Publications by authors named "Andrew M Allen"

65 Publications

Selective optogenetic stimulation of efferent fibers in the vagus nerve of a large mammal.

Brain Stimul 2021 Jan-Feb;14(1):88-96. Epub 2020 Nov 17.

Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK. Electronic address:

Background: Electrical stimulation applied to individual organs, peripheral nerves, or specific brain regions has been used to treat a range of medical conditions. In cardiovascular disease, autonomic dysfunction contributes to the disease progression and electrical stimulation of the vagus nerve has been pursued as a treatment for the purpose of restoring the autonomic balance. However, this approach lacks selectivity in activating function- and organ-specific vagal fibers and, despite promising results of many preclinical studies, has so far failed to translate into a clinical treatment of cardiovascular disease.

Objective: Here we report a successful application of optogenetics for selective stimulation of vagal efferent activity in a large animal model (sheep).

Methods And Results: Twelve weeks after viral transduction of a subset of vagal motoneurons, strong axonal membrane expression of the excitatory light-sensitive ion channel ChIEF was achieved in the efferent projections innervating thoracic organs and reaching beyond the level of the diaphragm. Blue laser or LED light (>10 mW mm; 1 ms pulses) applied to the cervical vagus triggered precisely timed, strong bursts of efferent activity with evoked action potentials propagating at speeds of ∼6 m s.

Conclusions: These findings demonstrate that in species with a large, multi-fascicled vagus nerve, it is possible to stimulate a specific sub-population of efferent fibers using light at a site remote from the vector delivery, marking an important step towards eventual clinical use of optogenetic technology for autonomic neuromodulation.
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http://dx.doi.org/10.1016/j.brs.2020.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836098PMC
November 2020

A Chemogenetic Tool that Enables Functional Neural Circuit Analysis.

Cell Rep 2020 09;32(11):108139

Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, Australia; Department of Physiology, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address:

Chemogenetics enables manipulation of neuronal activity in experimental animals. While providing information about the transduced neuron expressing a ligand-activated molecule, chemogenetics does not provide understanding about the antecedent circuit that drives that neuron's activity. For current approaches, this is not feasible, because the activating molecules are not genetically encoded. The insect allatostatin/allatostatin receptor system, a highly specific, powerful inhibitory chemogenetic approach, has this advantage, because the ligand, being a peptide, is genetically encoded. We developed viral vector-based systems to express biologically active allatostatin in neurons in vivo and allatostatin receptors in subpopulations of postsynaptic neurons. We demonstrate that activity-dependent release of allatostatin induces inhibition of allatostatin receptor-expressing neurons. We validate the approach in the vagal viscerosensory system where inhibitory, rather than the usual excitatory, viscerosensory input leads to sustained decreases in baroreceptor reflex sensitivity and bodyweight.
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http://dx.doi.org/10.1016/j.celrep.2020.108139DOI Listing
September 2020

PreBötzinger complex neurons drive respiratory modulation of blood pressure and heart rate.

Elife 2020 06 15;9. Epub 2020 Jun 15.

Department of Physiology, University of Melbourne, Victoria, Australia.

Heart rate and blood pressure oscillate in phase with respiratory activity. A component of these oscillations is generated centrally, with respiratory neurons entraining the activity of pre-sympathetic and parasympathetic cardiovascular neurons. Using a combination of optogenetic inhibition and excitation in vivo and in situ in rats, as well as neuronal tracing, we demonstrate that preBötzinger Complex (preBötC) neurons, which form the kernel for inspiratory rhythm generation, directly modulate cardiovascular activity. Specifically, inhibitory preBötC neurons modulate cardiac parasympathetic neuron activity whilst excitatory preBötC neurons modulate sympathetic vasomotor neuron activity, generating heart rate and blood pressure oscillations in phase with respiration. Our data reveal yet more functions entrained to the activity of the preBötC, with a role in generating cardiorespiratory oscillations. The findings have implications for cardiovascular pathologies, such as hypertension and heart failure, where respiratory entrainment of heart rate is diminished and respiratory entrainment of blood pressure exaggerated.
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http://dx.doi.org/10.7554/eLife.57288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326498PMC
June 2020

Vegetation productivity summarized by the Dynamic Habitat Indices explains broad-scale patterns of moose abundance across Russia.

Sci Rep 2020 01 21;10(1):836. Epub 2020 Jan 21.

SILVIS Lab, Department of Forest and Wildlife Ecology, University of Wisconsin-Madison, 1630 Linden Drive, Madison, WI, 53706, USA.

Identifying the factors that determine habitat suitability and hence patterns of wildlife abundances over broad spatial scales is important for conservation. Ecosystem productivity is a key aspect of habitat suitability, especially for large mammals. Our goals were to a) explain patterns of moose (Alces alces) abundance across Russia based on remotely sensed measures of vegetation productivity using Dynamic Habitat Indices (DHIs), and b) examine if patterns of moose abundance and productivity differed before and after the collapse of the Soviet Union. We evaluated the utility of the DHIs using multiple regression models predicting moose abundance by administrative regions. Univariate models of the individual DHIs had lower predictive power than all three combined. The three DHIs together with environmental variables, explained 79% of variation in moose abundance. Interestingly, the predictive power of the models was highest for the 1980s, and decreased for the two subsequent decades. We speculate that the lower predictive power of our environmental variables in the later decades may be due to increasing human influence on moose densities. Overall, we were able to explain patterns in moose abundance in Russia well, which can inform wildlife managers on the long-term patterns of habitat use of the species.
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http://dx.doi.org/10.1038/s41598-019-57308-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972780PMC
January 2020

Does glyceryl trinitrate cause central sympatholytic effects? Insights from a case of baroreflex failure.

Intern Med J 2020 01;50(1):114-117

Department of General Medicine, Royal Melbourne Hospital, Melbourne, Victoria, Australia.

Whether part of the blood pressure lowering effects of glyceryl trinitrate (GTN) is the result of centrally mediated reduction in sympathetic activity is debated. In humans, baroreflex activity potentially obscures the central sympatholytic effects of GTN. We examined this in a routine clinical tilt test in a patient with baroreflex failure secondary to previous neck radiotherapy. With reduced baroreflex function we observed an exaggerated fall in blood pressure and reduced sympathetic activity with GTN, supporting a peripheral vasodilation and central sympatholytic effect.
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http://dx.doi.org/10.1111/imj.14699DOI Listing
January 2020

Investigating the Role of the Eurasian Badger () in the Nationwide Distribution of the Western European Hedgehog () in England.

