The contribution of hypothalamic macroglia to the regulation of energy homeostasis.

This Document is Protected by copyright and was first published by Frontiers. All rights reserved. it is reproduced with permission.The hypothalamus is critical for the regulation of energy homeostasis. Genetic and pharmacologic studies have identified a number of key hypothalamic neuronal circuits that integrate signals controlling food intake and energy expenditure. Recently, studies have begun to emerge demonstrating a role for non-neuronal cell types in the regulation of energy homeostasis. In particular the potential importance of different glial cell types is increasingly being recognized. A number of studies have described changes in the activity of hypothalamic macroglia (principally astrocytes and tanycytes) in response to states of positive and negative energy balance, such as obesity and fasting. This article will review these studies and discuss how these findings are changing our understanding of the cellular mechanisms by which energy homeostasis is regulated

Changes in neuronal activity across the mouse ventromedial nucleus of the hypothalamus in response to low glucose: evaluation using an extracellular multi‐electrode array approach

The hypothalamic ventromedial nucleus (VMN) is involved in maintaining systemic glucose homeostasis. Neurophysiological studies in rodent brain slices have identified populations of VMN glucose‐sensing neurones: glucose‐excited (GE) neurones, cells which increased their firing rate in response to increases in glucose concentration, and glucose‐inhibited (GI) neurones, which show a reduced firing frequency in response to increasing glucose concentrations. To date, most slice electrophysiological studies characterising VMN glucose‐sensing neurones in rodents have utilised the patch clamp technique. Multi‐electrode arrays (MEAs) are a state‐of‐the‐art electrophysiological tool enabling the electrical activity of many cells to be recorded across multiple electrode sites (channels) simultaneously. We used a perforated MEA (pMEA) system to evaluate electrical activity changes across the dorsal‐ventral extent of the mouse VMN region in response to alterations in glucose concentration. Because intrinsic (ie, direct postsynaptic sensing) and extrinsic (ie, presynaptically modulated) glucosensation were not discriminated, we use the terminology ‘GE/presynaptically excited by an increase (PER)’ and ‘GI/presynaptically excited by a decrease (PED)’ in the present study to describe responsiveness to changes in extracellular glucose across the mouse VMN. We observed that 15%‐60% of channels were GE/PER, whereas 2%‐7% were GI/PED channels. Within the dorsomedial portion of the VMN (DM‐VMN), significantly more channels were GE/PER compared to the ventrolateral portion of the VMN (VL‐VMN). However, GE/PER channels within the VL‐VMN showed a significantly higher basal firing rate in 2.5 mmol l‐1 glucose than DM‐VMN GE/PER channels. No significant difference in the distribution of GI/PED channels was observed between the VMN subregions. The results of the present study demonstrate the utility of the pMEA approach for evaluating glucose responsivity across the mouse VMN. pMEA studies could be used to refine our understanding of other neuroendocrine systems by examining population level changes in electrical activity across brain nuclei, thus providing key functional neuroanatomical information to complement and inform the design of single‐cell neurophysiological studies

The Polynomial Carathéodory—Fejér Approximation Method for Jordan Regions

We propose a method for the approximation of analytic functions on Jordan regions that is based on a Carathéodory—Fejér type of economization of the Faber series. The method turns out to be very effective if the boundary of the region is analytic. It often still works when the region degenerates to a Jordan arc. We also derive related lower and upper bounds for the error of the best approximatio

The Carathéodory—Fejér Extension of a Finite Geometric Series

It is shown that the Caratheodory—Fejer extension of a finite geometric series can be given explicitly up to a simple polynomial equation in an auxiliary variable. This result allows us to analyse the Caratheodory-Fejer approximation method in the case where the quotients of successive Maclaurin coefficients of the given function tend to a limi

A survey of Faber methods in numerical approximation

AbstractAlthough well known in function theory. Faber polynomials and the Faber transform have only recently been systematically applied for numerical polynomial and rational approximation of complex valued functions. This paper surveys some recent work of this author and others in this area

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

This is the final version. Available on open access from Wiley via the DOI in this recor

Astrocytes in neuroendocrine systems: An overview

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record A class of glial cell, astrocytes are highly abundant in the CNS. In addition to maintaining tissue homeostasis, astrocytes regulate neuronal communication and synaptic plasticity. There is an ever-increasing appreciation that astrocytes are involved in the regulation of physiology and behaviour in normal and pathological states, including within neuroendocrine systems. Indeed, astrocytes are direct targets of hormone action in the CNS, via receptors expressed on their surface, and are also a source of regulatory neuropeptides, neurotransmitters, and gliotransmitters. Furthermore, as part of the neurovascular unit, astrocytes can regulate hormone entry into the CNS. This review is intended to provide an overview of how astrocytes are impacted by and contribute to the regulation of a diverse range of neuroendocrine systems: energy homeostasis and metabolism, reproduction, fluid homeostasis, the stress response, and circadian rhythms. This article is protected by copyright. All rights reserved.Medical Research Council (MRC)Diabetes UKUniversity of Exete

Astrocytes in the nucleus of the solitary tract: Contributions to neural circuits controlling physiology

