Altered sympathetic reflexes and vascular reactivity in rats after exposure to chronic intermittent hypoxia.

J Physiol. 2011 Mar 15;589(Pt 6):1463-76. Silva AQ, Schreihofer AM. “Exposure to chronic intermittent hypoxia (CIH) yields persistent elevations in sympathetic nerve activity (SNA) and mean arterial pressure (MAP) with exaggerated sympathetic chemoreflexes”. The authors determined whether rats that were exposed to CIH produce exaggerated sympathetic responses. They hypothesized that sympathetic reflexes initiated by peripheral nerves would be exaggerated after exposure to CIH. They also determined whether exposure to CIH enhanced sympathoexcitation produced by glutamatergic stimulation of the RVLM. The authors found that sympathoexcitatory reflexes initiated by peripheral nerves other than the carotid sinus nerve produced exaggerated increase in SNA after exposure to CIH. Also stimulation of the RVLM, produced an augmented increase in SNA after CIH. Interestingly, the sympathoexcitatory responses were not accompanied by enhanced pressor changes. This could be because of reduced pressor reactivity to adrenergic stimulation seen after CIH. To summarize, the authors suggest that sympathoexciatory responses may be exaggerated because of increased excitability of the RVLM and reduced adrenergic vascular reactivity after exposure to CIH.-Madhan

Modulation of the sympathetic response to acute hypoxia by the caudal ventrolateral medulla in rats.

J Physiol. 2009 Jan 15;587(Pt 2):461-75. Mandel DA, Schreihofer AM. “Hypoxia elevates splanchnic sympathetic nerve activity (SNA) with differential effects during inspiration and expiration by unresolved central mechanisms”. The authors tested the hypothesis whether baro-activated CVLM neurons contribute to sympathetic responses to acute hypoxia. Additionally the authors also tested whether selective inhibition of excitatory or inhibitory actions on the CVLM would alter the sympathetic responses to hypoxia. In this study, the authors demonstrated that stimulation of peripheral chemoreceptors by hypoxia produced differential responses in baro-activated CVLM neurons. Blocking excitation and inhibition of the CVLM augmented or reduced the sympathetic response to acute hypoxia respectively. This suggests that both glutamate and GABA in the CVLM could be involved in mediated sympathetic responses to acute hypoxia.-Madhan

In vivo axonal transport rates decrease in a mouse model of Alzheimer's disease

Smith, Karen Dell Brown, et al. "< i> In vivo axonal transport rates decrease in a mouse model of Alzheimer's disease." Neuroimage 35.4 (2007): 1401-1408. Introduction: Primarily, the neurodegenerative disease Alzheimer’s affects a large population of the elderly. The disease presents itself with cognitive pathologies that correspond to intracellular neurofibrillary tangles (NFT’s) and extracellular amyloid-β aggregations (plaques) that eventually lead to neural death. Previous research has shown that another factor that contributes to cell death is a decrease in axonal transport rates, mostly in fast response neurons. Presently, it is unknown if the aggregation of tau proteins within NFT’s or an increase in amyloid precursor protein that precede plaques are causative of slowing axonal transport rates or consequential. This study utilizes the novel in vivo technique manganese-enhanced MRI (MeMRI), to try and gain knowledge on the decrease in axonal transport rates within Alzheimer modeling rodents. Methods: • Mn2+ Administration: MnCl2 (4l of .75 mg/ml) was given via a nasal lavage. • MeMRI: Animals were imaged an hour prior to MnCl2 injection using a 9.5T Bruker Avance Biospec Spectrometer. • Colchicine Administration: Colchine (1mg/kg) was given via a nasal lavage 24hrs prior to Mn2+ injection. • Immunoblotting: for APP concentration • Immunohistochemistry: for plaque detection Conclusion: • 3-4 month old rats did not reveal any signs of soluble APP or plaque presentation. 7-8 month old rats exhibited significant increases in soluble APP, but no plaques were identified. Finally 11-14 month old rats revealed both increases in soluble APP as well as plaque formation. • MeMRI revealed that following a normal temperature of 37 degrees Celsius, a drop in temperature to 30 degrees Celsius significantly reduces changes in signal intensities over time (axonal transport rate of Mn2+). It also showed that if temperatures were restored to physiological body temperatures following hypothermia, Mn2+ transport regained normal function and transport rates returned to baseline. This experiment showed that using MnCl2 a neuronal tract tracer can also be used for functional analysis of axonal transport rates, not just structural identification. • It was then determined that after the administration of Colchine, that microtubule depolymerization can be achieved, as well as the block in axonal Mn2+ transport. This study was able to show the dependence of Mn2+ transport on microtubule axonal transport and that manganese intensity analysis is a valid quantification of axonal transport rates. • After conformation, both Alzheimer’s disease (AD) model rodents and control rodents were imaged at three different time points: 3-4 months, 7-8 months, and 11-14 months old. As discussed earlier, each time point representing a different state of disease progression. The study concluded that at months 3 and 4 axonal transport of Mn2+ did not differ from control rats. However, at 7-8 months there was a significant decrease in transport rates when compared to control rats. Finally, again at 11-14 months a further significant decrease from baseline was seen in AD models compared to the control rats. This finding is important in showing that axonal transports rates begin to decrease before the formation of plaques are identified, which has never been shown. One possible explanation for this finding is that the soluble APP is interfering with Ca2+ influx rates, slowing down transport. ~JI