Animals (Basel) 2019 Oct 2;9(10). Epub 2019 Oct 2.

Former: School of Biological Sciences, Royal Holloway, University of London, Egham TW20 0EX, UK.

Biodiversity is declining globally, which calls for effective conservation measures. It is, therefore, important to investigate the drivers behind species presence at large spatial scales. The Western European hedgehog () is one of the species facing declines in parts of its range. Yet, drivers of Western European hedgehog distribution at large spatial scales remain largely unknown. At local scales, the Eurasian badger (), an intraguild predator of the Western European hedgehog, can affect both the abundance and the distribution of the latter. However, the Western European hedgehog and the Eurasian badger have shown to be able to co-exist at a landscape scale. We investigated whether the Eurasian badger may play a role in the likelihood of the presence of the Western European hedgehog throughout England by using two nationwide citizen science surveys. Although habitat-related factors explained more variation in the likelihood of Western European hedgehog presence, our results suggest that Eurasian badger presence negatively impacts the likelihood of Western European hedgehog presence. Intraguild predation may, therefore, be influencing the nationwide distribution of hedgehogs in England, and further research is needed about how changes in badger densities and intensifying agricultural practices that remove shelters like hedgerows may influence hedgehog presence.
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http://dx.doi.org/10.3390/ani9100759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826801PMC
October 2019

Extensive Inhibitory Gating of Viscerosensory Signals by a Sparse Network of Somatostatin Neurons.

J Neurosci 2019 10 30;39(41):8038-8050. Epub 2019 Aug 30.

Florey Institute of Neuroscience and Mental Health, and

Integration and modulation of primary afferent sensory information begins at the first terminating sites within the CNS, where central inhibitory circuits play an integral role. Viscerosensory information is conveyed to the nucleus of the solitary tract (NTS) where it initiates neuroendocrine, behavioral, and autonomic reflex responses that ensure optimal internal organ function. This excitatory input is modulated by diverse, local inhibitory interneurons, whose functions are not clearly understood. Here we show that, in male rats, 65% of somatostatin-expressing (SST) NTS neurons also express GAD67, supporting their likely role as inhibitory interneurons. Using whole-cell recordings of NTS neurons, from horizontal brainstem slices of male and female SST-yellow fluorescent protein (YFP) and SST-channelrhodopsin 2 (ChR2)-YFP mice, we quantified the impact of SST-NTS neurons on viscerosensory processing. Light-evoked excitatory photocurrents were reliably obtained from SST-ChR2-YFP neurons ( = 16) and the stimulation-response characteristics determined. Most SST neurons (57%) received direct input from solitary tract (ST) afferents, indicating that they form part of a feedforward circuit. All recorded SST-negative NTS neurons ( = 72) received SST-ChR2 input. ChR2-evoked PSCs were largely inhibitory and, in contrast to previous reports, were mediated by both GABA and glycine. When timed to coincide, the ChR2-activated SST input suppressed ST-evoked action potentials at second-order NTS neurons, demonstrating strong modulation of primary viscerosensory input. These data indicate that the SST inhibitory network innervates broadly within the NTS, with the potential to gate viscerosensory input to powerfully alter autonomic reflex function and other behaviors. Sensory afferent input is modulated according to state. For example the baroreflex is altered during a stress response or exercise, but the basic mechanisms underpinning this sensory modulation are not fully understood in any sensory system. Here we demonstrate that the neuronal processing of viscerosensory information begins with synaptic gating at the first central synapse with second-order neurons in the NTS. These data reveal that the somatostatin subclass of inhibitory interneurons are driven by visceral sensory input to play a major role in gating viscerosensory signals, placing them within a feedforward circuit within the NTS.
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http://dx.doi.org/10.1523/JNEUROSCI.3036-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786816PMC
October 2019

Intrathecal Administration of Losartan Reduces Directly Recorded Cardiac Sympathetic Nerve Activity in Ovine Heart Failure.

Hypertension 2019 10 5;74(4):896-902. Epub 2019 Aug 5.

From the Florey Institute of Neuroscience and Mental Health (S.L., C.N.M., R.R.), University of Melbourne, Parkville, Australia.

Early and preferential activation of cardiac sympathetic nerve activity (CSNA) is one of the strongest prognostic markers of heart failure (HF) in patients. Our previous studies have implicated central angiotensin mechanisms as playing a critical role in generating this increase in cardiac sympathetic drive. However, it is unclear if inhibition of ATR (angiotensin type-1 receptors) in different neural groups in the sympathetic pathway to the heart, such as the sympathetic preganglionic neurons in the intermediolateral column of the spinal cord, can reduce cardiac sympathetic drive. We hypothesized that in HF, localized intrathecal administration of the ATR antagonist losartan, specifically into the T1-2 subarachnoid space, would decrease CSNA. In normal conscious sheep, intrathecal infusion of Ang II (angiotensin II; 3.0 nmol/mL per hour), significantly increased mean arterial pressure and CSNA; this effect was abolished by prior administration of losartan (1 mg/h). In an ovine rapid ventricular pacing model of HF, the resting levels of heart rate and CSNA were significantly elevated compared with normals. Intrathecal infusion of losartan (1 mg/h) in HF significantly reduced CSNA and heart rate but did not change arterial pressure. The ATR binding density in the spinal cord was also elevated in the HF group. Our data suggest that ATRs within the spinal cord are responsible, in part, for the increased CSNA in HF and may represent a target for the selective reduction of CSNA in HF.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.12937DOI Listing
October 2019

Neurohumoral interactions contributing to renal vasoconstriction and decreased renal blood flow in heart failure.

Am J Physiol Regul Integr Comp Physiol 2019 09 26;317(3):R386-R396. Epub 2019 Jun 26.

Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.

