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Average contour maps representing absolute changes in mean arterial pressure (MAP), lumbar sympathetic nerve activity (LSNA) and splanchnic sympathetic nerve activity (SSNA) after microinjection of glutamate (10 mM, 30 nl) into the RVLM. Diagrams (from B) have been replicated above each column to represent the rostrocaudal levels of each set of injections. Each row represents the responses of MAP, LSNA, or SSNA in the rostrocaudal plane for active (A) and sedentary (B) rats. Filled dots represent location of individual injection sites with each site separated by 200 μm in each plane. Mediolateral levels are shown by L1, L2, and L3 with L1 being most medial and L3 being most lateral.
Source publication
Despite the classically held belief of an “all-or-none” activation of the sympathetic nervous system, differential responses in sympathetic nerve activity (SNA) can occur acutely at varying magnitudes and in opposing directions. Sympathetic nerves also appear to contribute differentially to various disease states including hypertension and heart fa...
Contexts in source publication
Context 1
... order to more fully characterize the relationship between microinjection location and hemodynamic responses to glutamate, contour maps representing the average MAP, LSNA, and SSNA responses in each group were created and are shown in Figure 4. Figure 4A represents the average responses to glutamate in seven physically active rats. ...
Context 2
... order to more fully characterize the relationship between microinjection location and hemodynamic responses to glutamate, contour maps representing the average MAP, LSNA, and SSNA responses in each group were created and are shown in Figure 4. Figure 4A represents the average responses to glutamate in seven physically active rats. Figure 4B represents the average responses to glutamate in seven sedentary rats. ...
Context 3
... order to more fully characterize the relationship between microinjection location and hemodynamic responses to glutamate, contour maps representing the average MAP, LSNA, and SSNA responses in each group were created and are shown in Figure 4. Figure 4A represents the average responses to glutamate in seven physically active rats. Figure 4B represents the average responses to glutamate in seven sedentary rats. Diagrams taken from Figure 1 are reproduced above each rostral, central and caudal level of injection to approximate the rostrocaudal level of injection based on the group averaged results from post mortem histological examination (see below). ...
Context 4
... colors (blue and green) represent smaller cumulative responses whereas brighter colors (yellow, orange, red) represent larger cumulative responses (see scales in individual legends for each variable). Qualitatively, and similar to statistical outcomes above, sedentary rats had larger SSNA responses compared to physically active animals (compare third rows in Figure 4A vs. Figure 4B). In addition, areas with the largest SNA responses (red and orange) appeared to differ FIGURE 2 | Representative raw tracing demonstrating the effects of glutamate (10 mM, 30 nl) microinjection in the RVLM from one active (A) and one sedentary (B) rat on arterial pressure (AP), absolute and average changes in lumbar sympathetic nerve activity (LSNA) and splanchnic sympathetic nerve activity (SSNA) were shown. ...
Context 5
... colors (blue and green) represent smaller cumulative responses whereas brighter colors (yellow, orange, red) represent larger cumulative responses (see scales in individual legends for each variable). Qualitatively, and similar to statistical outcomes above, sedentary rats had larger SSNA responses compared to physically active animals (compare third rows in Figure 4A vs. Figure 4B). In addition, areas with the largest SNA responses (red and orange) appeared to differ FIGURE 2 | Representative raw tracing demonstrating the effects of glutamate (10 mM, 30 nl) microinjection in the RVLM from one active (A) and one sedentary (B) rat on arterial pressure (AP), absolute and average changes in lumbar sympathetic nerve activity (LSNA) and splanchnic sympathetic nerve activity (SSNA) were shown. ...
Similar publications
High salt (HS) intake sensitizes central autonomic circuitry leading to sympathoexcitation. However, its underlying mechanisms are not fully understood. We hypothesized that inhibition of PVN endoplasmic reticulum (ER) Ca2+ store function would augment PVN neuronal excitability and sympathetic nerve activity (SNA). We further hypothesized that a 2%...
