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Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the catecholamine (CA) biosynthesis pathway, making TH a molecular target for controlling CA production, specifically dopamine. Dysregulation of dopamine is correlated with neurological diseases such as Parkinson's disease (PD) and post-traumatic stress disorder (PTSD), among others. Previously, we showed that a 49-nucleotide guanine (G)-rich sequence within the human TH promoter adopts two different sets of G-quadruplex (GQ) structures (5'GQ and 3'GQ), where the 5'GQ uses G-stretches I, II, IV, and VI in TH49, which enhances TH transcription, while the 3'GQ utilizes G-stretches II, IV, VI, and VII, which represses transcription. Herein, we demonstrated targeted switching of these GQs to their active state using rationally designed DNA GQ Clips (5'GQ and 3'GQ Clips) to modulate endogenous TH gene expression and dopamine production. As a translational approach, we synthesized a targeted nanoparticle delivery system to effectively deliver the 5'GQ Clip in vivo. We believe this strategy could potentially be an improved approach for controlling dopamine production in a multitude of neurological disorders, including PD.

Foraging animals usually select foods that balance the intake of key nutrients, for example essential amino acids that cannot be synthesized and must be obtained from the diet. However, the ability to gain optimal ratios, proportions and amounts of nutrients may be hampered by a changing environment, competitive conspecifics or species and predators. Here, we used an experimental system in which house sparrows, Passer domesticus, were fed a manipulated diet with different compositions of amino acids (in the experimental diet phenylalanine and tyrosine content was 42% of that in the control diet). Phenylalanine and tyrosine are precursors of coping hormones: dopamine, noradrenaline (norepinephrine) and adrenaline (epinephrine) which are involved mainly in the expression of stress and fear, but also in learning and long-term memory formation. Accordingly, birds fed a diet deficient in these amino acids learned to avoid unpalatable food markedly slower, coped worse with stress in the presence of a novel object and were more aggressive towards other sparrows than control birds. Surprisingly, circulating amounts of the catecholamines in blood plasma were higher in these birds than in sparrows on the control diet. This study provides the first evidence that variation in amino acid composition in the diet is associated with variation in behaviours and hormone levels in birds. We conclude that food, besides its nutritional function, seems to represent one of the modulators of behavioural expression making a balanced diet crucial for survival.

The electrophysiological (EP) effects and safety of renal artery denervation (RDN) in chronic kidney disease (CKD) are unclear.The purpose of this study was to investigate the arrhythmogenicity of RDN in a rabbit model of CKD.Eighteen New Zealand white rabbits were randomized to control (n = 6), CKD (n = 6), and CKD-RDN (n = 6) groups. A 5/6 nephrectomy was selected for the CKD model. RDN was applied in the CKD-RDN group. All rabbits underwent cardiac EP studies for evaluation. Immunohistochemistry, myocardial fibrosis, and renal catecholamine levels were evaluated.The CKD group (34.8% ± 9.2%) had a significantly higher ventricular arrhythmia (VA) inducibility than the control (8.6% ± 3.8%; P.01) and CKD-RDN (19.5% ± 6.3%; P = .01) groups. In the CKD-RDN group, ventricular fibrosis was significantly decreased compared to the CKD group (7.4% ± 2.0 % vs 10.4% ± 3.7%; P = .02). Sympathetic innervation in the CKD group was significantly increased compared to the control and CKD-RDN groups [left ventricle: 4.1 ± 1.8 vs 0.8 ± 0.5 (10Neuromodulation by RDN demonstrated protective effects with less structural and electrical remodeling, leading to attenuated VAs. In a rabbit model of CKD, RDN plays a therapeutic role by lowering the risk of VA caused by autonomic dysfunction.

Adrenocorticotropic hormone (ACTH)-producing pheochromocytoma can cause a variety of clinical manifestations of excess catecholamine and corticosteroid. Anatomic localization of this source of ectopic ACTH is critical to facilitate unilateral adrenalectomy and prevent adrenal insufficiency due to bilateral adrenalectomy. Although nuclear scintigraphy remains the diagnostic gold standard, recent radiotracer supply shortages have necessitated alternative diagnostic paradigms to localize adrenal pheochromocytomas. We present a case where adrenal vein sampling (AVS) was utilized to lateralize an adrenal pheochromocytoma and discuss the approach and nuance as it differs from routine AVS for hyperaldosteronism or hypercortisolism.

Tyrosine hydroxylase (TH) catalyses the (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4)-dependent conversion of L-tyrosine to L-3,4-dihydroxyphenylalanine (L-Dopa), which is the rate-limiting step in the synthesis of dopamine and other catecholamine neurotransmitters and hormones. Dysfunctional mutant TH causes tyrosine hydroxylase deficiency (THD), characterized by symptoms ranging from mild l-Dopa responsive dystonia to severe neuropathy. THD-associated mutations often present misfolding and a propensity to aggregate, characteristics that can also be manifested by dysregulated wild-type TH. TH - and subsequently dopamine - is also reduced in Parkinson's disease (PD) due to the selective death of dopaminergic neurons. Thus, TH is a target for stabilizing small molecular weight compounds that can function as pharmacological chaperones, restoring enzyme folding and function. In this work we carried out a screening of a compound library with 1280 approved drugs and we identified levalbuterol, a beta2-adrenergic agonist that is broadly used in asthma treatment, as an interesting validated binder of human TH. Levalbuterol stabilized TH with reduced affinity compared to dopamine, the end-product and regulatory feedback inhibitor of TH, but without compromising enzymatic activity. Moreover, levalbuterol also delays the formation of TH aggregates and makes the enzyme less sensitive to dopamine, effects that could contribute to ameliorate disorders related to TH, such as THD and PD.

The catecholamine-containing brainstem nuclei locus coeruleus (LC) and ventral tegmental area (VTA) are critically involved in stress responses. Alterations of catecholamine systems during chronic stress may contribute to neurodegeneration, including cognitive decline. Stress-related catecholamine alterations, while contributing to anxiety and depression, might accelerate neuronal degeneration by increasing the formation of toxic dopamine and norepinephrine by-products. These, in turn, may impair proteostasis within a variety of cortical and subcortical areas. In particular, the molecular events governing neurotransmission, neuroplasticity, and proteostasis within LC and VTA affect a variety of brain areas. Therefore, we focus on alterations of autophagy machinery in these nuclei as a relevant trigger in this chain of events. In fact, these catecholamine-containing areas are mostly prone to autophagy-dependent neurodegeneration. Thus, we propose a dynamic hypothesis according to which stress-induced autophagy alterations within the LC-VTA network foster a cascade towards early neurodegeneration within these nuclei.