Control of sympathetic vasomotor tone by catecholaminergic C1 neurons of the rostral ventrolateral medulla oblongata

Marina, Nephtali, et al. "Control of sympathetic vasomotor tone by catecholaminergic C1 neurones of the rostral ventrolateral medulla oblongata." Cardiovascular research 91.4 (2011): 703-710. Obstructive sleep apnoea is a common sleep disorder that leads to many cardiovascular dysfunctions such as hypertension, coronary artery disease, and cerebrovascular disease. Symptoms of obstructive sleep apnoea usually include an increase in pCO2 levels and a decrease in pO2 levels (hypercapnia and hypoxia respectively). Many of these cardio pathologies are believe to come from chronic occurrences of hypercapnia and hypoxia increasing levels of sympathetic tone. However, little is known about how central chemoreceptors affect catecholaminergic neurons in the rostral ventrolateral medulla that control modulation of tonic sympathetic output. In this experiment rats were transfected with a lenivirus to express a drosophila allostatin receptor so that the administration of allostatin would cause reversible inhibition of selective CNS neurons. The drosophila allostatin receptor, upon activation has the ability to open potassium channels within the expressing neuron causing hyperpolarization. After verifying the transfection was successful in C1 neurons within the RVLM, allostatin was administered and the inhibition of these neurons produced a decrease in RSNA, ABP, and HR (not seen in control animals). Following, the transfected rats were then introduced to hypercapnia and at the peak of CO2, allostatin was applied and significant reductions were again seen in RSNA, ABP, and HR. In vitro allostatin applied to transfected rats lowered perfusion pressure and reduce the amplitude of respiratory tSNA bursts. With these data the authors were able to conclude that C1 neurons located in the RVLM are important for the modulation of resting sympathetic tone. However, they do not believe that these C1 neurons play an important role in increasing sympathetic tone via the stimulation of central chemoreceptors induced by hypercapnia. They were also able to observe that blockade of chemo-sensitive projections from the RTN had no effect on resting SNA. Conclusively, increase in SNA due to hypercapnia is not modulated by C1 RVLM neurons and may either be a product of non-C1 neurons within the RVLM or C1 neurons located in other regions of the brain. ~JI

Orexinergic activation of medullary premotor neurons modulates the adrenal sympathoexcitation to hypothalamic glucoprivation.

Diabetes. 2014 Feb 18. [Epub ahead of print] Korim WS, Bou-Farah L, McMullan S, Verberne AJ. I picked this paper because it has a couple of things we've been looking at - differential activation of sympathetic nerves and electrophysioslogical properties of RVLM neurons. It seems that in response to low glucose, the perifornical hypothalamus somehow becomes indirectly excited (which can be blocked with GABA agonists) and releases orexin into the RVLM (which can be blocked by orexin antagonists). The RVLM responds to orexin by increasing adrenal, but not lumbar SNA, which causes an increase in adrenaline release, as measured by an increase in its metabolites. So this paper a little bit of something cool for pretty much everybody in our lab. -DH

Fractionated manganese-enhanced MRI.

