Does acute hyperglycemia alter rat aortic depressor nerve function

Braz journal of Medical Biological Research (2007) 40: 15567-1576 Issn 0100-879x D.A Huber, J. M. do Carmo, J.A. Castania, R. Fazan Jr. and H.C. Salgado It has been shown that diabetes alters baroreflex function. In this present study they wanted to determine what arm of the baroreflex is being altered in response to diabetes. So the recorded the left aortic depressor nerve activity and blood pressure responses. They checked baroreflex activity before and 30minutes after infusion of 0.9% saline, 30% glucose, or 30% mannitol. They assessed baroflex activity in two ways one was by a single bolus of Phenylephrine (8ug/kg) and sodium nitroprusside (16ug/kg) and the other way was by remove and replacing blood in order to change blood pressure by 10mm Hg. What they found was that acute changes of glucose or mannitol in the blood do not lead to changes in the afferent arm of the baroreflex. This finding suggests that the changes that occur in the baroreflex in response to diabetes may be occurring either in the central nervous system or the efferent arm of the baroreflex. -MD

Inhibition of brown adipose tissue thermogenesis by neurons in the ventrolateral medulla and in the nucleus tractus solitarius.

Am J Physiol Regul Integr Comp Physiol. 2010 Jul;299(1):R277-90. Cao WH, Madden CJ, Morrison SF “Neurons in the ventrolateral medulla (VLM) and in the nucleus tractus solitarius (NTS) play important roles in the regulation of cardiovascular and other autonomic functions”. In this study, the authors demonstrated how activation of neurons in the VLM and intermediate NTS affected brown adipose tissue (BAT) thermogenesis. The authors performed a series of microinjection experiment in chloralose/urethane-anesthetized rats to test their hypothesis. First they tested the effects of activation of neurons in the VLM on cold evoked BAT thermogenesis. NMDA (glutamate agonist) was injected in the VLM to observe that it reversed the cold-evoked increase in BAT SNA, thermogenesis and end-expired CO2. Second they tested the effects of disinhibition of neurons in the VLM or in the NTS on BAT thermogenesis under different conditions using bicuculline (GABA-A receptor antagonist), which reversed the increase in BAT SNA, thermogenesis and end-expired CO2. Finally the tested the effects of inhibition of neurons in the VLM and NTS using muscimol (GABA-A receptor agonist), which produced increases in BAT SNA, thermogenesis and end-expired CO2. These effects were reversed using injection of glycine in the rRPa. These findings suggest that BAT thermogenesis is inhibited by activation of VLM and NTS neurons. -Madhan

α2 Adrenergic receptor-mediated inhibition of thermogenesis.

J Neurosci. 2013 Jan 30;33(5):2017-28. Madden CJ, Tupone D, Cano G, Morrison SF. “α2 adrenergic receptor (α2-AR) agonists have been used as antihypertensive agents, in the management of drug withdrawal, and as sedative analgesics”. In this study, the authors investigated the effects of α2-AR agonists as antipyretic agents. Clonidine (α2-AR agonist) was administered into the rostral raphe pallidus area (neurons in this region regulate sympathetic outflow to brown adipose tissue (BAT), which regulates thermogenesis), which inhibited BAT sympathetic nerve activity and thermogenesis. The authors reversed the effects of clonidine injection by administration of α2-AR antagonist idazoxan into rRPa. The effects of α2-AR agonists were also tested using systemic injections of its agonists, which produced responses similar to central administration. An interesting observation in the present study involves the use of CtB as a retrograde tracer from rRPa and pseudorabies virus as a transynaptic tracer from BAT to demonstrate that VLM was the source of catecholaminergic input to the rRPa and these neurons are synaptically connected to BAT. Furthermore, the authors used optogenetic technique to stimulate the neurons in the VLM and thereby activate 2-ARs in the rRPa, which inhibited BAT SNA. Taken together these findings suggest that α2-AR agonist can be used to treat excessive body temperature during fever. -Madhan

In vivo manganese MR imaging of calcium influx in spontaneous rat pituitary adenoma.

Cross DJ, Flexman JA, Anzai Y, Sasaki T, Treuting PM, Maravilla KR, Minoshima S. AJNR Am J Neuroradiol. 2007 Nov-Dec;28(10):1865-71 During a study on aged rats, the authors of this paper found that some of their critters had spontaneously developed pituitary adenomas. Not wanting to waste “bad” animals, they reasoned that they could use these rats to study the calcium-dependent release of hormones with manganese (Mn) enhanced magnetic resonance imaging. Because Mn enters cells through calcium channels, they used Mn as a way to study uptake of calcium in to cancerous neuroendocrine cells. They found that adenomas took up the Mn faster than pituitaries from normal rats, and that they were able to absorb it faster. However, efflux seemed to be about the same between groups from about 2 days on. The increase in pituitary voxel intensity showed dose-dependent decreases when an L-type calcium channel blocker was given intranasally to the rats with almost a complete block at the 3-uL 5mg/mL dose (rat weight not mentioned). Using radioactive fluorodeoxyglucose (FDG) and PET scans, they saw that manganese uptake was greatest in more metabolically active tissue and was correlated with tumor size, though FDG uptake was not as well correlated with tumor size. What I found most interesting about this paper was not addressed in the text; that the signal intensity was still strong (15%ish) even after 10 days. In our own lab we recently saw a rat with an unexpectedly high signal after 12 days, so maybe reading more papers like this could help us figure out where we should be setting our expectations. -DH

Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease.

