Identification of M4 muscarinic acetylcholine receptor expressing astrocytes that regulate locomotion and survival in murine prion disease

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 29, 2025

Abstract Whilst there has been much focus on the function of neuronally expressed members muscarinic acetylcholine receptor family (mAChR) less attention paid to expression profile and role five this (M 1 -M 5 mAChRs) in non-neuronal cells brain. Using genetically engineered mice we identify a previously unappreciated sub-population astrocytes expressing M 4 mAChR subtype. These are located various brain regions that include brainstem, hypothalamus and, most abundantly, cerebellum. Signalling proteomic analysis positive from cerebellum established functional subtype its regulation protein expression. Genetic ablation revealed specific locomotion behaviour. Importantly, context murine prion disease, model terminal neurodegeneration associated with profound neuroinflammation, observed significant expansion report experiments astrocyte detrimental effect late-stage disease. Together provide evidence play normal neurophysiology progression inflammatory neurodegenerative

Язык: Английский

---

The Role of Astrocytes in the Temporoammonic Pathway: Masticatory Behavior as a Neuroprotective Strategy Against Age-Related Cognitive Decline

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Фев. 17, 2025

Astrocytes undergo phenotypic changes with aging, contributing to neurodegenerative diseases and cognitive impairments in later life. The temporoammonic (TA) pathway terminates at the stratum lacunosum-moleculare (SLM) of CA1 region, where astrocytic support is crucial for synaptic plasticity information processing related spatial learning memory. This study tested hypothesis that age-related morphological astrocytes SLM affect performance we explored whether masticatory activity modulates these changes. Young (6 months) aged (18 female Swiss albino mice were subjected three distinct regimens: a hard diet (HD), HD followed by soft (HD/SD), or SD return (HD/SD/HD). Cognitive was assessed using Morris Water Maze (MWM), rates calculated from escape latencies throughout five days trials. After behavioral testing, culled immunohistochemical analysis glial fibrillary acidic protein (GFAP) expression performed. 3D reconstructions within generated analyzed. Hierarchical clustering identified astrocyte morphotypes, revealing significant shift high-complexity (AST1) toward lower-complexity subtypes (AST2 AST3. results demonstrate aging reduces complexity, especially dorsal which correlated impaired Notably, on HD/SD/HD regimen exhibited partial recovery function morphology, suggesting potential rehabilitation effect activity. Statistical confirmed differences complexity across age groups dietary regimens (p < 0.01). These findings highlight may contribute decline. Overall, maintaining proper mastication be an effective approach maintain integrity during preserve hippocampus-dependent function, particularly older individuals.

Язык: Английский

---

Macronutrients effects on satiety and food intake in older and younger adults: A randomised controlled trial

Appetite, Год журнала: 2023, Номер 189, С. 106982 - 106982

Опубликована: Июль 26, 2023

Older adults are advised to increase their protein intake maintain muscle mass. However, is considered the most satiating macronutrient and this recommendation may cause a decrease in total energy intake. To date, satiety studies comparing all three macronutrients have been undertaken young adults, it unclear if same response seen older adults. The objective of study was compare effect preloads high protein, fat, carbohydrate but equal (∼300 kcal) volume (250 ml) on intake, perceived appetite, gastric emptying younger Twenty 20 completed single-blinded randomised crossover trial involving visits. Participants consumed standard breakfast, followed by preload milkshake either carbohydrate, or protein. Three hours after preload, participants were offered an ad libitum meal assess food Visual analogue scales used measure appetite measured via 13C-octanoic acid breath test. There no significant type age at meal, self-recorded for rest test day subjective ratings. latency phase ascension time, lag such that had faster emptying. In conclusion, not affected content both times differed.

Язык: Английский

---

Constant light and high fat diet alter daily patterns of activity, feed intake and fecal corticosterone levels in pregnant and lactating female ICR mice

PLoS ONE, Год журнала: 2024, Номер 19(11), С. e0312419 - e0312419

Опубликована: Ноя. 20, 2024

The prevalence of constant light exposure and high-fat diet in modern society raises concerns regarding their impact on maternal offspring health outcomes. In rodents, to or continuous negatively program metabolic stress response outcomes offspring. A 2x3 factorial study was conducted investigate the (control–CON, 10% fat, high fat–HF, 60% fat) different lighting conditions: regular 12-hour light-dark cycles (LD), dim (L5), bright (L100) female ICR mice daily patterns time out nest, feed intake, fecal corticosterone levels during gestation lactation. Our previous analysis these found HF decreased number pups born, but increased litter growth rate postnatal (PN) d12. Whereas length tended increase PN growth. Here we report that grams an indicator feeding activity, were affected by light, diet, period day (day versus night) physiological state (gestation lactation), with significant interactions among all variables (P<0.05). treatment output (P<0.05) Dams exhibited 12 h 24 rhythms activity nest first 48 postnatal, outside greater second period. L100 attenuated shifted phase relative LD CON, respectively Alterations behavior affect physiology, including level timing release corticosteroids. Elevated due may have potential implications maternal-offspring health, potentially underlie some adverse effects lifestyle factors health.