Bock NA, Paiva FF, Silva AC. NMR Biomed. 2008 Jun;21(5):473-8. Special thanks to Dr. Holt for bringing this paper to my attention. I'm bloggingg on it because we've been doing manganese-enhanced MRI (MeMRI) and wondering about how to give sufficient manganese to detect changes in neuronal activity and if we can do repeated injections but still remain below the threshold of toxicity. In this paper, varying doses of MnCl2 were administered in one-shot boluses different fractions (180mg/kg, but divided up in to multiple injections to see if fractional doses would make a difference in the image enhancement) through both IP and IV routes in order to study the detectability of the manganese. They then imaged rats with T1-weighted and T1-map MeMRI. They saw that some regions (like the cortex) had low uptake after a single 30mg/kg dose, presumably due to reduced access to cerebrospinal fluid. This actually matched with existing data showing that different regions have different uptake. They also saw significant enhancement using both T1-weighted and T1-map imaging, but saw that T1-map gave a better result than T1-weighted - which makes sense, considering all we've been taught on MeMRI. When they looked for signs of manganese toxicity (referred to as MANGANISM, for those who don't believe it's a real word), they saw that rats given repeated injections of low concentration manganese initially lost a little weight (not more than 10%) but eventually gained it back and even put on some weight by the end of the study. Doses at 60mg/kg or above showed signs of toxicity at the injection site for a variety of reasons, one of which is that IP injections are not as consitent as people think they are. So I guess we're in good company with some of the problems we've had and we've been on the right track with the directions we're looking to go. -DH

Glutamatergic Receptor Activation in the Rostral Ventrolateral Medulla Mediates the Sympathoexcitatory Response to Hyperinsulinemia

Megan E. Bardgett, John J. McCarthy and Sean D. Stocker Hypertension. 2010;55:284-290; originally published online January 11, 2010; doi: 10.1161/HYPERTENSIONAHA.109.146605 We know that in rodent models of obesity it has been shown that there is elevated sympathetic nervous system activity. This article investigated whether this was due to increased glutametergic input to rvlm or some other type of excitatory input. In response glucose infusion, low fat diet and obese resistant rats had lower in plasma levels of insulin when compared to obesity prone rats. In animals that were hyperinsulinemic kyn injections into rvlm lead to caused lumber sna to increase but not arterial pressure. They injected AP5 into rvlm in irder to block NMDA receptors and showed that there was a drop in bp similar to the kyn response. They also gave NBQX and saw no effect on lsna an ABP. They also blocked AT1 and melanocortin receptors and found that it had no effect on sympathoexcitatory responses. They did western blot in order to look at insulin receptor expression in the RVLM they found that there was essentially no insulin receptor present. Also when they injected insulin into the RVLM it did not alter lsna and ABP. These data suggest that the elevated sympathetic nerve activity that is seen in metabolic syndromes is most likely due to enhanced glutamergic receptor activation.-MD

Increased Dietary Salt Enhances Sympathoexcitatory and Sympathoinhibitory Responses From the Rostral Ventrolateral Medulla

Julye M. Adams, Christopher J. Madden, Alan F. Sved, Sean D. Stocker (Hypertention. 2007;50:354-359.) In this article they investigated glutamate and gaba responses in RVLM during high salt diet. There was a control group that was given just water and another given 1% NaCl (high salt diet group). In the high salt diet group there were enhanced responses to Glutamate for MAP, renal and splanchnic nerve activity. In response to GABA there were enhanced depressor responses along with enhanced decreases in renal and splanchnic sympathetic nerve activity in the high salt diet group when compared to the control. They did a time course in order to see how long it would take to develop enhanced glutamate and gaba responses. They gave 1%$ NaCl for 1, 7, 14 and 21 days. They that at 14 days there was greater increases to glutamate and gaba for ABP and renal. Next they wanted to see if the changes were reversible. They gave water instead of 1% NaCl to rats for 1 or 7 days. They found that the 7 day water treatment lead to reversal of the effects of drinking 1% NaCl for 14days, the responses to glutamate and gaba were no different than control animals. These data suggest that high salt diet leads to both enhanced glutamate and gaba sensitivity in RVLM and that these neuroplastic changes are reversible with treatment. -MD

Angiotensin II slow-pressor hypertension enhances NMDA currents and NOX2-dependent superoxide production in hypothalamic paraventricular neurons.