Citations
... The procedures for sympathetic nerve recordings have been documented in detail in previous work by our laboratory Mueller et al., 2011;Subramanian and Mueller, 2016;Dombrowski and Mueller, 2017). In brief, rats were anesthetized initially with isoflurane (5% induction, 2% maintenance; Henry Schein, Melville, NY) to levels that resulted in an absence of withdrawal to firm toe pinch. ...
... The appropriate volume of drug was delivered during each microinjection by observing the meniscus level of the micropipette using a 150x compound microscope with a calibrated reticle. At the end of experiments, microinjections of Chicago Sky Blue dye (2%, 30 nL) were performed to localize injections sites, similar to our previous studies Subramanian and Mueller, 2016;Dombrowski and Mueller, 2017). ...
... In addition to functional verification of the RVLM with glutamate microinjections, microinjection sites were verified histologically by injections of Chicago Sky Blue dye (2%, 30 nL), similar to our previous studies (Dombrowski and Mueller, 2017) Subramanian and Mueller, 2016). Figure 4 contains a representative photomicrograph of a neutral red-stained hemi-section (right) juxtaposed with a diagram outlining the anatomical landmarks designating the region of the RVLM (left). ...
The rostral ventrolateral medulla (RVLM) is an important brain region involved in both resting and reflex regulation of the sympathetic nervous system. Anatomical evidence suggests that as a bilateral structure, each RVLM innervates sympathetic preganglionic neurons on both sides of the spinal cord. However, the functional importance of ipsilateral versus contralateral projections from the RVLM is lacking. Similarly, during hypotension, the RVLM is believed to rely primarily on withdrawal of tonic gamma aminobutyric acid (GABA) inhibition to increase sympathetic outflow but whether GABA withdrawal mediates increased activity of functionally different sympathetic nerves is unknown. We sought to test the hypothesis that activation of the ipsilateral versus contralateral RVLM produces differential increases in splanchnic versus adrenal sympathetic nerve activities, as representative examples of functionally different sympathetic nerves. We also tested whether GABA withdrawal is responsible for hypotension-induced increases in splanchnic and adrenal sympathetic nerve activity. To test our hypothesis, we measured splanchnic and adrenal sympathetic nerve activity simultaneously in Inactin-anesthetized, male Sprague-Dawley rats during ipsilateral or contralateral glutamatergic activation of the RVLM. We also produced hypotension (sodium nitroprusside, i.v.) before and after bilateral blockade of GABAA receptors in the RVLM (bicuculline, 5 mM 90 nL). Glutamate (100 mM, 30 nL) injected into the ipsilateral or contralateral RVLM produced equivalent increases in splanchnic sympathetic nerve activity, but increased adrenal sympathetic nerve activity by more than double with ipsilateral injections versus contralateral injections (p < 0.05; n = 6). In response to hypotension, increases in adrenal sympathetic nerve activity were similar after bicuculline (p > 0.05), but splanchnic sympathetic nerve activity responses were eliminated (p < 0.05; n = 5). These results provide the first functional evidence that the RVLM has predominantly ipsilateral innervation of adrenal nerves. In addition, baroreflex-mediated increases in splanchnic but not adrenal sympathetic nerve activity are mediated by GABAA receptors in the RVLM. Our studies provide a deeper understanding of neural control of sympathetic regulation and insight towards novel treatments for cardiovascular disease involving sympathetic nervous system dysregulation.
... The RVLM is also associated with sympathetic overactivity in several animal models of cardiovascular disease, including hypertension (Guyenet, 2006). Furthermore, an ever-increasing amount of evidence suggests that risk factors for hypertension, such as a lack of regular exercise, are associated with increased excitability of RVLM neurons (Martins-Pinge et al., 2005;Mischel et al., 2015;Subramanian and Mueller, 2016;Mueller et al., 2017). For example, RVLM neurons from sedentary vs. physically active rats demonstrate various forms of structural neuroplasticity, including increased dendritic branching (Mischel et al., 2014) and alterations in inhibitory and excitatory neurotransmitter receptors (Mueller et al., 2020;Fyk-Kolodziej et al., 2021), each suggestive of greater synaptic input and enhanced sympathoexcitatory and sympathoinhibitory responses following sedentary vs. physically active conditions. ...
