Testing the calcium hypothesis of aging in the rat hippocampus in vivo using manganese-enhanced MRI

Bissig, David, and Bruce A. Berkowitz. "Testing the calcium hypothesis of aging in the rat hippocampus in vivo using manganese-enhanced MRI." Neurobiology of aging 35 (2014) 1453-1458 This study used MeMRI to examine how aging affects changes in L-type calcium channels in the hippocampus. It has been hypothesized that increases in calcium influx through L-type calcium in the hippocampus that is associated with cognitive decreases. By utilizing MeMRI Dr. Berkowitz was able to non-invasively characterize L-type calcium channels in a longitudinal study. They found that aged rats have significantly increased manganese uptake in pyramidal neurons in the hippocampus compared to their younger selves. Although they were not able to look at mechanistic changes, the trends that they seen in increases in manganese uptake are consistent with the hypothesis of hippocampal plasticity linked to cognitive decline. In relation to our study this paper talks about imaging control rats as well. They found that their were no differences in the older control rats regions of interest when compared to the younger rats regions of interest. They also looked at differences in manganese uptake in animals that had been previously injected versus non-injected animals. There were no differences in animals that had been previously injected versus not injected. In the discussion they briefly talked about changes in the BBB with age that may affect manganese uptake over time. This is important to what we study since we are doing longitudinal studies. ~JI

ROSTROVENTROLATERAL MEDULLA NEURONS PREFERENTIALLY PROJECT TO TARGET-SPECIFIED SYMPATHETIC PREGANGLIONIC NEURONS

Christopher J. Madden , Alan F. Sved. American Journal of Physiology - Heart and Circulatory PhysiologyPublished 1 December 2003Vol. 285no. H2734-H2748DOI: 10.1152/ajpheart.00155.2003. These studies investigated the role of C1 neurons in th RVLM in the control of BP. They injected DBH-saporin into the RVLM and waited 2 weeks. They found that MAP was 10mm Hg lower in rats with greater than 80% depletion of RVLM C1 neurons when compared to control injected group. As for baroreflex function, in the greater than 80% C1 depleted group that was attenuated gain in respone to sodium nitroprusside. In the smaller depleted group that was no difference in in baroreflex function when compared to the control group, A5 depleted group and Mabzap group. In response to hydralazine 80$ depleted C1 group has lower MAP when compared to groups that received control injections. As for catecholamine release in response to hydralazine was attenuated in the 80% depleted C1 group when compared to the control groups. In response to sciatic nerve stimulation the anti DBH group demonstrated attenuated responses when compared to all other groups. Bezold-Jarisch reflex, chemoreflex, and glutamate responses were not different between groups. From these studies they concluded that the C1 are playing a role in the tonic and reflex control of BP.-MD

Functional cardiovascular action of L-cysteine microinjected into pressor sites of the rostral ventrolateral medulla of the rat

Yumi Takemoto Amino Acids (2014) 46:863–872 DOI 10.1007/s00726-013-1651-5 The main purpose of this study was to determine the cardiovascular response to L-cysteine microinjection into the RVLM. They also investigated cardiovascular responses to D- cysteine and N-acetyl-L-cysteine. They used Wistar rats and did microinjections using L-cysteine, D-cysteine, L-glumate, MK801 antagonist against NMDA iEAA receptors and CNQX is an antagonist against non NMDA. They injected L- cysteine caused and increase blood pressure. Injections of L-cysteine and L-glutamate caused a dose dependent increase in blood pressure and in HR. In response to D- cysteine and N-acetyl-cysteine there were no changes in BP and HR. When the CNQX and MK801 were given prior to the injection of L-cysteine, BP and HR responses were attenuated. These data suggest that t L-cysteine does have the ability to increase neuronal activity, and could be a possible neurotransmitter. This study also demonstrated that when MK801 was given alone and then L-cysteine was injected BP and HR responses were attenuated. The results from this study suggest that the response to L-cysteine was due to activation of iEAA receptors in the RVLM. –MD

Endogenous hydrogen sulfide in the rostral ventrolateral medulla/Bötzinger complex downregulates ventilatory responses to hypoxia.