To evaluate levels of plasma cerebellin, cortisol, adrenaline and noradrenaline in patients with central serous chorioretinopathy (CSC).This prospective study included 30 patients diagnosed with acute CSC (Group 1) and a control group of 30 age-matched, healthy subjects without CSC (Group 2). Levels of plasma cerebellin, cortisol, adrenaline and noradrenaline were examined in blood samples taken after 8-12hours of fasting. A value of p0.05 was considered statistically significant in the comparative analyses.The mean plasma cerebellin level was found to be 232.56±113.28 pg/ml in Group 1 and 174.07±82.04 pg/ml in Group 2 (p=0.02). Mean plasma cortisol was 13.19±3.87μg/ml in Group 1 and 9.55±2.92μg/ml in Group 2 (p0.01). Mean plasma adrenaline was 60.62±26.67 pg/ml in Group 1 and 46.17±19.20 pg/ml in Group 2 (p=0.03). Mean plasma noradrenaline was 206.66±73.90 pg/ml in Group 1 and 149.96±51.36 pg/ml in Group 2 (p0.01).It can be concluded that increased cerebellin may have a role in the etiology of CSC by increasing catecholamine expression from the adrenal medulla and indirectly by increasing cortisol levels via a paracrine effect from the adrenal cortex.

Pheochromocytoma (PCC) is a rare catecholamine-producing neuroendocrine tumor, generally located in the adrenal glands, which may occasionally cause refractory cardiogenic shock. The risk of surgical resection in this setting is considered prohibitive. By providing temporary circulatory support, veno-arterial extracorporeal membrane oxygenation (ECMO) has been used to attempt stabilization and bridge patients with PCC to elective adrenalectomy but increases left ventricular afterload and often requires additional catecholamine support. We report two patients on ECMO, who underwent transapical left ventricular unloading via a left minithoracotomy, allowing withdrawal of inotropes, administration of alpha- and beta-adrenergic antagonists, and, ultimately, weaning and successful PCC resection.

Objective Paradoxical hypertension after repair of coarctation of the aorta in children is associated with the release of catecholamines and activation of the renin-angiotensin system. The objective of the present study was to describe the effects of labetalol infusion on blood pressure, plasma catecholamine levels, and plasma renin activity in a series of children undergoing repair of coarctation of the aorta. Design Prospective, observational cohort study. Setting Tertiary children's hospital with university affiliation. Participants The study was comprised of 15 consecutive children older than 1 year undergoing repair of coarctation of the aorta. Interventions Intravenous infusion of labetalol, up to 20 µg/kg/min, was administered when patients became hypertensive after release of the aortic cross-clamp. Supplementation with nitroprusside was allowed as needed. Measurements and Main Results Blood pressure was maintained below baseline values throughout the labetalol infusion. Plasma norepinephrine increased from 160 ± 81 pg/mL (preoperative) to 657 ± 268 pg/mL (6 h after release of aortic cross-clamp). Plasma renin activity decreased from 16.6 ± 9.7 ng/kg/h (at cross-clamp release) to 2.2 ± 2.2 ng/kg/h (6 h after cross-clamp release). Nitroprusside was added for 12 patients, at a highest mean dose of 2.4 ± 2.5 μg/kg/min. Conclusions Labetalol inhibited activation of the renin-angiotensin system and helped control paradoxical hypertension after coarctation repair in children.

Sympathergic hyperactivity is considered one of the main trigger precipitating takotsubo syndrome (TTS). Chromogranin-A (CgA), a prognostic biomarker of sympatho-adrenal activation, is markedly high in acute coronary syndrome (ACS) and heart failure (HF), but its role in TTS is unknown.CgA serum levels from patients with TTS and symptoms onset24 hours were consecutively evaluated and compared with anterior ST-elevation myocardial infarction (STEMI) patients from November 2016 to December 2019. Short and long-term follow-up data were recorded.Eleven women with TTS and 10 subjects with anterior STEMI were analyzed and compared; differences were not significant in terms of age, gender and cardiovascular risk factors. NT-pro-BNP levels were similar (9,887 ± 12,170 vs 8,969 ± 15,053 pg/ml, p = .88), while troponin-I levels were higher in patients with STEMI (4 ± 3.2 vs 13.3 ± 10 ng/dl, p = .03). CgA admission levels were significantly lower in TTS patients (2.2 ± 1.5 vs 7.3 ± 6.2 nMol/l, p = .017), even after multivariable correction for principal bias. CgA levels correlated with NTproBNP levels (p = .02) and were higher in subjects with in-hospital events (3.7 ± 1.1 vs 1.6 ± 1.2 nMol/l, p = .03), even after multivariable forward stepwise analysis (p .01). CgA levels3.25 nMol/l (AUC 0.754, 95% C.I. 0.54-0.968) were able to discriminate TTS from anterior STEMI (negative predictive power of 99%).Systemic CgA levels in the acute phase of TTS are lower than in anterior STEMI, possibly indicating a greater myocardial catecholamine release rather than adrenal.

Ganglioneuroma, which arise from neural crest cells, typically occurs in adolescents and young adults. Most ganglioneuromas are clinically asymptomatic and hormonally silent, therefore may be diagnosed incidentally during imaging studies. Ganglioneuroma containing fat (lipomatous ganglioneuroma) is a rare variant of ganglioneuroma that is histologically characterized by a mature adipocytic component admixed with a conventional ganglioneuroma. Herein, we report the case of adrenal lipomatous ganglioneuroma with elevated urinary catecholamine level.

Purpose Perioperative myocardial dysfunction occurs frequently in cardiac surgery, and is a risk factor for morbidity and mortality. Levosimendan has been suggested to reduce mortality of patients with perioperative myocardial dysfunction. However, long-term outcome data on its efficacy in cardiac surgery are lacking. Materials and methods Cardiac surgery patients with perioperative myocardial dysfunction were randomized to levosimendan or placebo, in addition to standard inotropic care. One-year mortality data were collected. Results We randomized 506 patients (248 to levosimendan 258 to placebo). At 1-year follow-up, 41 patients (16.5%) died in the levosimendan group, while 47 (18.3%) died in the placebo group (absolute risk difference −1.8; 95% CI −8.4 to 4.9; P = .60). Female sex, history of chronic obstructive pulmonary disease, previous myocardial infarction, serum creatinine, hematocrit, mean arterial pressure, and duration of cardiopulmonary bypass were independently associated with 1-year mortality. Conclusions Levosimendan administration does not improve 1-year survival in cardiac surgery patients with perioperative myocardial dysfunction. One-year mortality in these patients is 17%. Six predictive factors for long-term mortality were identified. Study registration number NCT00994825 ( ClinicalTrials.gov ).