... For example, RVLM neurons from sedentary vs. physically active rats demonstrate various forms of structural neuroplasticity, including increased dendritic branching (Mischel et al., 2014) and alterations in inhibitory and excitatory neurotransmitter receptors (Mueller et al., 2020;Fyk-Kolodziej et al., 2021), each suggestive of greater synaptic input and enhanced sympathoexcitatory and sympathoinhibitory responses following sedentary vs. physically active conditions. Interestingly, the pattern of increased dendritic branching in more rostral regions of the RVLM of sedentary rats corresponds in vivo to greater sympathoexcitatory responses to glutamate microinjections (Subramanian and Mueller, 2016) compared to active animals and greater neuronal activity in rostral regions of the RVLM in unexercised rats (Huereca et al., 2018). Therefore, mechanisms that enhance glutamatergic neurotransmission and structural neuroplasticity in a subregionally specific manner could serve as new therapeutic targets to attenuate inactivitydependent neuroplasticity in the RVLM. ...
... Importantly, unlike other brain regions such as the hippocampus (Caldeira et al., 2007;Kim et al., 2012;Vigers et al., 2012), the RVLM exhibits decreased excitatory neurotransmission (not increased) following periods of regular physical exercise when compared to sedentary conditions (Mueller, 2010;Mischel et al., 2015;Mueller et al., 2017). Although a recent study found no difference in BDNF in the RVLM of treadmill trained rats when examining the RVLM as a single structure (Lee et al., 2020), our recent work has emphasized a significant need to characterize subregional differences in RVLM neuroplasticity following sedentary vs. active conditions (Mischel et al., 2014;Subramanian and Mueller, 2016). As mentioned above, we have reported significant forms of neuroplasticity in phenotypically identified, presympathetic neurons of the RVLM. ...
A sedentary lifestyle is the top preventable cause of death and accounts for substantial socioeconomic costs to society. The rostral ventrolateral medulla regulates blood pressure under normal and pathophysiological states, and demonstrates inactivity-related structural and functional neuroplasticity, which is subregionally specific. The purpose of this study was to examine pro- and mature forms of brain-derived neurotrophic factor (BDNF) and their respective receptors in the male rat rostral ventrolateral medulla (RVLM) and its rostral extension following sedentary vs. active (running wheels) conditions (10–12weeks). We used subregionally specific Western blotting to determine that the mature form of BDNF and its ratio to its pro-form were lower in more caudal subregions of the rostral ventrolateral medulla of sedentary rats but higher in the rostral extension when both were compared to active rats. The full-length form of the tropomyosin receptor kinase B receptor and the non-glycosylated form of the 75 kilodalton neurotrophin receptor were lower in sedentary compared to active rats. The rostrocaudal patterns of expression of the mature form of BDNF and the full-length form of the tropomyosin receptor kinase B receptor were remarkably similar to the subregionally specific patterns of enhanced dendritic branching, neuronal activity, and glutamate-mediated increases in sympathetic nerve activity observed in previous studies performed in sedentary rats. Our studies suggest signaling pathways related to BDNF within subregions of both the rostral ventrolateral medulla and its rostral extension contribute to cardiovascular disease and premature death related to a sedentary lifestyle.
... In addition to its role in baseline and reflex regulation of blood pressure, the RVLM has been implicated in sympathetic nervous system overactivity associated with a variety of risk factors for CVD (Guyenet, 2006). For example, we have reported greater increases in SNA in response to direct activation of the RVLM in sedentary versus physically active male rats (Mischel & Mueller, 2011;Subramanian & Mueller, 2016). However, it is unknown, whether the relative differences in resting and centrally-mediated sympathoexcitation are due to the effects of remaining sedentary, the influence of regular exercise or a combination of both. ...
... Therefore, the purpose of our study was threefold: (1) to compare centrally mediated blood pressure regulation between males and females prior to the onset of the oestrous cycle, which occurs in female rats between 5 and 6 weeks of age (Andrews & Ojeda, 1981;Westwood, 2008); (2) to examine potential sex-dependent and presumed progressive effects of sedentary conditions, to produce enhanced centrally mediated sympathoexcitation (Mischel & Mueller, 2011;Subramanian & Mueller, 2016);and (3) to compare the effects of sedentary versus active conditions in male versus female rats at two different ages to further understand how central regulation of blood pressure progresses after the onset of the oestrous cycle. ...