Am J Physiol Regul Integr Comp Physiol. 2013 Jun 15;304(12):R1096-106. Wang G1, Coleman CG, Chan J, Faraco G, Marques-Lopes J, Milner TA, Guruju MR, Anrather J, Davisson RL, Iadecola C, Pickel VM. “Adaptive changes in glutamatergic signaling within the hypothalamic paraventricular nucleus (PVN) may play a role in the neurohumoral dysfunction underlying the hypertension induced by "slow-pressor" ANG II infusion”. To test their hypothesis, the authors performed several elegant experiments. In experiment 1, the authors used electron microscope immunolabelling to show that in the PVN dendrities of ang II infused mice, there was colocalization of NOX2 and N-methyl-D-aspartate receptor (NMDAR) NR1 subunits. In experiment 2, there was increased reactive oxygen species but decreased nitric oxide (NO) production at baseline and after NMDA administration in cells isolated from ang II infused mice. In experiment 3, NMDA induced increases in inward current shown by whole cell recording in spinally projecting PVN cells in slices was reversed by ROS scavenger and NO donor in ang II group. These experiments clearly demonstrated the relationship between enhanced glutamatergic signaling in the PVN and other well-known mechanisms that are involved in the development of ang II slow-pressor hypertension.-Madhan

Membrane trafficking of NADPH oxidase p47(phox) in paraventricular hypothalamic neurons parallels local free radical production in angiotensin II slow-pressor hypertension.

J Neurosci. 2013 Mar 6;33(10):4308-16. Coleman CG1, Wang G, Faraco G, Marques Lopes J, Waters EM, Milner TA, Iadecola C, Pickel VM. “NADPH oxidase-generated reactive oxygen species (ROS) are highly implicated in the development of angiotensin II (AngII)-dependent hypertension mediated in part through the hypothalamic paraventricular nucleus (PVN)”. The authors tested the role of vasopressin and non-vasopressin neurons in the production of ROS in the PVN of ang II slow-pressor hypertension model. In the first set of experiments, the authors used ROS imaging to first confirm the increased production of ROS in ang II slow-pressor mice. Then the authors examined the baseline and NMDA induced ROS levels in vasopressin and non-vasopressin cells. Interestingly they found increased ROS production in vasopressin cells after NMDA infusion in ang II groups, however in non vasopressin cells the levels were increased in both the ang II groups and control groups. In the second set of examined the authors used electron microscopic dual labeling for vasopressin and a NADPH oxidase subunit, that was important for the production of ROS. The immunolabeling for p47 phox was decreased in the plasma membrane and increased in membranes just beneath the plasmalemmal surface in vasopressin and non-vasopressin cells of ang II mice respectively. Based on these findings the authors arrive at an interesting conclusion suggesting that the membrane assembly of vasopressin and non-vasopressin cells were differentially affected in the PVN of ang II slow-pressor model offsetting the homeostatic control of blood pressure.-Madhan

Tonic Glutamatergic Input in the Rostral Ventrolateral Medulla Is Increased in Rats With Chronic Heart Failure

Wei-Zhong Wang, Lie Gao, Han-Jun Wang, Irving H. Zucker, Wei Wang Hypertension.2009; 53: 370-374 Published online before print November 24, 2008, doi: 10.1161/​HYPERTENSIONAHA.108.122598 This article wanted to investigate the role of glutate receptors in CHF. In order to show that glutamatergic inputs are responsible for the elevated sympathetic outflow in CHF, they bilateral injected kyn, NMDA and non-NMDA reaceptor anatoginist. they recorded BP, renal sympathetic nerve activity and the also recorded. They also recorded the activity of the RVLM neurons themselves. They found that they was no significant difference in the sham rats from baseline responses for BP rSNA and neuronal aactivity in RVLM in response to kyn, and NMDA and non NMDA receptor antagonists. however. in the CHF rat they found that the was a difference in the response when compared to baseline for BP, rSNA and rvlm neuronal activity to kyn and NMDA antagonist. These data suggest that the elevated sympathetic outflow in CHF is mostly mediated by glutamergic input through the NMDA receptor.-MD