Based on the lately identified role for the interstitial cells of Cajal (ICCs) of mouse prostate in catecholamine production, as well as the well-established role for the master coregulator metastasis-associated protein 1 (MTA1) in inflammation, we probed into the functional link between aberrant MTA1 expression and pathogenesis of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) using both a MTA1−/− mouse model of experimental autoimmune prostatitis (EAP) and an in vitro chronic prostatitis model in cultured murine ICCs. EAP-induced MTA1 expression was enriched in ICCs of mouse prostate. EAP resulted in a higher increase in the pelvic pain response in MTA1−/− mice compared to WT mice. Consistently, the ICCs from MTA1−/− mice produced higher levels of catecholamines upon induction of in vitro chronic prostatitis. Mechanistically, MTA1 could directly suppress the transcription of Aadc, a rate-limiting enzyme during catecholamine synthesis, in a HDAC2-depdendent manner. Importantly, treatment with AADC inhibitor NSD-1015 significantly ameliorated EAP-elicited pain response and catecholamine overactivity in MTA1−/− mice. Taken together, our findings reveal an inherent regulatory role of the MTA1/AADC pathway in the maintenance of catecholamine production homeostasis in prostate ICCs, and also point to a potential use of HDAC inhibitors and/or AADC inhibitors to treat CP/CPPS.

Pheochromocytomas, arising from chromaffin cells, produce catecholamines, epinephrine and norepinephrine. The tumor biochemical phenotype is defined by which of these exerts the greatest influence on the cardiovascular system when released into circulation in high amounts. Action on the heart and vasculature can cause potentially lethal arrhythmias, often in the setting of comorbid blood pressure derangements. In a review of electrocardiograms obtained on pheochromocytoma patients (n = 650) treated at our institution over the last decade, severe and refractory sinus tachycardia, atrial fibrillation, and ventricular tachycardia were found to be the most common or life-threatening catecholamine-induced tachyarrhythmias. These arrhythmias, arising from catecholamine excess rather than from a primary electrophysiologic substrate, require special considerations for treatment and complication avoidance. Understanding the synthesis and release of catecholamines, the adrenoceptors catecholamines bind to, and the cardiac and vascular response to epinephrine and norepinephrine underlies optimal management in catecholamine-induced tachyarrhythmias.

Burn victims are reported to have more possibility of bone loss in acute phase of injury partly due to sympathetic dysfunction and catecholamine increase beside other hypermetabolic responses. These patients are also prone to autonomic neuropathy and sympathetic skin response (SSR) impairment. We aim to investigate the correlation between SSR in the acute phase and bone mineral density (BMD) parameters in electrical burn patients and determine whether the SSR parameter in initial weeks of the event is a good predictor of bone loss in long term.Sixty two individuals exposed to low voltage(1000 V) electrical current were invited to a cohort study. The SSR was recorded from their four limbs in 2-5 weeks after injury. Then, dual X-ray absorptiometry (DXA) was done to measure their BMD, T-score and Z -score, 9-12 months later. The correlation between SSR parameters in acute phase and DXA indexes was evaluated using Spearman test. A Roc curve was charted to point out a cut-off value for SSR amplitude and latency in respect to T-score to predict the subsequent bone loss.All the patients were male with a mean age of 34.09 years. Biphasic SSR parameters showed a significant correlation with lumbar BMD in a confidence interval of 99.9%. SSR amplitude threshold of 293.75 μV and latency of 2.15 s had a 100% sensitivity and 94% and 83% specificity respectively for predicting the bone loss (T-score-1) in long term. The area under Roc curve was 0.94 and 0.99 in terms of SSR amplitude and latency.SSR recorded in the first few weeks after electrical injury is a good predictor of bone loss in long term, so we recommend this test as a guide for screening the patients at risk for osteoporosis in electrical burn and formulating the preventive measurements.

Pheochromocytoma is a neuroendocrine tumor of the adrenal gland that secretes excess amount of catecholamine, which in turn leads to extremely varied clinical manifestations, such as hypertension, headache, sweating and palpitations. This eventually leads to delay or mistakes in diagnosing the disease. This could be fatal due to misdiagnosis as it receives a totally different treatment. We herein reported a case of pheochromocytoma with recurrent ventricular tachycardia. A literature review was conducted to investigate the clinical features of these patients.

A 44-year-old Japanese man was referred to our hospital for the evaluation of paroxysmal hypertension. (123)I-metaiodobenzylguanidine (MIBG) single-photon emission computed tomography (SPECT) revealed specific uptake in the left adrenal gland in addition to high levels of serum and urinary catecholamines although computed tomography and magnetic resonance imaging were not able to detect a definite adrenal mass. Left adrenalectomy was performed and he was diagnosed with adrenal medullary hyperplasia (AMH). A diagnosis of unilateral AMH is important because AMH resection can effectively treat hypertension.

Background Traumatic brain injury (TBI) is associated with reduced cerebral blood flow and impaired autoregulation after TBI, which may lead to poor outcome. Clinical evidence has implicated neurological injuries and associated neuroinflammation as causes of cardiac dysfunction. Studies on newborn pigs show an association of elevated catecholamines with a sex-dependent impairment of cerebral autoregulation after TBI. One strategy to decrease sympathetic hyperactivity is pharmacological intervention with beta blockade. We tested the hypothesis that propranolol would prevent the impairment of cerebral autoregulation and tissue changes after TBI via inhibition of interleukin-6 (IL-6) upregulation. Methods Using newborn pigs of both sexes equipped with a closed cranial window, TBI was induced via lateral fluid percussion injury. Propranolol was administered at 1 h post-TBI. Analyses included cerebral autoregulation (pial artery reactivity) before and 4 h post-TBI, CSF IL-6 analysed (enzyme-linked immunosorbent assay), and histopathology at 4 h post-TBI. Results Propranolol administration prevented impairment of hypotensive dilation in both male and female newborn pigs after fluid percussion injury, which was paralleled by reduced upregulation of IL-6 in the CSF. Moreover, propranolol prevented neuronal cell death in cornu amonis (CA)1 and CA3 hippocampus equivalently in male and female pigs after TBI. Papaverine-induced dilation was unchanged by TBI and propranolol. Conclusions These data indicate that sympathetic hyperactivity noted after TBI can be limited by propranolol administration to result in improved brain outcome post-injury via block of IL-6 upregulation, and this effect is irrespective of sex.

Nucleus incertus (NI) is a brainstem structure involved in the control of arousal, stress responses and locomotor activity. It was reported recently that NI neurons express the dopamine type 2 (D2) receptor that belongs to the D2-like receptor (D2R) family, and that D2R activation in the NI decreased locomotor activity. In this study, using multiplex in situ hybridization, we observed that GABAergic and glutamatergic NI neurons express D2 receptor mRNA, and that D2 receptor mRNA-positive neurons belong to partially overlapping relaxin-3- and cholecystokinin-positive NI neuronal populations. Our immunohistochemical and viral-based retrograde tract-tracing studies revealed a dense innervation of the NI area by fibers containing the catecholaminergic biosynthesis enzymes, tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DBH), and indicated the major sources of the catecholaminergic innervation of the NI as the Darkschewitsch, raphe and hypothalamic A13 nuclei. Furthermore, using whole-cell patch clamp recordings, we demonstrated that D2R activation by quinpirole produced excitatory and inhibitory influences on neuronal activity in the NI, and that both effects were postsynaptic in nature. Moreover, the observed effects were cell-type specific, as type I NI neurons were either excited or inhibited, whereas type II NI neurons were mainly excited by D2R activation. Our results reveal that rat NI receives a strong catecholaminergic innervation and suggest that catecholamines acting within the NI are involved in the control of diverse processes, including locomotor activity, social interaction and nociceptive signaling. Our data also strengthen the hypothesis that the NI acts as a hub integrating arousal-related neuronal information.