In heart failure (HF), increases in renal sympathetic nerve activity (RSNA), renal norepinephrine spillover, and renin release cause renal vasoconstriction, which may contribute to the cardiorenal syndrome. To increase our understanding of the mechanisms causing renal vasoconstriction in HF, we investigated the interactions between the increased activity of the renal nerves and the renal release of norepinephrine and renin in an ovine pacing-induced model of HF compared with healthy sheep. In addition, we determined the level of renal angiotensin type-1 receptors and the renal vascular responsiveness to stimulation of the renal nerves and α-adrenoceptors. In conscious sheep with mild HF (ejection fraction 35%-40%), renal blood flow (276 ± 13 to 185 ± 18 mL/min) and renal vascular conductance (3.8 ± 0.2 to 3.1 ± 0.2 mL·min·mmHg) were decreased compared with healthy sheep. There were increases in the burst frequency of RSNA (27%), renal norepinephrine spillover (377%), and plasma renin activity (141%), whereas the density of renal medullary angiotensin type-1 receptors decreased. In anesthetized sheep with HF, the renal vasoconstrictor responses to electrical stimulation of the renal nerves or to phenylephrine were attenuated. Irbesartan improved the responses to nerve stimulation, but not to phenylephrine, in HF and reduced the responses in normal sheep. In summary, in HF, the increases in renal norepinephrine spillover and plasma renin activity are augmented compared with the increase in RSNA. The vasoconstrictor effect of the increased renal norepinephrine and angiotensin II is offset by reduced levels of renal angiotensin type-1 receptors and reduced renal vasoconstrictor responsiveness to α-adrenoceptor stimulation.
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http://dx.doi.org/10.1152/ajpregu.00026.2019DOI Listing
September 2019

Respiratory sympathetic modulation is augmented in chronic kidney disease.

Respir Physiol Neurobiol 2019 04 2;262:57-66. Epub 2019 Feb 2.

Department of Biomedical Sciences, Macquarie University, Australia. Electronic address:

Respiratory modulation of sympathetic nerve activity (respSNA) was studied in a hypertensive rodent model of chronic kidney disease (CKD) using Lewis Polycystic Kidney (LPK) rats and Lewis controls. In adult animals under in vivo anaesthetised conditions (n = 8-10/strain), respiratory modulation of splanchnic and renal nerve activity was compared under control conditions, and during peripheral (hypoxia), and central, chemoreceptor (hypercapnia) challenge. RespSNA was increased in the LPK vs. Lewis (area under curve (AUC) splanchnic and renal: 8.7 ± 1.1 vs. 3.5 ± 0.5 and 10.6 ± 1.1 vs. 7.1 ± 0.2 μV.s, respectively, P < 0.05). Hypoxia and hypercapnia increased respSNA in both strains but the magnitude of the response was greater in LPK, particularly in response to hypoxia. In juvenile animals studied using a working heart brainstem preparation (n = 7-10/strain), increased respSNA was evident in the LPK (thoracic SNA, AUC: 0.86 ± 0.1 vs. 0.42 ± 0.1 μV.s, P < 0.05), and activation of peripheral chemoreceptors (NaCN) again drove a larger increase in respSNA in the LPK with no difference in the response to hypercapnia. Amplified respSNA occurs in CKD and may contribute to the development of hypertension.
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http://dx.doi.org/10.1016/j.resp.2019.02.001DOI Listing
April 2019

An uncertain future for the endemic Galliformes of the Caucasus.

Sci Total Environ 2019 Feb 19;651(Pt 1):725-735. Epub 2018 Sep 19.

Radboud University, Department of Animal Ecology and Physiology, NL - 6500, GL, Nijmegen, the Netherlands.

Impacts of climate change are already evident in ecosystems worldwide. High-latitude and altitude regions are at greatest risk because the effects of climate change are greater in these regions, and species from these areas have limited ability to track their climate envelopes. The Caucasian snowcock (Tetraogallus caucasicus) and the Caucasian grouse (Lyrurus mlokosiewiczi) are both high-altitude specialists that are endemic to a restricted range in the Caucasus mountains of Europe. Little research has been performed to determine the status of the populations or the potential impacts of climate change. We investigated how climate and land use change may impact both species in future and determined whether their life history traits may increase their vulnerability using a combined exposure and trait-based index. We compared several climate models, and in all instances, both species showed drastic range contractions although the extent of the contraction varied with each model. Traits like habitat specialism, ground nesting and incubation period meant that both species may be considered "most vulnerable" in the exposure and trait-based index. Given that both species already occur near the maximum elevations of the Caucasus, and that they lack any dispersal capabilities due to the isolation from alternative mountainous areas, research efforts need to be prioritized to improve our knowledge about their population status, to monitor future trends and to begin developing species action plans that conserve these endemic and iconic species of Europe. Both species are flagship and umbrella species and may serve as indicator species, their protection may therefore benefit a whole range of other species inhabiting this vulnerable Alpine ecosystem. Especially the Caucasian grouse has a high aesthetic value and is favoured by hunters in the region. The potential demise of this species may therefore also be negative for local communities.
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http://dx.doi.org/10.1016/j.scitotenv.2018.09.227DOI Listing
February 2019

Publisher Correction: Kif1bp loss in mice leads to defects in the peripheral and central nervous system and perinatal death.

Sci Rep 2018 Jun 8;8(1):9085. Epub 2018 Jun 8.

Department of Anatomy and Neuroscience, The University of Melbourne, Victoria, 3010, Australia.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-26661-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993823PMC
June 2018

Orphan receptor GPR37L1 contributes to the sexual dimorphism of central cardiovascular control.

Biol Sex Differ 2018 04 6;9(1):14. Epub 2018 Apr 6.

Molecular Pharmacology Laboratory, Division of Molecular Cardiology and Biophysics, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, 2010, Australia.

Background: Over 100 mammalian G protein-coupled receptors are yet to be matched with endogenous ligands; these so-called orphans are prospective drug targets for the treatment of disease. GPR37L1 is one such orphan, abundant in the brain and detectable as mRNA in the heart and kidney. GPR37L1 ablation was reported to cause hypertension and left ventricular hypertrophy, and thus, we sought to further define the role of GPR37L1 in blood pressure homeostasis.

Methods: We investigated the cardiovascular effects of GPR37L1 using wild-type (GPR37L1) and null (GPR37L1) mice established on a C57BL/6J background, both under baseline conditions and during AngII infusion. We profiled GPR37L1 tissue expression, examining the endogenous receptor by immunoblotting and a β-galactosidase reporter mouse by immunohistochemistry.

Results: GPR37L1 protein was abundant in the brain but not detectable in the heart and kidney. We measured blood pressure in GPR37L1 and GPR37L1 mice and found that deletion of GPR37L1 causes a female-specific increase in systolic, diastolic, and mean arterial pressures. When challenged with short-term AngII infusion, only male GPR37L1 mice developed exacerbated left ventricular hypertrophy and evidence of heart failure, while the female GPR37L1 mice were protected from cardiac fibrosis.

