Role of Dopaminergic Signaling in Social Deficits after Early Life Stress

Authors:

Aiden Bowers, Kyra Yehle, Takao Hensch

Date Created:

2025-01-01

Course Title:

Professor:

Not specified

About Paper:

Children experiencing Adverse Childhood Experiences (ACEs) fragmented care cohort was compared to a control care cohort, as suffer a variety of attention and social deficits. While it is well as before / after acute (30 minute) treatment with a dopamine well-known that early life environments play a critical role in D4 receptor agonist. The latter treatment was previously shown to physiological and social development, the mechanisms underlying relieve persistent attention deficits in adult male mice induced by these effects remain unclear. Here, we aimed to validate and early life fragmented care. address the root causes of a social deficit in a mouse model of unpredictable parenting (fragmented care) induced by limited We found that fragmented care male mice displayed a deficit in social novelty with no statistically significant preference for bedding and nesting material during the first postnatal week. familiar or unfamiliarmice. Ongoing experiments suggest a rescue A cohort of adult mice (>postnatal day P60) having experienced of this phenotype by acute D4 agonist treatment. This would fragmented maternal care months earlier was evaluated using indicate that social deficits lie downstream of attention deficits in the classical three-chamber assay, which sequentially measures this model, providing a potential framework for treating humans sociability (preference for social vs. inanimate stimulus) then who have suffered ACEs. social novelty (preference for a familiar vs. unfamiliar mouse). A Tuning Hydrogel Mechanics to Modulate ▯ T-cell Migration: Engineering a VD1-Like Phenotype in VD2 ▯ T-cells Through Viscoelastic Cues Michelle Chang, Favour Obuseh, David Mooney Harvard College | Winthrop House | Biomedical Engineering | 2026 Adoptive T-cell therapies are an emerging area of immunotherapy and viscoelasticity, we encapsulated ▯ T cells isolated from that have shown promise in treating blood-based tumors and peripheral blood mononuclear cells (PBMCs). Post-encapsulation, melanomas. Yet, their efficacy in solid tumors remains limited. we assessed protein expression and migratory behavior via flow Most studies utilize Alpha Beta (▯▯) T-cells, which are restricted cytometry and imaging analysis. Our findings uncovered that by MHC class presentation, allowing some tumors to evade encapsulated D2 cells exhibit increased mean square displacement immune detection. Recent attention has shifted toward gamma and average speed. Currently, we are observing the changes in delta ( ▯) T-cells, a functionally significant subset of T cells expression of tissue-homing receptors through flow cytometry. that can target tumors in an MHC-unrestricted manner, making Futureworkwillexpandlive-cellimagingtoassessmigrationpost- them promising candidates for immunotherapies. Among the two encapsulation within hydrogels, and additional flow cytometry primary ▯ T cell subsets, delta 2 (D2) cells are more accessible with more donors will be completed. Additionally, we aim to for clinical applications, yet exhibit limited tissue residency andtest these cells in vivo using tumor-bearing models to evaluate antitumor efficacy compared to tissue-resident delta 1 (D1) cells whetherthesephenotypicchangestranslatetoenhancedinfiltration due to their circulatory and blood-based nature. In this study, and antitumor efficacy. These findings support the potential of we determined that mechanical modulation of the cell culture using biomaterial-based mechanical conditioning to improve the environment through viscoelastic changes can shift D2 ▯ T cells functionalprofileofV▯2cellsforadoptiveimmunotherapyinsolid toward a more tissue-adapted, D1-like state. Using a collagen tumors. type I hydrogel system with independently tunable stiffness Investigating the Role of Reptin and AP-1 in Cardiomyocyte Polyploidy and Senescence Gissell Chapa, Felicia Wranitz, Caroline Burns Harvard College | Quincy House | Human Developmental and Regenerative Biology | 2026 The human heart has limited regenerative capacity following resultsshownochangeinventricularsizeorploidystatesuggesting injury,whichislargelyduetotheearlyexitofcardiomyocytesfrom that neither Jun nor A-Fos expression is a primary driver of the cell cycle. Understanding what regulates this exit is crucial polyploidy. To test whether the loss of Reptin drives cell cycle to developing therapeutic strategies. One potential regulatory exit (senescence), we stained 5 dpf embryos with senescence- factor is Reptin, a AAA+ ATPase that is required to maintain associated β-galactosidase (SA-β-gal), then dissected and imaged cardiomyocytes in a diploid proliferative state. Our lab has their hearts. We quantified the staining to compare senescence previously demonstrated using a zebrafish reptin knockout line, levels in wild-type and Reptin-null hearts. Finally, to validate that loss of Reptin drives cardiomyocyte polyploidization and conservation of phenotypes in human cells, we used CRISPR- decreased cell cycling by 5 days post fertilization (dpf). We Cas9 to create Reptin knockout iPSC lines. We designed hypothesize that the polyploidization is driven by AP-1 factor and generated gRNAs, and validated clones using PCR, Sanger ▯/▯ over expression observed in reptin cardiomyocytes and that sequencing, qPCR, and Western blot. While most clones were the polyploid cells permanently exit the cell cycle and become wild-type or heterozygous, new guide RNAs are being tested to senescent. Polyploidizationleadstocardiomyocyteandventricular improve knockout efficiency. Together, these findings suggest enlargement. Using tamoxifen-inducible Cre-lox systems, we that Reptin is essential for regulating cardiomyocyte senescence overexpressed Jun (an AP-1 factor) or A-Fos (an AP-1 dominant and maintaining normal cardiac growth. Exploring these pathways negative allele) in cardiomyocytes. At 4 dpf, we imaged hearts across both models may offer valuable insights for developing new from embryos and measured the ventricular area. Preliminary treatments for heart disease.

