Nicolas NunnLiverpool Women's NHS Foundation Trust
Nicolas Nunn
Doctor of Philosophy
About
33
Publications
2,888
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282
Citations
Citations since 2017
Introduction
I am a neuroscientist with an interest in techniques and technologies that allow us to study the most complex structure we know of, the brain. With a history in mouse genetics, obesity and neuroendocrinology, I have been a postdoctoral researcher for the best part of a decade. My driving goals in the lab are to improve how we study the brain through the use of technology, with a particular focus on optogenetics.
Publications
Publications (33)
Here we show that central administration of pyroglutamylated arginine-phenylamine-amide peptide (QRFP/26RFa) increases both food intake and locomotor activity, without any significant effect on energy expenditure, thermogenesis or reward. Germline knock out of either of the mouse QRFP receptor orthologs, Gpr103a and Gpr103b, did not produce a metab...
Objective
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective medications to reduce appetite and body weight. These actions are centrally mediated, however the neuronal substrates involved are poorly understood.
Methods
We employed a combination of neuroanatomical, genetic and behavioral approaches in the mouse to investigate the in...
Objectives:
To study the effects of an analogue of the gut-produced hormone peptide YY (PYY3-36), which has increased selectivity for the Y2 receptor; specifically, to record its effects on food intake and on hypothalamic neuropeptide Y/agouti-related peptide (NPY/AgRP) neuron activity.
Methods:
NNC0165-1273, a modified form of the peptide hormo...
Background: Glucose-sensing neurons are located in several parts of the brain, but are concentrated in the ventromedial nucleus of the hypothalamus (VMH). The importance of these VMH neurons in glucose homeostasis is well-established, however, little is known about their individual identity. In the present study, we identified a distinct glucose-se...
Changes in membrane potential following TTX application: a significant increase in membrane potential in response to low glucose in the presence of TTX was observed. Data are analyzed using paired t-test (*p < 0.05), n = 6.
Confirmation of observed efferent PACAPVMH connections: efferent connections of PACAPVMH neurons to the aBNST, PVH, LH, and PAG, previously observed using AAV-driven synaptophysin, were confirmed here using retrograde tracing. For each target region, the injection site is shown in the left panel and retrobead-containing PACAPVMH neurons in the righ...
Bilateral transfection in VMH: only mice showing bilateral transfection with the stimulatory DREADD, AAV8/hSyn-DIO-hM3D(Gq), were included in the analysis.
Changes in baseline glucose levels following activation of PACAPVMH neurons: 8–10 week old, male mice were injected with saline or CNO (i.p.) and changes in baseline glucose levels measured. A transient increase in baseline glucose levels following CNO injections was observed in mice after CNO injection.
cFos in PACAPVMH neurons using DREADD: cFos expression (green) in PACAPVMH neurons following (A) (i) Saline or (ii) CNO injections. (B) A significant increase in mCherry tagged neurons containing cFos was observed following CNO injections, compared with controls. Data are analyzed using unpaired t-test, ****p < 0.0001.
Effect of CNO in C57BL/6J: 8–10 weeks, male mice were injected with either saline or CNO followed by an IPGTT. No difference in (A) (i) glucose profiles and (ii) AUC was observed between the two groups. Two-way ANOVA with repeated measure and unpaired t- test, n = 6 in each group.
Inhibition of PACAPVMH neurons causes no change in glucose or glucagon during an insulin tolerance test (ITT): (A) Silencing of PACAPVMH neurons by CNO pretreatment did not change insulin-induced glucose response compared with controls. Data are analyzed using two-way ANOVA with repeated measure (****p < 0.0001). (B) Glucagon levels were unchanged...
Several reports have shown that the periventricular region of the brain, including the paraventricular nucleus (PVN), is critical to sensing and responding to changes in plasma osmolality. Further studies also implicate the transient receptor potential ion channel, type V4 (TRPV4) channel in this homeostatic behavior. In previous work we have shown...
Background and purpose:
Transient receptor potential vanilloid type 4 (TRPV4) and calcium-activated potassium channels (KCa ) mediate osmosensing in many tissues. Both TRPV4 and KCa channels are found in the paraventricular nucleus (PVN) of the hypothalamus, an area critical for sympathetic control of cardiovascular and renal function. Here, we ha...
Leptin is a critical regulator of metabolism, which acts on brain receptors (Lepr) to reduce energy intake and increase energy expenditure. Some of the cellular pathways mediating leptin's anorectic actions are identified, but those mediating the thermogenic effects have proven more difficult to decipher. We define a population of neurons in the do...