Язык: Английский

---

The emerging science of Glioception: Contribution of glia in sensing, transduction, circuit integration of interoception

Pharmacology & Therapeutics, Год журнала: 2023, Номер 245, С. 108403 - 108403

Опубликована: Апрель 5, 2023

Interoception is the process by which nervous system regulates internal functions to achieve homeostasis. The role of neurons in interoception has received considerable recent attention, but glial cells also contribute. Glial can sense and transduce signals including osmotic, chemical, mechanical status extracellular milieu. Their ability dynamically communicate "listening" "talking" necessary monitor regulate homeostasis information integration system. This review introduces concept "Glioception" focuses on sense, interpret integrate about inner state organism. are ideally positioned act as sensors integrators diverse interoceptive trigger regulatory responses via modulation activity neuronal networks, both physiological pathological conditions. We believe that understanding manipulating glioceptive processes underlying molecular mechanisms provide a key path develop new therapies for prevention alleviation devastating dysfunctions, among pain emphasized here with more focused details.

Язык: Английский

---

Time dependent changes in feeding behavior and energy balance associated with weight gain in mice fed obesogenic diets

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Янв. 12, 2024

Obesity is characterized by dysregulated homeostatic mechanisms resulting in positive energy balance, yet when this dysregulation occurs unknown. We assessed the time course of alterations to behaviors promoting weight gain male and female mice switched obesogenic 60% or 45% high fat diet (HFD). Switching diets promotes transient bouts hyperphagia during first 2 weeks followed persistent caloric hyperphagia. Energy expenditure increases but not sufficiently offset increased intake, a sustained net balance. Hyperphagia associated with consumption calorically larger meals (impaired satiation) more frequently satiety) particularly light-cycle. Running wheel exercise delays HFD-fed enhancing satiation increasing expenditure. However, effects on are no longer apparent after weeks, coinciding gain. Thus, exposure engages regulatory for ∼2 that ultimately fail, consequent impaired satiety. Insights into etiology obesity can be obtained investigating changes satiety initial HFD exposure.

Язык: Английский

---

Gastrointestinal dysfunction in the valproic acid induced model of social deficit in rats

Autonomic Neuroscience, Год журнала: 2024, Номер 253, С. 103161 - 103161

Опубликована: Фев. 29, 2024

Язык: Английский

---

Time‐dependent changes in feeding behavior and energy balance associated with weight gain in mice fed obesogenic diets

Obesity, Год журнала: 2024, Номер 32(7), С. 1373 - 1388

Опубликована: Июнь 27, 2024

Abstract Objective Obesity is characterized by dysregulated homeostatic mechanisms resulting in positive energy balance; however, when this dysregulation occurs unknown. We assessed the time course of alterations to behaviors promoting weight gain male and female mice switched an obesogenic high‐fat diet (HFD). Methods Male C57BL/6J were housed metabolic chambers from chow a 60% or 45% HFD for 4 3 weeks, respectively. Food intake, meal patterns, expenditure (EE), body continuously measured. A separate cohort was given access locked unlocked running wheels. Results Switching diets promotes transient bouts hyperphagia during first 2 weeks followed persistent caloric hyperphagia. EE increases but not sufficiently enough offset increased sustained net balance. Hyperphagia associated with consumption calorically larger meals (impaired satiation) more frequently satiety), particularly light cycle. Running wheel exercise delays fed enhancing satiation increasing EE. However, effects on are no longer apparent after coinciding gain. Conclusions Exposure engages regulatory ~2 that ultimately fail, consequent impaired satiety. Insights into etiology obesity can be obtained investigating changes satiety initial exposure.