Highlights • Temporary use of unusually high dose of catecholamines may help avoid unnecessary mechanical support after cardiac surgery. • In a stunned myocardium, increase of catecholamine over usual dose could be acceptable. • Short-term application of very high dose catecholamines under close monitoring may not be associated with poor outcome., Introduction Some cardiac surgical patients present low cardiac output syndrome due to ventricular dysfunction resulting from postischemic myocardial stunning. We present a case of using unusually high dose of inotropes so that we could avoid mechanical circulatory support after cardiac surgery. Presentation of case A 65-year-old man underwent elective cardiac surgery. His immediate cardiac output was poor and vital signs were unstable. We aggressively increased the dose of catecholamine above usual dose and the cardiac output was elevated. The patient recovered without significant myocardial injury. After a few years, TTE showed more improved left ventricular function compared with preoperative state. Discussion In a stunned myocardium, response to catecholamine is thought to be dull. Thus, if adequate response to usual dose of catecholamine is not achieved in a post cardiac surgical patient, we think that there may be a room for more increment of inotropes. Conclusion Unusually high dose of catecholamine may be helpful in a patient with severe ventricular dysfunction associated with stunned myocardium.

Vanillylmandelic acid, a catecholamine end-metabolite, has been shown to have several biological properties in previous studies, despite considered biologically inactive. We examined the potential effects of vanillylmandelic acid on the ischemic heart following myocardial infarction and reperfusion on a rat model. Thirty-four female Wistar rats were randomized into two groups, control and experimental. They were anesthetized and subjected to myocardial infarction through left anterior descending artery ligation. A previously studied dose of vanillylmandelic acid (10 mg/kg) was administered and the following parameters were studied during ischemia and reperfusion: a) mortality b) severity of ventricular tachyarrhythmias c) premature ventricular contractions and d) heart rate. Administration of vanillymandelic acid significantly reduced the severity of ventricular tachyarrhythmias and mortality rate during reperfusion, while it did not affect any other of the parameters studied. In conclusion, reperfusion injury was blunted through vanillylmandelic acid administration, which seems to be mediated by parasympathetic activation.

This first-attempt study provided novel electrochemical exploration via microbial fuel cells (MFCs), suggesting why catecholamine hormone-neurotransmitters epinephrine (EP) and dopamine (DA) could effectively trigger acute stress responses for humans. According to bioelectrochemical engineering, EP and DA are ortho-diphydroxyl (o-diOH) substituent(s)-bearing electron shuttles (ESs) that could effectively mediate electron-transfer capabilities for bioenergy extraction. This study quantitatively compared redox-mediating characteristics of EP and DA with other antioxidants and ESs, suggesting possible mechanisms of bioenergy-driven responses to organisms. Although some electrochemical activities of EP and DA were characterized in medical literature, this work clarified that EP and DA were also electrochemically favorable ESs for efficient bioenergy extraction. Compared to vitamin B2 (VB), vitamin C (VC) and gallic acid (GA), quantitative evaluation upon bioenergy-stimulating capabilities of EP and DA were clearly revealed via MFC modules. Apparently, both EP and DA as ESs significantly exhibited stable and reversible redox potential peaks in cyclic voltammetry. Evidently, power density performances of MFCs supplemented with EP and DA considerably increased ca. 127–385%, suggesting that DA and EP would be the most appropriate ESs to effectively stimulate electron-mediating capabilities in multicellular organisms. It was also suspected that highly efficient power-stimulating capabilities of DA and EP could be strongly associated with their electrochemically-steered disease-curative and life-threatening capabilities to humans.

Rapid and real-time monitoring of catecholamine neurotransmitter dopamine receives immense importance since it plays a crucial role as a local chemical messenger for interneuronal communications in mammalian central and peripheral nervous systems. In the present study, blue emitting copper nanocluster was synthesized in presence (BSA CuNC1) and absence (BSA CuNC2) of hydrogen peroxide and fluorescence response of the two systems towards dopamine was analysed. At an excitation of 355 nm, fast response towards dopamine detection was obtained for BSA CuNC1 system having limit of detection 0.1637 pM. The fast interaction of dopamine with BSA CuNC1 can be attributed to the intrinsic peroxidase like activity of CuNC in presence of H2O2. On the other hand, the response of dopamine towards BSA CuNC2 was very slow with a limit of detection 0.024 nM. Encouraged by the fast response and low limit of detection, the BSA CuNC1 system was effectively applied for dopamine detection in real sample matrices. The recovery percentage for serum sample obtained was in the range 90–98.33% and for urine sample was in the range 89–96.66%. In addition to that, a paper test strips using BSA CuNC1 was developed which exhibited colour change as well as fluorescence quenching, creates a low cost approach for the fast monitoring of dopamine.

The vesicular monoamine transporter is involved in presynaptic catecholamine storage and neurotransmission. Two isoforms of the transporter exist, VMAT1 and VMAT2, and both are expressed in the brain, though VMAT2 expression is more robust and has been more widely studied. In this study we investigated the role of VMAT1 KO on markers of dopaminergic function and neurotransmission, and dopamine-related behaviors. Null-mutant VMAT1 mice were studied behaviorally using the tail suspension test, elevated zero maze and locomotor activity assessments. Tissue monoamines were measured both ex vivo and by using in vivo microdialysis. Protein expression of tyrosine hydroxylase and D2 dopamine receptors was measured using western blot analysis. Results show that VMAT1 KO mice have decreased dopamine levels in the frontal cortex, increased postsynaptic D2 expression, and lower frontal cortex tyrosine hydroxylase expression compared to WT mice. VMAT1 KO mice also show an exaggerated behavioral locomotor response to acute amphetamine treatment. We conclude that dopaminergic signaling is robustly altered in the frontal cortex of VMAT1 null-mutant mice and suggest that VMAT1 may be relevant to the pathogenesis and/or treatment of psychiatric illnesses including schizophrenia and bipolar disease.

