A M Allen

University of Melbourne, Melbourne, Victoria, Australia

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Publications (56)154.12 Total impact

  • C Menuet · M.E. Wlodek · A.Y. Fong · A.M. Allen
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    ABSTRACT: Sympathetic nerve activity to the cardiovascular system displays prominent respiratory-related modulation which leads to the generation of rhythmic oscillations in blood pressure called Traube-Hering waves. An amplification of this respiratory modulation of sympathetic activity is observed in hypertension of both genetic, the spontaneously hypertensive rat, and induced, chronic intermittent hypoxia or maternal protein restriction during gestation, origin. Male offspring of mothers with uteroplacental insufficiency, induced by bilateral uterine vessel ligation at 18 days of gestation, are also hypertensive in adulthood. In this study we examined whether these male offspring display altered respiratory modulation of sympathetic activity at pre-hypertensive ages compared to controls. Respiratory, cardiovascular and sympathetic parameters were examined using the working heart-brainstem preparation in 35 day old male rats that had reduced birth weight due to uteroplacental insufficiency. Whilst all respiratory parameters were not different between groups, we observed an enhanced respiratory-related burst of thoracic sympathetic nerve activity and amplified Traube-Hering waves in the growth-restricted group. This group also showed an increased sympathetic and bradycardic response to activation of peripheral chemoreceptors. The observations add support to the view that altered respiratory modulation of sympathetic activity represents a common mechanism involved in the development of several forms of hypertension.
    No preview · Article · Nov 2015 · Respiratory Physiology & Neurobiology
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    Preview · Article · Nov 2015

  • No preview · Article · Nov 2015
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    ABSTRACT: Coordinated modulation of sympathetic and parasympathetic nervous activity is required for physiological regulation of tissue function. Anatomically, whilst the peripheral sympathetic and parasympathetic pathways are separate, the distribution of premotor neurons in higher brain regions often overlaps. This co-distribution would enable coordinated regulation and might suggest individual premotor neurons could project to both sympathetic and parasympathetic outflows. To investigate this one submandibular gland was sympathectomized. One of two isogenic strains of the pseudorabies virus, expressing different fluorophores, was injected into the cut sympathetic nerve and the other into the submandibular gland. Independent labeling of the peripheral sympathetic and parasympathetic pathways was observed. Dual-labeled neurons were observed in many CNS regions known to be involved in regulating salivary function. We propose these observations highlight a common pattern of organization of the CNS, providing the anatomical framework for the fine control of organ function required for homeostatic regulation and the coordination of organ responses to enable complex behaviors.
    No preview · Article · May 2014 · Brain Structure and Function
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    Full-text · Article · Sep 2011 · Autonomic Neuroscience
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    ABSTRACT: J. Neurochem. (2011) 119, 18–26. Astrocytes are the major source of angiotensinogen in the brain and play an important role in the brain renin-angiotensin system. Regulating brain angiotensinogen production alters blood pressure and fluid and electrolyte homeostasis. In turn, several physiological and pathological manipulations alter expression of angiotensinogen in brain. Surprisingly, little is known about the factors that regulate astrocytic expression of angiotensinogen. There is evidence that angiotensinogen production in both hepatocytes and cardiac myocytes can be positively regulated via the angiotensin type 1 receptor, but this effect has not yet been studied in astrocytes. Therefore, the aim of this project was to establish whether angiotensin II modulates angiotensinogen production in brain astrocytes. Primary astrocyte cultures, prepared from neonatal C57Bl6 mice, expressed angiotensinogen measured by immunocytochemistry and real-time PCR. Using a variety of approaches we were unable to identify angiotensin receptors on cultured astrocytes. Exposure of cultured astrocytes to angiotensin II also did not affect angiotensinogen expression. When astrocyte cultures were transduced with the angiotensin type 1A receptor, using adenoviral vectors, angiotensin II induced a robust down-regulation (91.4% ± 1.8%, p < 0.01, n = 4) of angiotensinogen gene expression. We conclude that receptors for angiotensin II are present in extremely low levels in astrocytes, and that this concurs with available data in vivo. The signaling pathways activated by the angiotensin type 1A receptor are negatively coupled to angiotensinogen expression and represent a powerful pathway for decreasing expression of this protein, potentially via signaling pathways coupled to Gαq/11.
    Preview · Article · Jul 2011 · Journal of Neurochemistry
  • E. L. O'Callaghan · W. G. Thomas · A. M. Allen

