Expression of orexin receptors in the brain and peripheral tissues of the male sheep

Conversion of testosterone to oestradiol plays a major role in the feedback inhibition of gonadotrophin secretion in male sheep but little is known of the distribution or control of aromatase activity among central and peripheral tissues. Changes in activity at those sites may mediate alterations in the effectiveness of negative feedback following, for example, a change in nutrition. Using a tritiated-water assay, we quantified aromatase in several tissues in mature male sheep, assessed their contribution to oestradiol production, and tested whether activity at each site was affected by a nutritional treatment that stimulates gonadotrophin secretion. Among the brain tissues, the preoptic area had the highest concentration of activity, followed by the hypothalamus, amygdala and cortex. Among the peripheral tissues, liver and testis had the highest activity and, due to their mass, they are the major sources of circulating oestradiol. Pituitary, muscle, kidney and adipose tissues had very low aromatase levels. The nutritional stimulus increased activity in testis but not in liver or brain. We conclude that changes in aromatase activity do not mediate the effects of nutrition on steroid feedback, but aromatisation in testis, liver and brain is important in the endocrine regulation of reproduction in the mature ram.

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Modeling temperature- and Cav3 subtype-dependent alterations in T-type calcium channel mediated burst firing

Molecular Brain ◽

10.1186/s13041-021-00813-7 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Fernando R. Fernandez ◽

Mircea C. Iftinca ◽

Gerald W. Zamponi ◽

Ray W. Turner

Keyword(s):

Calcium Channel ◽

Neuronal Excitability ◽

Neuronal Firing ◽

Mammalian Brain ◽

Peripheral Tissues ◽

Window Current ◽

Modeling Data ◽

The Brain ◽

Firing Neuron ◽

Cav3 Channel

AbstractT-type calcium channels are important regulators of neuronal excitability. The mammalian brain expresses three T-type channel isoforms (Cav3.1, Cav3.2 and Cav3.3) with distinct biophysical properties that are critically regulated by temperature. Here, we test the effects of how temperature affects spike output in a reduced firing neuron model expressing specific Cav3 channel isoforms. The modeling data revealed only a minimal effect on baseline spontaneous firing near rest, but a dramatic increase in rebound burst discharge frequency for Cav3.1 compared to Cav3.2 or Cav3.3 due to differences in window current or activation/recovery time constants. The reduced response by Cav3.2 could optimize its activity where it is expressed in peripheral tissues more subject to temperature variations than Cav3.1 or Cav3.3 channels expressed prominently in the brain. These tests thus reveal that aspects of neuronal firing behavior are critically dependent on both temperature and T-type calcium channel subtype.

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Understanding Quantitative Circadian Regulations Are Crucial Towards Advancing Chronotherapy

Cells ◽

10.3390/cells8080883 ◽

2019 ◽

Vol 8 (8) ◽

pp. 883 ◽

Cited By ~ 3

Author(s):

Debajyoti Chowdhury ◽

Chao Wang ◽

Ai-Ping Lu ◽

Hai-Long Zhu

Keyword(s):

Circadian Rhythms ◽

Molecular Mechanisms ◽

Temporal Stability ◽

Biological Rhythms ◽

Integrative Approach ◽

Peripheral Tissues ◽

Innovative Strategies ◽

Neural Connections ◽

Core Components ◽

The Brain

Circadian rhythms have a deep impact on most aspects of physiology. In most organisms, especially mammals, the biological rhythms are maintained by the indigenous circadian clockwork around geophysical time (~24-h). These rhythms originate inside cells. Several core components are interconnected through transcriptional/translational feedback loops to generate molecular oscillations. They are tightly controlled over time. Also, they exert temporal controls over many fundamental physiological activities. This helps in coordinating the body’s internal time with the external environments. The mammalian circadian clockwork is composed of a hierarchy of oscillators, which play roles at molecular, cellular, and higher levels. The master oscillation has been found to be developed at the hypothalamic suprachiasmatic nucleus in the brain. It acts as the core pacemaker and drives the transmission of the oscillation signals. These signals are distributed across different peripheral tissues through humoral and neural connections. The synchronization among the master oscillator and tissue-specific oscillators offer overall temporal stability to mammals. Recent technological advancements help us to study the circadian rhythms at dynamic scale and systems level. Here, we outline the current understanding of circadian clockwork in terms of molecular mechanisms and interdisciplinary concepts. We have also focused on the importance of the integrative approach to decode several crucial intricacies. This review indicates the emergence of such a comprehensive approach. It will essentially accelerate the circadian research with more innovative strategies, such as developing evidence-based chronotherapeutics to restore de-synchronized circadian rhythms.