Antipsychotic drugs are used to manage symptoms of pediatric psychiatric disorders despite the relative absence of research regarding the long-term effects of these drugs on brain development. Using rats as a model, research has demonstrated that administration of the antipsychotic drug, risperidone, during early postnatal development elevates locomotor activity and sensitivity to the locomotor effects of amphetamine during adulthood. Because risperidone targets neurotransmitter receptors and forebrain regions associated with working memory, the present study determined whether early-life risperidone altered working memory during adulthood and its sensitivity to amphetamine-induced impairment. Female and male rats received subcutaneous (sc) injections of risperidone daily on postnatal days 14-42. Early-life risperidone increased spontaneous locomotor activity and amphetamine-induced hyperactivity during adulthood, although the effects were significantly greater in females. Working memory was tested in an operant-based, delayed non-matching-to-sample task. Early-life risperidone did not affect the percentage of correct choices observed during sessions with 0–8 second delays but impaired performance during sessions with 0–24 second delays. In a subsequent set of tests using 0–24 second delays, amphetamine (0.75 and 1.25 mg/kg, sc) significantly reduced the percentage of correct choices at most delays, but risperidone did not exacerbate this effect. These data suggest that early-life risperidone leads to modest deficits in working memory during adulthood, but does not alter the perturbation of working memory by amphetamine.

Catecholamine transmitters dopamine (DA) and norepinephrine (NE) regulate prefrontal cortical (PFC) circuit activity and PFC-mediated executive functions. Accordingly, pharmacological agents that influence catecholamine neurotransmission exert prominent effects on cognition. Many such agents are used clinically to treat attention disorders. For example, methylphenidate blocks DA and NE reuptake and is the leading choice for attention deficit hyperactivity disorder (ADHD) treatment. Recently, we have designed SK609 – a selective small molecule agonist of the DA D3 receptor (D3R). In this study, we further characterized SK609's ability to selectively inhibit the reuptake of NE by NE transporters (NET). Our results indicate SK609 selectively inhibits NET with a Ki value of ∼500 nM and behaves as a NET substrate. Systemic dosing of SK609 (4 mg/kg; i.p.) in naive rats produced a 300% and 160% increase in NE and DA, respectively, in the PFC as measured by microdialysis. Based on these neurochemical results, SK609 was tested in a PFC-dependent, visually-guided sustained attention task in rats. SK609 improved performance in a dose-dependent manner with a classical inverted-U dose response function with a peak effect at 4 mg/kg. SK609's peak effect was blocked by a pre-treatment with either the D2/D3R antagonist raclopride (0.05 mg/kg; i.p) or the alpha-1 adrenergic receptor antagonist prazosin (0.25 mg/kg; i.p), confirming a role for both DA and NE in promoting sustained attention. Additionally, SK609 improved sustained attention more prominently among low-performing animals. Doses of SK609 (2, 4, and 8 mg/kg) associated with cognitive enhancement did not produce an increase in spontaneous locomotor activity, suggesting a lack of side effects mediated by DA transporter (DAT) activity. These results demonstrate that the novel catecholaminergic modulator SK609 has the potential to treat sustained attention deficits without affecting DAT activity, distinguishing it from amphetamines and methylphenidate.

Attention-deficit/hyperactivity disorder (ADHD) is a psychiatric disorder characterized by inattention, aberrant impulsivity, and hyperactivity. Although the underlying pathophysiology of ADHD remains unclear, dopamine and norepinephrine signaling originating from the ventral tegmental area (VTA) and locus coeruleus (LC) is thought to be critically involved. In this study, we employ Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) together with the mouse 5-Choice Serial Reaction Time Task (5-CSRTT) to investigate the necessary roles of these catecholamines in ADHD-related behaviors, including attention, impulsivity, and motivation. By selective inhibition of tyrosine hydroxylase (TH)-positive VTA dopamine neurons expressing the Gi-coupled DREADD (hM4Di), we observed a marked impairment of effort-based motivation and subsequently speed and overall vigor of responding. At the highest clozapine N-oxide (CNO) dose tested (i.e. 2 mg/kg) to activate hM4Di, we detected a reduction in locomotor activity. DREADD-mediated inhibition of LC norepinephrine neurons reduced attentional performance in a variable stimulus duration test designed to increase task difficulty, specifically by increasing trials omissions, reducing mean score, and visual processing speed. These findings show that VTA dopamine and LC norepinephrine neurons differentially affect attention, impulsive and motivational control. In addition, this study highlights how molecular genetic probing of selective catecholamine circuits can provide valuable insights into the mechanisms underlying ADHD-relevant behaviors.

Objectives The objective of this study was to investigate the effects of a new I1-imidazoline receptor-selective pyrroline compound on the hemodynamic, metabolic and microvascular alterations in a high-fat diet (HFD)-induced model of metabolic syndrome in rats. Methods In total, twenty adult male Wistar rats were fed a high-fat diet (HFD, n = 20) for 20 weeks. Thereafter, the rats received a new pyrroline compound selective for I1-imidazoline receptors (LNP599; 10 mg/kg/day) or vehicle (n = 10/group) orally by gavage for 4 weeks. Functional microcirculation was assessed using intravital video microscopy, and structural microcirculation was evaluated using histochemical analysis. Results LNP599 induced concomitant reductions in the SBP, HR and plasma catecholamine levels. The animals treated with this new antihypertensive compound also presented an improvement in body weight and the metabolic parameters related to metabolic syndrome, such as the glucose and lipid profiles. These effects were accompanied by a reversal of the functional and structural capillary rarefaction in the skeletal muscle. Conclusions The modulation of the sympathetic nervous system by a selective agonist for I1-imidazoline receptors improves the hemodynamic and metabolic parameters in an experimental model of metabolic syndrome. LNP599 can also contribute to the restoration of microcirculatory parameters.

Dopamine (DA) is a significant catecholamine neurotransmitter in the brain of mammal, and DA is one biological index of some diseases at the same time. Due to various drawbacks in clinical trials of the existing methods for detecting dopamine, there is an urgent need for rapid and sensitive detection methods to diagnose and monitor these diseases. In this study, we report a simple, effective, sensitive, non-toxic and environmentally friendly method for the DA detection based on fluorescence analysis, more specifically, we use the characteristic of dopamine, dopamine oxidative polymerization, so as to achieve testing of dopamine. The way only uses a common alkali, polyethyleneimine (PEI), to start the polymerization process, and make the experiment very simple and cheap. The optical properties of polydopamine (PDA) nanoparticles which formed under different response times and different concentrations were studied for the first time. After the experimental conditions were optimized, a good linear relationship was obtained from 1.0–200 μM with the correlation coefficient of 0.99904 and the detection limit was 0.3 μM. This method is highly selective and has great potential for detection of dopamine related diseases.

Summer leaves of the seasonally dimorphic Phlomis fruticosa were investigated concerning their mesophyll-cell fine structure, secondary metabolite accumulation, absorption of the photosynthetic pigments, ROS levels and L-Dopa DeCarboxylase (DDC) expression, after being exposed, in nature, to the routine, combined environmental stress (high temperature, high light intensity and high aridity) of the Mediterranean summer. Although the stressed summer leaves present rather unaffected tissue arrangement, ROS levels increase significantly after the severe stress of the midday, the photosynthetic pigments are dramatically reduced, the mesophyll cells accumulate large amounts of secondary metabolites and the presence of DDC is recorded at impressively high levels. Leaves appear to react to the severe oxidative stress through the activation of the shikimic acid pathway and the consequent accumulation of secondary metabolites. Among them, the toxic L-Dopa which, through the activity of the massively detected DDC, is converted to the catecholamine dopamine, a powerful, water-soluble antioxidant, which appears to be a “relief” compound produced whenever the leaves have to cope with the harmful effects of the oxidative stress.