Imbalances of energy homeostasis are often associated with cardiovascular complications. Previous work has shown that Gnasxl-deficient mice have a lean and hypermetabolic phenotype, with increased sympathetic stimulation of adipose tissue. The Gnasxl transcript from the imprinted Gnas locus encodes the trimeric G-protein subunit XLαs, which is expr...
Figure S1. Simplified diagram of the Gnas locus
Figure S4. Neuronal c-fos responses to Ex-4 in the amygdala.
Figure S2. Typical ECG and HR traces in conscious Gnasxl KO mice andWT siblings
Figure S5.Neuronal c-fos responses to Ex-4 in the area postrema (AP) andmedial region of the NTS
Figure S3. Empirical validation of LF and HF bandings in HRV model.
Figure S6. Control immunofluorescence for XLαs and c-fos in response to Ex-4 in the hypothalamic PVN of Gnasxl KO
Figure S7. c-fos response to Ex-4 in XLαs-expressing neurones of the amygdala
The alternatively spliced trimeric G-protein subunit XLαs, which is involved in cAMP signalling, is encoded by the Gnasxl transcript of the imprinted Gnas locus. XLαs deficient mice show neonatal feeding problems, leanness, inertia and a high mortality rate. Mutants that survive to weaning age develop into healthy and fertile adults, which remain l...
Plasma Ghrelin levels of Gnasxlm+/p− mice are elevated. Plasma Ghrelin levels (active Ghrelin and total Ghrelin) of Gnasxl-deficient (Plagge et al., 2004) adult females (n = 13) and their wild-type littermates (n = 15) under ad libitum fed normal chow diet conditions. Means ± SEM; ** p = 0.003 (active Ghrelin) and p<0.0001 (total Ghrelin) versus WT...
Summary of developmental changes in the brain expression pattern of Gnasxl. Data are collated from XLαs/XLN1 immunohistochemistry, XLlacZGT gene trap fusion protein expression and in situ hybridisation studies in this manuscript and from Plagge A., et al., Nat. Genet. 36: 818–826 (2004). For abbreviations see main text and figure legends.
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Control stainings of tissues. (A) No blue colour precipitate was visible in neonatal brain from wild-type or single transgenic Cre/+; +/+ or +/+; +/XLlacZGT mice. Shown is a XGal preparation of a wild-type whole-mount brain, cut sagittally along the midline before incubation in staining solution. (B) XGal preparation of a neonatal thoracic spine /...
Sequences of oligonucleotides used for genotyping, RT-PCR and qRT-PCR in
Figure 2
and Figure S1.
(PDF)
Analysis of Gnasxl transcript levels by qRT-PCR. RNA from neonatal brain of wild-type, Cre/+; +/XLlacZGT (inverted, active gene trap) and +/+; +/XLlacZGT (inactive gene trap) littermates was analysed using primers specific for Gnasxl exon 1. Expression levels were normalised to the housekeeping genes Gapdh and Trf (n = 4–5 per genotype).
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Expression and co-localisation of Gnasxl in the hypothalamus. (A) Expression of Gnasxl in the hypothalamic arcuate nucleus at postnatal day 4. An in situ hybridisation of a sagittal brain section with a Digoxigenin-labelled RNA probe is shown. (B) XLαs expression in A12 dopaminergic neurons of the arcuate nucleus of adult mice. (B i) Overview; XLαs...
Simplified scheme of the mTOR1-S6K nutrient sensing kinase pathway in the context of InsR and LepR signalling. Both receptors can activate mTOR1-S6K via their IRS-PI3K-Akt signalling branch. Additional intracellular nutrient sensing mechanisms further influence mTOR1-S6K activity (not shown). In a negative feedback loop p70S6K1 phosphorylates and i...
XGal staining of (A) neonatal and (B) adult adrenal glands of CMV-Cre/+; +/XLlacZGT mice. Tissues were cut transverse and stained as whole-mounts over night. Blue colour precipitate formed specifically in the adrenal medulla.
(PDF)
The paraventricular nucleus (PVN) of the hypothalamus has been described as the "autonomic master controller". It co-ordinates critical physiological responses through control of the hypothalamic-pituitary-adrenal (HPA)-axis, and by modulation of the sympathetic and parasympathetic branches of the central nervous system. The PVN comprises several a...
Projects
Project (1)
-Explore functional connections between two important neuronal mediators of feeding behavior and energy balance, Orexin and AgRP/NPY neurons
-Understand more fully how gut-derived peptides such as PYY 3-36 interact with central neurons to promote energy balance
-Work with a novel, coded PYY analogue to determine effects on feeding behavior and direct effects on AgRP/NPY neurons in the arcuate nucleus of the hypothalamus