Cardiovascular effects of angiotensin II and angiotensin-(1–7) at the RVLM of trained normotensive rats

Lenice K. Becker, Robson A.S. Santos, Maria José Campagnole-Santos Brain Research Volume 1040, Issues 1–2, 8 April 2005, Pages 121–128 http://dx.doi.org/10.1016/j.brainres.2005.01.085 They used wistar rats and microinjected ang II, ang 1-7, saline,for 5 days a week . They found that the trained rats had a greater pressor response to ang II whe compared to sedentary rats. Ang 1-7 responses were greater pressor responses in seds. then they gave an antagonist Lorstan and saw a greater depressor responses in sedentary than compared to trained. When they gave the A779 they saw a greater depressor responses in sedentary compared to trained animals. The differential effects produced in response to ang peptides in trained rats could be due to an increase in AT1 and decreased in MAS receptor expression on excitatory neurons.-MD

The effect of air puff stress on c-Fos expression in rat hypothalamus and brainstem: central circuitry mediating sympathoexcitation and baroreflex resetting.

Furlong TM, McDowall LM, Horiuchi J, Polson JW, Dampney RA. Eur J Neurosci. 2014 Mar 12. [Epub ahead of print] This was a pretty neat paper in showing the complexity of sympathetic control of blood pressure. They took rats, set them up for telemetry recording of heart rate and arterial pressure, and gave they psychological stressors in the form of repeated air puffs in the face. They then looked at what regions of the brain would come up as c-Fos positive. I was pretty surprised to see that the RVLM was pretty much not involved at all. They were able to show c-Fos expression in the RVLM after prolonged hypotension (via nitroprusside), just not after air puffs. They did see expression in NTS-projecting neurons in the VPAG and PVN though (CTB costain). So is it just me, or is it really cool how physical and psychological stressors can tie in to the same system, but still be completely separate. -DH

Activity-dependent regulation of NMDA receptors in substantia nigra dopaminergic neurones.

Wild AR, Jones S, Gibb AJ. J Physiol. 2014 Feb 15;592(Pt 4):653-68. doi: 10.1113/jphysiol.2013.267310. Epub 2013 Dec 16. Because Madhan is investigating the possibility of physical activity causing a downregulation in NMDA-Receptors, this paper caught my eye. In this study, the authors looked how dopaminergic cells show acute rundown in NMDAR currents in brain slices containing the substantia nigra (the area known to suffer massive cell loss in Parkinson’s Disease) after repeated stimulation. They used whole-cell patch clamp to recorded NMDAR currents after repeated doping of the perfusion medium with NMDA. They found that rundown occurred in a couple of different ways. Some of it was dependent on calcium influx (NMDAR allows calcium ions to pass through in addition to sodium ions), which they could show by voltage clamping the cell near the reversal of calcium. However, even after replacing extracellular Ca2+ with Ba2+, significant rundown occurred, suggesting there are calcium-independent mechanisms in effect too. They suspected that the Glu2NB receptor subunit was involved, but were not able to block current rundown after using a Glu2NB-preferring antagonist. They were, however, able to block current rundown with a dynamin antagonist, suggesting that receptor regulation occurs through clathrin-mediated endocytosis. One thing that was pretty cool was how they also patched on to GABAergic neurons in the same region and found that they had a higher rate of rundown, suggesting that they have a built in mechanism for protecting themselves against excitotoxicity that dopaminergic neurons lack. -DH

Autonomic regulation of brown adipose tissue thermogenesis in health and disease: potential clinical applications for altering BAT thermogenesis

