Adenosine reduces GABAergic IPSC frequency via presynaptic A1 receptors in hypothalamic paraventricular neurons projecting to rostral ventrolateral medulla

Tae Hee Han,Soo Hwa Jang,So Yeong Lee,Pan Dong Ryu. Neuroscience Letters

Volume 490, Issue 1, 18 February 2011, Pages 63–67. doi:10.1016/j.neulet.2010. 12.026. The paraventricular nucleus (PVN) is a brain region that has projections that go to RVLM and down to the IML in order to modulate sympathetic outflow. The purpose of this study was to determine whether adenosine was was playing a role in modulating gaba release from PVN-RVLM neurons. Using young male Sprague-Dawley they labelled PVN-RVLM neurons by injecting Fluospheres- Red into the RVLM and they allowed the animal to recover for 5-7 days. the brain was sectioned and the labelled PVN neurons were selected for recording. In response to adenosine, they saw inhibitory postsynaptic currents . When compared to the before activity there was a decrease in firing but not in amplitude and the response was concentration dependent. Then they used antagonist to A 1 receptor and the A2  receptor  and saw that there was no change in the firing of the neuron. however, when adenosine was given  after the  microinjection of the A1 antagonist they found that the iPSCs was inhibited.  the microinjection of  the A2 antagonist  did not prevent the IPSCs that occur in response to  adenosine injection. These data demonstrate that adenosine is playing a  role presynaptically  in attenuating GABA release and this mediated by adenosine acting on A1 receptors. -MD

Acute intermittent optogenetic stimulation of nucleus tractus solitarius neurons induces sympathetic long-term facilitation.

Yamamoto K, Lalley PM, Mifflin SW.

Am J Physiol Regul Integr Comp Physiol. 2014 Dec 17:ajpregu.00381.2014

                In this paper, they built on previous work that showed that the effect of acute intermittent hypoxia (AIH) on long term facilitation (LTF) of phrenic nerve activity (PNA) and renal sympathetic nerve activity (RSNA) seems to be routed through the nucleus tractus solitarius (NTS), and that you could induce the same effect by electrical stimulation of the carotid sinus, even without hypoxia. They took this idea a step further by causing expression of channelrhodopsin in the caudal NTS, via a virus that would cause preferential expression in glutamatergic neurons.

                Once they had this system in operation, they compared the effects of AIH with the effects of acute intermittent optogenetic stimulation (AIO) on RSNA and PNA immediately after, and 60 minutes after periods of stimuli. They found that AIO in the caudal NTS produces a similar, but weaker, response to that seen after AIH (RSNA and PNA increased by 60% and 100% after AIO, but by 80 and 130% after AIH).  They also found that, while both stimuli increased the power spectral density of RSNA and PNA at their own primary frequencies, neither stimulus was able to increase synchronization of PNA with RSNA. -DH

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