Cravo SL, Morrison SF, Reis DJ.
Am J Physiol. 1991 Oct;261(4 Pt 2):R985-94.
Leading up to this paper, there had been some disagreement over the role of CVLM neurons in regulating SNA via inhibition of the RVLM. Some groups had seen barorecepter-dependent inhibition, while others had seen baroreceptor-INdependent inhibition. This paper examined the possiblity that there were 2 different subpopulations of CVLM neurons, rostral and caudal, that had different functions in regulating RVLM activity. They used kainic acid (KA) as an excitotoxic agent to inactivate subregions of the CVLM and examined what happened to splanchnic sympathetic nerve activity (SSNA) when they "activated the baroreceptor" by electrically stimulating the aortic depressor nerve (ADN).
In control rats, baseline SSNA showed bursts tied to the pulse (frequency analysis of SSNA showed the most power at ~6Hz), and stimulation of the ADN caused inhibition of SSNA, as expected. However, after bilateral injections of KA into the rostral CVLM, they found that ADN stimulation no longer caused inhibition of SSNA and the power at 6Hz was almost completely eliminated. The arterial pressure and SSNA were both greatly increased following KA injection (after a brief decrease in both), consistent with excitotoxic lesioning of neurons that would normally inhibit the RVLM. This effect required bilateral lesioning of the rostral CVLM. Unilateral lesioning only abolished ADN-dependent inhibtion of SSNA when the ipsilateral ADN was stimulated.
When the caudal CVLM was lesioned by KA, an increase in arterial pressure and SSNA were seen, similar to what happened when the rostral CVLM was lesioned. However, with the caudal CVLM lesioned, stimulation of the ADN was still capable of causing an inhibition of SSNA and a drop in blood pressure. It also cause a huge increase in the relative power of the 6Hz SSNA frequency (or a huge decrease in all other frequencies, depending on how you look at it). The proposed reason for this is that with the baroreceptor-independent inhibition abolished, the increased arterial pressure caused a greater activation of baroreceptors, resulting in a greater coherence between SSNA and the frequency of the heart. The final "trick" they did in this paper was to take the same rats that had caudal CVLM lesions, and then give them lesions in the rostral CVLM. This was then able to wipe out the effect of ADN stimulation on SSNA and arterial pressure, showing that the baroreceptor-dependent inhibition of SSNA is tied to the rostral but not the caudal CVLM. -dh
Friday, May 20, 2016
Monday, May 16, 2016
Reticulospinal vasomotor neurons in the RVL mediate the somatosympathetic reflex.
Morrison SF, Reis DJ.
Am J Physiol. 1989 May;256(5 Pt 2):R1084-97.
In this paper, they wanted to see if the RVLM neurons responsible for basal sympathetic tone were also responsible for the somatosympathetic reflex. To do this, they stimulated the sciatic nerve to increase SNA while monitoring RVLM unit activity and efferent splanchnic SNA.
When they examined the effects of individual sciatic stimuli, they found 2 separate SNA were evoked in response. By varying stimulus intensity, they determined that these were not due to two separate populations of sciatic fibers. However they did estimate afferent conduction velocity (at the lumbar dorsal root) and found 2 lightly myelated types and 1 unmyelinated type when they gave a strong enough stimulus. This suggests that the sensory afferents that drive a sympathetic response are the lightly myelinated ones and that the C-fibers play a much smaller role in this effect.
They next used the classic technique of doing transections to find out which regions are necessary for the response, and found that the lower brainstem and below is sufficient. They then checked that the RVLM was involved in the reflex by microinjection of kainic acid, which caused a depolarization block that was able to reduce the SNA response to sciatic stimulation by ~90%.
To examine how individual neurons played into the response, they found barosensitive neurons and determined that they were spinally projecting and verified (in post processing) that they were cardiovascular-related and probably functioned to stimulate SNA. They then found that most of these neurons would show early and late action potentials linked to sciatic stimuli, very similar to what was seen for splanchnic SNA. The neurons also increased their rate of firing for about 20 milliseconds after each of the evoked action potentials.
Finally, in the discussion, they dedicate a lot of space to the argument (supported by addition of afferent and efferent conduction velocities) that the somatosympathetic effect occurs primarily by sensory neurons in the sciatic bundle synapsing onto two populations of neurons in the spinal cord, which have different conduction velocities but both directly excite the neurons in the RVLM that are responsible for stimulating the splanchnic nerve. - DH
Am J Physiol. 1989 May;256(5 Pt 2):R1084-97.
