Biology subjects

Coughlin, C. A.

Publications and source records attributed to Coughlin, C. A..

5 recordsLinked to original sources

bioRxiv2026

Hippocampal representations of temporal structure increase in scale and symmetry across development

Learning which experiences reliably co-occur in time is fundamental to episodic memory and improves markedly across childhood and adolescence. Although children and adults both engage the hippocampus while learning predictable sequences, the nature of the neural representations supporting statistical learning across development remains unknown. Here, we directly quantified item-level neural representations before and after children, early adolescents, and adults learned predictable temporal relationships between items, providing a direct measure of learning-related representational change. We identified three developmental shifts in hippocampal representation. First, although posterior hippocampus integrated temporally adjacent sequence elements similarly across age groups, integration of non-adjacent sequence elements increased with age in anterior hippocampus, indicating developmental expansion in the temporal scale of neural integration. Second, hippocampal representations changed in their directional organization, with children showing hippocampal representations reflecting only forward associations between adjacent events, whereas adolescents and adults exhibited bidirectional integration of sequence relationships. Third, functional connectivity between anterior hippocampus and frontoparietal cortex tracked statistical transition probabilities during learning and predicted memory performance. Together, these findings show that improvements in statistical learning during development reflect reorganization of hippocampal representations and hippocampal-cortical interactions, revealing how the developing brain constructs increasingly flexible representations of predictive temporal structure. HighlightsO_LIHippocampal representations of temporal sequences reorganize across development C_LIO_LITemporal integration expands from adjacent to non-adjacent events with age C_LIO_LISequence representations shift from forward-only to bidirectional integration C_LIO_LIHippocampal-frontoparietal connectivity predicts statistical learning ability C_LI

neuroscience↗

bioRxiv2025

Development of anterior hippocampal integration underlies the protracted emergence of cognitive map formation and generalization

Flexible memory depends on cognitive maps that integrate spatial relationships and guide behavior as environments change. The anterior hippocampus is well positioned to support integration across broad spatiotemporal scales, but its late maturation may constrain development of flexible, map-based navigation. Here, we tested whether hippocampal temporal autocorrelation, an index of neural activity stability over time, tracks the development of spatial integration. In a large resting-state fMRI sample (N = 382; ages 5-34 years), temporal autocorrelation increased with age in anterior, but not posterior, hippocampus. This anterior-specific pattern was replicated in an independent task-based fMRI sample of children, adolescents, and adults (N = 85; aged 6-12 years and adults), wherein we linked hippocampal autocorrelation to dissociable components of spatial behavior. The navigation task separated memory for object locations from the ability to update and generalize knowledge across rotations of the distal reference frame and to new object sets. Although all age groups learned object locations, only older participants showed evidence that prior spatial structure supported performance as the environment changed across runs. Critically, hippocampal autocorrelation related to behavior only when spatial knowledge was used across runs, rather than improved through within-run feedback, with the clearest profile emerging in adults. In adults, anterior and posterior autocorrelation jointly predicted precise object-location memory, whereas anterior autocorrelation uniquely predicted efficient trajectories from novel starting positions. These findings identify anterior hippocampal temporal autocorrelation as a later-maturing computation that supports the transition from local spatial learning in childhood to flexible navigation through changing environments in adulthood. Significance StatementFinding our way through the world requires more than remembering where things are. We also need to use what we have learned to take new routes, adjust when familiar places change, and apply old knowledge to new situations. These abilities improve from childhood to adulthood, but the brain changes that support this transition remain unclear. We show that a signal in anterior hippocampus, a brain region important for linking experiences, becomes more stable over development. Using a navigation task that separated remembering object locations from flexibly using a map, we found that this signal was most strongly tied to adults ability to navigate efficiently through changing environments. These findings reveal a hippocampal mechanism that supports flexible navigation as children mature.

neuroscience↗

bioRxiv2025

RHOA Loss of Function Impairs the IFNγ Response and Promotes CD19 Antigen Escape to Drive CAR-T Resistance in Diffuse Large B-cell Lymphoma