Cooper O, Seo H, Andrabi S, Guardia-Laguarta C, Graziotto J, Sundberg M, McLean JR, Carrillo-Reid L, Xie Z, Osborn T, Hargus G, Deleidi M, Lawson T, Bogetofte H, Perez-Torres E, Clark L, Moskowitz C, Mazzulli J, Chen L, Volpicelli-Daley L, Romero N, Jiang H, Uitti RJ, Huang Z, Opala G, Scarffe LA, Dawson VL, Klein C, Feng J, Ross OA, Trojanowski JQ, Lee VM, Marder K, Surmeier DJ, Wszolek ZK, Przedborski S, Krainc D, Dawson TM, Isacson O. Sci Transl Med. 2012 Jul 4;4(141):141ra90 This was a paper I read that I really thought I was going to like, but once I read through it something seemed to be missing. I thought that there were some experiments that probably should have been done that didn’t get included in the paper, and some things that were in there without a good rationale or explanation. Then again, I could have just missed out on finding their explanations… In this paper, the authors used fibroblasts isolated from people which were found positive for markers of familial Parkinson’s disease. They attempted to test the interaction of familial mutations and different chemical stressors by making the fibroblasts into induced pluripotent stem cells and then differentiating them into neural cells. They assessed the health of the induced dopaminergic neurons by measuring mitochondrial function as the mutations they studied were in PINK1 and LRRK2, two proteins known to be involved in mitochondrial turnover. So what kind of things do I think were missing? Well, one thing that concerned me was that the cultures of differentiated “neural cells” they used included dopaminergic cells along with non-dopaminergic and immature cells in unspecified proportions. All cells were treated the same way (with drugs that did not act specifically on dopaminergic cells), but the observed effects were attributed to the dopaminergic cells. One obvious thing that I would have done was to use a chemical stressor with a good specificity to dopaminergic cells, like MPTP. People have known how MPTP induces parkinsonism by selective dopaminergic neurotoxicity for decades, so why they would leave out something like that is kind of a mystery to me. I don’t want to bash the paper, because I liked the idea and some of the results, but it seems like the experimental design was lacking, or maybe that there were so many groups/authors each doing a part of the study that nobody could really agree on one central thread that they should follow. Given that we’re starting some new studies with a lot of input and help from different people/specialties, the hazard of this kind of thing has been wobbling around in my brain for a while. I’m just hoping that we can manage to keep our eyes on the prize of forming a grand unified theory of RVLM and not get caught with too many fingers in the pie. Also I’m hoping to stop mixing my metaphors. -DH

Neurosteroid modulation of arterial baroreflex function in the rostral ventrolateral medulla

Cheryl M. Heesch A positive modulator of GABA A receptors is progesterone metobilite 3α-hydroxy-dihydroprogesterone. We know that during pregnancy and ovarian cycle that the amount of progesterone fluctuates depending on the stage. The purpose of this study was to investigate the effects of pregnancy on pregnancy and if this could be imitated in non-pregnant rats. In order to test this GABA and 3α-OH-DHP or 3β-OH-DHP was injected into the RVLM. They used GABA in order to find RVLM.The right NTS was lesion in order to prevent baroreflex compensation. Then the baroreflex was tested before and after the injections. They found that the MAP baseline between the active metabolite 3α-OH_DHP and the inactive metabolite 3β-OH-DHP. When they checked the baroreflex they found that the difference within group for the active metabolite compared to the control value was different. As for the inactive the found no difference in comparison to control values. They found that 3α-OH-DHP lead to suppression of arterial baroreflex sympathoexcitation. -MD

Cardiovascular response to group I metabotropic glutamate receptor activation in NTS

C. Michael Foley, Helen W. Vogl, Patrick J. Mueller, Meredith Hay, and EileenM. Hasser The NTS plays a role in arterial baroreflex. We know that glutamate is the primary neurotransmitter. This article primary focus was group 1 mGLU receptors role in the control of the cardiovascular system. They recorded LSNA along with blood pressure. They microinjected 3,5 dihydroxyphenylglycine (DHPG) is a selective group 1 mGLUR agonist, and 1-aminocyclopentane-1S3 R dicarboxylic acid (ACPD) is a general mGLUR agonist. Both caused similar decreases in blood pressure and LSNA. Next they tested whether mGLUR receptor blockade would prevent the responses seen previously with DHPG and ACPD. They found in α-methyl-4-carboxyphenylgylcine blocked DHPG and ACPD responses. Next they looked at ionotropic glutamate receptors role in mediating the DHPG and ACPD response. They found that kyn did not attenuate DHPG response but potentiated the ACPD response. These data show that DHPG and ACPD activate group I mGLUR and that even in the presence of ionotropic glutamate receptor blocade they are able to still cause changes in blood pressure and nerve activity. -MD