Biology subjects

Fried, N. T.

Publications and source records attributed to Fried, N. T..

5 recordsLinked to original sources

bioRxiv2024

Sphingosine-1-phosphate receptor 3 activation promotes sociability and regulates the expression of genes associated with anxiolytic-like behavior

We previously demonstrated that sphingosine-1-phosphate receptor 3 (S1PR3) in the medial prefrontal cortex (mPFC) prevents stress-mediated reductions in sociability. S1PR3 is a ubiquitously expressed G-protein coupled receptor that regulates immune system function, although its regulation of other biological processes is not well understood. Pharmacological activators of S1PR3 might provide important insights for understanding the neural substrates underlying sociability and/or serve as novel, preclinical treatments for social anxiety. Here we show that in mice, systemic injections of an S1PR3-specific agonist, CYM5541, promotes sociability in males and females whereas an S1PR3-specific antagonist, CAY10444, increases amygdala activation and promotes social anxiety-like behavior in females. S1PR3 expression is increased in the mPFC and dentate gyrus of females compared to males. RNA sequencing in the mPFC reveals that S1PR3 activation alters the expression of transcripts related to immune function, neurotransmission, transmembrane ion transport, and intracellular signaling. This work provides evidence that S1PR3 agonists, which have classically been used as immune modulators, might also be used as novel anxiolytics. S1PR3 might be an important hub gene for anxiolytic effects as it reduces inflammatory processes caused by stress and increases transcripts linked to anxiolytic neurotransmission. HighlightsO_LIThe Sphingosine-1-phosphate receptor 3 (S1PR3) agonist CYM5541 promotes sociability C_LIO_LIThe S1PR3 antagonist CAY10444 reduces sociability and promotes anxiety-like behavior in females C_LIO_LICAY10444 increases neuronal activity markers in the amygdala C_LIO_LIPharmacological activation of S1PR3 regulates the expression of genes in the prefrontal cortex that control a wide range of biological processes, including increasing GABAergic neurotransmission and reducing inflammatory processes C_LI

neuroscience↗

bioRxiv2021

Flying in the Face of Adversity: A Drosophila-based Virtual CURE Provides Semester-long Authentic Research Opportunity to the Flipped Classroom.

A call for the integration of research experiences into all biology curricula has been a major goal for educational reform efforts nationally. Course-Based Undergraduate Research Experiences (CUREs) have been the predominant method of accomplishing this, but their associated costs and complex design can limit their wide adoption. In 2020, the COVID-19 pandemic forced programs to identify unique ways to still provide authentic research experiences while students were virtual. We report here a full guide for the successful implementation of a semester-long virtual CURE that uses Drosophila behavioral assays to explore the connection between pain and addiction with the use of a "lab-in-a-box" sent home to students. Individual components were piloted across three semesters and launched as a 100-level introductory course with 19 students. We found that this course increased science identity and successfully improved key research competencies as per the Undergraduate Research Student Self-Assessment (URSSA) survey. This course is ideal for flipped classrooms ranging from introductory biology to upper-level neuroscience courses and can be integrated directly into the lecture period without the need for building a new course. Given the low cost, recent comfort with virtual learning environments, and the current proliferation of flipped biology classrooms following the 2020 pandemic, this curriculum could serve as an ideal project-based active-learning tool for equitably increasing access to authentic research experiences.

scientific communication and education↗

bioRxiv2021

Chronic paternal morphine exposure increases sensitivity to morphine-derived antinociception

Parental exposure to drugs of abuse such as opioids can have profound and long-lasting effects on reward processing and drug sensitivity across generations. However, little is known about the impact of long-term paternal exposure to morphine on offspring sensitivity to morphine-derived antinociception during painful experiences. To address this question, we constructed a rat pain scale at millisecond timescales to measure mechanical nociception in a multigenerational morphine exposure paradigm. Surprisingly, while developing the pain scale, we found that von Frey hair filaments (VFHs), the most common stimuli used in pain research, are not painful to rats and morphine did not change the touch-like responses elicited by VFHs. We next deployed this novel pain scale to determine whether chronic morphine exposure in sires impacted pain sensitivity in the next generation. Offspring produced from a cross of morphine-treated sires and drug-naive dams, did not show any baseline changes in sensitivity to mechanical nociception. However, morphine-sired male progeny displayed a higher sensitivity to the antinociceptive properties of morphine, as measured by our pain scale. These findings demonstrate that long-term paternal exposure to morphine increases sensitivity to morphine-derived analgesia in the subsequent generation.