Conclusions: Despite its absence in the heart and kidney, GPR37L1 regulates baseline blood pressure in female mice and is crucial for cardiovascular compensatory responses in males. The expression of GPR37L1 in the brain, yet absence from peripheral cardiovascular tissues, suggests this orphan receptor is a hitherto unknown contributor to central cardiovascular control.
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http://dx.doi.org/10.1186/s13293-018-0173-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889568PMC
April 2018

Cholinergic Submucosal Neurons Display Increased Excitability Following Cholera Toxin Exposure in Mouse Ileum.

Front Physiol 2018 21;9:260. Epub 2018 Mar 21.

Department of Physiology, The University of Melbourne, Parkville, VIC, Australia.

Cholera-induced hypersecretion causes dehydration and death if untreated. Cholera toxin (CT) partly acts via the enteric nervous system (ENS) and induces long-lasting changes to enteric neuronal excitability following initial exposure, but the specific circuitry involved remains unclear. We examined this by first incubating CT or saline (control) in mouse ileal loops for 3.5 h and then assessed neuronal excitability using Ca imaging and immunolabeling for the activity-dependent markers cFos and pCREB. Mice from a C57BL6 background, including -Cre;R26R- mice which express the fluorescent Ca indicator GCaMP3 in its ENS, were used. Ca-imaging using this mouse model is a robust, high-throughput method which allowed us to examine the activity of numerous enteric neurons simultaneously and immunohistochemistry enabled the neurochemical identification of the active neurons. Together, this provided novel insight into the CT-affected circuitry that was previously impossible to attain at such an accelerated pace. Ussing chamber measurements of electrogenic ion secretion showed that CT-treated preparations had higher basal secretion than controls. Recordings of Ca activity from the submucous plexus showed that increased numbers of neurons were spontaneously active in CT-incubated tissue (control: 4/149; CT: 32/160; Fisher's exact test, < 0.0001) and that cholinergic neurons were more responsive to electrical (single pulse and train of 20 pulses) or nicotinic (1,1-dimethyl-4-phenylpiperazinium (DMPP; 10 μM) stimulation. Expression of the neuronal activity marker, pCREB, was also increased in the CT-treated submucous plexus neurons. c-Fos expression and spontaneous fast excitatory postsynaptic potentials (EPSPs), recorded by intracellular electrodes, were increased by CT exposure in a small subset of myenteric neurons. However, the effect of CT on the myenteric plexus is less clear as spontaneous Ca activity and electrical- or nicotinic-evoked Ca responses were reduced. Thus, in a model where CT exposure evokes hypersecretion, we observed sustained activation of cholinergic secretomotor neuron activity in the submucous plexus, pointing to involvement of these neurons in the overall response to CT.
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http://dx.doi.org/10.3389/fphys.2018.00260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871806PMC
March 2018

Insights into the neurochemical signature of the Innervation of Beige Fat.

Mol Metab 2018 05 10;11:47-58. Epub 2018 Feb 10.

Department of Physiology, Monash University, Clayton, Victoria, Australia; Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. Electronic address:

Objective: The potential for brown adipose tissue (BAT) to be targeted as a therapeutic option to combat obesity has been heightened by the discovery of a brown-like form of inducible "beige" adipose tissue in white fat which has overlapping structural and functional properties to "classical" BAT. The likelihood that both beige and brown fat are recruited functionally by neural mechanisms, taken together with the lack of a detailed understanding of the nature of changes in the nervous system when white adipose tissue (WAT) is transformed to brown, provides the impetus for this study. Here, we aim to identify whether there is a shift in the gene expression profile in neurons directly innervating inguinal white adipose tissue (iWAT) that has undergone "beiging" to a signature that is more similar to neurons projecting to BAT.

Methods: Two groups of rats, one housed at thermoneutrality (27 °C) and the other exposed to cold (8 °C) for 7 days, were killed, and their T13/L1 ganglia, stellate ganglion (T1/T2), or superior cervical ganglion (SCG, C2/3) removed. This approach yielded ganglia containing neurons that innervate either beiged white fat (8 °C for 7 days), inguinal WAT (27 °C for 7 days), BAT (both 27 °C and 8 °C for 7 days) or non-WAT (8 °C for 7 days), the latter included to isolate changes in gene expression that were more aligned with a response to cold exposure than the transformation of white to beige adipocytes. Bioinformatics analyses of RNA sequencing data was performed followed by Ingenuity Pathway Analysis (IPA) to determine differential gene expression and recruitment of biosynthetic pathways.

Results: When iWAT is "beiged" there is a significant shift in the gene expression profile of neurons in sympathetic ganglia (T13/L1) innervating this depot toward a gene neurochemical signature that is similar to the stellate ganglion projecting to BAT. Bioinformatics analyses of "beiging" related genes revealed upregulation of genes encoding neuropeptides proopiomelanocortin (POMC) and calcitonin-gene related peptide (CGRP) within ganglionic neurons. Treatment of differentiated 3T3L1 adipocytes with αMSH, one of the products cleaved from POMC, results in an elevation in lipolysis and the beiging of these cells as indicated by changes in gene expression markers of browning (Ucp1 and Ppargc1a).

Conclusion: These data indicate that, coincident with beiging, there is a shift toward a "brown-like" neurochemical signature of postganglionic neurons projecting to inguinal white fat, an increased expression of POMC, and, consistent with a causative role for this prohormone in beiging, an αMSH-mediated increase in beige gene markers in isolated adipocytes.
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http://dx.doi.org/10.1016/j.molmet.2018.01.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001285PMC
May 2018

Moving in the Anthropocene: Global reductions in terrestrial mammalian movements.