In this paper, they wanted to see if the RVLM neurons responsible for basal sympathetic tone were also responsible for the somatosympathetic reflex. To do this, they stimulated the sciatic nerve to increase SNA while monitoring RVLM unit activity and efferent splanchnic SNA.
When they examined the effects of individual sciatic stimuli, they found 2 separate SNA were evoked in response. By varying stimulus intensity, they determined that these were not due to two separate populations of sciatic fibers. However they did estimate afferent conduction velocity (at the lumbar dorsal root) and found 2 lightly myelated types and 1 unmyelinated type when they gave a strong enough stimulus. This suggests that the sensory afferents that drive a sympathetic response are the lightly myelinated ones and that the C-fibers play a much smaller role in this effect.
They next used the classic technique of doing transections to find out which regions are necessary for the response, and found that the lower brainstem and below is sufficient. They then checked that the RVLM was involved in the reflex by microinjection of kainic acid, which caused a depolarization block that was able to reduce the SNA response to sciatic stimulation by ~90%.
To examine how individual neurons played into the response, they found barosensitive neurons and determined that they were spinally projecting and verified (in post processing) that they were cardiovascular-related and probably functioned to stimulate SNA. They then found that most of these neurons would show early and late action potentials linked to sciatic stimuli, very similar to what was seen for splanchnic SNA. The neurons also increased their rate of firing for about 20 milliseconds after each of the evoked action potentials.
Finally, in the discussion, they dedicate a lot of space to the argument (supported by addition of afferent and efferent conduction velocities) that the somatosympathetic effect occurs primarily by sensory neurons in the sciatic bundle synapsing onto two populations of neurons in the spinal cord, which have different conduction velocities but both directly excite the neurons in the RVLM that are responsible for stimulating the splanchnic nerve. - DH
Saturday, May 7, 2016
In vivo axonal transport rates decrease in a mouse model of Alzheimer's disease.
Smith KD, Kallhoff V, Zheng H, Pautler RG.
Neuroimage. 2007 May 1;35(4):1401-8.
Some in vitro models of alzehimers disease (AD) show a decreased rate of axonal transport linked with accumulations of tau and amyloid-B (AB) proteins. Adding AB to cultured neurons also inhibits transport, possibly through interactions with actin that change its level of polymerization. The aim of this study was to develop a new way to measure in vivo axonal transport. To study in vivo transport rates, the group used MEMRI and a strain of mouse which expressed an aggressive mutant form of amyloid precursor protein and accumulations of AB plaques. Mice were given Mn through nasal lavage and repeatedly imaged for an hour to see how transport to and uptake into the olfactory bulbs occurred. Post-Mn signal intensities were normalized to pre-Mn levels to find when Mn had reached regions of interest. As expected, MRI signals incrased over time in manganese-treated mice, but it did not increase in control animals. They then used decreased temperature and cholchicine (which prevents polymerization of actin microtubules) to show that by inhibiting axonal transport, they could prevent the the transport-dependent increase in signal intensity observed in control animals.
To look at developing an assay for diagonsing AD, they used MEMRI and a model of mouse which expressed a mutant form of amyloid precursor protein and increasing accumulations of AB plaques with age. They found that after manganese treatment, young AD mice showed similar transport rates (as demonstrated by MEMRI signal increases) to regular mice, but the signal was reduced in 7-8 month old mice, and reduced even further in 11-14 month old mice. This is cool because there aren't currently good ways to diagnoze alzheimers disease while a person is still alive. Diagnosis is usually done post-mortem, after years of AD-like symptoms. Finding a way to diagnose it in the early stages might be a great way to prevent it from getting worse before it's too late to treat. -DH
Neuroimage. 2007 May 1;35(4):1401-8.
Some in vitro models of alzehimers disease (AD) show a decreased rate of axonal transport linked with accumulations of tau and amyloid-B (AB) proteins. Adding AB to cultured neurons also inhibits transport, possibly through interactions with actin that change its level of polymerization. The aim of this study was to develop a new way to measure in vivo axonal transport. To study in vivo transport rates, the group used MEMRI and a strain of mouse which expressed an aggressive mutant form of amyloid precursor protein and accumulations of AB plaques. Mice were given Mn through nasal lavage and repeatedly imaged for an hour to see how transport to and uptake into the olfactory bulbs occurred. Post-Mn signal intensities were normalized to pre-Mn levels to find when Mn had reached regions of interest. As expected, MRI signals incrased over time in manganese-treated mice, but it did not increase in control animals. They then used decreased temperature and cholchicine (which prevents polymerization of actin microtubules) to show that by inhibiting axonal transport, they could prevent the the transport-dependent increase in signal intensity observed in control animals.