Respir Physiol Neurobiol. 2014 Jun 17. pii: S1569-9048(14)00154-2. doi: 10.1016/j.resp.2014.06.007. [Epub ahead of print] Donatti AF, Soriano RN, Sabino JP1 Branco LG. Previous studies using neonatal rat brainstem slices had shown that application of a compound that results in H2S production has a bilateral effect on the activity of the hypoglossal nerve rootlet, first decreasing and then increasing activity. These slices contained RVLM and BotC, so they thought that RVLM activity might be involved. In this paper, they decided to look at how hydrogen sulfide (H2S) regulates sympathetic nerve activity after activation in the RVLM. H2S is a common environmental toxin, and also acts as an endogenous neurotransmitter - so to study the effect of H2S in the RVLM, they did microinjections in to the region of the RVLM/BotC with Na2S to induce production of H2S or aminooxyacetate (AOA) to inhibit it via inhibition of cystathionine-B-synthase. They found that AOA injections up to 2pmol did nothing in normoxic rats, however in hypoxic rats, 1pmol injection of AOA was sufficient to increase breathing over the already increased hypoxia-inducd increase in respiration. On the other hand, 2pmol of Na2S could attenuate the increased respiration induced by exposure to hypoxia. When they measured the endogenous levels of H2S in rats experiencing hypoxia, they found it was lower than in normoxic rats. So my question is, I guess, is if this Na2S turns to H2S, doesn't that mean it's acting as a base. If that's true, is it reducing activation of chemoreceptors by decreasing free protons? It makes sense in my head, but I'm not a chemist. -DH

Age-Related Impairment in Choroidal Blood Flow Compensation for Arterial Blood Pressure Fluctuation in Pigeons

Reiner, Anton, et al. "Age-related impairment in choroidal blood flow compensation for arterial blood pressure fluctuation in pigeons." Investigative ophthalmology & visual science 52.10 (2011): 7238-7247. It is well known in our area of research that increased sympathetic nerve activity is a risk factor for many cardiovascular disease states. Well we mainly focus on peripheral vascular consequences associated with cardiovascular disease states, there is also end organ damage that can have other damaging affects. This study in particular is examining changes in the regulation of choroidal blood flow (ChBF) with age. Similarly to the kidneys, the choroid will regulate blood flow by changing vascular resistance in correlation with blood pressure. In healthy individuals, an increase in blood pressure will cause an increase in vascular resistance and the maintenance of blood flow. Vice versa, if blood pressure decreases the choroid will vasodialate as much as possible to compensate and maintain blood flow. Using Doppler flowmetry to measure ChBF and telemetry in pigeons ranging from .5 to 17 years, Fitzgerald's laboratory was able to longitudinally charaterize ChBF regulation with age. They found that between a arterial blood pressures (ABP) of approximately 55mmHg-135mmHg pigeons younger than 8 years of age were able to properly maintain ChBF with changes in vascular resistance. However, in pigeons older than 8 years of age this baroreflex was impaired. Specifically, above 90mmHg and below 60mmHg these pigeons had a positive correlation between changes in ABP and changes in ChBF. It was also found that between 60mmHg-90mmHg older pigeons were only able to maintain ChBF between 60 and 70% of basal level. Where as, in young pigeons ChBF was maintained at 100% between 55mmHg-135mmHg. To support both sets of data, a positive correlation between changes in vascular resistance and ABP existed in the younger cohort of pigeons, but not the older cohort. These data suggest that regulation in ChBF is effected with age, and Reiner suggest two possible mechanisms. Either changes in neurogenic baroreflex regulation or myogenic regulation at the level of the vasculature. However, more studies need to be done in order to determine which and or if both are playing a role. Conclusively, the study determined this loss of ChBF regulation may in part be responsible for onset ocular disease states, and that these disease states may be perpetuated by risk factors that alter sympathetic nerve activity such as hypertension or age. ~JI

Brain-selective overexpression of angiotensin-converting enzyme 2 attenuates sympathetic nerve activity and enhances baroreflex function in chronic heart failure.