Authors:
Marlee A Tucker Katrin Böhning-Gaese William F Fagan John M Fryxell Bram Van Moorter Susan C Alberts Abdullahi H Ali Andrew M Allen Nina Attias Tal Avgar Hattie Bartlam-Brooks Buuveibaatar Bayarbaatar Jerrold L Belant Alessandra Bertassoni Dean Beyer Laura Bidner Floris M van Beest Stephen Blake Niels Blaum Chloe Bracis Danielle Brown P J Nico de Bruyn Francesca Cagnacci Justin M Calabrese Constança Camilo-Alves Simon Chamaillé-Jammes Andre Chiaradia Sarah C Davidson Todd Dennis Stephen DeStefano Duane Diefenbach Iain Douglas-Hamilton Julian Fennessy Claudia Fichtel Wolfgang Fiedler Christina Fischer Ilya Fischhoff Christen H Fleming Adam T Ford Susanne A Fritz Benedikt Gehr Jacob R Goheen Eliezer Gurarie Mark Hebblewhite Marco Heurich A J Mark Hewison Christian Hof Edward Hurme Lynne A Isbell René Janssen Florian Jeltsch Petra Kaczensky Adam Kane Peter M Kappeler Matthew Kauffman Roland Kays Duncan Kimuyu Flavia Koch Bart Kranstauber Scott LaPoint Peter Leimgruber John D C Linnell Pascual López-López A Catherine Markham Jenny Mattisson Emilia Patricia Medici Ugo Mellone Evelyn Merrill Guilherme de Miranda Mourão Ronaldo G Morato Nicolas Morellet Thomas A Morrison Samuel L Díaz-Muñoz Atle Mysterud Dejid Nandintsetseg Ran Nathan Aidin Niamir John Odden Robert B O'Hara Luiz Gustavo R Oliveira-Santos Kirk A Olson Bruce D Patterson Rogerio Cunha de Paula Luca Pedrotti Björn Reineking Martin Rimmler Tracey L Rogers Christer Moe Rolandsen Christopher S Rosenberry Daniel I Rubenstein Kamran Safi Sonia Saïd Nir Sapir Hall Sawyer Niels Martin Schmidt Nuria Selva Agnieszka Sergiel Enkhtuvshin Shiilegdamba João Paulo Silva Navinder Singh Erling J Solberg Orr Spiegel Olav Strand Siva Sundaresan Wiebke Ullmann Ulrich Voigt Jake Wall David Wattles Martin Wikelski Christopher C Wilmers John W Wilson George Wittemyer Filip Zięba Tomasz Zwijacz-Kozica Thomas Mueller

Science 2018 Jan;359(6374):466-469

Senckenberg Biodiversity and Climate Research Centre, Senckenberg Gesellschaft für Naturforschung, 60325 Frankfurt (Main), Germany.

Animal movement is fundamental for ecosystem functioning and species survival, yet the effects of the anthropogenic footprint on animal movements have not been estimated across species. Using a unique GPS-tracking database of 803 individuals across 57 species, we found that movements of mammals in areas with a comparatively high human footprint were on average one-half to one-third the extent of their movements in areas with a low human footprint. We attribute this reduction to behavioral changes of individual animals and to the exclusion of species with long-range movements from areas with higher human impact. Global loss of vagility alters a key ecological trait of animals that affects not only population persistence but also ecosystem processes such as predator-prey interactions, nutrient cycling, and disease transmission.
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http://dx.doi.org/10.1126/science.aam9712DOI Listing
January 2018

Kif1bp loss in mice leads to defects in the peripheral and central nervous system and perinatal death.

Sci Rep 2017 11 30;7(1):16676. Epub 2017 Nov 30.

Department of Anatomy and Neuroscience, The University of Melbourne, Victoria, 3010, Australia.

Goldberg-Shprintzen syndrome is a poorly understood condition characterized by learning difficulties, facial dysmorphism, microcephaly, and Hirschsprung disease. GOSHS is due to recessive mutations in KIAA1279, which encodes kinesin family member 1 binding protein (KIF1BP, also known as KBP). We examined the effects of inactivation of Kif1bp in mice. Mice lacking Kif1bp died shortly after birth, and exhibited smaller brains, olfactory bulbs and anterior commissures, and defects in the vagal and sympathetic innervation of the gut. Kif1bp was found to interact with Ret to regulate the development of the vagal innervation of the stomach. Although newborn Kif1bp mice had neurons along the entire bowel, the colonization of the gut by neural crest-derived cells was delayed. The data show an essential in vivo role for KIF1BP in axon extension from some neurons, and the reduced size of the olfactory bulb also suggests additional roles for KIF1BP. Our mouse model provides a valuable resource to understand GOSHS.
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http://dx.doi.org/10.1038/s41598-017-16965-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709403PMC
November 2017

The angiotensin receptor blocker, Losartan, inhibits mammary tumor development and progression to invasive carcinoma.

Oncotarget 2017 Mar;8(12):18640-18656

Cancer Drug Discovery, Hudson's Institute of Medical Research, Clayton, VIC, Australia.

Drugs that target the Renin-Angiotensin System (RAS) have recently come into focus for their potential utility as cancer treatments. The use of Angiotensin Receptor Blockers (ARBs) and Angiotensin-Converting Enzyme (ACE) Inhibitors (ACEIs) to manage hypertension in cancer patients is correlated with improved survival outcomes for renal, prostate, breast and small cell lung cancer. Previous studies demonstrate that the Angiotensin Receptor Type I (AT1R) is linked to breast cancer pathogenesis, with unbiased analysis of gene-expression studies identifying significant up-regulation of AGTR1, the gene encoding AT1R in ER+ve/HER2-ve tumors correlating with poor prognosis. However, there is no evidence, so far, of the functional contribution of AT1R to breast tumorigenesis. We explored the potential therapeutic benefit of ARB in a carcinogen-induced mouse model of breast cancer and clarified the mechanisms associated with its success.Mammary tumors were induced with 7,12-dimethylbenz[α]antracene (DMBA) and medroxyprogesterone acetate (MPA) in female wild type mice and the effects of the ARB, Losartan treatment assessed in a preventative setting (n = 15 per group). Tumor histopathology was characterised by immunohistochemistry, real-time qPCR to detect gene expression signatures, and tumor cytokine levels measured with quantitative bioplex assays. AT1R was detected with radiolabelled ligand binding assays in fresh frozen tumor samples.We showed that therapeutic inhibition of AT1R, with Losartan, resulted in a significant reduction in tumor burden; and no mammary tumor incidence in 20% of animals. We observed a significant reduction in tumor progression from DCIS to invasive cancer with Losartan treatment. This was associated with reduced tumor cell proliferation and a significant reduction in IL-6, pSTAT3 and TNFα levels. Analysis of tumor immune cell infiltrates, however, demonstrated no significant differences in the recruitment of lymphocytes or tumour-associated macrophages in Losartan or vehicle-treated mammary tumors.Analysis of AT1R expression with radiolabelled ligand binding assays in human breast cancer biopsies showed high AT1R levels in 30% of invasive ductal carcinomas analysed. Furthermore, analysis of the TCGA database identified that high AT1R expression to be associated with luminal breast cancer subtype.Our in vivo data and analysis of human invasive ductal carcinoma samples identify the AT1R is a potential therapeutic target in breast cancer, with the availability of a range of well-tolerated inhibitors currently used in clinics. We describe a novel signalling pathway critical in breast tumorigenesis, that may provide new therapeutic avenues to complement current treatments.
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http://dx.doi.org/10.18632/oncotarget.15553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386636PMC
March 2017

Mapping and Analysis of the Connectome of Sympathetic Premotor Neurons in the Rostral Ventrolateral Medulla of the Rat Using a Volumetric Brain Atlas.

