Biology subjects

Burns, M. R.

Publications and source records attributed to Burns, M. R..

4 recordsLinked to original sources

bioRxiv2026

Ventral tegmental area dopamine neuron activity mediates multi-valent outcomes during decision making under risk of punishment

Dopamine contributes to reward-related decision making, but its contributions to decision contexts that include explicit punishment are less well understood. To elucidate the role of ventral tegmental area (VTA) dopamine neurons in decision making under risk of punishment, we used fiber photometry to record activity in these neurons during a decision-making task in which rats choose between a small, "safe" reward and a large reward associated with varying probabilities of explicit punishment. Dopamine neuron activity exhibited phasic increases during risky "Wins" (reward without punishment) and phasic decreases during risky "Losses" (reward plus punishment), each of which scaled with punishment probability and intensity. Further analyses revealed that this outcome-evoked activity predicted choices on subsequent trials. To determine whether VTA dopamine neuron activity plays a causal role in these risk-based decisions, we used optogenetics to selectively inhibit these neurons during risky Wins and Losses. Inhibition of VTA dopamine neurons during Wins selectively reduced the frequency of risky choices after a Win, whereas inhibition during Losses selectively reduced the frequency of risky choices after a Loss. These data reveal that VTA dopamine neuron activity during outcome receipt is causally related to subsequent decision-making behavior. In addition, the fact that the effects of inhibition on choice behavior were specific to the outcome with which the inhibition was paired suggests that VTA dopamine neuron activity contributes to updating after Wins and Losses independently. Significance StatementDopamine is implicated in movement, motivation, and learning, and has been strongly linked with substance use and risk-seeking behavior. Despite these associations, it is unclear how the activity of dopamine neurons influences decision making under risk of punishment. To elucidate this, we recorded from ventral tegmental area (VTA) dopamine neurons and found that their activity at the population level integrates reward alongside the probability and intensity of punishment experienced during risky outcomes. Further, inhibition of VTA dopamine neuron activity during risky outcomes decreased risk-seeking behavior in an outcome-specific manner. Our findings align with models suggesting that VTA dopamine neurons signal prediction errors, and provide insight into the role of these neurons in adaptive decision making.

neuroscience↗

bioRxiv2026

Dissociable species-specific impact of Aβ on static and dynamic functional connectomes

Temporal dynamics in functional connectomes offer a physiologically grounded signature of hidden pathologies during preclinical stages of Alzheimers disease (AD). We evaluated the effect of beta-amyloid (A{beta}) on dynamic functional connectomes in transgenic mice and human subjects. Functional magnetic resonance images (fMRI) were collected in two strains of A{beta} mice. fMRI-derived connectomes were segmented into discrete states using a hidden Markov model and network strength, efficiency, and transitivity were analyzed per state. Human fMRI-derived connectome measures were analyzed across 3 states. Static network measures were significantly different between A{beta} mice and controls, the former having high values for strength, efficiency and clustering coefficient in anterior cingulate, hippocampus and retrosplenium. Dynamic network measures were stable within-states in A{beta} mice. Similarly, human subjects with high A{beta} had high node strength in precuneus and temporoparietal areas compared to low A{beta}. In contrast, however, high A{beta} was associated with high state switch rates, high fractional occupancy and state dwell times. Also, global strength, efficiency, and transitivity were less stable within states in the high A{beta} group. Our results indicate that static, but not dynamic, connectome strength, efficiency and network integration are increased in A{beta} mice, while dynamic network states appear less stable in human functional connectomes. This data supports a dissociable, species-specific impact of A{beta}, with dynamic network alterations present in humans but not in A{beta} mouse models, suggesting additional non-A{beta}-driven influences on dynamic functional connectivity in preclinical AD. SIGNIFICANT STATEMENTDetecting Alzheimers disease before symptoms appear remains a critical challenge. This study reveals that beta-amyloid -- a hallmark Alzheimers protein -- disrupts brain network dynamics differently across species. While both transgenic mice and humans with elevated amyloid show stronger static brain connectivity, only humans exhibit unstable, rapidly shifting brain network states. This dissociation suggests that the dynamic network disruptions seen in preclinical Alzheimers patients are not solely driven by amyloid accumulation, but likely reflect additional biological factors absent in mouse models. These findings highlight an important translational gap between animal models and human disease, with implications for how we design and interpret preclinical Alzheimers research and develop early diagnostic biomarkers.