Hypertension. 2011 Dec;58(6):1057-65. doi: 10.1161/HYPERTENSIONAHA.111.176636. Epub 2011 Oct 24. Xiao L, Gao L, Lazartigues E, Zucker IH. Most of the papers we read are about ACE, AngII, and AT1/2 receptors, but ths group decided to look at ACE2 and how it can affect production of Ang-(1-7) and activation of the mas receptor. This is important to look at because different groups have shown that microinjection of Ang-(1-7) in to the RVLM can be sympathoexcitatory in rabbits and rats. To do this, they created synapsin-ACE2 (SA) mice that would overexpress ACE2 production in all neurons. They gave SA and wild type control mice CHF by coronary artery ligation (CAL) and saw lower MAP in SA mice. They then got an indirect measure of SNA by measuring urinary NE and saw that while WT mice had increased urinary NE, SA mice didn't. This presumed decrease in SNA was directly observed by seeing lower renal SNA in SA CAL mice than WT CAL mice. They then looked at heart rate and SNA baroreflex during administration of phenylephrine and saw that while little or no reflex was seen in WT CHF mice, SA CHF mice decreased HR and SNA similar to what sham mice showed. But if ACE2 causes Ang-(1-7) that can be sympathoexcitatory, how come mice overexpressing ACE2 have LESS SNA? Possibly because they found attenuated ACE and AT1 receptor upregulation in the RVLM and NTS of SA CHF mice compared to WT CHF... So I guess that's cool and all, but I have to ask a couple of questions... what concentrations of ACE2 are normally in a brain, what concentrations of ACE2 were in these mice brains, and what concentration is normally active in hypertensive critters vs what concentration throws the whole thing out of whack? These are questions that I didn't see addressed in the discussion, but ones that kind of stick out to me. I guess it's time for a mas agonst in the WT mice and antagonists in the SA mice. These drugs exist and it would be cool to see them used in a follow up paper. -DH

Immunoreactivity for the NMDA NR1 subunit in bulbospinal catecholamine and serotonin neurons of rat ventral medulla.

Auton Neurosci. 2013 Oct;177(2):114-22. doi: 10.1016/j.autneu.2013.02.024. Epub 2013 Apr 4. Llewellyn-Smith IJ, Mueller PJ. In this paper, the two awesome authors tackled a pretty good question that had always been overlooked; we know that presympathetic RVLM neurons can be excited by glutamate and that they show expression of the NMDAR1/NR1 subunit... but do ALL of these neurons express it, and if not, what percentage do and don't? To figure this out, they started with CTB injections at T9-T10 to retrogradely label spinally projecting neurons, and then they looked at TH+ and TH- neurons in the RVLM. They also looked at spinally projecting serotonergic (TpH+) and non-serotonergic (TpH-) neurons in the raphe pallidus (RPa). Once they had CTB labeled cells, they used fluorescent-conjugated antibodies to label CTB in blue, NR1 in red, and TH or TpH in green. Then it was just an issue of counting single, double, and triple labeled cells. They found that pretty much all spinally projecting neurons in the RVLM had NR1, with 100% of C1 neurons and ~96% of non-C1 showing expression. The overall distribution of CTB labeled C1 and non-C1 was about 50/50, with a slightly higher proportion (60%) in the 120um rostral to FN0. The story was pretty much the same with TpH in the RPa, except that about 80% of the cells were TpH+ vs 20% TpH-. The conclusion here is that yes, basically 100% of these cells express the NR1 subunit, so probably 100% of these cells use NMDAR to control their release of neurotransmitter. In the case of the RVLM, as we suspect, NMDAR regulation may be altered in disease states. -DH

Swimming exercise changes hemodynamic responses evoked by blockade of excitatory amino receptors in the rostral ventrolateral medulla in spontaneously hypertensive rats.

Biomed Res Int. 2014;2014:487129. doi: 10.1155/2014/487129. Epub 2014 Feb 18. Ogihara CA, Schoorlemmer GH, Lazari Mde F, Giannocco G, Lopes OU, Colombari E, Sato MA. In this paper, they looked at differences in glutamate-mediated RVLM activity between sedentary and swim-exercise-trained rats. Previous work from the group showed that using GABA to inhibit the NTS results in enhanced hindlimb vasodilation in exercise-trained SHR rats. This time, they wanted to look at things further down the autonomic regulation line, so they used SHR rats again (exercised and sedentary) and gave microinjections of kynurenic acid into the RVLM. They found the same enhanced conductance/vasodilation in swimmers compared to seds as before, and that these results seen in SHR rats were not seen in WKY rats. To look at how that vasodilation was regulated peripherally, they blocked nitricic oxide production via L-NAME inhibition of nitric oxide synthase. They saw that the RVLM-glutamate-receptor-blockade-induced-vasodilation was attenuated in exercised rats but not in sedentary rats. Again, these results were not seen in WKY rats, suggesting that SHR rats' disorder is rooted in the RVLM as well as in peripheral effects. Just like we talked about in our lab meeting today, we tend to look at the RVLM as the end of the story, but there are a lot of other things involved that we have to keep in mind. -DH

The neurogenic phase of angiotensin II-salt hypertension is prevented by chronic intracerebroventricular administration of benzamil.

