Biology subjects

Dennison, J. B.

Publications and source records attributed to Dennison, J. B..

9 recordsLinked to original sources

bioRxiv2025

Trait reward sensitivity and behavioral motivation shape connectivity between the default mode network and the striatum during reward anticipation

Individuals vary substantially in their responses to rewarding events and their motivation to pursue rewards. While the ventral striatum (VS) plays a central role in reward anticipation, its functional connectivity with the default mode network (DMN)--critical for self-referential processing and value integration--potentially represents a key mechanism through which trait differences manifest in reward-related behavior. Here, we examine how trait reward sensitivity and state-level behavioral motivation relate to connectivity between the DMN and VS during reward anticipation. Forty-six participants completed the Monetary Incentive Delay task while undergoing fMRI, with trial types reflecting varying levels of reward and loss salience. Behavioral motivation, indexed by reaction time modulation across high-stakes and low-stakes trials, and self-report measures of anticipatory pleasure and reward sensitivity were assessed. Reward sensitivity interacted with anticipatory pleasure to predict behavioral motivation, such that individuals with higher anticipatory pleasure showed weaker behavioral motivation when reward sensitivity was greater, while those with lower anticipatory pleasure showed stonger behavioral motivation when reward sensitivity was greater. Critically, during high-stakes trials, reward sensitivity was associated with stronger DMN-VS connectivity in highly motivated individuals and weaker connectivity in less motivated participants. This moderation effect was consistent across gain and loss contexts, though with distinct directionality patterns. These findings provide novel insights into the neural correlates of individual differences in reward processing, demonstrating that trait reward sensitivity, anticipatory pleasure, and behavioral motivation are associated with distinct patterns of DMN-VS interactions during reward anticipation. These findings highlight the importance of considering motivational context when investigating reward-related neural mechanisms.

neuroscience↗

bioRxiv2024

Aberrant expression of CD14 in breast tumor cells is associated with poor outcome

Emerging evidence suggests that cancer cells can mimic features of immune cells during oncogenic transformation to drive disease progression. We assessed the occurrence of immunological markers in breast cancer cells to determine their expression pattern. We initially analyzed 18 immune protein markers (CCR4, CCR6, CCR7, CD11, CD123, CD14, CD16, CD19, CD24, CD25, CD27, CD3, CD38, CD4, CD45, CD56, CD8 and CXCR3) expressed on the surface of 28 breast cancer cell lines using mass spectrometry. CD14 protein expression in tumor cells and its association with clinical outcomes was subsequently evaluated by tissue microarray (TMA) analysis of 346 breast tumors. Single-cell RNA sequencing data from breast cancer tumors and bulk transcriptomic data of breast cancer cell lines were interrogated for molecular signatures associated with CD14 tumor cell expression. Among the markers interrogated, CD14 protein was aberrantly expressed on the surface of 13 out of 15 triple-negative breast cancer (TNBC), one of six hormone receptor positive (HR+), one of five hormone receptors negative (HR-)/Her2+ cell lines. Likewise, RNA expression revealed higher levels of CD14 in TNBC cell lines compared to other subtypes. Tumor tissue microarray analysis revealed elevated levels of CD14 membrane expression predominantly in TNBC and was associated with higher tumor grade and increased incidence of disease recurrence compared to CD14-negative tumors. The CD14-positive subgroup exhibited Nuclear Factor Kappa Beta (NFkB) and TGF-{beta} centric networks at both the protein and Single-cell RNA levels. We have uncovered a novel subset of breast cancers characterized by aberrant surface expression of CD14 associated with aggressive disease. CD14 identifies a subset of breast cancers with poor outcome and is a potential therapeutic target.

cancer biology↗

bioRxiv2024

Vesicle-mediated mitochondrial clearance underlies an actionable metabolic vulnerability in triple-negative breast cancer

Selective autophagy of mitochondria is known to promote survival and progression of cancer cells in various malignancies including triple-negative breast cancer (TNBC). Here, we aimed to identify the essential metabolic adaptations that support mitochondrial quality control with the goal to uncover actionable metabolic vulnerabilities with therapeutic potential. Using an integrated approach of proteomics and untargeted and stable-isotope resolved metabolomics, coupled with functional experimental analyses, we define an alternative mechanism to mitophagy enabled by an onco-metabolic program of heightened extracellular sphingomyelin salvaging in TNBC that facilitates extracellular vesicle (EV)-mediated intracellular clearance of mitochondrial damage. Targeting of the cancer cell sphingolipid onco-metabolic pathway via repurposing of eliglustat, a selective small molecule inhibitor of glucosylceramide synthase (UGCG), resulted in ceramide-induced lethal mitophagy and attenuated tumor growth and prolonged overall survival at clinically achievable doses in an orthotopic syngeneic mouse model of TNBC. Our study defines a mechanism of aberrant sphingolipid metabolism that underlies an actionable metabolic vulnerability for anti-cancer treatment.

