Physiology - Research Publications

Permanent URI for this collection

Search Results

Now showing 1 - 7 of 7
  • Item
    Thumbnail Image
    A Chemogenetic Tool that Enables Functional Neural Circuit Analysis
    Ngo, HB ; Melo, MR ; Layfield, S ; Connelly, AA ; Bassi, JK ; Xie, L ; Menuet, C ; McDougall, SJ ; Bathgate, RAD ; Allen, AM (CELL PRESS, 2020-09-15)
    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.
  • Item
    Thumbnail Image
    PreBotzinger complex neurons drive respiratory modulation of blood pressure and heart rate
    Menuet, C ; Connelly, AA ; Bassi, JK ; Melo, MR ; Le, S ; Kamar, J ; Kumar, NN ; McDougall, SJ ; McMullan, S ; Allen, AM (ELIFE SCIENCES PUBLICATIONS LTD, 2020-06-15)
    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.
  • Item
    Thumbnail Image
    Leptin Mediates the Increase in Blood Pressure Associated with Obesity
    Simonds, SE ; Pryor, JT ; Ravussin, E ; Greenway, FL ; Dileone, R ; Allen, AM ; Bassi, J ; Elmquist, JK ; Keogh, JM ; Henning, E ; Myers, MG ; Licinio, J ; Brown, RD ; Enriori, PJ ; O'Rahilly, S ; Sternson, SM ; Grove, KL ; Spanswick, DC ; Farooqi, IS ; Cowley, MA (CELL PRESS, 2014-12-04)
    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.
  • Item
    Thumbnail Image
    Orphan receptor GPR37L1 contributes to the sexual dimorphism of central cardiovascular control
    Coleman, JLJ ; Mouat, MA ; Wu, J ; Jancovski, N ; Bassi, JK ; Chan, AY ; Humphreys, DT ; Mrad, N ; Yu, Z-Y ; Ngo, T ; Iismaa, S ; dos Remedios, CG ; Feneley, MP ; Allen, AM ; Graham, RM ; Smith, NJ (BIOMED CENTRAL LTD, 2018-04-06)
    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 (GPR37L1wt/wt) and null (GPR37L1KO/KO) 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 GPR37L1wt/wt and GPR37L1KO/KO 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 GPR37L1KO/KO mice developed exacerbated left ventricular hypertrophy and evidence of heart failure, while the female GPR37L1KO/KO 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.
  • Item
    No Preview Available
    Stimulation of Angiotensin Type 1A Receptors on Catecholaminergic Cells Contributes to Angiotensin-Dependent Hypertension
    Jancovski, N ; Bassi, JK ; Carter, DA ; Choong, Y-T ; Connelly, A ; Thu-Phuc, N ; Chen, D ; Lukoshkova, EV ; Menuet, C ; Head, GA ; Allen, AM (LIPPINCOTT WILLIAMS & WILKINS, 2013-11-01)
    Hypertension contributes to multiple forms of cardiovascular disease and thus morbidity and mortality. The mechanisms inducing hypertension remain unclear although the involvement of homeostatic systems, such as the renin-angiotensin and sympathetic nervous systems, is established. A pivotal role of the angiotensin type 1 receptor in the proximal tubule of the kidney for the development of experimental hypertension is established. Yet, other systems are involved. This study tests whether the expression of angiotensin type 1A receptors in catecholaminergic cells contributes to hypertension development. Using a Cre-lox approach, we deleted the angiotensin type 1A receptor from all catecholaminergic cells. This deletion did not alter basal metabolism or blood pressure but delayed the onset of angiotensin-dependent hypertension and reduced the maximal response. Cardiac hypertrophy was also reduced. The knockout mice showed attenuated activation of the sympathetic nervous system during angiotensin II infusion as measured by spectral analysis of the blood pressure. Increased reactive oxygen species production was observed in forebrain regions, including the subfornical organ, of the knockout mouse but was markedly reduced in the rostral ventrolateral medulla. These studies demonstrate that stimulation of the angiotensin type 1A receptor on catecholaminergic cells is required for the full development of angiotensin-dependent hypertension and support an important role for the sympathetic nervous system in this model.
  • Item
    Thumbnail Image
    Angiotensin Type 1A Receptors in C1 Neurons of the Rostral Ventrolateral Medulla Modulate the Pressor Response to Aversive Stress
    Chen, D ; Jancovski, N ; Bassi, JK ; Thu-Phuc, N-H ; Choong, Y-T ; Palma-Rigo, K ; Davern, PJ ; Gurley, SB ; Thomas, WG ; Head, GA ; Allen, AM (SOC NEUROSCIENCE, 2012-02-08)
    The rise in blood pressure during an acute aversive stress has been suggested to involve activation of angiotensin type 1A receptors (AT(1A)Rs) at various sites within the brain, including the rostral ventrolateral medulla. In this study we examine the involvement of AT(1A)Rs associated with a subclass of sympathetic premotor neurons of the rostral ventrolateral medulla, the C1 neurons. The distribution of putative AT(1A)R-expressing cells was mapped throughout the brains of three transgenic mice with a bacterial artificial chromosome-expressing green fluorescent protein under the control of the AT(1A)R promoter. The overall distribution correlated with that of the AT(1A)Rs mapped by other methods and demonstrated that the majority of C1 neurons express the AT(1A)R. Cre-recombinase expression in C1 neurons of AT(1A)R-floxed mice enabled demonstration that the pressor response to microinjection of angiotensin II into the rostral ventrolateral medulla is dependent upon expression of the AT(1A)R in these neurons. Lentiviral-induced expression of wild-type AT(1A)Rs in C1 neurons of global AT(1A)R knock-out mice, implanted with radiotelemeter devices for recording blood pressure, modulated the pressor response to aversive stress. During prolonged cage-switch stress, expression of AT(1A)Rs in C1 neurons induced a greater sustained pressor response when compared to the control viral-injected group (22 ± 4 mmHg for AT(1A)R vs 10 ± 1 mmHg for GFP; p < 0.001), which was restored toward that of the wild-type group (28 ± 2 mmHg). This study demonstrates that AT(1A)R expression by C1 neurons is essential for the pressor response to angiotensin II and that this pathway plays an important role in the pressor response to aversive stress.
  • Item
    Thumbnail Image
    Angiotensin 1A receptors transfected into caudal ventrolateral medulla inhibit baroreflex gain and stress responses
    Palma-Rigo, Kesia ; BASSI, JASPREET ; Nguyen-Huu, Thu-Phuc ; Jackson, Kristy L. ; Davern, Pamela J. ; CHEN, DAIAN ; Elghozi, Jean-Luc ; Thomas, Walter G ; ALLEN, ANDREW ; Head, Geoffrey A. ( 2012)