To look at developing an assay for diagonsing AD, they used MEMRI and a model of mouse which expressed a mutant form of amyloid precursor protein and increasing accumulations of AB plaques with age. They found that after manganese treatment, young AD mice showed similar transport rates (as demonstrated by MEMRI signal increases) to regular mice, but the signal was reduced in 7-8 month old mice, and reduced even further in 11-14 month old mice. This is cool because there aren't currently good ways to diagnoze alzheimers disease while a person is still alive. Diagnosis is usually done post-mortem, after years of AD-like symptoms. Finding a way to diagnose it in the early stages might be a great way to prevent it from getting worse before it's too late to treat. -DH
Role of presympathetic C1 neurons in the sympatholytic and hypotensive effects of clonidine in rats
Schreihofer AM, Guyenet PG.
Am J Physiol Regul Integr Comp Physiol. 2000 Nov;279(5):R1753-62
Clonidine is an a2-adrenergic receptor agonist that works in multiple places in the CNS. It is frequently used as an antihypertensive drug for its ability to decrease blood pressure. Microinjections of clonidine into the RVLM produce a drop in MAP, similar to IV administration, and the effect can be blocked by co-injection with an a2 antagonist. Earlier work had shown that slow firing (likely C1) neurons in the RVLM were affected by clonidine injection, but it wasn't clear if it was a direct effect on C1 neurons or if it was mediated by receptors on presynaptic cells. Also, the effect of clonidine on non-C1 presympathetic neurons was similarly unclear.
To investigate these questions, RVLM neurons were recorded in rats that were treated with multiple IV doses of clonidine. Cells were also labeled with biotinamide for later reconstruction and examination of phenotype. They also used anti-DBH-saporin in some rats to lesion C1 cells to see what effect clonidine would have when the majority of C1 neurons had been eliminiated.
They found that increasing doses of clonidine contributed to a gradually decreasing frequency of action potential frequency among all cell types - slow conducting (unmyelinated C1), medium conducting (mostly lightly myelinated C1) and fast conducting (mostly non-C1). They pointed out that the response was extremely variable within each group, and that overall SNA was more inhibited than any group was. So either something else which contributes to SNA was also inhibited, or that the nerve itself was inhibited somehow.
After they reduced PNMT positive neurons in the rostral end of the C1 region by ~76% using anti-DBH-sapporin, they saw the same effect of clonidine as they did in untreated control and IgG-saporin control rats. So in this paper they showed that even though C1 neurons are inhibited by systemic clonidine and the inhibition could contribute to a decrease in SNA, C1 neurons aren't NECESSARY for this to happen, and that other non-C1 presympathetic neurons act the same way. - DH
Am J Physiol Regul Integr Comp Physiol. 2000 Nov;279(5):R1753-62
Clonidine is an a2-adrenergic receptor agonist that works in multiple places in the CNS. It is frequently used as an antihypertensive drug for its ability to decrease blood pressure. Microinjections of clonidine into the RVLM produce a drop in MAP, similar to IV administration, and the effect can be blocked by co-injection with an a2 antagonist. Earlier work had shown that slow firing (likely C1) neurons in the RVLM were affected by clonidine injection, but it wasn't clear if it was a direct effect on C1 neurons or if it was mediated by receptors on presynaptic cells. Also, the effect of clonidine on non-C1 presympathetic neurons was similarly unclear.
To investigate these questions, RVLM neurons were recorded in rats that were treated with multiple IV doses of clonidine. Cells were also labeled with biotinamide for later reconstruction and examination of phenotype. They also used anti-DBH-saporin in some rats to lesion C1 cells to see what effect clonidine would have when the majority of C1 neurons had been eliminiated.
They found that increasing doses of clonidine contributed to a gradually decreasing frequency of action potential frequency among all cell types - slow conducting (unmyelinated C1), medium conducting (mostly lightly myelinated C1) and fast conducting (mostly non-C1). They pointed out that the response was extremely variable within each group, and that overall SNA was more inhibited than any group was. So either something else which contributes to SNA was also inhibited, or that the nerve itself was inhibited somehow.
After they reduced PNMT positive neurons in the rostral end of the C1 region by ~76% using anti-DBH-sapporin, they saw the same effect of clonidine as they did in untreated control and IgG-saporin control rats. So in this paper they showed that even though C1 neurons are inhibited by systemic clonidine and the inhibition could contribute to a decrease in SNA, C1 neurons aren't NECESSARY for this to happen, and that other non-C1 presympathetic neurons act the same way. - DH
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