Physiol Rep. 2014 Feb 26;2(2):e00245. Osborn JW, Olson DM, Guzman P, Toney GM, Fink GD. “Hypertension induced by chronic administration of angiotensin II (AngII) is exacerbated by high‐salt intake”. The authors from this study tested whether intracerebroventricular (ICV) administration of the sodium channel/transporter blocker benzamil would prevent AngII‐induced hypertension. As previously known, high salt diet with AngII increased mean arterial pressure in the presence of ICV vehile administration. Benzamil administration ICV had effect on MAP changes only after day 5 and reversed Ang II-induced MAP to control levels by day 13. Sodium or water balance was not different between the control and treatment groups. The results from this study suggest that sodium channels and/or transporters in the brain play a role in mediating AngII salt hypertension. However the molecular targets or the precise locations (within the brain) at which benzamil acts are unknown. It would be interesting to pursue this in the future studies.- Madhan

Manganese-enhanced magnetic resonance imaging reveals increased DOI-induced brain activity in a mouse model of schizophrenia

Malkova, Natalia V., et al. "Manganese-enhanced magnetic resonance imaging reveals increased DOI-induced brain activity in a mouse model of schizophrenia." Proceedings of the National Academy of Sciences (2014): 201323287. It is well known that mental illnesses, such as schizophrenia, are difficult to study in an animal model for a number or reasons, so many laboratory do their best by studying mental illness like symptoms. For this study, in order to better understand the role that the environmental risk factor maternal immune activation (MIA) plays in schizophrenia and autism, Malkova and colleges examined DOI-induced brain activity. DOI, 2,5-dimethoxy-4-iodoamphetamine, is a drug that through activation of the serotonin receptor 5-HT2AR, produces similar hallucinations as experienced in schizophrenia. Multiple methods (quantitative PCR, behavioral analysis, and MeMRI) were then used to compare differences in DOI-induced activity in control versus MIA animals. They found that there was an upregulation of drug induced head twitches, manganese accumulation in multiple areas of the brain (primary and secondary motor cortex, caudate putamen, medial group of the dorsal thalamus, and parafascicular thalamic nucleus), and expression of 5-HT2A receptor and its down stream signaling molecules in MIA mice compared to controls. What I found most interesting in this paper was the MeMRI protocol. For this experiment they first took baseline scans one week prior to the injection of manganese. Following the the I.P injection a week later they then imaged the animals at 24hrs, injected the animals with DOI, and then imaged them again 27hrs post the I.P injection. For statistical analysis, they then compared baseline levels to the 24hr image as well as the 27hr image. This may be applicable for our studies looking at differences in exercising versus sedentary brain activity of the RVLM. If we were to take baseline scans, inject manganese one week later, image the animals at 24hrs, raise and/or lower blood pressure for 8 hours and then immediately image the animals at 32hrs we may see different results then previously observed. This is one possibility I had not previously thought of. ~JI

Three-dimensional inversion recovery manganese-enhanced MRI of mouse brain using super-resolution reconstruction to visualize nuclei involved in higher brain function.