neuroscience↗

bioRxiv2020

Adenosine modulates extracellular glutamate levels via adenosine A2A receptors in the delayed-ethanol induced headache.

Identifying the mechanism behind delayed ethanol-induced headache (DEIH), otherwise known as the hangover headache, may provide insight into the mechanisms behind common headache triggers. Acetate was previously shown to be the key ethanol metabolite behind DEIH in the recurrent inflammatory stimulation (IS) rat model of headache. The reversal of trigeminal sensitivity following ethanol exposure with caffeine previously suggested a role of adenosine in DEIH. To characterize this, behavioral analysis and measurement of brainstem adenosine and glutamate with microdialysis and HPLC was performed while pharmacologically manipulating adenosine signaling in the IS and Spontaneous Trigeminal Allodynia (STA) rat models of headache. Blocking adenosine A2A receptor activation with istradefylline or acetate transport into astrocytes with the monocarboxylate transporter competitive inhibitor, alpha-cyano-4-hydroxycinnamate (4-CIN), prevented acetate-induced trigeminal sensitivity. Blocking adenosine A1, A2B, and A3 receptor signaling did not prevent trigeminal sensitivity. Compared to control rats, IS rats had greater increases in extracellular adenosine and glutamate within the trigeminal nucleus caudalis (TNC) of the brainstem during local acetate perfusion. Blocking transport of acetate into astrocytes with 4-CIN prevented the increase in adenosine and glutamate. Blocking A2A receptor activation prevented the increase in extracellular glutamate, but not adenosine in the TNC. These data are the first to demonstrate the physiological consequence of acetate on adenosinergic systems within trigeminal pain by suggesting that acetate-induced trigeminal sensitivity in DEIH is mediated by adenosine A2A receptor activation which modulates extracellular glutamate levels in the TNC. Significance StatementIt is unknown how several common headache triggers induce headache pain. Since migraineurs are more sensitive to these triggers, studying the mechanisms behind their effects may reveal unique migraine pathophysiology. In this study, we explored the common headache trigger, ethanol, which migraineurs are particularly sensitive to. When ethanol is ingested, its quickly metabolized to acetaldehyde and subsequently into acetate. We find that acetate increases brainstem adenosine and causes trigeminal sensitivity, which is exacerbated in the rat headache model. Blocking either acetate uptake or adenosine signaling prevents trigeminal sensitivity and brainstem glutamatergic signaling, suggesting that adenosine is involved in the hangover headache and that differences in acetate metabolism may account for the increased sensitivity to ethanol in migraineurs.

neuroscience↗

bioRxiv2018

High-Speed Imaging of Paw Withdrawal Reflex to Objectively Assess Pain State in Mice

Rodents are often used for studying chronic pain mechanisms and developing new pain therapeutics, but objectively determining the animals pain state is a major challenge. To improve the precision of using reflexive withdrawal behaviors for interpreting the mouse pain state, we adopted high-speed videography to capture sub-second movement features of mice upon hind paw stimulation. We identified several parameters that are significantly different between behaviors evoked by innocuous and noxious stimuli, and combined them to map the mouse pain state through statistical modeling and machine learning. To test the utility of this approach, we determined the pain state triggered by von Frey hairs (VFHs) and optogenetic activation of two nociceptor populations. Our method reliably assesses the \"pain-like\" probability for each mouse paw withdrawal reflex under all scenarios, highlighting the improved precision of using this high resolution behavior-centered composite methodology to determine the mouse pain state from reflexive withdrawal assays.

neuroscience↗