Autonomic regulation of brown adipose tissue thermogenesis in health and disease: potential clinical applications for altering BAT thermogenesis. Domenico Tupone, Christopher J. Madden and Shaun F. Morrison. Frontiers In Neuroscience 9:1-14, 2014 (open access) doi: 10.3389/fnins.2014.00014. This is an excellent and timely review from the standpoint of the field and in terms of our collaboration with Dr. Granneman's laboratory. Shaun Morrison has been studying brown adipose tissue or BAT for a number of years. His and his postdoc's (Chris Madden) work have really come into clinical significance with the discovery of BAT in humans and its ties to obesity. Basically BAT is a source of thermogenesis and therefore can be important in terms of burning calories to stay warm in a cold environment. Interestingly for our laboratory is the fact the BAT is innervated by the sympathetic nerves which release norepinephrine onto beta 3 receptors to activate BAT. Dr. Morrision's laboratory has worked out a lot of the central circuitry or brainstem pathways by which BAT and BAT SNA is regulated under a variety of conditions, mostly associated with cold temperature exposure and the turning on of BAT. Interestingly, BAT is one set of sympathetic nerves that are not controlled by the RVLM but by a neighboring structure in the ventral medulla, the midline raphe. There are some really beautiful figures in this review and is worth reading for anyone interested in BAT, BAT SNA, and pathwways involved in thermogenesis. In the next few weeks in fact, Madhan and Priya hope to have BAT SNA recordings up and going in the laboratory, comparing runners versus sedentary rats. Should be exciting to see it develop and be sure to keep an eye out at Experimental Biology for both Shaun Morrison's and Chris Madden's work. ~PJM

Central Command Neurons of the Sympathetic Nervous System: Basis of the Fight-or-Flight Response.

Central Command Neurons of the Sympathetic Nervous System: Basis of the Fight-or-Flight Response. Arthur S. P. Jansen, Xay Van Nguyen, Vladimir Karpitskiy,Thomas C. Mettenleiter, Arthur D. Loewy. Science 270:644-646, 1995. This is a classic paper by Arthur Loewy's group at Washington University in St. Louis in which they propose the existence of "central command" neurons. These central command neurons are hypothesized to innervate multiple sympathetic targets and be responsible for the all or none, fight or flight response that has been traditionally associated with activation of the sympathetic nervous system. One thing to keep in mind here was that this paper was published in the mid-1990s when it was still controversial whether there were neurons that controlled some or all of the sympathetic outputs, whether there existed individual neurons that controlled individual sympathetic outputs, or if both types existed (likely the reality). Unlike the Australians (i.e. McAllen and colleagues), who had just the year prior shown differential control of sympathetic outputs with very small (5ul) microinjections in the RVLM of cats, Loewy's group was trying to demonstrate the reverse idea; that is, individual neurons have the anatomical connections to control multiple sympathetic outputs. To do so, they injected rats with two different viruses to produce retrograde and transynaptic tract tracing. They put one virus in the stellate ganglion which contains the axons of sympathetic preganglionics to the heart and they put a different virus in the adrenal gland which contains the sympathetic preganglionics controlling epinephrine release. While they did show that both viruses wound up within cells of the RVLM, there were several caveats pointed out in the paper and additional ones not pointed out. First, the number of cells that did show double labeling in the RVLM were very small and if you look in the Methods sections you will see it took them hundreds of rats to get this to work out. Second, there are several technical issues in using viruses that likely preclude definitive conclusions about the double-labeled cells. In any case, it was published in Science and is often quoted as the paper that demonstrated the existence of these neurons. It also propagates the still pervasive idea that sympathetics are an all or none phenomenon. We know now that this is not the case in several instances of physiology and pathophysiology. ~PJM

