Major Contribution of the Medial Amygdala to Hypertension in BPH/2J Genetically Hypertensive MiceNovelty and Significance
BPH/2J mice are recognized as a neurogenic model of hypertension primarily based on overactivity of the sympathetic nervous system and greater neuronal activity in key autonomic cardiovascular regulatory brain regions. The medial amygdala (MeAm) is a forebrain region that integrates the autonomic response to stress and is the only region found to have greater Fos during the night and daytime in BPH/2J compared with BPN/3J mice. To determine the contribution of the MeAm to hypertension, the effect of neuronal ablation on blood pressure (BP) was assessed in BPH/2J (n=7) and normotensive BPN/3J mice (n=7). Mice were preimplanted with radiotelemetry devices to measure 24-hour BP and cardiovascular responses to stress, before and 1 to 3 weeks after bilateral lesions of the MeAm. Baseline BP was 121±4 mm Hg in BPH/2J and 101±2 mm Hg in BPN/3J mice (Pstrain<0.001). MeAm lesions reduced BP by 11±2 mm Hg in BPH/2J mice (Plesion<0.001) but had no effect in BPN/3J mice. The hypotensive effect of lesions in BPH/2J mice was similar during both day and night, suggesting that the MeAm has tonic effects on BP, but the pressor response to stress was maintained in both strains. Midfrequency BP power was attenuated in both strains (Plesion<0.05) and the depressor responses to pentolinium after enalaprilat pretreatment was attenuated after lesions in BPH/2J mice (Plesion<0.001; n=3). These findings indicate that the MeAm provides a tonic contribution to hypertension in BPH/2J mice, which is independent of its role in stress reactivity or circadian BP influences.
BPH/2J mice are a genetic model of hypertension developed in the 1970s by Schlager et al.1 These mice were selectively bred for elevated blood pressure (BP) alongside a normotensive (BPN/3J) and hypotensive control strain (BPL/1J), from a base population of 8 inbred strains of mice. Since then a range of pathophysiological factors have been studied to determine the cause of hypertension in BPH/2J mice, and the relatively modest characterization has been increasing in recent years, possibly because of advances in technology used to study mice.2,3 Our own findings suggest that hypertension in BPH/2J mice is sympathetically mediated, based on the greater depressor response to ganglion blockade, which ultimately abolishes the hypertension in BPH/2J mice and also greater midfrequency mean arterial pressure variability (MAP power).4 Even the percentage depressor response to ganglion blockade is greater in BPH/2J mice compared with normotensive controls.4 This contrasts findings in spontaneously hypertensive rats (SHRs) that are likely confounded by a vascular amplifier effect5 caused by vascular structural changes, which contribute to hypertension in adult SHRs.6 Recently, we have also reported that BPH/2J mice have renal sympathetic hyperinnervation and enhanced renin synthesis, which results in a greater contribution of the renin–angiotensin system (RAS) to BP maintenance during the dark period of the 24-hour light cycle in BPH/2J mice compared with BPN/3J mice.7 Early studies indicated that BPH/2J mice have aberrant brain catecholamine levels,8 suggesting that the hypertension may be centrally mediated. Furthermore, using Fos as a marker of neuronal activity, BPH/2J mice were also shown to have greater neuronal activity in key cardiovascular regulatory brain regions compared with normotensive control BPN/3J mice.4 Importantly, of the limbic, hypothalamic, and medullary brain regions analyzed using Fos immunohistochemistry, the medial amygdala (MeAm) was the only region to show greater neuronal activity during the light (inactive) and the dark (active) period in BPH/2J compared with BPN/3J mice,4 suggesting that this region may be inherently overactive in BPH/2J mice. Furthermore, neuronal activity within the MeAm correlated strongly with BP level (R=0.98), suggesting that neuronal activity in the MeAm may be related to BP level.4
The MeAm is an important limbic region that integrates sensory information, including stress and fear as well as reproductive-related inputs, and regulates the subsequent cardiovascular, behavioral, and hormonal responses.9–11 The MeAm is activated by stressful stimuli particularly of psychological rather than a physiological nature12 and is involved in the integration of olfactory and chemosensory signaling involved in predator and territorial responses and reproduction.13,14 Many studies using Fos as a marker of neuronal activity have shown strong activation of the MeAm associated with stressful stimuli.13,15,16 Moreover, inhibition of the MeAm has demonstrated that it does indeed mediate the cardiovascular response to stress in rats, indicating that Fos activity is not merely a response to the stressor.17,18 The contribution of the MeAm to baseline BP is not as widely studied. Importantly, Fukumori et al19 performed MeAm lesions in prehypertensive 4-week-old SHRs, which attenuated the elevation in BP by 14 weeks. Although there was no normotensive control strain, this study demonstrates that the MeAm contributes modestly to the development of hypertension in SHRs compared with sham controls.