Muscarinic receptor stimulation induces depolarizing inward currents and catecholamine secretion in adrenal medullary (AM) cells from various mammals. In guinea-pig AM cells muscarine and oxotremorine at concentrations ≤ 1 μM produce activation of nonselective cation channels with a similar potency and efficacy, whereas muscarine at higher concentrations produces not only nonselective cation channel activation, but also TASK1 channel inhibition. In rat AM cells, the muscarinic M1 receptor is involved in TASK1 channel inhibition in response to muscarinic agonists, and the efficacy of oxotremorine is half that of muscarine. These pharmacological findings might indicate that different muscarinic receptor subtypes are responsible for the regulation of nonselective cation and TASK1 channel activities. The present study aimed to determine the muscarinic receptor subtypes involved in nonselective cation channel activation in guinea-pig and mouse AM cells. The inward current evoked by 1 μM muscarine was completely suppressed by 100 μM quinine, whereas 30 μM muscarine-induced inward currents were comprised of quinine-sensitive and -insensitive components. The electrophysiological and pharmacological properties of the muscarine-induced currents indicated that the quinine-sensitive and insensitive components are due to nonselective cation channel activation and TASK1 channel inhibition, respectively. Muscarine at 30 μM failed to induce any current in AM cells treated with muscarinic toxin 7 or genetically deleted of the M1 receptor. The KD value of VU0255035 against the muscarinic receptor mediating nonselective cation channel activation was 17.5 nM. These results indicate that the M1 receptor mediates nonselective cation channel activation as well as TASK1 channel inhibition.

Dopamine (DA) is an important catecholamine neurotransmitter in the mammalian central nervous system, and is involved in many behavioral responses and brain functions, and thus the detection of DA is much important. Chiral nanoparticles (NPs) have aroused much attention and showed many potential applications. In this work, Chiral ZnO NPs was prepared, and the nanoparticles can disperse well without aggregation. The Circular dichroism (CD) test showed strong chiroptical signals, demonstrating it is an effect method to prepare Chiral ZnO with cysteine as ligand. The photoluminescent properties of Chiral ZnO was investigated and showed quenching effect to dopamine, which make it possible to be used as probes to detect dopamine in biological samples with high selectivity and sensitivity.

Rationale A higher expression/activity of type 1 serine/threonine protein phosphatase 1 (PP1) may contribute to dephosphorylation of cardiac regulatory proteins triggering the development of heart failure. Objective Here, we tested the putatively protective effects of PP1 inhibitor-2 (I2) overexpression using a heart failure model induced by chronic β-adrenergic stimulation. Methods and results Transgenic (TG) and wild-type (WT) mice were subjected to isoprenaline (ISO) or isotonic NaCl solution supplied via osmotic minipumps for 7 days. I2 overexpression was associated with a depressed PP1 activity. Basal contractility was unchanged in catheterized mice and isolated cardiomyocytes between TGNaCl and WTNaCl. TGISO mice exhibited more fibrosis and a higher expression of hypertrophy marker proteins as compared to WTISO. After acute administration of ISO, the contractile response was accompanied by a higher sensitivity in TGISO as compared to WTISO. In contrast to basal contractility, the peak amplitude of [Ca]i and SR Ca load were reduced in TGNaCl as compared to WTNaCl. These effects were normalized to WT levels after chronic ISO stimulation. Cardiomyocyte relaxation and [Ca]i decay kinetics were hastened in TGISO as compared to WTISO, which can be explained by a higher phospholamban phosphorylation at Ser16. Chronic catecholamine stimulation was followed by an enhanced expression of GSK3β, whereas the phosphorylation at Ser9 was lower in TG as compared to the corresponding WT group. This resulted in a higher I2 phosphorylation that may reactivate PP1. Conclusion Our findings suggest that the basal desensitization of β-adrenergic signaling and the depressed Ca handling in TG by inhibition of PP1 is restored by a GSK3β-dependent phosphorylation of I2.

International audience; Engineered nanomaterials are used in various applications due to their particular properties. Among them, Iron Oxide Nanoparticles (Fe2O3-NPs) are used in Biomedicine as theranostic agents i.e. contrast agents in Magnetic Resonance Imaging and cancer treatment. With the increasing production and use of these Fe2O3-NPs, there is an evident raise of Fe2O3-NPs exposure and subsequently a higher risk of adverse outcomes for the environment and Human. In the present paper, we investigated the effects of an intravenous daily Fe2O3-NPs exposure on Wistar rat for one week. As results, we showed that several hematological parameters and transaminase (ALT and AST) levels as well as organ histology remained unchanged in treated rats. Neither the catecholamine levels nor the emotional behavior and learning / memory capacities of rats were impacted by the sub-acute intravenous exposure to Fe2O3-NPs. However, iron level in plasma and iron content homeostasis in brain were disrupted after this exposure. Thus, our results demonstrated that Fe2O3-NPs could have transient effects on rat but the intravenous route is still safer that others which is encouraging for their use in medical and/or biological applications.

Despite the potential biological importance of sympathetic activity in human bone metabolism, its effects on bone microarchitecture, a key determinant of bone quality, has not been thoroughly studied. In the present study, we investigated the lumbar spine trabecular bone score (TBS) as an indicator of skeletal deterioration in pheochromocytoma. Among 620 consecutive patients with newly diagnosed adrenal incidentaloma, 29 with histologically confirmed pheochromocytoma (a catecholamine-secreting neuroendocrine tumor) and 266 with nonfunctional adrenal incidentaloma were defined as cases and controls, respectively. After adjustment for confounders, subjects with pheochromocytoma had 2.9% lower lumbar spine TBS than those without pheochromocytoma (P = 0.038). Moreover, urinary normetanephrine level, but not urinary metanephrine level, was inversely correlated with lumbar spine TBS (P = 0.009). Subjects in the highest urinary normetanephrine quartile showed markedly lower lumbar spine TBS than those in the lowest quartile (P = 0.018), in a dose-response manner across increasing urinary normetanephrine quartile categories (P for trend = 0.021). Consistent with the results of previous studies, subjects with pheochromocytoma had significantly lower bone mass at the lumbar spine and higher serum level of C-terminal telopeptide of type I collagen than controls (P = 0.013 and 0.002, respectively). These findings provide clinical evidence that catecholamine excess and the resultant sympathetic overstimulation in pheochromocytoma may contribute to bone fragility, especially in the trabecular bone, through a weak microarchitecture in addition to a lower bone mass and increased bone resorption, and support the possibility of pheochromocytoma as a secondary cause of osteoporosis.

