Biology subjects

Park, A. J.

Publications and source records attributed to Park, A. J..

6 recordsLinked to original sources

bioRxiv2026

Endothelium-Dependent Vasodilation is Impaired in Chronic Spinal Cord Injury and is Associated with Oxidative Stress

BackgroundIndividuals with spinal cord injury (SCI) experience accelerated atherosclerotic cardiovascular disease that is not fully explained by traditional risk factors. Endothelial dysfunction is a key mechanism in atherosclerosis. We tested the hypothesis that endothelium-dependent vasodilation is impaired in adults with SCI and is due, at least in part, to oxidative stress. MethodsTwenty-four adults (age:19-58 yr) free of overt cardiometabolic disease were studied: 12 non-injured adults (9 M/3 F) and 12 adults with chronic SCI (8 M/4 F; time since injury 1.5 - 25 years). Forearm blood flow was determined (FBF; via strain-gauge plethysmography) in response to intra-arterial infusion of acetylcholine and isoproterenol in the absence and presence of the antioxidant vitamin C as well as the FBF response to sodium nitroprusside. ResultsAdults with SCI demonstrated significantly lower vasodilator response to acetylcholine (from 4.1{+/-}0.6 to 10.7{+/-}2.6 mL/100 mL tissue/min vs 4.1{+/-}1.1 to 15.7{+/-}3.4 mL/100 mL tissue/min) and isoproterenol (4.0{+/-}0.6 to 11.2{+/-}2.2 mL/100 mL tissue/min vs 4.3{+/-}1.0 to 15.0{+/-}2.6 mL/100 mL tissue/min) compared with non-injured adults. FBF response to sodium nitroprusside was not significantly different between the groups. Co-infusion of vitamin C significantly increased the vasodilator response to acetylcholine (~45%) and isoproterenol (~25%) in the adults with SCI to levels comparable with non-injured adults. ConclusionsChronic SCI is associated with endothelial-dependent vasodilator dysfunction. Impaired vasodilation across two distinct endothelial agonists suggests that chronic SCI is associated with endothelial dysfunction not confined to a specific receptor or intracellular signaling pathway. Moreover, oxidative stress is a contributing factor underlying SCI-related endothelial vasodilator dysfunction. NCT06443151 CLINICAL PERSPECTIVEO_LIThe novel finding of this study is that individuals with SCI demonstrate impaired endothelial vasodilator function in absence of traditional cardiovascular risk factors. C_LIO_LIOxidative stress is a contributing factor to SCI-related endothelial vasodilator dysfunction. C_LIO_LIFuture studies are needed to determine the efficacy of therapeutic interventions, either lifestyle or pharmacologic, in improving endothelial function in order to mitigate the elevated ASCVD risk after SCI. C_LI

physiology↗

bioRxiv2024

Prelimbic corticopontine neurons gate extinction learning

The prelimbic cortex is essential for association of temporally separated events, and impedes extinction of learned association. The network mechanism underlying reversal learning, however, remains elusive. Here, we found that mitochondria-dependent post-tetanic potentiation at synapses onto prelimbic corticopontine neurons impedes extinction learning without affecting initial associative learning. Rats underwent trace fear conditioning followed by extinction sessions. Pharmacological inhibition of post-tetanic potentiation using tetaraphenylphosphnium (TPP), a mitochondrial Ca2+ release blocker, accelerated extinction of trace fear memory, leaving trace fear memory formation intact. Optogenetic inhibition of corticopontine, but not commissural, neurons phenocopied these effects. Electrophysiological recordings and Ca2+ imaging revealed that TPP treatment reduced the persistent activity of corticopontine neurons encoding tone presentation. Mechanistically, associative learning triggers the bursting activity of prelimbic pyramidal neurons that induces post-tetanic potentiation of corticopontine neurons, an effect blocked by TPP treatment. Thus, we identified a prelimbic cell type- and local circuit-specific mechanism that selectively gates extinction learning.

neuroscience↗

bioRxiv2023

Input-specific bi-directional regulation of CA3 pyramidal cell excitability: implication in sequential memory formation