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Cholecystokinin octapeptide analogues suppress food intake via central CCK-A receptors in mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1993.265.3.r481 ◽

1993 ◽

Vol 265 (3) ◽

pp. R481-R486 ◽

Cited By ~ 5

Author(s):

Y. Hirosue ◽

A. Inui ◽

A. Teranishi ◽

M. Miura ◽

M. Nakajima ◽

...

Keyword(s):

Food Intake ◽

Receptor Antagonist ◽

Rank Order ◽

Peripheral Circulation ◽

Inhibitory Effect ◽

Peripheral Tissues ◽

Cholecystokinin Octapeptide ◽

The Central Nervous System ◽

The Difference ◽

The Brain

To examine the mechanism of the satiety-producing effect of cholecystokinin (CCK) in the central nervous system, we compared the potency of intraperitoneally (ip) or intracerebroventricularly (icv) administered CCK-8 and its analogues on food intake in fasted mice. The icv administration of a small dose of CCK-8 (0.03 nmol/brain) or of Suc-(Thr28, Leu29, MePhe33)-CCK-7 (0.001 nmol/brain) suppressed food intake for 20 min, whereas CCK-8 (1 nmol/kg, which is equivalent to 0.03 nmol/brain) or Suc-(Thr28, Leu29, MePhe33)-CCK-7 (1 nmol/kg) had satiety effect after ip administration. Dose-response studies indicated the following rank order of potency: Suc-CCK-7 > or = Suc-(Thr28, Leu29, MePhe33)-CCK-7 > or = CCK-8 > or = (Nle28,31)-CCK-8 >> desulfated CCK-8 = CCK-4 = 0 in the case of ip administration and Suc-(Thr28, Leu29, MePhe33)-CCK-7 >> Suc-CCK-7 > or = CCK-8 > or = (Nle28,31)-CCK-8 >> desulfated CCK-8 = CCK-4 = 0 in the case of icv administration. The selective CCK-A receptor antagonist MK-329 reversed the inhibitory effect of the centrally as well as peripherally administered CCK-8, or of Suc-(Thr28, Leu29, MePhe33)-CCK-7, whereas the selective CCK-B receptor antagonist L-365260 did not. The icv administered CCK-8 did not appear in the peripheral circulation. These findings suggest the participation of CCK-A receptors in the brain in mediating the satiety effect of CCK and the difference in CCK-A receptors in the brain and peripheral tissues.

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Microglia, Cytokines, and Neural Activity: Unexpected Interactions in Brain Development and Function

Frontiers in Immunology ◽

10.3389/fimmu.2021.703527 ◽

2021 ◽

Vol 12 ◽

Author(s):

Austin Ferro ◽

Yohan S. S. Auguste ◽

Lucas Cheadle

Keyword(s):