The major aim of the present study was to determine whether there is a causal relationship between the greater neuronal activity within the MeAm and the hypertension or exaggerated stress response in BPH/2J mice. To assess the contribution of the MeAm to hypertension, the effect of MeAm lesions on BP and cardiovascular reactivity to stress was assessed.
Experiments were performed on normotensive BPN/3J (n=13) and hypertensive BPH/2J (n=13) 18-week-old male mice.
BP telemetry transmitters (model TA11PA-C10; Data Sciences International, St Paul, MN) were implanted as detailed in the online-only Data Supplement.
Protocol and Experimental Procedures
After a 10-day recovery period from telemetry surgery, baseline cardiovascular parameters of MAP, heart rate (HR), and locomotor activity were recorded continuously across 48 hours in freely moving mice in their home cage. During the 4 subsequent days, animals were then exposed to a series of behavioral stimuli, including restraint, dirty-cage switch and shaker stress, conducted on separate days during the light period when the animals were inactive, as described previously.20,21 Animals underwent the same 48-hour cardiovascular and locomotor recordings and stress test regime 1 and 3 weeks after MeAm lesion or sham surgery. At the conclusion of the study immediately after 1 hour of dirty cage stress, all mice were anesthetized and perfused and brains collected for Fos analysis.
Lesions of the MeAm
Lesions were produced in anesthetized BPN/3J and BPH/2J mice (n=7 per group) by performing bilateral microinjections of ibotenic acid into the MeAm. Sham controls underwent the same surgery but no injection was performed (n=6 per group). Details of the lesion surgery are available in the online-only Data Supplement.
On separate days mice were exposed to 60 minutes of restraint stress, 60 minutes of dirty-cage switch stress, and 5 minutes of shaker stress, as detailed in the online-only Data Supplement.
Cardiovascular Variability and the Cardiac Baroreceptor Sensitivity
Spectral analysis of cardiovascular variability and the baroreceptor HR reflex are detailed in the online-only Data Supplement.
Cardiovascular Response to Angiotensin-Converting Enzyme Inhibition and Ganglion Blockade
BPH/2J mice (n=3) were administered ganglion blocker, pentolinium (5 mg/kg, IP), 30 minutes after administration of the angiotensin-converting enzyme inhibitor, enalaprilat (1.5 mg/kg, IP). The cardiovascular responses to these drugs were measured at baseline and 3 weeks after MeAm lesions. Angiotensin-converting enzyme inhibition before ganglion blockade has been shown to reduce the compensatory response of the RAS after ganglion blockade, unmasking the full contribution of the sympathetic nervous system (SNS) in these mice.7
Fos immunohistochemistry and analysis were performed on brain sections from mice 4 weeks after sham or MeAm lesion surgery, which were anesthetized and perfused immediately after dirty-cage switch stress. Details on Fos immunohistochemical analysis are available in the online-only Data Supplement.
Cardiovascular data were expressed as mean±SEM. The data were analyzed by multi-factor, nested split-plot ANOVA, which allowed for within animal and between animal contrasts.22 A combined residual was used that pooled the between and within animal variance as described previously.23 A P value of <0.05 was considered significant.
Dirty-cage switch stress–induced Fos activation was used to determine the extent of MeAm lesions. Animals were considered to have adequate lesions and were included in analysis only if the extent of the lesion was >60%,24 as indicated by Fos counts which were <40% of that found in sham controls of each strain. Approximately 60% of mice injected with ibotenic acid were considered to have adequate MeAm lesions. Fos counts in the MeAm of BPH/2J mice with lesions (n=7) were 73% lower than sham controls and in BPN/3J mice (n=7) were 81% lower than sham controls (Plesion<0.001; Figure 1B). Despite Fos activity being markedly reduced in both strains after MeAm lesions, Fos counts were still marginally higher in BPH/2J than in BPN/3J mice (Pstrain=0.04; Figure 1B).