Neuronal excitability is a key determinant for recruitment of a neuron to an ensemble. High-frequency mossy fiber (MF) inputs induce a prolonged increase in the excitability of a CA3 pyramidal cell (called long-term potentiation of intrinsic excitability, LTP-IE), thereby weak perforant pathway (PP) inputs can induce long-term potentiation at PP synapses (PP-LTP). However, sustained hyperexcitability is detrimental, and a mechanism to reverse this primed state is necessary. Here, we show that burst firings of CA3 pyramidal cells elicited by PP or recurrent synaptic inputs reverse the MF-induced LTP-IE. Moreover, the high-frequency PP inputs to MF-primed CA3 pyramidal cells induced not only PP-LTP but also restored the high excitability state. Labeling a neuronal ensemble using c-fos promoter in animals exposed to a novel context, we found most CA3 ensemble cells exhibited increased excitability, indicative of LTP-IE. Moreover, when the animals experienced novel contexts twice with an interval, a substantial subset of putative twice-activated CA3 ensemble cells exhibited reduced excitability, implying depotentiation of LTP-IE. We developed an in silico model based on these experimental results and found that MF-induced LTP-IE and its depotentiation are critical for association of orthogonal neuronal ensembles representing temporally discontiguous events. HighlightsO_LIIt is unknown how non-overlapping ensembles are linked in the hippocampal CA3 area. C_LIO_LIMossy fiber inputs prime CA3 pyramidal cells by enhancing dendritic excitability. C_LIO_LIPerforant pathway (PP) inputs to the primed cells induce synaptic strengthening. C_LIO_LIAt the same time, the high excitability state is restored by PP inputs. C_LIO_LIThis learning rule may play a key role in sequence learning in CA3 network. C_LI

neuroscience↗

bioRxiv2020

Ventral tegmental area GABA neurons mediate stress-induced anhedonia.

Stressful experiences frequently precede depressive episodes1. Depression results in anhedonia, or disrupted reward-seeking, in most patients2. In humans3,4 and rodents5,6, stress can disrupt reward-seeking, providing a potential mechanism by which stress can precipitate depression7-9. Yet despite decades investigating how stress modulates dopamine neuron transmission between the ventral tegmental area (VTA) and nucleus accumbens (NAc), the underpinnings of the stress-anhedonia transition remain elusive10-13. Here we show that during restraint stress, VTA GABA neurons drive low frequency NAc LFP oscillations, rhythmically modulating NAc firing rates. The strength of these stress-induced NAc oscillations predict the degree of impaired reward-seeking upon release from restraint. Inhibiting VTA GABA neurons disrupts stress-induced NAc oscillations and reverses the effect of stress on reward-seeking. By contrast, mimicking these oscillations with rhythmic VTA GABA stimulation in the absence of stress blunts subsequent reward-seeking. These experiments demonstrate that VTA GABA inputs to the NAc are both necessary and sufficient for stress-induced decreases in reward seeking behavior, elucidating a key circuit-level mechanism underlying stress-induced anhedonia.

neuroscience↗

bioRxiv2020

Selective role of the translin/trax RNase complex in hippocampal synaptic plasticity

Activity-dependent local protein synthesis is critical for synapse-specific, persistent plasticity. Abnormalities in local protein synthesis have been implicated in psychiatric disorders. We have recently identified the translin/trax microRNA-degrading enzyme as a novel mediator of protein synthesis at activated synapses. Additionally, mice lacking translin/trax exhibit some of the behavioral abnormalities found in a mouse model of fragile X syndrome. Therefore, identifying signaling pathways interacting with translin/trax to support persistent synaptic plasticity is a translationally relevant goal. Here, as a first step to achieve this goal, we have assessed the requirement of translin/trax for multiple hippocampal synaptic plasticity paradigms that rely on distinct molecular mechanisms. We found that mice lacking translin/trax exhibited selective impairment in a form of persistent hippocampal plasticity, which requires postsynaptic PKA activity. In contrast, enduring forms of plasticity that are dependent on presynaptic PKA were unaffected. Furthermore, these mice did not display exaggerated metabotropic glutamate receptor-mediated long-term synaptic depression, a hallmark of the mouse model of fragile X syndrome. Taken together, these findings demonstrate that translin/trax mediates long-term synaptic plasticity that is dependent on postsynaptic PKA signaling.

neuroscience↗

bioRxiv2018

KRASG12D and TP53R167H Cooperate to Induce Pancreatic Ductal Adenocarcinoma in Sus Scrofa Pigs

Although survival has improved in recent years, the prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) remains poor. Despite substantial differences in anatomy, physiology, genetics, and metabolism, the overwhelming majority of preclinical testing relies on transgenic mice. Hence, while mice have allowed for tremendous advances in cancer biology, they have been a poor predictor of drug performance/toxicity in the clinic. Given the greater similarity of sus scrofa pigs to humans, we engineered transgenic sus scrofa expressing a LSL-KRASG12D-TP53R167H cassette. By applying Adeno-Cre to pancreatic duct cells in vitro, cells self-immortalized and established tumors in immunocompromised mice. When Adeno-Cre was administered to the main pancreaticduct in vivo, pigs developed extensive PDAC at the injection site hallmarked by excessive proliferation and desmoplastic stroma. This serves as the first large animal model of pancreatic carcinogenesis, and may allow for insight into new avenues of translational research not before possible in rodents.

cancer biology↗