Summary The intestinal microbiota closely interacts with the neuroendocrine system and exerts profound effects on host physiology. Here, we report that nucleotide-binding oligomerization domain 1 (Nod1) ligand derived from intestinal bacteria modulates catecholamine storage and secretion in mouse adrenal chromaffin cells. The cytosolic peptidoglycan receptor Nod1 is involved in chromogranin A (Chga) retention in dense core granules (DCGs) in chromaffin cells. Mechanistically, upon recognizing its ligand, Nod1 localizes to DCGs, and recruits Rab2a, which is critical for Chga and epinephrine retention in DCGs. Depletion of Nod1 ligand or deficiency of Nod1 leads to a profound defect in epinephrine storage in chromaffin cells and subsequently less secretion upon stimulation. The intestine-adrenal medulla cross talk bridged by Nod1 ligand modulates adrenal medullary responses during the immobilization-induced stress response in mice. Thus, our study uncovers a mechanism by which intestinal microbes modulate epinephrine secretion in response to stress, which may provide further understanding of the gut-brain axis., Graphical abstract, Highlights • Nod1 expressed in adrenal chromaffin cells senses intestinal bacteria • Bacterial Nod1 ligand promotes catecholamine storage and secretion • The microbiota-intestine- adrenal medulla axis modulates fight and flight response, Molecular biology; Neuroscience; Microbiome

Cardiotoxicity remains the most common reason for failure during drug development. Recently, the zebrafish (Danio rerio) model has emerged for the evaluation of drug-dependent cardiotoxicity and for the identification of cardioprotective molecules. However, it remains unknown how closely the zebrafish-based results may be translated to humans. To tackle this issue, we established embryonic zebrafish models of doxorubicin-, adrenaline- and terfenadine-induced cardiotoxicity with unified dosing regimen which eventually enabled head-to-head comparison of the drugs. Subsequently, we determined whether human cardioprotective medications - dexrazoxane, metoprolol, carvedilol and valsartan - are able to manage heart dysfunction in zebrafish. Our results indicated that doxorubicin, adrenaline and terfenadine elicited overt signs of cardiotoxicity in fish, and we further showed that the blockade of the renin-angiotensin system and, to a lesser extent, β-adrenergic system, ameliorated the heart disease in zebrafish. From the drug development standpoint, our work opens the possibility to determine the cardiovascular properties of tested compounds using the rapid and affordable zebrafish model.

Challenges in the aquatic environment disrupt the homeostasis mechanisms of many teleost fishes. Induction of stress affects the circulating levels of catecholamine and has an impact on development and reproduction. It is not known how osmotic and hypoxic stress could affect the catecholamine and serotonin levels in zebrafish despite its well-known action in the vertebrate brain. This study thus investigates how serotonin (5-HT), epinephrine (E), norepinephrine (NE), and dopamine (DA) in the brain of female zebrafish respond to hypoxic (air) and osmotic conditions (salinity of 10 ppt). Analysis of zebrafish brain utilizing HPLC with PDA detector using reverse-phase PrimeSep column indicated that osmotic stress, air response and its combination modified 5-HT, NE and E levels. The tested stressors elevated 5-HT (2.8 μM) while lowering NE (3.00 μM) and E (1.02 μM) levels in the brain as opposed to exposure to non-stressed fish. In addition, reproductive markers such as vitellogenin (Vtg1) and estrogen receptor (ERα) mRNA expression in the brain were up-regulated after osmotic stress, whereas air exposure down-regulated ERα mRNA expression but up-regulated Vtg1 compared to non-stressed fish. Overall, the data indicate that acute osmotic stress and air exposure that lowered catecholamine E and NE and elevated 5-HT levels could up-regulate mRNA expression of ERα and Vtg1 genes in the zebrafish brain, thus presenting evidence for a role of neurotransmitters on reproductive signals during acute conditional stress in the brain of wild zebrafish.

The regulatory role of physiological glucagon (Gcg) in the cardiovascular system remains uncertain. Employing a mouse model harboring a functional deficiency of the preproglucagon gene (GCG-null), we found that lack of endogenous Gcg caused hypertension and systolic left ventricular (LV) dysfunction due to abnormal rise in circulating epinephrine (Ep) level, which was completely restored by the supplemental injection of Gcg (Sup-Gcg) or adrenergic β1-receptor blockers. More interestingly, GCG-null exhibited adrenal hypertrophy with the upregulation of phenylethanolamine N-methyltransferase (PNMT), a key enzyme that synthesizes Ep. Gcg directly facilitated mRNA decay via augmentation of enhancer of mRNA decapping protein 4 (EDC4) in a PKA-dependent fashion, thereby suppressing PNMT in adrenal chromaffin cells. Our data unveiled the novel action of Gcg like a circuit breaker against the Ep surge in the context of disease condition.

Iron is an essential nutrient for bacteria growth and microorganisms have developped several strategies to access iron, the most common being the production of siderophores, iron-chelating molecules secreted into the bacterial environment. Here, we demonstrate that catecholamine neurotransmitters (dopamine, L-DOPA, epinephrine, and norepinephrine) are able to chelate iron and bring iron into Pseudomonas aeruginosa cells via an energy-dependent transport mechanism that relies on TonB-dependent transporters (TBDTs). Using bacterial growth assay under strong iron-restricted conditions, we show that the TBDTs involved are PiuA and PirA. PiuA exhibited more pronounced specificity for dopamine uptake, whereas PirA specificity appeared to be higher for L-DOPA and norepinephrine. Proteomic and qRT-PCR approaches showed pirA transcription and expression to be induced in the presence of all four catecholamines. Finally, the oxidative properties of catecholamines enable them to reduce iron, and we observed ferrous iron uptake via the FeoABC system in the presence of L-DOPA.

Monoamine neurotransmitters such as catecholamines [dopamine (DA), norepinephrine (NE) and epinephrine (E)] and serotonin have been shown to influence feeding in vertebrates. In order to better understand the role of monoamine neurotransmitters in the regulation of feeding in fish, we examined the effects of fasting on the brain and intestine gene expression of enzymes involved in their synthesis pathways (SPR: sepiapterin reductase; DHPR: dihydropteridine reductase; TH: tyrosine hydroxylase; TPH: tryptophan hydroxylase; AADC: aromatic l-amino acid decarboxylase; DBH: dopamine β-hydroxylase) in goldfish. In order possible interactions between the monoaminergic pathways and appetite-regulating hormones, we examined the effects of intraperitoneal injections of orexin, CCK and irisin on the brain and intestine gene expression of these enzymes. Fasting increased the expressions of SPR, TH, DBH, TPH1 and DHPR in the brain but did not affect the intestinal expressions of any of the enzymes examined, suggesting that nutritional status might affect the synthesis of monoamines in the central nervous system. CCK injections decreased feeding and increased SPR, TH, and TPH expressions in both brain and intestine. Orexin injections increased feeding and SPR and AADC expressions in the brain but did not affect the expressions of any of the enzymes in the intestine. Irisin injections decreased feeding and increased TPH2 and AADC brain expressions and TH and SPR intestinal expressions, and decreased TPH1 brain expression and AADC intestinal expression. Our results suggest that feeding/fasting and appetite-regulating hormones modulate in part the catecholamine and serotonin synthesis pathways in goldfish.

