroup intermediates can restore CoQ₁₀ synthesis in vivo.

BACKGROUND:MRI plays a critical role in prostate cancer (PCa) detection and management. Bi-parametric MRI (bpMRI) offers a faster, contrast-free alternative to multi-parametric MRI (mpMRI). Routine use of mpMRI for all patients may not be necessary, and a tailored imaging approach (bpMRI or mpMRI) based on individual risk might optimize resource utilization. PURPOSE/OBJECTIVE:To develop and evaluate a deep learning (DL) model for classifying clinically significant PCa (csPCa) using bpMRI and to assess its potential for optimizing MRI protocol selection by recommending the additional sequences of mpMRI only when beneficial. STUDY TYPE/METHODS:Retrospective and prospective. POPULATION/METHODS:The DL model was trained and validated on 26,129 prostate MRI studies. A retrospective cohort of 151 patients (mean age 65 ± 8) with ground-truth verification from biopsy, prostatectomy, or long-term follow-up, alongside a prospective cohort of 142 treatment-naïve patients (mean age 65 ± 9) undergoing bpMRI, was evaluated. FIELD STRENGTH/SEQUENCE/UNASSIGNED:3 T, Turbo-spin echo T2-weighted imaging (T2WI) and single shot EPI diffusion-weighted imaging (DWI). ASSESSMENT/RESULTS:The DL model, based on a 3D ResNet-50 architecture, classified csPCa using PI-RADS ≥ 3 and Gleason ≥ 7 as outcome measures. The model was evaluated on a prospective cohort labeled by consensus of three radiologists and a retrospective cohort with ground truth verification based on biopsy or long-term follow-up. Real-time inference was tested on an automated MRI workflow, providing classification results directly at the scanner. STATISTICAL TESTS/METHODS:AUROC with 95% confidence intervals (CI) was used to evaluate model performance. RESULTS:In the prospective cohort, the model achieved an AUC of 0.83 (95% CI: 0.77-0.89) for PI-RADS ≥ 3 classification, with 93% sensitivity and 54% specificity. In the retrospective cohort, the model achieved an AUC of 0.86 (95% CI: 0.80-0.91) for Gleason ≥ 7 classification, with 93% sensitivity and 62% specificity. Real-time implementation demonstrated a processing latency of 14-16 s for protocol recommendations. DATA CONCLUSION/CONCLUSIONS:The proposed DL model identifies csPCa using bpMRI and integrates it into clinical workflows. EVIDENCE LEVEL/METHODS:1. TECHNICAL EFFICACY/UNASSIGNED:Stage 2.

The subgenual anterior cingulate cortex (sgACC) plays a central role in the pathophysiology of major depressive disorder (MDD). Its functional interactive profile with the left dorsal lateral prefrontal cortex (DLPFC) is associated with transcranial magnetic stimulation (TMS) treatment outcomes. Previous research on sgACC functional connectivity (FC) in MDD has yielded inconsistent results, partly due to small sample sizes and limited statistical power. Furthermore, calculating sgACC-FC to target TMS individually is challenging. We used a large multi-site cross-sectional sample (1660 patients with MDD vs. 1341 healthy controls) from Phase II of the Depression Imaging REsearch ConsorTium (DIRECT) to systematically delineate case-control difference maps of sgACC-FC. We explored the potential impact of group-level abnormality profiles on TMS target localization and clinical efficacy. Next, we developed an MDD big data-guided, individualized TMS targeting algorithm to integrate group-level statistical maps with individual-level brain activity to individually localize TMS targets. We found enhanced sgACC-DLPFC FC in patients with MDD compared with healthy controls (HC). These group differences altered the position of the sgACC anti-correlation peak in the left DLPFC. We showed that the magnitude of case-control differences in the sgACC-FC was related to clinical improvement in two independent clinical samples. This targeting algorithm may generate targets demonstrating stronger associations with clinical efficiency than group-level targets. We reliably delineated MDD-related abnormalities of sgACC-FC profiles in a large, independently ascertained sample and demonstrated the potential impact of such case-control differences on FC-guided localization of TMS targets.

Dialectical thinking represents a cognitive style emphasizing change, contradiction, and holism. Cross-cultural studies reveal a stark contrast of dialectical thinking between East Asian and Western cultures, highlighting East Asians' superior ability to embrace contradictions and foresee transformation, fostering psychological resilience through emotional complexity and tolerance for contradictions. Despite its importance, the neural basis of dialectical thinking remains underexplored. This review synthesizes current neuroscientific findings and introduces the dialectical-integration network (DIN) hypothesis, which identifies key brain regions such as the dorsal anterior cingulate cortex (dACC), medial prefrontal cortex (mPFC), dorsal lateral prefrontal cortex (DLPFC), nucleus accumbens, basal ganglia, and amygdala. These regions, along with networks like the default mode network (DMN) and frontoparietal network (FPN), facilitate holistic reasoning, conflict resolution, and sensory-emotional integration. The psychological benefits of dialectical thinking include enhanced cognitive flexibility, reduced emotional extremes, and improved conflict resolution. This review emphasizes the need for cross-cultural and neuroscientific research to explore the principle of change, a core aspect of dialectical cognition. By bridging cultural psychology and cognitive neuroscience, this work offers theoretical and methodological insights into culturally shaped cognitive styles, with practical applications in education, mental health, and intercultural communication. The DIN model provides a framework for future research on dynamic neural interactions supporting dialectical thinking.

Animals need daily intakes of three macronutrients: sugar, protein, and fat. Under fasted conditions, however, animals prioritize sugar as a primary source of energy. They must detect ingested sugar-specifically D-glucose-and quickly report its presence to the brain. Hypothalamic neurons that can respond to the caloric content in the gut regardless of the identity of macronutrient have been identified, but until now, the existence of neurons that can encode the specific macronutrients remained unknown. We found that a subset of corticotropin-releasing factor (CRF)-expressing neurons in the hypothalamic paraventricular nucleus (CRF^PVN) respond specifically to D-glucose in the gut, separately from other macronutrients or sugars. CRF^PVN neuronal activity is essential for fasted mice to develop a preference for D-glucose. These responses of CRF^PVN neurons to intestinal D-glucose require a specific spinal gut-brain pathway including the dorsal lateral parabrachial nuclei. These findings reveal the neural circuit that encodes the identity of D-glucose.