Fos counts were ≈2-fold higher in the central amygdala after MeAm lesions compared with sham in both BPH/2J and BPN/3J (Plesion<0.001, both; Table S1 in the online-only Data Supplement) mice (n=3 per group). Likewise, the Fos counts in the anterior cortical nucleus of the amygdala were greater after MeAm lesions compared with sham in BPH/2J and BPN/3J mice (Plesion<0.001, both; Table S1). However, Fos counts in the basolateral amygdala (BLA) were comparable between BPN/3J mice with MeAm lesions or sham surgery (Plesion=0.1) and were only greater in BPH/2J mice with MeAm lesions compared with sham (Plesion<0.001; Table S1).
Baseline Cardiovascular Measurements
MAP in BPH/2J mice was higher than BPN/3J mice during a 24-hour period (P<0.001; n=13 per strain; baseline pooled from sham and lesion groups). During the dark (active) period, MAP in BPH/2J mice was 25% greater, HR was 37% greater, and locomotor activity was 4.4-fold greater than BPN/3J mice (Pstrain<0.001 all). During the light (inactive) period, MAP in BPH/2J mice was 12% greater than in BPN/3J mice (Pstrain=0.04) and HR was 21% greater (Pstrain=0.002), but locomotor activity was comparable between strains (Pstrain=0.9).
Effect of MeAm Lesions on Cardiovascular and Locomotor Measurements
After MeAm lesions, 24-hour MAP was reduced in BPH/2J mice by –10.3±2.8 mm Hg after 1 week (Plesion<0.001) and by –12.6±4.2 mm Hg after 3 weeks (Plesion<0.001; Table 1; n=7). The hypotensive effect of MeAm lesions in BPH/2J was similar at 1 and 3 weeks post lesion (Pweek=0.7) and was also similar during the light (inactive) and dark (active) periods (Pstate>0.1; Figure 2A). By contrast, BPN/3J mice showed no change in MAP at 1 or 3 weeks after MeAm lesion (Plesion>0.8; Pweek=1.0; n=7). Furthermore, 1 and 3 weeks after sham surgery, MAP was comparable with baseline in BPN/3J or BPH/2J mice (Psham>0.3; Table 2; Figure 2B; n=6 per group). The hypotensive effect of MeAm lesions was markedly different from that in BPN/3J mice (Pstrain=0.002) and also different from the effect of sham surgery in BPH/2J mice (P=0.03). Furthermore, the elevated MAP during the light (inactive) period at baseline in BPH/2J compared with BPN/3J mice was abolished after MeAm lesions (Pstrain=0.8) although MAP during the dark (active) period still remained greater in BPH/2J mice (Pstrain=0.001).
MeAm lesions reduced HR in BPH/2J mice at 1 and 3 weeks post lesion (Plesion<0.03; Tables 1 and 2) but HR was not changed in BPN/3J mice (Plesion>0.6). Likewise, after sham surgery, HR was lower by 3 weeks in BPH/2J mice (Psham<0.001) but HR was not changed in BPN/3J mice (Psham>0.3). However the mild bradycardic effect of MeAm lesions in BPH/2J mice was similar to the effect of MeAm lesions in BPN/3J mice (Pstrain=0.3) and also similar to the effect of sham surgery in BPH/2J mice (Pstrain=0.8). After MeAm lesions there was no strain difference in HR during the light (inactive) period (Pstrain=0.1) but HR still remained markedly elevated in BPH/2J mice compared with BPN/3J mice during the dark (active) period (Pstrain<0.001; Figure S1). MeAm lesions or sham surgery did not affect locomotor activity in BPN/3J or BPH/2J mice at 1 or 3 weeks after lesion (Plesion>0.8; Psham>0.5; Tables 1 and 2).
Cardiovascular Variability and Cardiac Baroreflex Sensitivity
During the light (inactive) period, midfrequency MAP was 33% greater in BPH/2J than in BPN/3J mice at baseline (Pstrain=0.04) and midfrequency HR power and baroreflex gain were also greater in BPH/2J mice (Figure 3, top; Pstrain<0.001; baseline pooled from sham and lesion groups). Measurements from 1 and 3 weeks after sham or lesion were combined. Midfrequency MAP power was markedly reduced in both strains after MeAm lesions (Plesion<0.01) but was not effected by sham surgery (Psham>0.2). Midfrequency HR power was not affected by MeAm lesions in either strain (Plesion<0.01) but was markedly augmented after sham surgery in both strains (Psham<0.001). Baroreflex gain was increased in both strains after sham surgery (Psham<0.01) and MeAm lesions (Plesion<0.001).