Front Neural Circuits 2017 1;11. Epub 2017 Mar 1.

Faculty of Medicine and Health Sciences, Neurobiology of Vital Systems, Macquarie University Sydney, NSW, Australia.

Spinally projecting neurons in the rostral ventrolateral medulla (RVLM) play a critical role in the generation of vasomotor sympathetic tone and are thought to receive convergent input from neurons at every level of the neuraxis; the factors that determine their ongoing activity remain unresolved. In this study we use a genetically restricted viral tracing strategy to definitively map their spatially diffuse connectome. We infected bulbospinal RVLM neurons with a recombinant rabies variant that drives reporter expression in monosynaptically connected input neurons and mapped their distribution using an MRI-based volumetric atlas and a novel image alignment and visualization tool that efficiently translates the positions of neurons captured in conventional photomicrographs to Cartesian coordinates. We identified prominent inputs from well-established neurohumoral and viscero-sympathetic sensory actuators, medullary autonomic and respiratory subnuclei, and supramedullary autonomic nuclei. The majority of inputs lay within the brainstem (88-94%), and included putative respiratory neurons in the pre-Bötzinger Complex and post-inspiratory complex that are therefore likely to underlie respiratory-sympathetic coupling. We also discovered a substantial and previously unrecognized input from the region immediately ventral to nucleus prepositus hypoglossi. In contrast, RVLM sympathetic premotor neurons were only sparsely innervated by suprapontine structures including the paraventricular nucleus, lateral hypothalamus, periaqueductal gray, and superior colliculus, and we found almost no evidence of direct inputs from the cortex or amygdala. Our approach can be used to quantify, standardize and share complete neuroanatomical datasets, and therefore provides researchers with a platform for presentation, analysis and independent reanalysis of connectomic data.
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http://dx.doi.org/10.3389/fncir.2017.00009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331070PMC
October 2017

Excessive Respiratory Modulation of Blood Pressure Triggers Hypertension.

Cell Metab 2017 03 16;25(3):739-748. Epub 2017 Feb 16.

Department of Physiology, University of Melbourne, Parkville, VIC 3010, Australia; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address:

The etiology of hypertension, the world's biggest killer, remains poorly understood, with treatments targeting the established symptom, not the cause. The development of hypertension involves increased sympathetic nerve activity that, in experimental hypertension, may be driven by excessive respiratory modulation. Using selective viral and cell lesion techniques, we identify adrenergic C1 neurons in the medulla oblongata as critical for respiratory-sympathetic entrainment and the development of experimental hypertension. We also show that a cohort of young, normotensive humans, selected for an exaggerated blood pressure response to exercise and thus increased hypertension risk, has enhanced respiratory-related blood pressure fluctuations. These studies pinpoint a specific neuronal target for ameliorating excessive sympathetic activity during the developmental phase of hypertension and identify a group of pre-hypertensive subjects that would benefit from targeting these cells.
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http://dx.doi.org/10.1016/j.cmet.2017.01.019DOI Listing
March 2017

Optogenetic Demonstration of Functional Innervation of Mouse Colon by Neurons Derived From Transplanted Neural Cells.

Gastroenterology 2017 05 20;152(6):1407-1418. Epub 2017 Jan 20.

Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia. Electronic address:

Background & Aims: Cell therapy offers the potential to treat gastrointestinal motility disorders caused by diseased or absent enteric neurons. We examined whether neurons generated from transplanted enteric neural cells provide a functional innervation of bowel smooth muscle in mice.

Methods: Enteric neural cells expressing the light-sensitive ion channel, channelrhodopsin, were isolated from the fetal or postnatal mouse bowel and transplanted into the distal colon of 3- to 4-week-old wild-type recipient mice. Intracellular electrophysiological recordings of responses to light stimulation of the transplanted cells were made from colonic smooth muscle cells in recipient mice. Electrical stimulation of endogenous enteric neurons was used as a control.

Results: The axons of graft-derived neurons formed a plexus in the circular muscle layer. Selective stimulation of graft-derived cells by light resulted in excitatory and inhibitory junction potentials, the electrical events underlying contraction and relaxation, respectively, in colonic muscle cells. Graft-derived excitatory and inhibitory motor neurons released the same neurotransmitters as endogenous motor neurons-acetylcholine and a combination of adenosine triphosphate and nitric oxide, respectively. Graft-derived neurons also included interneurons that provided synaptic inputs to motor neurons, but the pharmacologic properties of interneurons varied with the age of the donors from which enteric neural cells were obtained.

Conclusions: Enteric neural cells transplanted into the bowel give rise to multiple functional types of neurons that integrate and provide a functional innervation of the smooth muscle of the bowel wall. Circuits composed of both motor neurons and interneurons were established, but the age at which cells are isolated influences the neurotransmitter phenotype of interneurons that are generated.
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http://dx.doi.org/10.1053/j.gastro.2017.01.005DOI Listing
May 2017

Habitat-performance relationships of a large mammal on a predator-free island dominated by humans.

Ecol Evol 2017 01 20;7(1):305-319. Epub 2016 Dec 20.

Department of Wildlife, Fish and Environmental Studies Faculty of Forest Sciences Swedish University of Agricultural Sciences Umeå Sweden.

The demographic consequences of changes in habitat use driven by human modification of landscape, and/or changes in climate, are important for any species. We investigated habitat-performance relationships in a declining island population of a large mammal, the moose (), in an environment that is predator-free but dominated by humans. We used a combination of demographic data, knowledge of habitat selection, and multiannual movement data of female moose ( = 17) to understand how space use patterns affect fecundity and calf survival. The calving rate was 0.64 and was similar to calving rates reported in other populations. Calf survival was 0.22 (annually) and 0.32 (postsummer), which are particularly low compared to other populations where postsummer survival is typically above 0.7. Home ranges were mainly composed of arable land (>40%), and selection for arable land was higher in winter than in summer, which contrasts with previous studies. Females that spent more time in broadleaf forest in the summer prior to the rut had higher fecundity rates, while more time spent in arable land resulted in lower fecundity rates. Females that spent more time in thicket/scrubland habitats during winter had lower calf survival, while females that had higher use of mixed forests tended to have higher calf survival. The dominance, and subsequent use, of suboptimal foraging habitats may lead to poor body condition of females at parturition, which may lower calf body weights and affect the mother's ability to lactate. In addition, our results indicated that the growing season has advanced significantly in recent decades, which may be causing a mismatch between parturition and optimal resource availability. These effects may exacerbate the female's ability to meet the energetic demands of lactation. Therefore, the observed low calf survival appears to be caused by a combination of factors related to current land use and may also be due to changing vegetation phenology. These results have important implications for the management of species in human-dominated landscapes in the face of climate change, and for an increased understanding of how species may adapt to future land use and climate change.
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http://dx.doi.org/10.1002/ece3.2594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216668PMC
January 2017

Vulnerability of Subarctic and Arctic breeding birds.