neuroscience↗

bioRxiv2024

The polyamine transporter ATP13A3 mediates DFMO-induced polyamine uptake in neuroblastoma

High-risk neuroblastomas, often associated with MYCN oncogene amplification, are addicted to polyamines, small polycations vital for cellular functioning. We have shown that neuroblastoma cells increase polyamine uptake when exposed to the polyamine biosynthesis inhibitor DFMO, currently in clinical trial, and that this mechanism limits the efficacy of the drug. While this finding resulted in the clinical development of polyamine transport inhibitors including AMXT 1501, presently under clinical investigation in combination with DFMO, the mechanisms and transporters involved in DFMO-induced polyamine uptake are unknown. Knockdown of ATP13A3, a member of the P5B-ATPase family, limited basal and DFMO-induced polyamine uptake, attenuated MYCN-amplified and non-MYCN-amplified neuroblastoma cell growth and potentiated the inhibitory effects of DFMO. Overexpression of ATP13A3 in neuroblastoma cells increased polyamine uptake, which was inhibited by AMXT 1501, highlighting ATP13A3 as a key target of the drug. The association between high ATP13A3 expression and poorer survival in neuroblastoma further supports a role of this transporter in neuroblastoma progression. Thus, this study identified ATP13A3 as a critical regulator of basal and DFMO-induced polyamine uptake and a novel therapeutic target for neuroblastoma. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=186 SRC="FIGDIR/small/581161v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@11bef78org.highwire.dtl.DTLVardef@106c250org.highwire.dtl.DTLVardef@bf39b1org.highwire.dtl.DTLVardef@64d05f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Polyamine transport inhibition and cisplatin synergistically enhance tumor control through oxidative stress in murine head and neck cancer models

BackgroundSurgery and/or platinum-based chemoradiation remain standard of care for patients with head and neck squamous cell carcinoma (HNSCC). While these therapies are effective in a subset of patients, a substantial proportion experience recurrence or treatment resistance. As cisplatin mediates cytotoxicity through oxidative stress while polyamines play a role in redox regulation, we posited that combining cisplatin with polyamine transport inhibitor, AMXT-1501, would increase oxidative stress and tumor cell death in HNSCC cells. MethodsCell proliferation was measured in syngeneic mouse HNSCC cell lines treated with cisplatin {+/-} AMXT-1501. Synergy was determined by administering cisplatin and AMXT-1501 at a ratio of 1:10 to cancer cells in vitro. Cancer cells were transferred onto mouse flanks to test the efficacy of treatments in vivo. Reactive oxygen species (ROS) were measured. Cellular apoptosis was measured with flow cytometry using Annexin V/PI staining. High-performance liquid chromatography (HPLC) was used to quantify polyamines in cell lines. Cell viability and ROS were measured in the presence of exogenous cationic amino acids. ResultsThe combination of cisplatin and AMXT-1501 synergize in vitro on HNSCC cell lines. In vivo combination treatment resulted in tumor growth inhibition greater than either treatment individually. The combination treatment increased ROS production and induced apoptotic cell death. HPLC revealed the synergistic mechanism was independent of intracellular polyamine levels. Supplementation of cationic amino acids partially rescued cancer cell viability and reduced ROS. ConclusionAMXT-1501 enhances the cytotoxic effects of cisplatin in vitro and in vivo in aggressive HNSCC cell lines through a polyamine-independent mechanism.

cancer biology↗