Activation of Corticotropin Releasing Factor Receptors in the Rostral Ventrolateral Medulla is Required for Glucose-Induced Sympathoexcitation

Megan E. Bardgett, Amanda L. Sharpe, Glenn M. Toney.Am J Physiol Endocrinol Metab (September 30, 2014). doi:10.1152/ajpendo.00291.2014.

Glucose leads to increased energy expenditure  through activation sympathetic nerve activity (SNA). The mechanism that leads to the activation of SNA is unknown. PVN and RVLM play an important role in the control of SNA and BP.  We already know that PVN not directly projects down to the IML in order to control SNA and BP but there is a direct projection to RVLM from PVN. Also neurons in the PVN are activated by glucose. The activity of RVLM is controlled mainly by Glutamate and GABA but we also know that there are other neurotransmitters that may be involved such as corticotropin releasing factor (CRF). So it has been shown that there are CRFergic neuron in the PVN. The hypothesis for the study in this article was that glucose leads to increases in SNA through activation of CRFergic neurons in the PVN that ultimately lead to activation of RVLM neuron by activating CRF receptor that lead to sympathoexcitation.  In order to prove this they provided anatomical along with function data. The data provided showed that glucose infusion elevates both LSNA and SSNA. They also demonstrated that glucose does, in fact, activate neurons in both RVLM and PVN. Not only that but the majority of PVN neurons that expressed c-fos was also a CRFergic neuron. As for RVLM, they showed that glucose activated a significant portion of TH RVLM neurons. Blockade of CRF receptor blunted the increases in LSNA and SSNA in response to glucose infusion. They also showed that kyn blocks the increase in SNA in response to glucose. Final they demonstrated that blockade of PVN blocked the response to glucose infusion. These data demonstrate that glucose leads to activation of SNA by activating CRFergic neurons in the PVN and this leads to the release of CRF and this leads to activation or the CRF receptor and this may facilitate the release of glutamate in the RVLM and this leads to increases in SNA and thus energy expenditure. I wonder how SNA in our model might behave in response to glucose infusion…-MD

CNS neuroplasticity and salt-sensitive hypertension induced by prior treatment with subpressor doses of ANG II or aldosterone

Sarah C. Clayton, Zhongming Zhang, Terry Beltz, Baojian Xue, and Alan Kim Johnson.

Am J Physiol Regul Integr Comp Physiol 306: R908–R917, 2014.First published April 2, 2014; doi:10.1152/ajpregu.00010.2014. Hypertension is obviously a problem in today’s society.  About 25% of all hypertensive patients are salt sensitive. However the mechanism that is responsible for salt sensitivity leading to hypertension is still not clearly understood. It has been shown that pretreatment with  nonpressor doses of ANG II and aldosterone can lead to enhanced responses to ANG II. This sensitization depends on a functional brain renin angiotensin aldosterone system. Long term changes in the CNS could occur in response to sensitization. This studied investigated whether BDNF a protein that plays a role in many models neuroplasticity is involved in the changes that are occurring in the lamina terminalis (LT) in response to sensitization to ANGII.  the study showed that pretreatment to ANGII or Aldosterone in the brain can lead sensitization to salt. They also showed that the BDNF is enhanced along with p38 MARK and pCREB in response to pretreatment to ANGII and aldosterone. These data demonstrate that pretreatment with subpressor doses of ANGII and aldosterone can lead long term structural changes by increasing the the BDNF pathway in LT and this contributes to the development of salt sensitivity. I wished they would have investigated the RVLM, wouldn’t that be interesting.-MD

Medullary lateral tegmental field mediates the cardiovascular but not respiratory component of the Bezold-Jarisch reflex in the cat.

Am J Physiol Regul Integr Comp Physiol. 2005 Dec;289(6):R1693-702. Epub 2005 Aug 11.

Barman SM, Phillips SW, Gebber GL.

In this study, they tried to find out if the medullary lateral tegmental field (LTF) had a role in mediating the Bezold-Jarisch reflex in cats. They did this in two ways – they inactivated LTF neurons using microinjections of either the GABAA agonist, muscimol, or with the excitatory amino acid receptor antagonist, AP5, and got similar results with both methods. These results were that the phenylbiguanide-induced Bezold-Jarisch reflex, which normally decreases SNA, heart rate, and MAP, was either sharply attenuated or reversed. However, two aspects of the Bezold-Jarisch reflex, an increase in apnea and a decrease in phrenic nerve activity, were not affected. When they switched from AP5 to NBQX, a non-NMDA receptor antagonist, they did not see these effects.

They came away with three main conclusions from this paper. 1) that the LTF plays an important role in activating the Bezold-Jarisch reflex, 2) that there is a separation in the respiratory and cardiovascular effects of the Bezold-Jarisch reflex in the LTF, and 3) the Bezold-Jarisch reflex is mediated by NMDA receptors. They closed this paper by mentioning that people normally think of the CVLM as the major inhibitory control over the RVLM, and note that their experiments in this paper don’t contradict this since they use cats when most people use rats and rabbits, so they don’t know if species differences come into play here or not. -DH

Fractal noises and motions in time series of presympathetic and sympathetic neural activities.

J Neurophysiol. 2006 Feb;95(2):1176-84. Epub 2005 Nov 23.

Gebber GL, Orer HS, Barman SM.