    No preview · Conference Paper · Jun 2010
  • M.J. McKinley · A.M. Allen · B.J. Oldfield
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    ABSTRACT: The renin-angiotensin system, via actions of its effector peptide angiotensin II, regulates body fluid balance and arterial pressure. Circulating angiotensin II acts on circumventricular organs of the brain to stimulate thirst, sodium appetite, vasopressin secretion, and sympathetic nerve activity, complementing its peripheral actions. Angiotensin II, III, and IV may also be generated within the brain, and a separate central angiotensinergic system may also participate in regulating body fluids and arterial pressure via angiotensin II receptors of the AT 1 subtype.
    No preview · Article · Jan 2010
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    ABSTRACT: Many tissues, including the brain, contain all components of the renin-angiotensin system and generate angiotensin peptides independent of the systemic, circulating system. Within the brain renin, some questions remain as to how the precursor, angiotensinogen, and its processing enzymes interact to produce the active compounds, angiotensin II/III, because they are rarely localized to the same brain nucleus let alone the same cell. These questions aside, there is clear evidence for actions of angiotensin peptides in regions behind the blood-brain barrier. Receptors for angiotensin peptides, including AT 1 and AT 2 receptors, are distributed in a characteristic pattern throughout the brain, with many of these sites behind the blood-brain barrier. Stimulation of these receptors affects multiple physiological functions - actions which often complement the physiological roles established for the systemic renin-angiotensin system. These include effects on fluid and electrolyte homeostasis, autonomic and neuroendocrine regulation, and modulation of sensory function. Moreover, administration of selective receptor antagonists attenuates several of these functions when they are activated in response to physiological stimuli, such as dehydration. Together, these observations point to important roles for brain-derived angiotensin peptides in a wide range of physiological functions.
    No preview · Article · Jan 2010
  • E. L. O'Callaghan · W. G. Thomas · A. M. Allen

    No preview · Conference Paper · Jun 2009
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    ABSTRACT: Vesicular monoamine transporter 2 (VMAT2) packages biogenic amines into large dense core and synaptic vesicles for either somatodendritic or synaptic release from neurons of the CNS. Whilst the distribution of VMAT2 has been well characterized in many catecholaminergic cell groups, its localization amongst C1 adrenergic neurons in the medulla has not been examined in detail. Within the rostral ventrolateral medulla (RVLM), C1 neurons are a group of barosensitive, adrenergic neurons. Rostral C1 cells project to the thoracic spinal cord and are considered sympathetic premotor neurons. The majority of caudal C1 cells project rostrally to regions such as the hypothalamus. The present study sought to quantitate the somatodendritic expression of VMAT2 in C1 neurons, and to assess the subcellular distribution of the transporter. Immunoreactivity for VMAT2 occurred in 31% of C1 soma, with a high proportion of these in the caudal part of the RVLM. Retrograde tracing studies revealed that only two of 43 bulbospinal C1 neurons contained faint VMAT2-immunoreactivity, whilst 88 +/- 5% of rostrally projecting neurons were VMAT2-positive. A lentivirus, designed to express green fluorescent protein exclusively in noradrenergic and adrenergic neurons, was injected into the RVLM to label C1 neurons. Eighty-three percent of C1 efferents that occurred in close proximity to sympathetic preganglionic neurons within the T(3) intermediolateral cell column contained VMAT2-immunoreactivity. These data demonstrate differential distribution of VMAT2 within different subpopulations of C1 neurons and suggest that this might reflect differences in somatodendritic vs. synaptic release of catecholamines.
    No preview · Article · Nov 2008 · European Journal of Neuroscience
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    ABSTRACT: Renin plays a critical role in fluid and electrolyte homeostasis by cleaving angiotensinogen to produce Ang peptides. Whilst it has been demonstrated that renin mRNA is expressed in the brain, the distribution of cells responsible for this expression remains uncertain. We have used a transgenic mouse approach in an attempt to address this question. A transgenic mouse, in which a 12.2 kb fragment of the human renin promoter was used to drive expression of Cre-recombinase, was crossed with the ROSA26-lac Z reporter mouse strain. Cre-recombinase mediated excision of the floxed stop cassette resulted in expression of the reporter protein, beta-galactosidase. This study describes the distribution of beta-galactosidase in the brain of the crossed transgenic mouse. In all cases where it was examined the reporter protein was co-localized with the neuronal marker NeuN. An extensive distribution was observed with numerous cells labeled in the somatosensory, insular, piriform and retrosplenial cortices. The motor cortex was devoid of labeled cells. Several other regions were labeled including the parts of the amygdala, periaqueductal gray, lateral parabrachial nucleus and deep cerebellar nuclei. Overall the distribution shows little overlap with those regions that are known to express receptors for the renin-angiotensin system in the adult brain. This transgenic approach, which demonstrates the distribution of cells which have activated the human renin promoter at any time throughout development, yields a unique and extensive distribution of putative renin-expressing neurons. Our observations suggest that renin may have broader actions in the brain and may indicate a potential for interaction with the (pro)renin receptor or production of a ligand for non-AT(1)/AT(2) receptors.
    No preview · Article · Oct 2008 · Brain research