During the dark (active) period, midfrequency MAP power was 74% greater in BPH/2J than in BPN/3J mice (Pstrain<0.001), whereas midfrequency HR power (Pstrain=1.0) and baroreflex gain were similar between strains (Figure 3, bottom; Pstrain=0.8). MeAm lesions reduced midfrequency MAP power by 46% in both BPH/2J (Plesion<0.001) and BPN/3J mice (Plesion=0.02) and resulted in similar postlesion midfrequency MAP power between strain (Pstrain=0.1). Moreover, sham treatment had no effect on midfrequency MAP power in either strain (Psham>0.2). Midfrequency HR power was increased after MeAm lesion in BPH/2J (Plesion<0.001) but not BPN/3J mice (Plesion=1.0), and sham surgery had no effect in either strain (Psham>0.2). Baroreflex gain was augmented in each strain after MeAm lesions (Plesion<0.001) but unchanged after sham surgery (Psham=1.0).
Cardiovascular Response to Angiotensin-Converting Enzyme Inhibition and Ganglion Blockade
Treatment with enalaprilat reduced MAP from baseline in BPH/2J during the dark period (–11±2 mm Hg; P<0.001; n=3) but not during the light period (+3±3 mm Hg; P=0.25; n=3; Figures 4 and S2). MeAm lesions abolished the enalaprilat-induced depressor response during the dark period in BPH/2J (Plesion<0.04; n=3) and did not influence the effect of enalaprilat during the light period (Plesion<0.6; n=3).
After pretreatment with enalaprilat in BPH/2J, intraperitoneal injection of pentolinium caused marked depressor responses during the light (–54±2 mm Hg; n=3) and dark periods (–50±2 mm Hg; n=3; Figure 4 and S3), which were in addition to the effect of enalaprilat. After MeAm lesions, the depressor responses to pentolinium were attenuated by 29% and 27% during the light and dark periods, respectively (Plesion<0.05).
Cardiovascular Response to Behavioral Tests
Dirty-cage switch stress induced rises in MAP, which were 45% greater in BPH/2J compared with BPN/3J mice at baseline (Pstrain<0.001; baseline pooled from sham and lesion groups). This was accompanied by increased locomotor activity that was 1.9-fold greater in BPH/2J mice (Pstrain<0.001) and tachycardic responses, which were comparable between strains (Pstrain=1.0). Cardiovascular responses to stress measured 1 and 3 weeks after sham or lesion surgery were combined. The pressor response to dirty-cage switch in BPH/2J mice was augmented by 14% after MeAm lesions (Plesion=0.052) but was attenuated by 12% after sham surgery (Psham=0.05; Figure 5). This resulted in a time by treatment interaction (PInt<0.001). The pressor response induced by dirty-cage switch was unaffected by MeAm lesion or sham surgery in BPN/3J mice (Plesion=1.0; Psham=0.2). Tachycardic and locomotor activity responses to dirty-cage switch were not influenced by MeAm lesion or sham surgery in either strain (Plesion>0.5; Psham>0.6).
Pressor and tachycardic responses induced by 2 other aversive stressors, 1 hour of restraint stress and 5 minutes of shaker stress, were unaffected by MeAm lesion or sham surgery in BPN/3J and BPH/2J mice (Plesion>0.2; Psham>0.1; Figures S4 and S5).