Ecol Appl 2017 01;27(1):219-234

Landscape Ecology Group, Department of Ecology and Environmental Science, Umeå University, Umeå, SE-901 87, Sweden.

Recent research predicts that future climate change will result in substantial biodiversity loss associated with loss of habitat for species. However, the magnitude of the anticipated biodiversity impacts are less well known. Studies of species vulnerability to climate change through species distribution models are often limited to assessing the extent of species' exposure to the consequences of climate change to their local environment, neglecting species sensitivity to global change. The likelihood that species or populations will decline or go extinct due to climate change also depends on the general sensitivity and adaptive capacity of species. Hence, analyses should also obtain more accurate assessments of their vulnerability. We addressed this by constructing a vulnerability matrix for 180 bird species currently breeding in Subarctic and Arctic Europe that integrates a climatic exposure-based vulnerability index and a natural-history trait-based vulnerability index. Species that may need extra conservation attention based on our matrix include the Great Snipe (Gallinago media), the Rough-legged Buzzard (Buteo lagopus), the Red-throated Pipit (Anthus cervinus), the Common Swift (Apus apus), the Horned Lark (Eremophila alpestris), and the Bar-tailed Godwit (Limosa lapponica). Our vulnerability matrix stresses the importance of looking beyond exposure to climate change when species conservation is the aim. For the species that scored high in our matrix the future in the region looks grim and targeted conservation actions, incorporating macroecological and global perspectives, may be needed to alleviate severe population declines. We further demonstrate that climate change is predicted to significantly reduce the current breeding range of species adapted to cold climates in Subarctic and Arctic Europe. The number of incubation days and whether the species was a habitat specialist or not were also among the variables most strongly related to predicted contraction or expansion of species' breeding ranges. This approach may aid the identification of vulnerable bird species worldwide.
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http://dx.doi.org/10.1002/eap.1434DOI Listing
January 2017

Quantifying Migration Behaviour Using Net Squared Displacement Approach: Clarifications and Caveats.

PLoS One 2016 3;11(3):e0149594. Epub 2016 Mar 3.

Department of Wildlife, Fish and Environmental Studies, Swedish University of Agricultural Sciences, Umeå, SE-90183, Sweden.

Estimating migration parameters of individuals and populations is vital for their conservation and management. Studies on animal movements and migration often depend upon location data from tracked animals and it is important that such data are appropriately analyzed for reliable estimates of migration and effective management of moving animals. The Net Squared Displacement (NSD) approach for modelling animal movement is being increasingly used as it can objectively quantify migration characteristics and separate different types of movements from migration. However, the ability of NSD to properly classify the movement patterns of individuals has been criticized and issues related to study design arise with respect to starting locations of the data/animals, data sampling regime and extent of movement of species. We address the issues raised over NSD using tracking data from 319 moose (Alces alces) in Sweden. Moose is an ideal species to test this approach, as it can be sedentary, nomadic, dispersing or migratory and individuals vary in their extent, timing and duration of migration. We propose a two-step process of using the NSD approach by first classifying movement modes using mean squared displacement (MSD) instead of NSD and then estimating the extent, duration and timing of migration using NSD. We show that the NSD approach is robust to the choice of starting dates except when the start date occurs during the migratory phase. We also show that the starting location of the animal has a marginal influence on the correct quantification of migration characteristics. The number of locations per day (1-48) did not significantly affect the performance of non-linear mixed effects models, which correctly distinguished migration from other movement types, however, high-resolution data had a significant negative influence on estimates for the timing of migrations. The extent of movement, however, had an effect on the classification of movements, and individuals undertaking short- distance migrations can be misclassified as other movements such as sedentary or nomadic. Our study raises important considerations for designing, analysing and interpreting movement ecology studies, and how these should be determined by the biology of the species and the ecological and conservation questions in focus.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149594PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4777320PMC
August 2016

Recording, labeling, and transfection of single neurons in deep brain structures.

Physiol Rep 2015 Jan 19;3(1). Epub 2015 Jan 19.

Australian School of Advanced Medicine, Macquarie University, Sydney, 2109, NSW, Australia.

Genetic tools that permit functional or connectomic analysis of neuronal circuits are rapidly transforming neuroscience. The key to deployment of such tools is selective transfection of target neurons, but to date this has largely been achieved using transgenic animals or viral vectors that transduce subpopulations of cells chosen according to anatomical rather than functional criteria. Here, we combine single-cell transfection with conventional electrophysiological recording techniques, resulting in three novel protocols that can be used for reliable delivery of conventional dyes or genetic material in vitro and in vivo. We report that techniques based on single cell electroporation yield reproducible transfection in vitro, and offer a simple, rapid and reliable alternative to established dye-labeling techniques in vivo, but are incompatible with targeted transfection in deep brain structures. In contrast, we show that intracellular electrophoresis of plasmid DNA transfects brainstem neurons recorded up to 9 mm deep in the anesthetized rat. The protocols presented here require minimal, if any, modification to recording hardware, take seconds to deploy, and yield high recovery rates in vitro (dye labeling: 89%, plasmid transfection: 49%) and in vivo (dye labeling: 66%, plasmid transfection: 27%). They offer improved simplicity compared to the juxtacellular labeling technique and for the first time offer genetic manipulation of functionally characterized neurons in previously inaccessible brain regions.
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http://dx.doi.org/10.14814/phy2.12246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387759PMC
January 2015

Leptin mediates the increase in blood pressure associated with obesity.