  • No preview · Article · Sep 2008 · Appetite

  • No preview · Conference Paper · Jun 2007
  • B.J. Oldfield · A.M. Allen · P Davern · M.E. Giles · N.C. Owens
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    ABSTRACT: The concept of 'command neurons', whereby single neurons mediate complex and complementary motor functions to generate a stereotyped behaviour, is well developed in invertebrate physiology. The term has also been adopted more recently to explain the neural basis of 'fight or flight'. In this study we have investigated the possibility that single lateral hypothalamic neurons have the necessary neuroanatomical connections to coordinate two complementary limbs of body weight control, feeding and thermogenesis, thereby acting as 'command neurons'. The transynaptic retrograde transport of pseudorabies virus (Bartha) from a thermogenic endpoint in the brown adipose tissue of rats has been used in conjunction with other neuronal tracers, introduced into putative CNS feeding centres, to assess the potential for the involvement of command neurons in coordinating these processes. In discrete regions of the lateral hypothalamus, neurons have been identified which have the necessary complement of orexigenic peptides and collateral branching axons to both putative feeding sites and thermogenic sites in brown fat to qualify as candidate central command neurons controlling body weight.
    No preview · Article · May 2007 · European Journal of Neuroscience
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    ABSTRACT: The sympathetic innervation of the rat heart was investigated by retrograde neuronal tracing and multiple label immunohistochemistry. Injections of Fast Blue made into the left ventricular wall labelled sympathetic neurons that were located along the medial border of both the left and right stellate ganglia. Cardiac projecting sympathetic postganglionic neurons could be grouped into one of four neurochemical populations, characterised by their content of calbindin and/or neuropeptide Y (NPY). The subpopulations of neurons contained immunoreactivity to both calbindin and NPY, immunoreactivity to calbindin only, immunoreactivity to NPY only and no immunoreactivity to calbindin or NPY. Sympathetic postganglionic neurons were also labelled in vitro with rhodamine dextran applied to the cut end of a cardiac nerve. The same neurochemical subpopulations of sympathetic neurons were identified by using this technique but in different proportions to those labelled from the left ventricle. Preganglionic terminals that were immunoreactive for another calcium-binding protein, calretinin, preferentially surrounded retrogradely labelled neurons that were immunoreactive for both calbindin and NPY. The separate sympathetic pathways projecting to the rat heart may control different cardiac functions.
    No preview · Article · May 2006 · Cell and Tissue Research
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    ABSTRACT: Central administration of angiotensin IV (Ang IV) or its analogues enhance performance of rats in passive avoidance and spatial memory paradigms. The purpose of this study was to examine the effect of a single bolus injection of two distinct AT4 ligands, Nle1-Ang IV or LVV-haemorphin-7, on spatial learning in the Barnes circular maze. Mean number of days for rats treated with either Nle1-Ang IV or LVV-haemorphin-7 to achieve learner criterion is significantly reduced compared with controls (P < 0.001 and P < 0.05 respectively). This is due to enhanced ability of the peptide-treated rats to adopt a spatial strategy for finding the escape hatch. In all three measures of learning performance, (1) the number of errors made, (2) the distance travelled and (3) the latency in finding the escape hatch, rats treated with either 100 pmol or 1 nmol of Nle1-Ang IV or 100 pmol LVV-haemorphin-7 performed significantly better than the control groups. As early as the first day of testing, the rats treated with the lower dose of Nle1-Ang IV or LVV-haemorphin-7 made fewer errors (P < 0.01 and P < 0.05 respectively) and travelled shorter distances (P < 0.05 for both groups) than the control animals. The enhanced spatial learning induced by Nle1-Ang IV (100 pmol) was attenuated by the co-administration of the AT4 receptor antagonist, divalinal-Ang IV (10 nmol). Thus, administration of AT4 ligands results in an immediate potentiation of learning, which may be associated with facilitation of synaptic transmission and/or enhancement of acetylcholine release.
    Full-text · Article · Dec 2004 · Neuroscience