The main finding from the present study was that MeAm lesions caused marked reductions in BP in BPH/2J hypertensive mice, which abolished the BP difference between BPN/3J and BPH/2J mice during the light (inactive) period and reduced the BP difference by more than half during the dark (active) period. The MeAm lesions did not affect BP in BPN/3J mice, suggesting that the activity of neurons within the MeAm is causally associated with hypertension but may not be critical for maintenance of BP in normotensive mice. The hypotensive effect of MeAm lesions in BPH/2J mice was similar during both the inactive and active periods, suggesting that the MeAm contains neurons that exert a tonic effect on BP, independent of the animal’s state. MeAm lesions also reduced midfrequency MAP power in both strains, suggesting that the activity of neurons in the MeAm may influence SNS outflow. The depressor response induced by ganglion blockade was also attenuated in BPH/2J mice after MeAm lesions, supporting the notion that the MeAm may influence the SNS. Finally, MeAm lesions did not reduce the pressor response to any of the stressors in BPH/2J mice, suggesting that the hypotensive effect of MeAm lesions is not a consequence of attenuated stress reactivity. Together these results suggest that the MeAm is contributing to the hypertension in BPH/2J mice possibly via tonic activation of the SNS, which is independent of its role in stress reactivity and circadian BP influences.
The hypotensive effect of MeAm lesions in BPH/2J mice is consistent with studies in SHRs, which showed that lesions of the entire amygdala or neurons specifically within the MeAm of SHRs at an early age attenuate the development of hypertension.19,25 Galeno et al26 also suggested that the central amygdala contributes to hypertension in SHRs, but further examination of this hypothesis revealed that this was likely because of an effect on reduced body weight gain rather than a specific effect on hypertension,27 which is not the case in the present study. Unfortunately, none of these studies included normotensive controls, which precludes any conclusion as to whether the effect was specific to hypertension or related to general effects on BP in rodents. The MeAm has been demonstrated previously to mediate phasic changes in cardiovascular parameters during stress, chemoreflex, and baroreflex activation.18,28 However, acute inhibition of the MeAm in normotensive rats has consistently demonstrated no effect on resting BP, indicating that neurons in this region are unlikely affecting tonic levels of BP.18,28 The lack of effect of MeAm lesions on BP in BPN/3J mice supports these prior findings in normotensive animals but the same was not true in hypertensive BPH/2J mice. It is interesting to note that there were greater Fos counts in the BLA after stress in BPH/2J mice with MeAm lesions but not in BPN/3J mice. One might suggest that the hypotensive effect of MeAm lesions in BPH/2J mice may be secondary to changes in the neuronal activity in the BLA. However, electric stimulation of the BLA in conscious rats and pharmacological dis-inhibition of the BLA in anesthetized rats can cause increases in BP.29,30 Therefore, it seems unlikely that increased neuronal activity within the BLA is driving the hypotensive effect of MeAm lesions in BPH/2J mice. Another surprising finding was that comparable reductions of BP in BPH/2J mice occurred across the entire 24-hour period, which suggests that the contribution of the MeAm to elevated BP is likely mediated by a tonic pressor influence, which is independent of phasic changes in BP associated with the circadian cycle. Taken together, these studies suggest that neurons within the MeAm normally have little influence on long-term levels of BP but make a considerable contribution to the development and maintenance of hypertension in ≥2 genetic models, namely SHRs and BPH/2J mice.19
We have reported previously that neuronal activity within the MeAm, as indicated by Fos expression, correlates strongly with the depressor response to ganglion blockade in BPH/2J and BPN/3J mice,4 suggesting that neuronal activity in the MeAm may be related to the contribution of the SNS to BP level.4 The reduction in midfrequency MAP power in both strains after MeAm lesions suggests that the MeAm may indeed influence SNS activity and this was further supported by the attenuation of the depressor response to ganglion blockade apparent in a cohort of BPH/2J mice. Therefore 2 indicators of SNS activity suggest that neurons within the MeAm influence the SNS although these measures cannot rule out postsynaptic effects, and direct sympathetic nerve recording would be necessary to definitively confirm an influence of the MeAm on sympathetic outflow. In addition, MeAm lesions abolish the depressor response to angiotensin-converting enzyme inhibition during the dark period in BPH/2J mice, suggesting that the MeAm also influences BP in BPH/2J mice via actions on the RAS, presumably through neurally (sympathetic) mediated renin release. This is consistent with our recent findings, which suggest that the sympathetic activation of the renal RAS likely contributes to the hypertension in BPH/2J mice.7 Indeed, if the MeAm does influence BP in BPH/2J mice via sympathetically mediated enhancement of the RAS, this could potentially explain why MeAm lesions reduced midfrequency MAP power in both strains but only reduced BP in BPH/2J mice.