NMR Biomed. 2014 Jul;27(7):749-59. doi: 10.1002/nbm.3108. Epub 2014 May 10. Poole DS, Plenge E, Poot DH, Lakke EA, Niessen WJ, Meijering E, van der Weerd L. In this paper, they wanted to look at a different way of processing MRI images (inversion recovery spin echo (IR-SE), which can give better contrast than gradient echo (GE) imaging) to see if it could improve upon current MEMRI techniques. Since IR-SE tends to have lower resolution than would be really useful for an in vivo study, they wanted to merge multiple images taken at different angles to produce a super-resolution reconstruction that would give the resolution necessary to resolve functional regions of brain tissue. To do this SRR IR-SE MEMRI study, they started with two mice that received 300mg/kg MnCl2 over 8 days via subcutaneous osmotic minipump. They imaged the brains under both GE and SRR IR-SE and compared results for a lot of regions of the brain (including such favorites as PAG, PVN, and IC). The results of the comparison were kind of a 50/50 toss-up. Some regions could only be seen by GE, others could only be seen by SRR IR-SE, and some regions were just better visualized with one technique than the other. However, this study was all just about imaging contrast, and none of it was looking at functional changes (or at least not looking at intentional functional changes). It would be interesting to see them compare techniques in a region that had similar results with the two techniques, but do it AFTER causing an activity-dependent change in Mn uptake. I'll take a wild guess and say that they're probably already working on this. -DH

Sympathoexcitatory CVLM neurons mediate responses to caudal pressor area stimulation

Madhusudan Natarajan , Shaun F. Morrison, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology Published 1 August 2000 Vol. 279 no. R364-R374. The caudal pressor area is capable of causing increases in BP and sympathetic nerve activity when stimulated. The purpose of this article was to determine the mechanism by which the CPA is able to increase SNA and BP. Using microinjection technique they gave bic into the RVLM and saw they got increases in BP and SSNA. Next they wanted to determine whether CPA was mediating its response by removal of inhibitory input to RVLM. Bilateral Bic injections into RVLM was done and resulted in increases in BP and SSNA. Following disinhibition of RVLM they gave Bic into the CPA and that SSNA and BP went up even further. Next they want to determine the role of CVLM in in the CPA sympathoexcitatory pathway, so GABA A receptors were blocked in the CVLM and Bic was injected in the CPA and this resulted in decrease in BP and SNA. When the reverse was done there were increases in BP and SSNA. They investigated whether glutamate was playing a role in driving CVLM activity. Bic was injected bilateral into both CVLM and the CPA followed by a unilateral microinjection of DLH into CPA and saw increases in BP and SSNA. Next they wanted to see if kynurenic acid would block the effects of DLH activation of CPA. So They unilateral blocked glutamate receptors in the CVLM and gave DLH into the contralateral CPA and showed that the response was abolished. These data demonstrate that CPA activates excitatory neurons in the CVLM with glutamate as its neurotransmitter. -MD

Ventral Lamina Terminalis Mediates Enhanced Cardiovascular Responses of Rostral Ventrolateral Medulla Neurons During Increased Dietary Salt

Julye M. Adams, Megan E. Bardgett, Sean D. Stocker, Hypertension. 2009;54:308-314; originally published online June 8, 2009; http://hyper.ahajournals.org/content/54/2/308. The purpose of this study was to determine if the forebrain lamina terminalis was playing a role to the development of enhanced cardiovascular responses when RVLM receives excitatory and inhibitory stimulation. Similar to previous findings they showed that were enhanced BP and RSNA responses to Glutamate and GABA in the 0.9 % rat group when compared to the control group. In order to determine whether the OVLT is playing a role they lesioned this area and repeated that injection of glutamate and GABA into the RVLM. They found that when compared to that 0.9 % saline group with LT lesion were not different from control with LT lesion. They also investigated the responses to glutamate and GABA in acute lesion of LT and found that the 0.9% saline group still demonstrated enhanced cardiovascular responses when compared to the control. These data suggest that high diet mediates the increased sensitivity of RVLM to glutamate and GABA through the LT. -MD

Vesicular glutamate transporter 2 is required for the respiratory and parasympathetic activation produced by optogenetic stimulation of catecholaminergic neurons in the rostral ventrolateral medulla of mice in vivo.