Abstract:

Children experiencing Adverse Childhood Experiences (ACEs) fragmented care cohort was compared to a control care cohort, as suffer a variety of attention and social deficits. While it is well as before / after acute (30 minute) treatment with a dopamine well-known that early life environments play a critical role in D4 receptor agonist. The latter treatment was previously shown to physiological and social development, the mechanisms underlying relieve persistent attention deficits in adult male mice induced by these effects remain unclear. Here, we aimed to validate and early life fragmented care. address the root causes of a social deficit in a mouse model of unpredictable parenting (fragmented care) induced by limited We found that fragmented care male mice displayed a deficit in social novelty with no statistically significant preference for bedding and nesting material during the first postnatal week. familiar or unfamiliarmice. Ongoing experiments suggest a rescue A cohort of adult mice (>postnatal day P60) having experienced of this phenotype by acute D4 agonist treatment. This would fragmented maternal care months earlier was evaluated using indicate that social deficits lie downstream of attention deficits in the classical three-chamber assay, which sequentially measures this model, providing a potential framework for treating humans sociability (preference for social vs. inanimate stimulus) then who have suffered ACEs. social novelty (preference for a familiar vs. unfamiliar mouse). A Tuning Hydrogel Mechanics to Modulate ▯ T-cell Migration: Engineering a VD1-Like Phenotype in VD2 ▯ T-cells Through Viscoelastic Cues Michelle Chang, Favour Obuseh, David Mooney Harvard College | Winthrop House | Biomedical Engineering | 2026 Adoptive T-cell therapies are an emerging area of immunotherapy and viscoelasticity, we encapsulated ▯ T cells isolated from that have shown promise in treating blood-based tumors and peripheral blood mononuclear cells (PBMCs). Post-encapsulation, melanomas. Yet, their efficacy in solid tumors remains limited. we assessed protein expression and migratory behavior via flow Most studies utilize Alpha Beta (▯▯) T-cells, which are restricted cytometry and imaging analysis. Our findings uncovered that by MHC class presentation, allowing some tumors to evade encapsulated D2 cells exhibit increased mean square displacement immune detection. Recent attention has shifted toward gamma and average speed. Currently, we are observing the changes in delta ( ▯) T-cells, a functionally significant subset of T cells expression of tissue-homing receptors through flow cytometry. that can target tumors in an MHC-unrestricted manner, making Futureworkwillexpandlive-cellimagingtoassessmigrationpost- them promising candidates for immunotherapies. Among the two encapsulation within hydrogels, and additional flow cytometry primary ▯ T cell subsets, delta 2 (D2) cells are more accessible with more donors will be completed. Additionally, we aim to for clinical applications, yet exhibit limited tissue residency andtest these cells in vivo using tumor-bearing models to evaluate antitumor efficacy