Biology subjects

Leong, J. K.

Publications and source records attributed to Leong, J. K..

5 recordsLinked to original sources

bioRxiv2026

Mapping Mesolimbic Dopamine Projections to Subcortical Circuits Underlying Adaptive Behavior: A Human 7T Diffusion Tractography Atlas

The mesolimbic dopamine system supports broad aspects of adaptive behavior including salience, learning, memory, and decision making, yet the structural organization supporting these functions remains incompletely mapped in humans. Using high-resolution 7T diffusion magnetic resonance imaging (up to N=173), we reconstructed seven bilateral ventral tegmental area (VTA)-subcortical pathways spanning direct mesolimbic projections and the hippocampus-VTA (HPC-VTA) loop regulatory circuit. Projection-endpoint analyses revealed long-axis and subfield organization of VTA-hippocampal pathways and superior-inferior VTA-nucleus accumbens (NAc) topography. Consistent with the HPC-VTA loop framework, neurite density covaried across mesolimbic pathways but not the arcuate fasciculus, demonstrating circuit-level organization. Nodewise analyses identified localized associations between pathway microstructure and delay discounting across VTA-hippocampal, VTA-NAc, and VTA-amygdala pathways. Together, these findings parse the human mesolimbic system into distinct pathways supporting adaptive behavior. The probabilistic atlas, MesoConnect, is freely available with tutorials to facilitate reconstruction and investigation of circuits in independent datasets.

neuroscience↗

bioRxiv2023

Cerebellum-Midbrain Reward Circuitry in Humans: an in vivo dissection

Emerging research in non-human animals implicates cerebellar projections to the ventral tegmental area (VTA) in appetitive behaviors, but these circuits have not been characterized in humans. Here, we mapped cerebello-VTA white-matter connectivity in humans using probabilistic tractography on diffusion imaging data from the Human Connectome Project. We uncovered the topographical organization of these connections by separately tracking from parcels of cerebellar lobule VI, crus I/II, vermis, paravermis, and cerebrocerebellum. Results revealed that connections from the cerebellum to the VTA predominantly originate in the right hemisphere, interposed nucleus, and paravermal cortex, and terminate mostly ipsilaterally. Paravermal crus I sends the most connections to the VTA compared to other lobules. We discovered a medial-to-lateral gradient of connectivity, such that the medial cerebellum has the highest connectivity with the VTA. Individual differences in microstructure were associated with measures of negative affect and social functioning. By splitting the tracts into quarters, we found that the socio-affective effects were driven by the third quarter of the tract, corresponding to the point at which the fibers leave the deep nuclei. Taken together, we produced detailed maps of cerebello-VTA structural connectivity for the first time in humans and established their relevance for trait differences in socio-affective regulation.

neuroscience↗

bioRxiv2022

T cell landscape definition by multi-omics identifies Galectin-9 as novel immunotherapy target in chronic lymphocytic leukemia

Failure of cancer immunotherapy is linked to T cell exhaustion. To decipher the underlying mechanisms, we explored the T cell landscape in blood, bone marrow and lymph node samples of patients with chronic lymphocytic leukemia (CLL), and spleen samples of a CLL mouse model. By single-cell RNA-sequencing, mass cytometry (CyTOF), and multiplex image analysis of tissue microarrays, we identified a disease-specific accumulation of distinct regulatory T cell subsets and T cell exhaustion stages and their trajectories in CLL lymph nodes. Integration of T cell receptor sequencing data revealed a clonal expansion of CD8+ precursor exhausted T cells (TPEX), suggesting their CLL reactivity. Interactome analyses identified the TIM3 ligand Galectin-9 as a novel immunoregulatory molecule in CLL. Blocking of Galectin-9 in CLL-bearing mice slowed down disease development and reduced the number of TIM3-expressing T cells. Galectin-9 expression correlated with shorter survival of patients with CLL, renal cell carcinoma or glioma. Statement of significanceOur findings for the first time define the T cell landscape in CLL lymph nodes and reshape the current understanding of T cell exhaustion in this malignancy. They further introduce Galectin-9 as novel immune checkpoint with a high potential to overcome resistance to PD1 targeting drugs in CLL and beyond.