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    ABSTRACT: The dorsomedial hypothalamic nucleus (DMH) is believed to play a key role in mediating vasomotor and cardiac responses evoked by an acute stress. Inhibition of neurons in the rostral ventrolateral medulla (RVLM) greatly reduces the increase in renal sympathetic nerve activity (RSNA) evoked by activation of the DMH, indicating that RVLM neurons mediate, at least in part, the vasomotor component of the DMH-evoked response. In this study, the first aim was to determine whether neurons in the medullary raphe pallidus (RP) region also contribute to the DMH-evoked vasomotor response, because it has been shown that the DMH-evoked tachycardia is mediated by the RP region. The second aim was to directly assess the effect of DMH activation on the firing rate of RVLM sympathetic premotor neurons. In urethane-anesthetized rats, injection of the GABA(A) receptor agonist muscimol (but not vehicle solution) in the RP region caused a modest ( approximately 25%) but significant reduction in the increase in RSNA evoked by DMH disinhibition (by microinjection of bicuculline). In other experiments, disinhibition of the DMH resulted in a powerful excitation (increase in firing rate of approximately 400%) of 5 out of 6 spinally projecting barosensitive neurons in the RVLM. The results indicate that neurons in the RP region make a modest contribution to the renal sympathoexcitatory response evoked from the DMH and also that sympathetic premotor neurons in the RVLM receive strong excitatory inputs from DMH neurons, consistent with the view that the RVLM plays a key role in mediating sympathetic vasomotor responses arising from the DMH.
    Full-text · Article · Nov 2004 · AJP Regulatory Integrative and Comparative Physiology
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    ABSTRACT: Angiotensinogen, the precursor molecule for angiotensins I, II and III, and the enzymes renin, angiotensin-converting enzyme (ACE), and aminopeptidases A and N may all be synthesised within the brain. Angiotensin (Ang) AT(1), AT(2) and AT(4) receptors are also plentiful in the brain. AT(1) receptors are found in several brain regions, such as the hypothalamic paraventricular and supraoptic nuclei, the lamina terminalis, lateral parabrachial nucleus, ventrolateral medulla and nucleus of the solitary tract (NTS), which are known to have roles in the regulation of the cardiovascular system and/or body fluid and electrolyte balance. Immunohistochemical and neuropharmacological studies suggest that angiotensinergic neural pathways utilise Ang II and/or Ang III as a neurotransmitter or neuromodulator in the aforementioned brain regions. Angiotensinogen is synthesised predominantly in astrocytes, but the processes by which Ang II is generated or incorporated in neurons for utilisation as a neurotransmitter is unknown. Centrally administered AT(1) receptor antagonists or angiotensinogen antisense oligonucleotides inhibit sympathetic activity and reduce arterial blood pressure in certain physiological or pathophysiological conditions, as well as disrupting water drinking and sodium appetite, vasopressin secretion, sodium excretion, renin release and thermoregulation. The AT(4) receptor is identical to insulin-regulated aminopeptidase (IRAP) and plays a role in memory mechanisms. In conclusion, angiotensinergic neural pathways and angiotensin peptides are important in neural function and may have important homeostatic roles, particularly related to cardiovascular function, osmoregulation and thermoregulation.
    Full-text · Article · Jul 2003 · The International Journal of Biochemistry & Cell Biology
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    ABSTRACT: 1. The lamina terminalis, a region of the brain with a high concentration of angiotensin AT1 receptors, consists of three distinct nuclei, the median preoptic nucleus, the subfornical organ and organum vasculosum of the lamina terminalis (OVLT). These latter two regions lack a blood–brain and detect changes in plasma angiotensin (Ang) II concentration and osmolality. 2. Efferent neural pathways from the lamina terminalis to the hypothalamic paraventricular and supraoptic nuclei mediate vasopressin secretion in response to plasma hypertonicity and increased circulating levels of AngII. 3. Studies using the neurotropic virus pseudorabies, which undergoes retrograde transynaptic neuronal transport following injection into peripheral sites, show that neurons in the lamina terminalis have efferent polysynaptic neural connections to the peripheral sympathetic nervous system. Some of these neurons have been shown to have polysynaptic connections to the kidney and to express AT1 receptor mRNA. We propose that circulating AngII acts at AT1 receptors in the subfornical organ and OVLT to influence the sympathetic nervous system. It is likely that the neural pathway subserving this influence involves a synapse in the hypothalamic paraventricular nucleus. 4. The lamina terminalis may exert an inhibitory osmoregulatory influence on renin secretion by the kidney. This osmoregulatory influence may be mediated by inhibition of renal sympathetic nerve activity and appears to involve a central angiotensinergic synapse. 5. The lamina terminalis exerts an osmoregulatory influence on renal sodium excretion that is independent of the renal nerves and is probably hormonally mediated.
    No preview · Article · Jan 2002 · Clinical and Experimental Pharmacology and Physiology