So I read this paper, but I think I’m going to have to read it a few more times with a lot of different highlighters if I’m really going to understand it. I understand that they were trying to analyze rhythmic activity among LTF and RVLM neurons in cats that correlates with SNA. This is not easy since not every action potential correlates with bursts in SNA, and a neuron will often NOT fire in a lot of places where a simple rhythm would dictate that it should fire. However, using spike-triggered averaging, they analyzed the interspike intervals of neurons to see how they would correlate with cardiac SNA. They showed that even though some neurons might miss more than 10 bursts before firing a second action potential, they still were able to construct histograms that showed how the action potentials correlated with SNA, and what phase of the cardiac cycle and SNA burst the neuron was most likely to fire at. After that, the paper kind of got away from me. Although this is the exact kind of stuff we’re trying to get in to, so I’ll be reading this a little more closely and brushing up on my math skills so that I can understand all of this a little better. -DH

Role of the hypothalamic arcuate nucleus in cardiovascular regulation

Hreday N. Sapru.Autonomic Neuroscience. Volume 175, Issues 1–2, April 2013, Pages 38–50.DOI: 10.1016/j.autneu.2012.10.016.  In ths review article the role of the arcuate nucleus was discussed.The arc is located in the hypothalamus and it has some projections that go to RVLM, NTS, CVLM, IML just to name some. The PVN receives the highest amount of projections from the arc when compared to the other regions mentioned above.  The arc extends to the median eminence, which is area that lacks a BBB. This allows for the arc to be exposed to leptin, glucose and angiotensin.  What I found most interesting was that stimulation of the arc can cause both depressor and pressor responses. When blood pressor is normal activation of the arc leads to depressor responses ( release of GABA, neuropeptide y, and beta endorphin) most likely due to inactivation of neurons in the PVN that project down to the spinal cord or RVLM and lead to decreased sympathetic activity. However when blood pressure is low, activation of neurons in the arc leads to pressor responses (most likely due to the release of glutamate). The baroreceptor reflex may play also play role in how blood pressure is modulated in response to activation of the arc neurons. It has been shown that following barodenervation, stimulation of the arc leads to pressor responses. This may suggest that the baroreceptors are important for providing inhibitory input on to glutamate releasing arc neurons. overall I thought that this could be a region that we investigate in the future since it could be

 playing a role in both  activation and inhibition of the rvlm neurons. -MD

Role of the caudal pressor area in the regulation of sympathetic vasomotor tone

Full cite: Campos, R.R., Carillo, B.A., Oliveira-Sales, E.B., Silva, A.M., Silva, N.F., Futuro Neto, H.A., Bergamaschi, C.T. Role of the caudal pressor area in the regulation of sympathetic vasomotor tone  (2008) Brazilian Journal of Medical and Biological Research, 41 (7), pp. 557-562.

Role of the caudal pressor area in the regulation of sympathetic vasomotor tone

R.R. Campos¹, B.A. Carillo¹, E.B. Oliveira-Sales¹, A.M. Silva¹, N.F. Silva²,

H.A. Futuro Neto^3,4 and C.T. Bergamaschi⁵

1Departamento de Fisiologia, Disciplina de Fisiologia Cardiovascular e Respiratória, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil

2Laboratório de Neuromorfologia,

3Programa de Pós-Graduação em Ciências Fisiológicas, Universidade Federal do Espírito Santo, Vitória, ES, Brasil

4Escola Superior de Ciências, Santa Casa de Misericórdia de Vitória (EMESCAM), Vitória, ES, Brasil

5Departamento de Biociênicas, Universidade Federal de São Paulo, Campus Baixada Santista, Santos, SP, Brasil

This review examines how the Caudal Pressor Area (CPA) controls sympathetic outflow. The CPA is a relatively undefined region that is located at the caudal end of the Caudal Ventrolateral Medulla (CVLM). This region has shown to illicit sympathoexcitatory responses when it is directly stimulated, suggesting that the CPA either contains SPNs or innervates SPNs via a direct or indirect pathway. The CPA is not widely considered to be one of the main contributors to SPN innervation, however, there is quite a bit of ambiguity as to where the SPNs receive their excitatory drive from. One of the main statements of this paper is that the CPA provides a significant source of tonic excitatory drive to the RVLM, which I find that surprising considering this is one of the very few times I have read about the CPA, so there must be some complication to the CPA that I simply do not know yet. Apparently the effect of the CPA is mediated through the RVLM, suggesting some direct projection from CPA to the RVLM. According to this review, the CPA projects to the CVLM as well, and that inhibition of the CPA neurons has the greatest effect on the slow frequency neurons in the RVLM, not the fast ones. This response may suggest that the CPA has a selected enhancement of C₁ neurons. It would be interesting to see how the CPA relates to our model, especially if it does have as significant of an effect on RVLM neurons as this review suggests. It would also be interesting to see if the Caudal Pressor Area is stimulating the RVLM via glutamate or a different excitatory agonist. Also the CPA could be selectively innervating particular neuronal beds in the RVLM which could account of the differential control of nerve activity results that we have shown previously. It is certainly possible those different brain regions are responsible for stimulating different subsets of RVLM neurons and that these brain regions are stimulated by different phenomena throughout the body. That being said, I do not necessarily know of any evidence of preferential control of RVLM in regards to different brain regions, however, I believe that it is certainly possible given the fact that the RVLM has to manage MANY inputs and I do not believe that it is sophisticated enough to act as an integration center as well as a delivery center without some help from its neuronal circuitry.  - M.T.L.