... n values are represented below symbols for male (♂) and female (♀) rats, and are defined as a single measurement from one animal of either sex at 4, 8 or 16 weeks of age and under either sedentary or active conditions. J Physiol 599.17 Eaton, PA, USA) (Mischel & Mueller, 2011;Subramanian & Mueller, 2016) and running wheel data were recorded daily. ...
Key points
The rostral ventrolateral medulla (RVLM) may contribute to sex‐based differences in cardiovascular disease (CVD) based on overactivation of the sympathetic nervous system observed in sedentary male rats; however, the added influence of the reproductive cycle in females is currently unknown.
To our knowledge this is the first study to demonstrate greater increases in sympathetic nerve activity in response to direct activation of the RVLM in female versus male rats prior to the onset of the reproductive cycle, which persisted after the onset of the reproductive cycle.
Lower resting blood pressures in females also suggest peripheral adaptations contribute to sex‐based differences in CVD.
Sedentary versus physically active conditions appear to promote higher resting sympathetic outflow independent of age and sex.
Our results demonstrate the importance of examining sedentary conditions in the context of sex differences and the reproductive cycle in contributing to sympathetic overactivity associated with cardiovascular disease.
Abstract
Female reproductive hormones are considered cardioprotective based on higher risks of cardiovascular disease (CVD) in post‐ versus pre‐menopausal women. Similarly, based on epidemiological studies, a sedentary lifestyle is also a major risk factor for CVD. The mechanisms by which sedentary conditions contribute to CVD, and their influences in the presence and absence of female reproductive hormones are unknown. We hypothesized that sexually immature male and female rats would have similar centrally mediated regulation of blood pressure, but upon sexual maturation, female rats would have lower resting blood pressure and centrally‐mediated sympathoexcitation compared to age‐matched males. We also predicted resting sympathetic activity would increase upon exposure to sedentary versus active conditions (voluntary wheel running) in males but not in females. We recorded splanchnic sympathetic nerve activity (SSNA) and blood pressure in 4‐, 8‐ and 16‐week‐old male and female rats under Inactin anaesthesia before and during microinjections of glutamate (1–100 mM) into the rostral ventrolateral medulla (RVLM). Four‐week‐old female rats had lower resting blood pressure and greater sympathoexcitation following activation of the RVLM, as did 8‐ and 16‐week‐old female rats, independent of age or activity condition. Sedentary animals had higher baseline SSNA compared to active animals, independent of sex or age. Our results reveal a complex influence of the interactions between the female reproductive cycle and sedentary conditions. They also demonstrate the importance of examining sedentary conditions in the context of sex‐ and female reproductive cycle‐dependent incidences of cardiovascular disease.
... Our HRV analyses have revealed an increased sympathetic tone in PHFD-exposed young male rats which was abolished by preadministration of beta-adrenergic receptor antagonist propranolol. The sympathetic neuronal activity plays an important role in the control of arterial blood pressure, whereas association of over-activated sympathetic tone has been demonstrated in rodent studies (Guyenet 2006;Subramanian and Mueller 2016). Moreover, we have detected alterations in the expressions of several proteins in caudal, and rostral parts of the ventrolateral medulla (CVLM; RVLM), well-identified with the cardio-inhibitory, and vasomotor actions, respectively (Guyenet 2006;Kumagai et al. 2012;Xu et al. 2012). ...