CD19-directed chimeric antigen receptor (CAR)-T cells are breakthrough therapies for aggressive B-cell lymphomas, but less than half of patients achieve durable responses. We previously showed through whole-genome sequencing of tumors from CAR-T-treated patients that deletions of RHOA (3p21.31) are enriched in cases progressing after treatment. RHOAs roles in resistance and pathogenesis are poorly defined, despite loss-of-function alterations that occur in [~]20% of newly diagnosed large B-cell lymphoma (LBCL) cases. We created RHOA-deficient LBCL systems and confirmed cell-intrinsic loss of response to CAR-19 in vitro and in vivo driven by CD19 downregulation. Impact on CD19, however, was variable and would not explain selection for RHOA deletion in newly diagnosed cases. We therefore created RHOA-deficient tumors in immunocompetent mice and found remarkable correlation with dysfunctional lymphoma microenvironment (LME) signatures in CAR-19 resistant patients. These LMEs are marked by a type 1-like immune infiltrate with terminally exhausted CD8 T cells, Th1-like CD4 cytotoxic lymphocytes (CTLs), and increased production of interferon gamma (IFN{gamma}). RHOA-deficient tumor cells themselves have significantly impaired IFN{gamma} responses, providing resistance to CD8 T cell clearance by way of diminished induction of major histocompatibility complex class I (MHC-I). These findings support a model that depletion of healthy effector populations by RHOA-deficient lymphoma is a key driver of immune dysfunction thwarting CAR-19 clinical responses. Overall, we describe for the first time how a single-gene alteration found recurrently in CAR-19-resistant LBCL contributes to treatment failures.

cancer biology↗

bioRxiv2024

The cyclin-G associated kinase (GAK) is a novel mitotic kinase and therapeutic target in diffuse large B-cell lymphoma

New drug targets are needed for diffuse large B-cell lymphoma (DLBCL), the most common lymphoma subtype, to enable enable development better treatments for patients not cured by standard care. We conducted a phenotypic screen of kinase inhibitors and identified the cyclin G-associated kinase (GAK) as a tumor-selective target. Though GAK is previously described primarily as a participant in membrane trafficking, we found its kinase activity is a key mitotic regulator in DLBCL. Inhibition caused G2/M-phase arrest, chromosome misalignment, and spindle distortion, effects absent in non-malignant controls. Transcriptomics data from clinical samples showed increased GAK expression associates with RB1 deficiency in DLBCL cases, suggesting dependency on GAK linked to retinoblastoma associated protein (RB) loss of function, a common DLBCL driver. RB-deficient DLBCL cells treated with a selective GAK tool compound showed complete arrest at G2/M, pronounced distortion of mitotic spindles, and widespread chromosomal damage. High-content live-cell imaging revealed onset of mitotic catastrophe in response to GAK inhibition, which was more rapid and severe in isogenic cells with RB1 deletion. No GAK-selective inhibitors suitable for clinical development are currently available, but several drugs approved or under development inhibit GAK activity even more potently than thier intended clinical targets. For instance, OTS167, developed against MELK for use in solid tumors, has particularly potent anti-GAK potency and has achieved single-agent tumor-burden reduction in vivo against a DLBCL patient-derived xenograft. GAK is therefore a novel mitotic kinase in DLBCL, linked to the common, undruggable RB loss of function biomarker, and suitable for rapid clinical translation through drug repurposing. SignificanceWe identify cyclin-G associated kinase (GAK) as a novel therapeutic vulnerability in diffuse large B-cell lymphoma. Clinical kinase inhibitors with GAK activity create an opportunity for rapid therapeutic translation through drug repurposing.

cancer biology↗

bioRxiv2021

Genomic drivers of large B-cell lymphoma resistance to CD19 CAR-T therapy

Chimeric antigen receptor-reprogrammed autologous T cells directed to CD19 are breakthrough immunotherapies for heavily pretreated patients with aggressive B-cell lymphomas but still fail to cure most patients. Host inflammatory and tumor microenvironmental factors associate with CAR-19 resistance, but the tumor-intrinsic factors underlying these phenomena remain undefined. To characterize genomic drivers of resistance, we interrogated whole genome sequencing of 30 tumor samples from 28 uniformly CAR-19-treated large-cell lymphoma patients. We reveal that patterns of genomic complexity (i.e., chromothripsis and APOBEC mutational activity), and distinct genomic alterations (deletions of RB1 or RHOA) associate with more exhausted immune microenvironments and poor outcome after CAR-19 therapy. Strikingly, pretreatment reduced expression or sub-clonal mutation of CD19 did not affect responses, suggesting CAR-19 therapy successes are due not only to direct antigen-dependent cytotoxicity but require surmounting immune exhaustion in tumor microenvironments to permit broader host responses that eliminate tumors.

cancer biology↗