Brain Development ◽

Signaling Pathways ◽

Immune Cells ◽

Neural Activity ◽

Signaling Molecules ◽

Evolutionary Strategy ◽

Inflammatory Signaling ◽

Peripheral Tissues ◽

And Function ◽

The Brain

Intercellular signaling molecules such as cytokines and their receptors enable immune cells to communicate with one another and their surrounding microenvironments. Emerging evidence suggests that the same signaling pathways that regulate inflammatory responses to injury and disease outside of the brain also play powerful roles in brain development, plasticity, and function. These observations raise the question of how the same signaling molecules can play such distinct roles in peripheral tissues compared to the central nervous system, a system previously thought to be largely protected from inflammatory signaling. Here, we review evidence that the specialized roles of immune signaling molecules such as cytokines in the brain are to a large extent shaped by neural activity, a key feature of the brain that reflects active communication between neurons at synapses. We discuss the known mechanisms through which microglia, the resident immune cells of the brain, respond to increases and decreases in activity by engaging classical inflammatory signaling cascades to assemble, remodel, and eliminate synapses across the lifespan. We integrate evidence from (1) in vivo imaging studies of microglia-neuron interactions, (2) developmental studies across multiple neural circuits, and (3) molecular studies of activity-dependent gene expression in microglia and neurons to highlight the specific roles of activity in defining immune pathway function in the brain. Given that the repurposing of signaling pathways across different tissues may be an important evolutionary strategy to overcome the limited size of the genome, understanding how cytokine function is established and maintained in the brain could lead to key insights into neurological health and disease.

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A novel antioxidant ergothioneine PET radioligand for in vivo imaging applications

Scientific Reports ◽

10.1038/s41598-021-97925-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

William J. Behof ◽

Clayton A. Whitmore ◽

Justin R. Haynes ◽

Adam J. Rosenberg ◽

Mohammed N. Tantawy ◽

...

Keyword(s):

Amino Acid ◽

Mouse Model ◽

Peripheral Tissues ◽

Molar Activity ◽

Model Of Alzheimer’S Disease ◽

Specific Retention ◽

5Xfad Mice ◽

The Brain

AbstractErgothioneine (ERGO) is a rare amino acid mostly found in fungi, including mushrooms, with recognized antioxidant activity to protect tissues from damage by reactive oxygen species (ROS) components. Prior to this publication, the biodistribution of ERGO has been performed solely in vitro using extracted tissues. The aim of this study was to develop a feasible chemistry for the synthesis of an ERGO PET radioligand, [11C]ERGO, to facilitate in vivo study. The radioligand probe was synthesized with identical structure to ERGO by employing an orthogonal protection/deprotection approach. [11C]methylation of the precursor was performed via [11C]CH3OTf to provide [11C]ERGO radioligand. The [11C]ERGO was isolated by RP-HPLC with a molar activity of 690 TBq/mmol. To demonstrate the biodistribution of the radioligand, we administered approximately 37 MBq/0.1 mL in 5XFAD mice, a mouse model of Alzheimer’s disease via the tail vein. The distribution of ERGO in the brain was monitored using 90-min dynamic PET scans. The delivery and specific retention of [11C]ERGO in an LPS-mediated neuroinflammation mouse model was also demonstrated. For the pharmacokinetic study, the concentration of the compound in the serum started to decrease 10 min after injection while starting to distribute in other peripheral tissues. In particular, a significant amount of the compound was found in the eyes and small intestine. The radioligand was also distributed in several regions of the brain of 5XFAD mice, and the signal remained strong 30 min post-injection. This is the first time the biodistribution of this antioxidant and rare amino acid has been demonstrated in a preclinical mouse model in a highly sensitive and non-invasive manner.

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Insights into kinetics, release, and behavioral effects of brain-targeted hybrid nanoparticles for cholesterol delivery in Huntington’s disease

10.1101/2020.11.24.395525 ◽

2020 ◽

Author(s):

Giulia Birolini ◽

Marta Valenza ◽

Ilaria Ottonelli ◽

Alice Passoni ◽

Monica Favagrossa ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Neurodegenerative Disorder ◽

Polymeric Nanoparticles ◽

Cholesterol Biosynthesis ◽

Hybrid Nanoparticles ◽

Neural Cells ◽

Peripheral Tissues ◽

Brain Cholesterol ◽

The Brain

AbstractSupplementing brain cholesterol is emerging as a potential treatment for Huntington’s disease (HD), a genetic neurodegenerative disorder characterized, among other abnormalities, by inefficient brain cholesterol biosynthesis. However, delivering cholesterol to the brain is challenging due to the bloodbrain barrier (BBB), which prevents it from reaching the striatum, especially, with therapeutically relevant doses.Here we describe the distribution, kinetics, release, and safety of novel hybrid polymeric nanoparticles made of PLGA and cholesterol which were modified with an heptapeptide (g7) for BBB transit (hybrid-g7-NPs-chol). We show that these NPs rapidly reach the brain and target neural cells. Moreover, deuterium-labeled cholesterol from hybrid-g7-NPs-chol is released in a controlled manner within the brain and accumulates over time, while being rapidly removed from peripheral tissues and plasma. We confirm that systemic and repeated injections of the new hybrid-g7-NPs-chol enhanced endogenous cholesterol biosynthesis, prevented cognitive decline, and ameliorated motor defects in HD animals, without any inflammatory reaction.In summary, this study provides insights about the benefits and safety of cholesterol delivery through advanced brain-permeable nanoparticles for HD treatment.