C1 Neurons: The Body's EMTs

Guyenet, Patrice G., et al. "C1 neurons: the body's EMTs." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 305.3 (2013): R187-R204. Definition: C1 neurons commonly thought of as the body’s emergency medical technicians, are defined as neurons containing phenylethanolamine N-Methyl transferase (PNMT). The enzyme PNMT is allows for the production of the catecholamine epinephrine from norepinephrine. The majority of C1 neurons also have the enzymes tyrosine hydroxylase and dopamine β-hydroxylase as well which allows for the synthesis for norepinephrine and dopamine. Presently, it is suspected that most C1 neurons are clustered in the ventrolateral medulla (VLM), however the VLM also contains A1 neurons (catecholaminergic neurons that do not make PNMT). C1 neurons have projections to a variety of areas that largely play a role in autonomic responses or stress behaviors. Although C1 neurons are classified as catecholaminergic, there is no direct evidence of catecholamine release to intended targets. Instead, most C1’s are thought to use glutamatergic signaling transmission mainly through the use of vesicular glutamate transporter 2. There is also evidence to show the release of certain neuropeptides along with glutamate including TRH, Substance P, NPY and Enkephalin to produce a greater variety of excitatory and or inhibitory effects. About one third of all C1 neurons are located specifically in the rostral ventrolateral medulla (RVLM) and target sympathetic pre-ganglionic neurons. This region is referred to as the “pressor” region due to the fact that excitation of these neurons with glutamate leads to an increase in arterial blood pressure via vasoconstriction and cardimotor output. It is thought then that the responsibility of these C1 neurons within the RVLM is to maintain arterial blood pressure on a second to second basis. Regulation of these tonic neurons comes from another region in the VLM called the intermediate VLM (CVLM) that contains GABAergic neurons, and is meditated by a mechanism known as the baroreflex. It was also found that non-C1 neurons also reside in the RVLM, but their exact function is unknown. Interestingly, it was found that if the majority of C1 neurons are killed off using anti-DβH-saporin only a 10 mmHg change in arterial blood pressure is witnessed. Factors that could potentially account for this are compensation with non-C1 neurons, volume expansion of the kidney, baroreflex compensation, or peripheral catecholaminergic receptor supersensitivity. Other autonomic/stressor responses C1 neurons have been linked to include hypoxia, the CRH-ACTH-Corticosterone Cascade, the glucoprivic responses, as well as some parasympathetic sympathetic responses. Although it is thought that C1 neurons contribute to homeostatic regulation under a variety of physiological conditions, there are still many questions and functions yet to be discovered and understood. ~JI

Exercise training attenuates hypertension and cardiac hypertrophy by modulating neurotransmitters and cytokines in hypothalamic paraventricular nucleus.

PLoS One. 2014 Jan 17;9(1):e85481. Jia LL, Kang YM, Wang FX, Li HB, Zhang Y, Yu XJ, Qi J, Suo YP, Tian ZJ, Zhu Z, Zhu GQ, Qin DN. “Regular exercise as an effective non-pharmacological antihypertensive therapy is beneficial for prevention and control of hypertension, but the central mechanisms are unclear”. The authors investigated whether exercise training in spontaneously hypertensive rats (SHRs) could delay the progression of hypertension and reduce cardiac hypertrophy in them by balancing the excitatory and inhibitory neurotransmitters and pro and anti-inflammatory cytokines in the paraventricular nucleus (PVN). The rats were treadmill trained from 7 to 16 weeks. The authors observed that sedentary SHRs had higher mean arterial pressure and cardiac hypertrophy and these factors were significantly attenuated in the exercise trained SHRs. They authors found that sedentary SHRs had greater concentration of glutamate and norepinephrine and lower concentration of GABA in the PVN compared to their exercise trained counterparts. The authors also measured a number of pro and anti-inflammatory cytokines in the PVN and plasma to suggest that these factors could be involved in mediating reduced sympathetic nerve activity and blood pressure observed in the exercise trained SHRs compared to sedentary SHRs. More translational approach would take these findings along with other similar findings to the next level.-Madhan

Exercise training lowers the enhanced tonically active glutamatergic input to the rostral ventrolateral medulla inhypertensive rats.

CNS Neurosci Ther. 2013 Apr;19(4):244-51. Zha YP, Wang YK, Deng Y, Zhang RW, Tan X, Yuan WJ, Deng XM, Wang WZ. “It is well known that low-intensity exercise training (ExT) is beneficial to cardiovascular dysfunction in hypertension”. The authors investigated the effects of exercise training on glutamatergic inputs in the RVLM of a spontaneously hypertensive rats. The animals were treadmill trained for about 12 weeks. The authors observed that exercise trained SHR rats had significantly blunted responses of arterial pressure, heart rate and renal sympathetic nerve activity to bilateral microinjection of Kynurenic acid in the RVLM compared to sedentary SHRs. The authors found that exercise trained SHRs had reduced glutamate concentration (measured by HPLC) and the lower protein expression of vesicular glutamate transporter 2 (that packs the glutamate in the presynaptic terminal). The authors suggest that exercise training lowered the enhanced glutamatergic input in the RVLM in SHRs and this could be the possible mechanism by which it reduced blood pressure and sympathetic nerve activity in them.-Madhan