Eur J Neurosci. 2014 Jan;39(1):98-106. doi: 10.1111/ejn.12421. Epub 2013 Nov 18. Abbott SB, Holloway BB, Viar KE, Guyenet PG. As we all know, The RVLM communicates by releasing glutamate on to all of its targets, including respiratory groups... Or so we thought we knew. It turns out that this has really only been implied, suggested, hinted at, and supported - which resulted in us all believing it to be true regardless of the fact that direct evidence for it was pretty much absent. That's what this group set out to change with this paper - they wanted to directly link RVLM neuron activity with activation of target regions through glutamatergic transmission. To do this, they crossed DBH-Cre mice with mice that had the sequence for part of VGLUT2 flanked by loxP sites. The offspring mice then had selective knockout of VGlut2 in the DBH-expressing cells, including the C1 neurons. Animals were injected with a virus that would cause expression of Channelrhodopsin2 (ChR2) conditional to expression of Cre - which would be the DBH-expressing cells, which were the same cells that had deleted their own VGLUT2. They found that their ChR2 expression worked well and that RVLM cells in brainstem slices could be stimulated with light. They extended this to show that it worked in vivo as well. They found that in mice with intact VGLUT2, photostimulation of the RVLM could increase breathing frequency, but knockout mice did not show the effect. They found the same effect when they monitored the activity of the Vagus, presumably because RVLM neurons are known to directly innervate the dorsal motor nucleus of the vagus. Finally, they used prazosin to block A1-adrenoreceptors and found that this blockade did not change the results of photostimulation in either strain, suggesting that none of the effects were mediated by catecholaminergic signaling. -DH

Glutamatergic inputs to the CVLM independent of the NTS promote tonic inhibition of sympathetic vasomotor tone in rats

Daniel A. Mandel and Ann M. Schreihofer Am J Physiol Heart Circ Physiol 295: H1772–H1779, 2008. First published August 29, 2008; doi:10.1152/ajpheart.216.2008. We know that the CVLM is important providing inhibitory input to RVLM. It has been shown that GABAergic input from CVLM that is not baroreceptor sensitive. This study investigates what is driving the baro-independent input that is coming from CVLM. They inhibited the baroreceptors by lower AP using SNP and then they inhibited the NTS bilateral using muscimol, AP did not change in response to muscimol in NTS. Finally, CVLM was inhibited with muscimol resulting in an increase in AP, SNA and HR. In order to determine whether the baro-independent neuronal activity was driven by glutamatergic input, the glutamate receptor antagonist, kynurenate was bilaterally microinjected into CVLM. After they confirmed that the NTS was blocked they gave kynurenate into the CVLM bilaterally. This lead to increased AP, SNA and HR. In order to whether the central respiratory drive was playing a role in the control of baro-independent gabaergic neurons activity, While AP was lowered with SNP and NTS was blocked with muscimol, in vagotomized rats, PCO2 was altered. When PCO2 was increased this greater increases in SNA in response to kynurenate in CVLM were observed. These data suggest, that baro-independent neuronal activity is driven by glutamate and a possible source of this glutamatergic driven may be from central respiratory areas.-MD

Baro-Activated Neurons With Pulse-modulated Activity in the Rat Caudal Ventrolateral Medulla Express GAD67 mRNA

Ann M. Schreihofer and Patrice G. Guyenet j.neurophysiology 89: 1265-1277, 2003 10, 1152/jn00737.2002 We already know that the CVLM is important because it baro-dependent and independent input to RVLM. This study investigated whether CVLM neurons actually projected to the RVLM and that they were GABAergic. Using extracellular recording, they recorded neuronal activity in the CVLM in response to loading and unloading the baroreceptor along with activating other reflexes. They showed in 17 rats that there are baro- activated neurons in the CVLM that are silenced by decreases in AP and some that were not. They also showed that the majority of the baro- activated neurons displayed an increase in activity in response to phenyl biguanide. They also showed that there were baro-inhibited neurons in the CVLM. These neurons that were baro inhibited also were inhibited by phenyl biguanide. In order to determine the phenotype of the neurons they recorded they did some histology along with in situ hybridization. Once the extracellular recording was completed they filled the cell they were recording from with biotinamide. Sectioning was done and they stained for the biotinamide and once they located the cell they did immuno for GAD67 and ChaT. They found a high density of GAD67 neurons in CVLM and a smaller portion of only ChaT IR neurons in CVLM.TH was also found in the CVLM but this as distinct from the GAD67 and Chat IR neurons. The 12 baro-activated neurons that were GAD 67 IR, 5 were examined for ChaT IR. They found that there was no ChaT IR. As for the baro-inhibited cells they found that all of them were baro-inhibited and none displayed GAD 67 IR. This study demonstrates that baro activated neurons are GABAergic and not only play role in the baroreflex but in the Bezold-jarisch reflex and noxious tail pinch. -MD