One unexpected finding was the lack of effect of MeAm lesions on the acute cardiovascular response to stress or arousal. Dirty-cage switch stress did induce marked neuronal activation in sham mice, consistent with increased neuronal activity measured after many different types of stressful stimuli.13,15,31 Interestingly, despite dirty-cage switch–induced Fos activity being markedly lower in mice with MeAm lesions, the cardiovascular response was unaltered, suggesting that the MeAm may not be essential for producing the cardiovascular response. However, the MeAm has been demonstrated previously to influence the cardiovascular response to stress, as inhibition of the MeAm with a γ-aminobutyric acidA agonist muscimol attenuated pressor responses induced by restraint stress in rats by approximately one third.17 Thus, the MeAm certainly seems capable of influencing the magnitude of the cardiovascular response to stress. Yet, the reason for a lack of effect of lesions on cardiovascular response to stress in the present study is unclear. One possibility is that sufficient neuronal activity in the MeAm may have remained after lesions such that the stress-mediating function of the MeAm was preserved. In the present study, the extent of lesions was determined by a functional assessment of stress-induced neuronal activation. To this end, we found that lesions reduced Fos activation induced by exposure to stress by >70%. Thus, if the relatively few remaining neurons were adequate to maintain the cardiovascular response, this would indicate a high level of redundancy within the MeAm. Alternatively, adaptive neuronal remodeling may occur in the weeks after lesions,32 such that other brain regions assume greater regulatory control over the stress response, perhaps because of a high degree of functional redundancy within the extended amygdala. Indeed, preliminary findings show greater Fos counts in the anterior cortical nucleus of the amygdala and central amygdala after dirty-cage switch stress in mice with MeAm lesions compared with sham animals. These findings suggest that neuronal activity within the extended amygdala was altered by lesions of the MeAm. However, whether the increased neuronal activation of other amygdaloid regions occurs only transiently in response to stress after MeAm lesions or whether this is a change independent of stress is unclear. To investigate this finding more extensively in the future, measurement of longer lasting immunohistochemical indicators of neuronal activity would need to be assessed in nonstressed mice with and without MeAm lesions. However, regardless of the reason for the lack of effect of MeAm lesions on the stress response, these findings indicate that phasic BP responses were unaffected by MeAm lesions. Thus, the hypotensive effect of MeAm lesions in BPH/2J mice was not caused by reductions in acute cardiovascular responses to stress or arousal.
The results of the present study demonstrate that neurons located within the MeAm contribute to elevated BP in hypertensive BPH/2J mice, suggesting that altered function within this region makes a profound contribution to the hypertension.7 To our knowledge, no study has explored directly the association between the amygdala and hypertension in humans. However, clinically there is an association between amygdala activity with exaggerated pressor responses to stress,33 which in turn is associated with greater risk of developing hypertension.34 Hypertension in BPH/2J mice has been likened to that of white-coat hypertensive patients based on SNS hyper-responsivity in addition to exaggerated circadian-related BP surges and cardiovascular hyper-reactivity to stressful situations shown in both BPH/2J mice and white-coat hypertensive patients.4,20,35–38 Given that the present study demonstrates a substantial contribution from the MeAm to maintenance of the hypertensive state in BPH/2J mice, this may prompt more extensive investigation into the role of this and possibly other forebrain regions, which have been suggested to be a major cause of hypertension in humans.39
Sources of Funding
This work was supported by grants from the National Health and Medical Research Council of Australia (NHMRC; project grant 526662) and in part by the Victorian Government’s OIS Program. Investigators were supported by NHMRC (1012881) and National Heart Foundation (PF10M5334) Postdoctoral Fellowships to P.J. Davern and NHMRC Principal Research Fellowship (1002186) to G.A. Head.
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.113.02020/-/DC1.
- Received October 15, 2013.
- Revision received November 6, 2013.
- Accepted December 9, 2013.
- © 2014 American Heart Association, Inc.
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Novelty and Significance
What Is New?
The medial nucleus of the medial amygdala contributes to the established hypertension in BPH/2J mice but not blood pressure maintenance in normotensive control mice.
What Is Relevant?
The present study demonstrates a substantial contribution of a relatively understudied limbic brain region to a genetic/neurogenic model of hypertension
The present study demonstrates that the medial amygdala contributes markedly to the hypertension in BPH/2J genetically hypertensive mice possibly via the SNS but independent of its role in stress reactivity or circadian blood pressure influences.