cancer biology↗

bioRxiv2023

Social Context and Reward Sensitivity Enhance Corticostriatal Function during Experiences of Shared Rewards

Although prior research has demonstrated enhanced striatal response when sharing rewards with close social connections, less is known about how individual differences affect ventral striatal (VS) activation and connectivity when experiencing rewards within social contexts. Given that self-reported reward sensitivity and level of substance use have been associated with differences in VS activation, we set out to investigate whether these factors would be independently associated with enhancements to neural reward responses within social contexts. In this pre-registered study, participants (N=45) underwent fMRI while playing a card guessing game in which correct or incorrect guesses resulted in monetary gains and losses that were shared evenly with either a close friend, stranger (confederate), or non-human partner. Consistent with our prior work, we found increased VS activation when sharing rewards with a socially close peer as opposed to an out-of-network stranger. As self-reported reward sensitivity increased, the difference in VS response to rewards shared with friends and strangers decreased. We also found enhanced connectivity between the VS and temporoparietal junction when sharing rewards with close friends as opposed to strangers. Finally, exploratory analyses revealed that as reward sensitivity and sub-clinical substance use increase, the difference in VS connectivity with the right fusiform face area increases as a function of social context. These findings demonstrate that responsivity to the context of close friends may be tied to individual reward sensitivity or sub-clinical substance use habits; together these factors may inform predictions of risk for future mental health disorders.

neuroscience↗

bioRxiv2023

Trait Reward Sensitivity Modulates Connectivity with the Temporoparietal Junction and Anterior Insula during Strategic Decision Making

Many decisions happen in social contexts such as negotiations, yet little is understood about how people balance fairness versus selfishness. Past investigations found that activation in brain areas involved in executive function and reward processing was associated with people offering less with no threat of rejection from their partner, compared to offering more when there was a threat of rejection. However, it remains unclear how trait reward sensitivity may modulate activation and connectivity patterns in these situations. To address this gap, we used task-based fMRI to examine the relation between reward sensitivity and the neural correlates of bargaining choices. Participants (N = 54) completed the Sensitivity to Punishment (SP)/Sensitivity to Reward (SR) Questionnaire and the Behavioral Inhibition System/Behavioral Activation System scales. Participants performed the Ultimatum and Dictator Games as proposers and exhibited strategic decisions by being fair when there was a threat of rejection, but being selfish when there was not a threat of rejection. We found that strategic decisions evoked activation in the Inferior Frontal Gyrus (IFG) and the Anterior Insula (AI). Next, we found elevated IFG connectivity with the Temporoparietal junction (TPJ) during strategic decisions. Finally, we explored whether trait reward sensitivity modulated brain responses while making strategic decisions. We found that people who scored lower in reward sensitivity made less strategic choices when they exhibited higher AI-Angular Gyrus connectivity. Taken together, our results demonstrate how trait reward sensitivity modulates neural responses to strategic decisions, potentially underscoring the importance of this factor within social and decision neuroscience.

neuroscience↗

bioRxiv2023

Integrated spatial transcriptomics and lipidomics of precursor lesions of pancreatic cancer identifies enrichment of long chain sulfatide biosynthesis as an early metabolic alteration

BackgroundThe development of diverse spatial profiling technologies has provided an unprecedented insight into molecular mechanisms driving cancer pathogenesis. Here, we conducted the first integrated cross-species assessment of spatial transcriptomics and spatial metabolomics alterations associated with progression of intraductal papillary mucinous neoplasms (IPMN), bona fide cystic precursors of pancreatic ductal adenocarcinoma (PDAC). MethodsMatrix Assisted Laster Desorption/Ionization (MALDI) mass spectrometry (MS)-based spatial imaging and Visium spatial transcriptomics (ST) (10X Genomics) was performed on human resected IPMN tissues (N= 23) as well as pancreata from a mutant Kras;Gnas mouse model of IPMN. Findings were further compared with lipidomic analyses of cystic fluid from 89 patients with histologically confirmed IPMNs, as well as single-cell and bulk transcriptomic data of PDAC and normal tissues. ResultsMALDI-MS analyses of IPMN tissues revealed long-chain hydroxylated sulfatides, particularly the C24:0(OH) and C24:1(OH) species, to be selectively enriched in the IPMN and PDAC neoplastic epithelium. Integrated ST analyses confirmed that the cognate transcripts engaged in sulfatide biosynthesis, including UGT8, Gal3St1, and FA2H, were co-localized with areas of sulfatide enrichment. Lipidomic analyses of cystic fluid identified several sulfatide species, including the C24:0(OH) and C24:1(OH) species, to be significantly elevated in patients with IPMN/PDAC compared to those with low-grade IPMN. Targeting of sulfatide metabolism via the selective galactosylceramide synthase inhibitor, UGT8-IN-1, resulted in ceramide-induced lethal mitophagy and subsequent cancer cell death in vitro, and attenuated tumor growth of mutant Kras;Gnas allografts. Transcript levels of UGT8 and FA2H were also selectively enriched in PDAC transcriptomic datasets compared to non-cancerous areas, and elevated tumoral UGT8 was prognostic for poor overall survival. ConclusionEnhanced sulfatide metabolism is an early metabolic alteration in cystic pre-cancerous lesions of the pancreas that persists through invasive neoplasia. Targeting sulfatide biosynthesis might represent an actionable vulnerability for cancer interception.