cancer biology↗

bioRxiv2022

Radiogenomics of C9orf72 expansion carriers reveals global transposable element de-repression and enables prediction of thalamic atrophy and clinical impairment

Hexanucleotide repeat expansion (HRE) within C9orf72 is the most common genetic cause of frontotemporal dementia (FTD). Thalamic atrophy occurs in both sporadic and familial FTD but is thought to distinctly affect HRE carriers. Separately, emerging evidence suggests widespread de-repression of transposable elements (TEs) in the brain in several neurodegenerative diseases, including C9orf72 HRE-mediated FTD (C9-FTD). Whether TE activation can be measured in peripheral blood and how the reduction in peripheral C9orf72 expression observed in HRE carriers relates to atrophy and clinical impairment remain unknown. We used the FreeSurfer pipeline and its extensions to assess the effects of C9orf72 HRE and clinical diagnosis (n = 78) on atrophy of thalamic nuclei. We also generated a novel, whole-blood RNA-seq dataset to determine the relationships between peripheral C9orf72 expression, TE activation, thalamic atrophy, and clinical severity (n = 114). We confirmed global thalamic atrophy and reduced C9orf72 expression in HRE carriers. Moreover, we identified disproportionate atrophy of the right mediodorsal lateral nucleus in HRE carriers and showed that C9orf72 expression associated with clinical severity, independent of thalamic atrophy. Strikingly, we found global peripheral activation of TEs, including the human endogenous LINE-1 element, L1HS. L1HS levels were associated with atrophy of multiple pulvinar nuclei, a thalamic region implicated in C9-FTD. Integration of peripheral transcriptomic and neuroimaging data from HRE carriers revealed atrophy of specific thalamic nuclei; demonstrated that C9orf72 levels relate to clinical severity; and identified marked de-repression of TEs, including L1HS, which predicted atrophy of FTD-relevant thalamic nuclei. Significance StatementPathogenic repeat expansion in C9orf72 is the most frequent genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (C9-FTD/ALS). The clinical, neuroimaging, and pathological features of C9-FTD/ALS are well-characterized, whereas the intersections of transcriptomic dysregulation and brain structure remain largely unexplored. Herein, we utilized a novel radiogenomic approach to examine the relationship between peripheral blood transcriptomics and thalamic atrophy, a neuroimaging feature disproportionately impacted in C9-FTD/ALS. We confirmed reduction of C9orf72 in blood and found broad dysregulation of transposable elements--genetic elements typically repressed in the human genome--in symptomatic C9orf72 expansion carriers, which associated with atrophy of thalamic nuclei relevant to FTD. C9orf72 expression was also associated with clinical severity, suggesting that peripheral C9orf72 levels capture disease-relevant information.

neuroscience↗

bioRxiv2018

Wanting to like: Motivation influences behavioral and neural responses to social feedback

Human beings revel in social approval and social connection. For example, individuals want to be liked, and frequently surround themselves with people who provide such positive reinforcement. Past work highlights a \"common currency\" between social rewards like social approval, and non-social rewards like money. But social and motivational contexts can reshape reward experiences considerably. Here, we examine the boundary conditions that deem social approval subjectively valuable. Participants received feedback about their attractiveness from others. Neural activity in reward-related brain structures (e.g., ventral striatum) increased in response to positive feedback, but only when such feedback came from well-liked targets. These heightened reward responses predicted increases in subsequent attraction to well-liked targets. This work suggests that motivational contexts amplify or diminish the value of social approval in a target-specific manner. The value of social approval is thus defined by the extent to which these experiences bring us closer to people we like.

neuroscience↗