Background Protein intake, particularly branched chain amino acids (BCAAs), and exercise have opposing actions on insulin secretion, but the same action on protein anabolism. We examined the effects of BCAA-rich fat-free milk intake and/or exercise on levels of insulin secretion and indices related to muscle protein metabolism in order to assess the potency of dietary and exercise therapies against metabolic and locomotive disorders. Methods Eight adult female volunteers participated in all four 24 h experiments; control diet intake with or without exercise, and fat-free milk-containing diet intake with or without exercise. Fat-free milk was replaced with one-sixth of all foods in the control diet. Exercise was set at an equal-energy level as fat-free milk. Urine and fasting blood samples were collected for each experiment. Results Urinary C-peptide immunoreactivity excretion and serum insulin levels were significantly higher, but urinary 3-methyl-histidine excretion levels were significantly lower with low urinary adrenaline and dopamine excretion in the fat-free milk-containing diet than in the control diet. These findings were reduced by exercise with high urinary adrenaline and noradrenaline excretion. Conclusions BCAA-rich fat-free milk intake enhanced insulin secretion and suppressed muscle protein degradation, but these effects are attenuated by exercise accompanied with increase in catecholamine secretion.

The release of dopamine (DA) is one of the main steps in the control of neuronal functioning and all CNS. It was demonstrated that many factors such as protein kinases and synaptic proteins are tightly involved in the regulation of DA secretion, but the data are contradictory. Here we analysed an effect of ERK1/2 inhibition on DA secretion from differentiated PC12 cells and evaluated the correlation between the activity of kinases/synaptic proteins and the level of released DA. PC12 cells were differentiated by NGF for 6 days. On the 7th day the cells were incubated for 1, 2 and 4 h with 10μM U0126. Obtained data demonstrated a significant accumulation of DA in the media after 4 h incubation with U0126 that accompanied with upregulation of PKG activity. Analysis of exocytosis proteins demonstrated decreased phosphorylation level of synapsin I and content of SNAP25. Taken together our data proposed an inhibitory role of ERK1/2 in the regulation of catecholamine secretion and demonstrated that balance between PKG and ERK1/2 activity could have a substantial impact on the regulation of DA release from the cells.

Objective The vascular system is central to sustaining tissue survival and homeostasis. Blood vessels are densely present in adipose tissues and exert essential roles in their metabolism. However, conventional immunohistochemistry methods have intrinsic limitations in examining the 3D vascular network in adipose tissues as well as other organs in general. Methods We established a 3D volume fluorescence-imaging technique to visualize the vasculatures in mouse adipose tissues by combining the optimized steps of whole-mount immunolabeling, tissue optical clearing, and lightsheet volume fluorescence-imaging. To demonstrate the strength of this novel imaging procedure, we comprehensively assessed the intra-adipose vasculatures under obese conditions or in response to a cold challenge. Results We show the entirety of the vascular network in mouse adipose tissues on the whole-tissue level at a single-capillary resolution for the first time in the field. We accurately quantify the pathological changes of vasculatures in adipose tissues in wild-type or obese mice (ob/ob, db/db, or diet-induced obesity). In addition, we identify significant and reversible changes of the intra-adipose vasculatures in the mice subjected to cold challenge (i.e., 4°). Furthermore, we demonstrate that the cold-induced vascular plasticity depends on the sympathetic-derived catecholamine signal and is involved in the beiging process of white adipose tissues. Conclusions We report a 3D volume fluorescence-imaging procedure that is compatible with many areas of vascular research and is poised to serve the field in future investigations of the vascular system in adipose tissues or other research scenarios., Graphical abstract Image 1, Highlights • 3D vascular network in adipose tissues is visualized at single-capillary resolution. • Pathological remodeling of vasculatures is characterized under the obese conditions. • Vascular plasticity during cold challenge is involved in the beiging process of WAT. • Sympathetic-derived catecholamine signal regulates the vascular plasticity in WAT.

Acute stress influences learning and memory in humans and rodents, enhancing performance in some tasks while impairing it in others. Typically, subjects preferentially employ striatal-mediated stimulus-response strategies in spatial memory tasks following stress, making use of fewer hippocampal-based strategies which may be more cognitively demanding. Previous research demonstrated that the acquisition of rodent paired associates learning (PAL) relies primarily on the striatum, while task performance after extensive training is impaired by hippocampal disruption. Therefore, we sought to explore whether the acquisition of PAL, an operant conditioning task involving spatial stimuli, could be enhanced by acute stress. Male Long-Evans rats were trained to a predefined criterion in PAL and then subjected to either a single session of restraint stress (30 min) or injection of corticosterone (CORT; 3 mg/kg). Subsequent task performance was monitored for one week. We found that rats subjected to restraint stress, but not those rats injected with CORT, performed with higher accuracy and efficiency, when compared to untreated controls. These results suggest that while acute stress enhances the acquisition of PAL, CORT alone does not. This dissociation may be due to differences between these treatments and their ability to produce sufficient catecholamine release in the amygdala, a requirement for stress effects on memory.

Methylmercury (MeHg) is the causative substance of Minamata disease, which is associated with various neurological disorders such as sensory disturbance and ataxia. It has been suggested low-level dietary intake of MeHg from MeHg-containing fish during gestation adversely affects the fetus. In our study, we investigated the toxicological effects of MeHg exposure on neuronal differentiation focusing on epigenetics. We used human fetal brain-derived immortalized cells (LUHMES cells) as a human neuronal differentiation model. Cell viability, neuronal, and catecholamine markers in LUHMES cells were assessed after exposure to MeHg (0–1000 nM) for 6 days (from day 2 to day 8 of neuronal differentiation). Cell viability on day 8 was not affected by exposure to 1 nM MeHg for 6 days. mRNA levels of AADC, DBH, TUJ1, and SYN1 also were unaffected by MeHg exposure. In contrast, levels of TH, the rate-limiting enzyme for dopamine synthesis, were significantly decreased after MeHg exposure. Acetylated histone H3, acetylated histone H3 lysine 9, and tri-methyl histone H3 lysine 9 levels at the TH gene promoter were not altered by MeHg exposure. However, tri-methylation of histone H3 lysine 27 levels, related to transcriptional repression, were significantly increased at the TH gene promotor after MeHg exposure. In summary, MeHg exposure during neuronal differentiation led to epigenetic changes that repressed TH gene expression. This study provides useful insights into the toxicological mechanisms underlying the effects of developmental MeHg exposure during neuronal differentiation.