Язык: Английский

---

Gastrocytes and GLUttony – astrocyte regulation of calorie intake via glutamatergic modulation of gastric activity in rats

The Journal of Physiology, Год журнала: 2023, Номер 601(4), С. 709 - 710

Опубликована: Янв. 27, 2023

The brain dorsal vagal complex (DVC) is a bi-directional relay between the and gastrointestinal tract controlling satiety, feeling of fullness after consumption meal. Understanding physiological mechanisms underlying satiety may aid development new therapeutic approaches for disordered eating, particularly in relation to calorie-dense foods implicated obesity. Focusing on class cells central nervous system called astrocytes, comprehensive study by Clyburn colleagues provides mechanistic insights into early-stage molecular cellular adaptations within DVC following calorie-rich refined high-fat diet (HFD) (Clyburn et al., 2023). Astrocytes are highly adaptive glial which work concert with neurons serving structural functional roles brain. Numerous studies now show that modulation astrocyte function can impact variety aspects physiology, pathology behaviour. Modulation food intake body weight rodents sufficient and, turn, facets signalling change feeding behaviour (García-Cáceres 2019). astrocytes involved regulation intake, glucose homeostasis, cardiovascular breathing (MacDonald & Ellacott, 2020). Common threads these include astrocytic glutamatergic neurotransmission release gliotransmitter ATP. regions constitute DVC: area postrema (AP), circumventricular site where hormones circulating factors more readily enter exert endocrine actions; nucleus solitary (NTS), termination inputs from periphery integration higher centres such as hypothalamus; motor vagus (DMV), origin parasympathetic output periphery, including signals function. A direct neuronal NTS DMV neural regulatory feedback loop. Prior revealed increases NTS–DMV transmission via NMDA receptors during homeostatic adaptions caloric introduction HFD rats Browning, 2021). Consolidating extending evidence this other published studies, herein explored role process. When laboratory first have access they undergo period ‘binge-like’ consuming up twice their normal daily 24−48 h. Over next 5−7 days restore closer isocaloric level. Despite adaptations, continued typically remains elevated leading gain This experimental paradigm used changes density. In 2012 using paradigm, Thaler described inflammation reactivity hypothalamus temporally mirror pattern adjustments (Thaler 2012). Using histology approach rats, observed increased expression an marker 3−5 HFD. both pharmacological chemogenetic subsequently inhibiting activity rat phase prevent reduction seen; thus, implicate adaptation addition changing amount consumed, impacts patterns gastric function, delay emptying reduced tone motility. demonstrate here time inhibition HFD-induced modifications 4th day switch. series electrophysiological authors identify astrocyte-mediated purinergic NTS→DMV→gastric neuron pathway mechanism. Together, elegantly provide basis act key components brainstem neurocircuits advances our understanding how mediate early challenge 2023), many interesting angles still pursue. focuses circuits, but significant distention occurs hyperphagia immediately HFD, it would be fascinating examine at vagal-NTS synapse paradigm. Furthermore, even though express hormone nutrient-sensing capabilities, integrate hormonal, neuropeptide nutrient sensing dietary unclear. pertinent level AP exposed hormonal nutritional flux. Multiple regions, DVC, morphology obese rodents, some areas region-specific Increasingly, also being loss anorexia associated disease. More regional like colleagues, needed advance contribution different pathological contexts. Please note: publisher not responsible content or functionality any supporting information supplied authors. Any queries (other than missing content) should directed corresponding author article. has no conflicts declare. Sole author. None work.

Язык: Английский

---

Impact of chemogenetic activation of dorsal vagal complex astrocytes in mice on adaptive glucoregulatory responses

Journal of Neuroendocrinology, Год журнала: 2023, Номер 35(8)

Опубликована: Июнь 9, 2023

The dorsal vagal complex (DVC) regulates diverse aspects of physiology including food intake and blood glucose homeostasis. Astrocytes play an active role in regulating DVC function and, by extension, physiological parameters. astrocytes ex vivo slices respond to low tissue glucose. response neurons is conditional on intact astrocyte signalling slice preparations, suggesting are primary sensors deprivation (glucoprivation). Based these published findings we hypothesised that manipulation with chemogenetics would be sufficient alter responses control We found 2-h after systemic 2-DG-induced glucoprivation there were no observable changes morphology glial fibrillary acidic protein (GFAP)-immunoreactive cells, specifically those the nucleus solitary tract (NTS). Chemogenetic activation was suppress nocturnal reducing both meal size number this also suppressed glucoprivic intake. did not increase basal nor protect against insulin-induced hypoglycaemia. In male mice, chemogenetic tolerance. female initial excursion reduced a tolerance test, enhanced absorption. our data work, propose may indispensable homeostatic role, is, necessary maintain glucoregulatory neuronal circuitry, but alone their bulk result adaptive responses. It possible state-dependent effects and/or subsets have specialised unresolvable using experimental approaches employed here.

Язык: Английский

---