This is the final version. Available from Elsevier via the DOI in this record. The nucleus of the solitary tract (NTS) is the primary brainstem centre for the integration of physiological information from the periphery transmitted via the vagus nerve. In turn, the NTS feeds into downstream circuits regulating physiological parameters. Astrocytes are glial cells which have key roles in maintaining CNS tissue homeostasis and regulating neuronal communication. Recently an increasing number of studies have implicated astrocytes in the regulation of synaptic transmission and physiology. This review aims to highlight evidence for a role for astrocytes in the functions of the NTS. Astrocytes maintain and modulate NTS synaptic transmission contributing to the control of diverse physiological systems namely cardiovascular, respiratory, glucoregulatory, and gastrointestinal. In addition, it appears these cells may have a role in central control of feeding behaviour. As such these cells are a key component of signal processing and physiological control by the NTS.Medical Research Council (MRC)Diabetes U

Regulation of food intake by astrocytes in the brainstem dorsal vagal complex

This is the final version. Available on open access from Wiley via the DOI in this recordA role for glial cells in brain circuits controlling feeding has begun to be identified with hypothalamic astrocyte signaling implicated in regulating energy homeostasis. The nucleus of the solitary tract (NTS), within the brainstem dorsal vagal complex (DVC), integrates vagal afferent information from the viscera and plays a role in regulating food intake. We hypothesized that astrocytes in this nucleus respond to, and influence, food intake. Mice fed high‐fat chow for 12 hr during the dark phase showed NTS astrocyte activation, reflected in an increase in the number (65%) and morphological complexity of glial‐fibrillary acidic protein (GFAP)‐immunoreactive cells adjacent to the area postrema (AP), compared to control chow fed mice. To measure the impact of astrocyte activation on food intake, we delivered designer receptors exclusively activated by designer drugs (DREADDs) to DVC astrocytes (encompassing NTS, AP, and dorsal motor nucleus of the vagus) using an adeno‐associated viral (AAV) vector (AAV‐GFAP‐hM3Dq_mCherry). Chemogenetic activation with clozapine‐N‐oxide (0.3 mg/kg) produced in greater morphological complexity in astrocytes and reduced dark‐phase feeding by 84% at 4 hr postinjection compared with vehicle treatment. hM3Dq‐activation of DVC astrocytes also reduced refeeding after an overnight fast (71% lower, 4 hr postinjection) when compared to AAV‐GFAP‐mCherry expressing control mice. DREADD‐mediated astrocyte activation did not impact locomotion. hM3Dq activation of DVC astrocytes induced c‐FOS in neighboring neuronal feeding circuits (including in the parabrachial nucleus). This indicates that NTS astrocytes respond to acute nutritional excess, are involved in the integration of peripheral satiety signals, and can reduce food intake when activated.Diabetes UKMedical Research Council (MRC

Interaction of self-assembling cyclic peptide-polymer nanotubes with biological models

Cyclic peptide-polymer nanotubes (CPNT) are an emerging class of nanomaterials with a strong potential for biological applications. This thesis aims to investigate the interaction of different CPNT systems with different biological models. Firstly, the place of CPNT in the wider family of synthetic nanocylinders is put into perspective, with a focus on existing applications. Secondly, the behaviour of a library of CPNT with differing polymer composition and proclivity for self-assembly was studied in cellular models (cell lines and tumour spheroids). This study focuses on the relationship between self-assembly and cellular uptake and its findings show that relatively short CPNT (~15 nm) are taken up the most effectively, with specific patterns in intracellular localisation in both type of models. Thirdly, the cellular uptake and the in vivo properties of stabilised elongated CPNT (>100 nm) are compared to those of short dynamic CPNT (~10 nm), using cell lines and rat models. Despite exhibiting lower levels of cellular uptake than their dynamic counterparts, stabilised CPNT are shown to be promising drug delivery vehicles thanks to their longer circulation in vivo allied to an efficient excretion. In parallel, the addition of integrin-targeting moieties to dynamic CPNT is also looked into. Targeting CPNT promote uptake in cell lines overexpressing αvβ3 integrins. Clear limitations for any use for drug delivery purposes can be highlighted, as their blood clearance is accelerated compared to non-targeting CPNT. This was explained by a higher propensity for recognition by the immune system as demonstrated by the high levels detected in the liver and spleen. Fourthly, the interaction of a library of charged polymers and CPNT with lipid bilayer models is investigated, using complementary techniques. Charged CPNT show higher levels of interaction than charged polymers and neutral CPNT on the lipid model employed. Further studies employing spectroscopy techniques and neutron reflectivity support a model of interaction for charged CPNT. The interaction is demonstrated to lead to the formation of pores in the bilayer, excluding any embedding of the CP in the hydrophobic tail regions. By anchoring to negatively charged head groups, the CPNT can insert in the bilayer and form a diffuse hydrated layer at the surface of the outer leaflet. Antibacterial activity is also briefly assessed in this work. Overall, this thesis gathers key insights on the behaviour of various CPNT in lipid bilayer, cellular and animal models