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Atrial Natriuretic Factors and the Brain (Les facteurs natriurétiques auriculaires et le cerveau)

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y88-043 ◽

1988 ◽

Vol 66 (3) ◽

pp. 253-254 ◽

Cited By ~ 1

Author(s):

Rémi Quirion

Keyword(s):

International Society ◽

Natriuretic Peptides ◽

Salt Intake ◽

Atrial Natriuretic Peptides ◽

Peripheral Tissues ◽

The Brain ◽

Biological Actions ◽

Atrial Natriuretic Factors ◽

Natriuretic Factors ◽

Atrial Natriuretic

Canadian scientists have played a major role in the discovery and characterization of various atrial natriuretic factors (ANF). It is now clear that this family of polypeptides induces multiple biological actions in a broad variety of peripheral tissues including the kidney, adrenal gland, and blood vessels. One generalized observation derived from multiple studies reveals that these peptides most likely act as important modulators of homeostasis by modulating the production of various body fluids. Recently, it became clear that the atrial natriuretic factors present in the central nervous system could influence various brain functions. Thus, the ANF-like peptides should be considered as a new family of brain–heart peptides.The present symposium, the first of its kind, was organized to examine and critically discuss the evidence for putative roles of atrial natriuretic peptides in the brain. It was clearly demonstrated that atrial natriuretic peptide-like immunoreactivity is widely distributed in mammalian and nonmammalian brains with a high number of cell bodies and (or) fiber terminals present in areas associated with water and salt intake and with the control of cardiovascular parameters. The gene transcripts responsible for the production of brain atrial natriuretic polypeptides have been isolated and their characteristics appear to be similar to those found in peripheral tissues. The presence and plasticity of specific brain ANF receptor sites have also been reported. It appears that at least one population of sites is associated with the activation of guanylate cyclase and it was also shown that specific ANF receptors are located on brain microvessels and can modulate the permeability of the blood-brain barrier. Finally, it has been shown that atrial natriuretic polypeptides exert various biological actions in the brain including electrophysiological effects in the hypothalamus, modulation of water and salt intake, alteration of various cardiovascular parameters, and release of certain pituitary hormones.Interactions with dopaminergic pathways, vasopressin, and (or) angiotensin II systems could be associated with some biological effects of atrial natriuretic peptides in the brain. Naturally, much remains to be known on the exact physiological role of brain atrial natriuretic factors, but this meeting represents the first attempt towards the integration of the most recent findings in this exciting research area.This symposium was an official satellite of the first joint meeting of the International Society for Neurochemistry and the American Society for Neurochemistry, held in Venezuela in May–June 1987. The success of the symposium has been ensured by generous donations from the International Society for Neurochemistry, the Medical Research Council of Canada, and various companies including Amersham International (England), ANAWA Trading SA (Switzerland), Ayerst Laboratories (U.S.A.), Bachem (Switzerland), Bayer AG (West Germany), Bio-Mega Inc. (Canada), Ciba-Geigy Corporation (U.S.A.), Dupont Canada – New England Nuclear Co. (Canada), Eli Lilly Research Laboratories (U.S.A.), Farmitalia Carlo Erba (Italy), Institut Henri Beaufour (France), Merck Sharp &Dohme Research Laboratories (U.S.A.), Miles Laboratories Inc. (U.S.A.), Monsanto Co. (U.S.A.), Novabiochem (Switzerland), Novopharm Ltd. (Canada), Peninsula Laboratories (U.S.A.), and the Peptide Institute and Protein Research Foundation (Japan).