cancer biology↗

bioRxiv2023

EGFR inhibition in lung adenocarcinoma upregulates cell surface expression of the placental antigen ALPP and enhances efficacy of ALPP-ADC therapy

Alkaline phosphatase placental type (ALPP) and ALPPL2 are closely related and regulated GPI anchored proteins that are known to be expressed on the cell surface in some cancers, whereas normal tissue expression is largely limited to the placenta. Clinical utility of ALPP is potentially limited by heterogenous expression in tumors. Here, we assessed ALPP and ALPPL2 surfaceome protein levels in 158 cancer cell lines and mRNA expression levels in 10,967 tumors representing 32 cancer types from The Cancer Genome Atlas (TCGA), which revealed ALPP, and to a lesser extent ALPPL2, to be variably expressed in several cancer types including lung adenocarcinoma (LUAD). Surface expression of ALPP was confirmed by tissue microarray analysis of 204 lung tumors. Using LUAD as a model system, we demonstrated that treatment with EGFR inhibitors, or induction of cancer cell quiescence via nutrient deprivation greatly enhanced ALPP surface expression. Mechanistic studies revealed that enhancement of surface ALPP expression in LUAD following gefitinib treatment was mediated through repression of EGFR signaling and activation of the transcription factor FoxO3a, which was identified as an upstream transcriptional regulator of ALPP. Using xenograft models of LUAD, we further demonstrated that gefitinib treatment upregulates surface expression of ALPP in LUAD cells but not in normal tissues. Combination therapy with gefitinib and an ALPP antibody conjugated with Monomethylauristatin F (ALPP-ADC-MAF) resulted in superior anti-cancer efficacy compared with gefitinib or ALPP-ADC-MAF alone. Our findings support a novel combination treatment modality that boosts the efficacy of ALPP-ADC directed therapy.

cancer biology↗

bioRxiv2023

Substance use is related to differential activation and connectivity for social relative to monetary rewards

Aberrant levels of reward sensitivity have been linked to substance use disorder and are characterized by alterations in reward processing in the ventral striatum (VS). Less is known about how reward sensitivity and subclinical substance use relate to striatal function during social rewards (e.g., positive peer feedback). Testing this relation is critical for predicting risk for development of substance use disorder. In this pre-registered study, participants (N=44) underwent fMRI while completing well-matched tasks that assess neural response to reward in social and monetary domains. Contrary to our hypotheses, aberrant reward sensitivity blunted the relationship between substance use and striatal activation during receipt of rewards, regardless of domain. Moreover, exploratory whole-brain analyses showed unique relations between substance use and social rewards in temporoparietal junction. Psychophysiological interactions demonstrated that aberrant reward sensitivity is associated with increased connectivity between the VS and ventromedial prefrontal cortex during social rewards. Finally, we found that substance use was associated with decreased connectivity between the VS and dorsomedial prefrontal cortex for social rewards, independent of reward sensitivity. These findings demonstrate nuanced relations between reward sensitivity and substance use, even among those without substance use disorder, and suggest altered reward-related engagement of cortico-VS responses as potential predictors of developing disordered behavior.

neuroscience↗

bioRxiv2022

Tensorial Independent Component Analysis Reveals Social and Reward Networks Associated with Major Depressive Disorder

Major depressive disorder (MDD) has been associated with changes in functional brain connectivity. Yet, typical analyses of functional connectivity, such as spatial ICA for resting-state data, often ignore sources of between-subject variability, which may be crucial for identifying functional connectivity patterns associated with MDD. Typically, methods like spatial ICA will identify a single component to represent a network like the default mode network (DMN), even if groups within the data show differential DMN coactivation. To address this gap, this project applies a tensorial extension of ICA (tensorial ICA)--which explicitly incorporates between-subject variability--to identify functionally connected networks using fMRI data from the Human Connectome Project (HCP). Data from the HCP included individuals with a diagnosis of MDD, a family history of MDD, and healthy controls performing a gambling and social cognition task. Based on evidence associating MDD with blunted neural activation to rewards and social stimuli, we predicted that tensorial ICA would identify networks associated with reduced spatio-temporal coherence and blunted social and reward-based network activity in MDD. Across both tasks, tensorial ICA identified three networks showing decreased coherence in MDD. All three networks included ventromedial prefrontal cortex (vmPFC), striatum, and cerebellum and showed different activation across the conditions of their respective tasks. However, MDD was only associated with differences in task-based activation in one network from the social task. Additionally, these results suggest that tensorial ICA could be a valuable tool for understanding clinical differences in relation to network activation and connectivity.

neuroscience↗