Cell 2014 Dec;159(6):1404-16

Department of Physiology, Monash Obesity and Diabetes Institute, Monash University, Clayton, VIC 3800, Australia. Electronic address:

Obesity is associated with increased blood pressure (BP), which in turn increases the risk of cardiovascular diseases. We found that the increase in leptin levels seen in diet-induced obesity (DIO) drives an increase in BP in rodents, an effect that was not seen in animals deficient in leptin or leptin receptors (LepR). Furthermore, humans with loss-of-function mutations in leptin and the LepR have low BP despite severe obesity. Leptin's effects on BP are mediated by neuronal circuits in the dorsomedial hypothalamus (DMH), as blocking leptin with a specific antibody, antagonist, or inhibition of the activity of LepR-expressing neurons in the DMH caused a rapid reduction of BP in DIO mice, independent of changes in weight. Re-expression of LepRs in the DMH of DIO LepR-deficient mice caused an increase in BP. These studies demonstrate that leptin couples changes in weight to changes in BP in mammalian species.
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http://dx.doi.org/10.1016/j.cell.2014.10.058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259491PMC
December 2014

Catecholaminergic C3 neurons are sympathoexcitatory and involved in glucose homeostasis.

J Neurosci 2014 Nov;34(45):15110-22

Department of Physiology, University of Melbourne, Victoria, 3010 Australia,

Brainstem catecholaminergic neurons play key roles in the autonomic, neuroendocrine, and behavioral responses to glucoprivation, yet the functions of the individual groups are not fully understood. Adrenergic C3 neurons project widely throughout the brain, including densely to sympathetic preganglionic neurons in the spinal cord, yet their function is completely unknown. Here we demonstrate in rats that optogenetic stimulation of C3 neurons induces sympathoexcitatory, cardiovasomotor functions. These neurons are activated by glucoprivation, but unlike the C1 cell group, not by hypotension. The cardiovascular activation induced by C3 neurons is less than that induced by optogenetic stimulation of C1 neurons; however, combined stimulation produces additive sympathoexcitatory and cardiovascular effects. The varicose axons of C3 neurons largely overlap with those of C1 neurons in the region of sympathetic preganglionic neurons in the spinal cord; however, regional differences point to effects on different sympathetic outflows. These studies definitively demonstrate the first known function of C3 neurons as unique cardiovasomotor stimulatory cells, embedded in the brainstem networks regulating cardiorespiratory activity and the response to glucoprivation.
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http://dx.doi.org/10.1523/JNEUROSCI.3179-14.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608368PMC
November 2014

Angiotensin type 1A receptor expression in C1 neurons of the rostral ventrolateral medulla contributes to the development of angiotensin-dependent hypertension.

Exp Physiol 2014 Dec 18;99(12):1597-610. Epub 2014 Sep 18.

Department of Physiology, University of Melbourne, Melbourne, Victoria, 3010, Australia Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, 3010, Australia

Chronic low-dose systemic infusion of angiotensin II induces hypertension via activation of the angiotensin II type 1A receptor (AT1AR). Previously, we have demonstrated that expression of the AT1AR on catecholaminergic neurons is necessary for the full development of angiotensin-dependent hypertension. In the present study, we examined the mechanism by which selective deletion of the AT1AR from these cells affects the development of hypertension. We also tested the hypothesis that AT1ARs expressed by catecholaminergic C1 neurons in the rostral ventrolateral medulla play an important role in angiotensin-induced hypertension. A Cre-lox approach was used to delete the AT1AR from all catecholaminergic cells or from C1 neurons selectively. Subcutaneous administration of angiotensin II induced hypertension in all mice, with delayed onset and reduced maximal response in the global AT1AR catecholaminergic knockout mice. The AT1AR catecholaminergic knockout mice had decreased renal fluid and electrolyte retention and urinary noradrenaline excretion. The blood pressure response was reduced only during the second week of angiotensin II infusion in the mice with selective C1 AT1AR deletion, demonstrating that AT1AR expression by C1 neurons plays a moderate role in angiotensin-induced hypertension. The difference in the time course of development of hypertension between the mice with global AT1AR knockout from catecholaminergic cells and the mice with C1 AT1AR deletion suggests that other catecholaminergic neurons are important.
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http://dx.doi.org/10.1113/expphysiol.2014.082073DOI Listing
December 2014

Baroreceptor reflex control of heart rate in angiotensin type 1A receptor knockout mice.

Physiol Rep 2013 Nov 26;1(6):e00171. Epub 2013 Nov 26.

Department of Physiology and Florey Institute of Neuroscience and Mental Health, The University of Melbourne Victoria, 3010, Australia.

The baroreceptor reflex dampens the short-term fluctuations in blood pressure by feedback modulation of heart rate (HR) and vascular resistance. Impairment of this reflex has been observed in hypertension and heart failure. Angiotensin II, a blood borne hormone, acts via its type 1A receptor to attenuate the baroreceptor reflex and this reflex is reported to be dramatically altered in angiotensin type 1A receptor knockout mice. This study sought to further investigate changes in the arterial and cardiopulmonary baroreceptor reflex control of HR in angiotensin II type 1A receptor knocked out mice. In artificially ventilated, isoflurane anesthetized mice, the arterial and cardiopulmonary baroreceptor reflexes were activated via injection or slow infusions, respectively, of phenylephrine and sodium nitroprusside through the jugular vein. We observed no impairment of either the arterial or cardiopulmonary baroreceptor reflex control of HR in angiotensin type 1A receptor knockout mice.
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http://dx.doi.org/10.1002/phy2.171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871483PMC
November 2013

Male contraception via simultaneous knockout of α1A-adrenoceptors and P2X1-purinoceptors in mice.

Proc Natl Acad Sci U S A 2013 Dec 2;110(51):20825-30. Epub 2013 Dec 2.

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.

Therapeutic targets for male contraception are associated with numerous problems due to their focus on disrupting spermatogenesis or hormonal mechanisms to produce dysfunctional sperm. Here we describe the dual genetic deletion of α1A-adrenergic G protein-coupled receptors (adrenoceptors) and P2X1-purinoceptor ligand gated ion channels in male mice, thereby blocking sympathetically mediated sperm transport through the vas deferens during the emission phase of ejaculation. This modification produced 100% infertility without effects on sexual behavior or function. Sperm taken from the cauda epididymides of double knockout mice were microscopically normal and motile. Furthermore, double knockout sperm were capable of producing normal offspring following intracytoplasmic sperm injection into wild-type ova and implantation of the fertilized eggs into foster mothers. Blood pressure and baroreflex function was reduced in double knockout mice, but no more than single knockout of α1A-adrenoceptors alone. These results suggest that this autonomic method of male contraception appears free of major physiological and behavioral side effects. In addition, they provide conclusive proof of concept that pharmacological antagonism of the P2X1-purinoceptor and α1A-adrenoceptor provides a safe and effective therapeutic target for a nonhormonal, readily reversible male contraceptive.
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http://dx.doi.org/10.1073/pnas.1318624110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870707PMC
December 2013