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Central and peripheral pathology of kuru: pathological analysis of a recent case and comparison with other forms of human prion disease

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2008.0091 ◽

2008 ◽

Vol 363 (1510) ◽

pp. 3755-3763 ◽

Cited By ~ 39

Author(s):

Sebastian Brandner ◽

Jerome Whitfield ◽

Ken Boone ◽

Anderson Puwa ◽

Catherine O'Malley ◽

...

Keyword(s):

Prion Protein ◽

Human Prion Disease ◽

Peripheral Tissues ◽

Prion Strain ◽

Pathological Analysis ◽

Lymphoreticular Tissue ◽

Jakob Disease ◽

Strain Type ◽

Few Data ◽

The Brain

While the neuropathology of kuru is well defined, there are few data concerning the distribution of disease-related prion protein in peripheral tissues. Here we report the investigation of brain and peripheral tissues from a kuru patient who died in 2003. Neuropathological findings were compared with those seen in classical (sporadic and iatrogenic) Creutzfeldt–Jakob disease (CJD) and variant CJD (vCJD). The neuropathological findings of the kuru patient showed all the stereotypical changes that define kuru, with the occurrence of prominent PrP plaques throughout the brain. Lymphoreticular tissue showed no evidence of prion colonization, suggesting that the peripheral pathogenesis of kuru is similar to that seen in classical CJD rather than vCJD. These findings now strongly suggest that the characteristic peripheral pathogenesis of vCJD is determined by prion strain type alone rather than route of infection.

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BIOLOGICAL AGE ESTIMATION BASED ON THE SPECTRAL ANALYSIS OF THE HUMAN BRAIN BIOELECTRIC ACTIVITY

Успехи геронтологии ◽

10.34922/ae.2021.34.3.018 ◽

2021 ◽

pp. 466-471

Author(s):

Г. А. Шабанов ◽

А. А. Рыбченко ◽

Е. А. Луговая ◽

С.И. Вдовенко

Keyword(s):

Spectral Analysis ◽

Human Brain ◽

Research Work ◽

Risk Groups ◽

Healthy People ◽

Biological Age ◽

Bioelectric Activity ◽

Peripheral Tissues ◽

Oncological Patients ◽

The Brain

В работе впервые предложен способ оценки биологического возраста человека на основе спектрального анализа биоэлектрической активности головного мозга. Был разработан индекс децентрализации (IDC), который учитывал суммарную степень снижения фоновых нейротрофических влияний активирующей системы мозга на периферические ткани и органы. Получена близкая к линейной зависимость величины индекса IDC от возраста практически здоровых людей 10-90 лет и степени дифференцировки раковых клеток G1 G4 у онкологических пациентов. Накопление клеточных нарушений и мутаций с возрастом отражалось в увеличении индекса IDC от 100 до 900 у. е. Еще большее количество клеточных мутаций у онкологических пациентов со степенью дифференцировки клеток от G1 до G4 приводило к увеличению IDC до 3 000 у. е. и более. Полученные данные позволили проводить оценку биологического возраста после 10-минутной регистрации биоэлектрической активности головного мозга человека. Достоверность оценки повышалась при усреднении нескольких данных у одного человека. Технология полезна для научных исследований в области геронтологии, при мониторинге состояния практически здоровых людей, формирования групп риска и контроля лечебного процесса у онкологических пациентов. For the first time, the research work offers a method of estimating human biological age based on the spectral analysis of the brain bioelectric activity. IDC decentralization index, which could consider summary degree of reduction of the background neurotrophic influences of the brain activating system on the peripheral tissues and organs, was developed. The close to linear dependence of the IDC index on the age of healthy people aged 10-90 as well as on the oncological patients cancer G 1 G 4 cells differentiation was obtained. The cell disorders and mutations in relation with the age from 10 to 90 could be seen in growth of the IDC index from 100 to 900 units. The greater amount of the cell mutations in the oncological patients with the G 1 G 4 differentiation resulted in the IDC index growth up to the 3 000 units and more. All the obtained data allowed estimating the real biological age after a 10-minute registration of the human brain bioelectric activity. The accuracy increased with the averaging several surveys taken from one particular person. The technology will be highly efficient for scientific researches in the field of gerontology, monitoring of healthy people, revealing of risk groups, and for controlling of the cancer patients medical treatment.

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