Non-invasive, in vivo monitoring of neuronal transport impairment in a mouse model of tauopathy using MEMRI

Bertrand, Anne, et al. "Non-invasive,< i> in vivo monitoring of neuronal transport impairment in a mouse model of tauopathy using MEMRI." NeuroImage 64 (2013): 693-702. The tau protein is a well define protein involved in the stability of microtubules, found mainly in the axonal compartment of neurons. Unfortunately, under certain disease states referred to as tauopathies, such as Alzheimer's disease, there is a dysfunction in the tau protein due to over expression or increased phosphorylation that leads to aggregated tau protein. This tau protein aggregation is thought to blunt microtubule stabilization found under normal conditions and cause impairment of axonal transport, further leading to synaptic dysfunction. Previous to this study, the only methods used to examine axonal transport were either invasive in vivo techniques or in vitro techniques that came with many limitations. Anne Bertrand et. al, were interested in developing manganese enhanced MRI (MEMRI) as a non-invasive, in vivo technique that would allow for the observation of axonal transport viability under normal and tauopathy conditions. To do this a cross section study was done with both transgenic (tau pathology) and control mice, each population were injected intranasally with 1.5ul of 5M manganese chloride and groups were imaged at 3, 6, and 9 months at 1, 4, 8, 12, 24, 36, 48hrs, and 7-10 days following the injection. Each cohort was then sacrificed and used for immunhistochemistry examining tau protein concentrations. What Bertrand found was that there were significant decreases in MnCl2 signal propagation between WT and transgenic mice at 6 months in age in two tissue layers throughout the olfactory track that were examined (glomerular and mitral cell layers). There was also a significant decreases in signal propagation due to age between the transgenic mice 3 months of age and 6 months of age within the glomerular and mitral cell layer (smaller differences seen in the mitral cell layer). After immunohistochemistry, they were then able to correlate tau pathology to the observed MEMRI parameters. In this case, there was a significant negative correlation between tau pathology and signal propagation of manganese. Correspondingly, there was a greater correlation to dendritic tau staining and the MEMRI parameters compared to somatic tau staining and MEMRI parameters. Interestingly, this paper also did GFAP staining for astrogliosis to rule out differences in manganese accumulation from discrepancies in astroglial cells. They found no differences between GFAP staining in the WT and transgenic mice. Conclusively, this study demonstrated that MEMRI can be used as a viable in vivo technique for the analysis of axonal transport function, which may possibly be used for clinical analysis of tau protein as a biomarker for many disease states or possibly treatment options. ~JI

Chronic absense of baroreceptor inputs prevents training-induced cardiovascular adjustments in normotensive and spontaneously hypertensive rats

Ceroni, Alexandre, et al. "Chronic absence of baroreceptor inputs prevents training‐induced cardiovascular adjustments in normotensive and spontaneously hypertensive rats." Experimental physiology 94.6 (2009): 630-640. It has been shown in both rats and humans, that a low intensity exercise regiment can be used to lower resting heart rate and consequentially blood pressure, in both normotensive and hypertensive individuals. Currently, cardiovascular responses during exercise are known to be driven by both a feedforward pathway (central command) and a feedback pathway (baroreceptors, chemoreceptors, muscle metaboreflex) that are synergistic in modifying cardiovascular responses. However, it is still unclear as to the underlying mechanisms during exercise drive the beneficial . Dr. Michelini's laboratory hypothesized that an intact baroreceptor reflex is necessary for training-induced adjustments of cardiovascular control to occur. To investigate their hypothesis they performed sino-aortic denervations in both normotensive (WKY) and spontaneously hypertensive rats (SHRs) and looked at the effects of low intensity exercising training in both sham WKYs and SHRs compared to SAD WKYs and SHRs. They found that a sino-aortic denervation completely blunted the affects of exercise training in both WKYs and SHRs compared to what was seen in both sham populations. More specifically, the SAD populations did not experience bradycardia or decreased blood pressure after a training as the sham groups (normotensive did not experience decreases in BP). They were however, able to observe reduce pressure variability and heart rate variability in SAD SHRs on an exercising regiment compared to the SAD SHRs not exercising. Overall, the study was able to show that the baroreceptor reflex input plays some role in allowing for cardiovascular adjustments driven by exercise training. ~JI