compared to tissue-resident delta 1 (D1) cells whetherthesephenotypicchangestranslatetoenhancedinfiltration due to their circulatory and blood-based nature. In this study, and antitumor efficacy. These findings support the potential of we determined that mechanical modulation of the cell culture using biomaterial-based mechanical conditioning to improve the environment through viscoelastic changes can shift D2 ▯ T cells functionalprofileofV▯2cellsforadoptiveimmunotherapyinsolid toward a more tissue-adapted, D1-like state. Using a collagen tumors. type I hydrogel system with independently tunable stiffness Investigating the Role of Reptin and AP-1 in Cardiomyocyte Polyploidy and Senescence Gissell Chapa, Felicia Wranitz, Caroline Burns Harvard College | Quincy House | Human Developmental and Regenerative Biology | 2026 The human heart has limited regenerative capacity following resultsshownochangeinventricularsizeorploidystatesuggesting injury,whichislargelyduetotheearlyexitofcardiomyocytesfrom that neither Jun nor A-Fos expression is a primary driver of the cell cycle. Understanding what regulates this exit is crucial polyploidy. To test whether the loss of Reptin drives cell cycle to developing therapeutic strategies. One potential regulatory exit (senescence), we stained 5 dpf embryos with senescence- factor is Reptin, a AAA+ ATPase that is required to maintain associated β-galactosidase (SA-β-gal), then dissected and imaged cardiomyocytes in a diploid proliferative state. Our lab has their hearts. We quantified the staining to compare senescence previously demonstrated using a zebrafish reptin knockout line, levels in wild-type and Reptin-null hearts. Finally, to validate that loss of Reptin drives cardiomyocyte polyploidization and conservation of phenotypes in human cells, we used CRISPR- decreased cell cycling by 5 days post fertilization (dpf). We Cas9 to create Reptin knockout iPSC lines. We designed hypothesize that the polyploidization is driven by AP-1 factor and generated gRNAs, and validated clones using PCR, Sanger ▯/▯ over expression observed in reptin cardiomyocytes and that sequencing, qPCR, and Western blot. While most clones were the polyploid cells permanently exit the cell cycle and become wild-type or heterozygous, new guide RNAs are being tested to senescent. Polyploidizationleadstocardiomyocyteandventricular improve knockout efficiency. Together, these findings suggest enlargement. Using tamoxifen-inducible Cre-lox systems, we that Reptin is essential for regulating cardiomyocyte senescence overexpressed Jun (an AP-1 factor) or A-Fos (an AP-1 dominant and maintaining normal cardiac growth. Exploring these pathways negative allele) in cardiomyocytes. At 4 dpf, we imaged hearts across both models may offer valuable insights for developing new from embryos and measured the ventricular area. Preliminary treatments for heart disease.

Source:

Harvard / Ella Borgman, Camille Le Gall, Novalia Pishesha / 2025

Topics:

cell, reptin, social, deficit, using, care, tumor, cardiomyocyte, fragmented, senescence, heart, attention

Co-authors:

@aidenbowers258 , @kyrayehle259 , @takaohensch260