Exposure to high fat diet during perinatal period (PHFD) leads to neuroplastic changes in autonomic circuits, however, the role of gender has been incompletely understood. This study aims to investigate (i) short, and (ii) long-term effects of PHFD on autonomic outflow, and (iii) sexual dimorphic variations emerge at adulthood. Male and female rats were fed a control diet (13.5 % kcal from fat) or PHFD (60 % kcal from fat) from embryonic day-14 to postnatal day-21. To assess changes in autonomic outflow, heart rate variability (HRV) was analyzed at 10- and 20-week-old ages. Expressions of tyrosine hydroxylase (TH), metabotropic glutamate2/3 receptor (mGlu2/3R), N-methyl-D-aspartate1 receptor (NMDA1R), and gamma aminobutyric acidA receptor (GABAAR) were evaluated by immunohistochemistry. PHFD did not affect the body weight of 4-, 10-or 20-week-old male or female offsprings. PHFD significantly increased the sympathetic marker low frequency (LF) component, and sympatho-vagal balance (LF:HF) only in 10-week-old PHFD males. Compared with control, the propranolol-induced (4 mg·kg− 1, ip) decline in LF was observed more prominently in PHFD rats, however, these changes were found to be restored at the age of 20 weeks. In caudal ventrolateral medulla and nucleus tractus solitarius, expression of mGlu2/3R was downregulated in PHFD males, whereas no change was detected in NMDA1R. The number of GABAAR-expressing TH-immunoreactive cells was decreased in rostral ventrolateral medulla of PHFD males. The findings of this study suggest that exposure to maternal high-fat diet could lead to autonomic imbalance with increased sympathetic tone in the early adulthood of male offspring rats without developing obesity.
... Besides, it has been reported that the sympathetic system plays a key role in controlling daily energy expenditure (28). Visceral autonomic sympathetic hyperactivity has been reported in obese and sedentary people (29). Unlike the liver, pancreas, and skeletal muscle which are controlled by both sympathetic and parasympathetic nerve, adipose tissue is innervated only by the sympathetic nerve (28). ...
Background
The background of most metabolic diseases is obesity and overweight. The purpose of this study was to compare the relationship between resting metabolic rate and body composition factors in obese and normal-weight gymnast children.
Materials and Methods
In this semi-experimental study, 20 obese and 21 normal-weight boys age 8 to 12 year old participated in the study. In the first session, anthropometrical (weight, height, waist to hip ratio (WHR), and body composition [(body fat percentage (BF%), body fat weight (BFW), and lean body weight (LBW)] data were measured. In the next session, at first, subjects rested for 15 min and then performed a modified Bulk exhausting test. The subjects were connected to the mouthpiece of gas analyzer throughout the rest and exhausting test andthemaximal oxygen consumption (VO2max), respiratory exchange ratio (RER), and resting metabolic rate (RMR) was measured in both groups.
Results
A significant difference was observed for a mean of VO2max, weight, BF%, BFW, LBW, and WHR between the two groups (P<0.001). The mean of RMR per kg body weight was significantly lower in the obese group than the normal-weight group (P<0.05). There was no significant difference in the RER variable between the two groups (P>0.05). There was a significant linear relationship between RMR with weight, WHR, BFW, LBW, and VO2max in the obese group (P≤0.05).
Conclusion
Based on the results of the present study it can be concluded that the difference between the weight of obese and normal-weight beginner gymnastics children is partly due to low RMR and lower RMR in obese children might be due to their low cardiorespiratory fitness.
Keywords: Resting Metabolic Rate Obese children Maximal Oxygen Consumption Body Composition
... Previous studies suggest that sympathetic outputs to muscle (peroneal), heart and renal vascular beds are differentially regulated (Park et al., 2007;Kuroki et al., 2012;Frithiof et al., 2014). This regulation may be highly variable between different organs and individuals and be a source of disease susceptibility (Simms et al., 2007;Subramanian and Mueller, 2016). Choroid VPD is highly correlated and predictive of MSNA as assessed by linear correlation and Bland Altman analysis. ...
... Distinguishing it from these other techniques and opening new avenues for research, drug discovery and clinical use, choroid VPD provides information about sympathetic control of a vascular bed within the central nervous system. Having the ability to measure from multiple branches of the sympathetic nervous system in humans is likely to be important for research, given animal studies demonstrating differential regulation of different sympathetic outflows (Park et al., 2007;Kuroki et al., 2012;Frithiof et al., 2014;Subramanian and Mueller, 2016). Moreover, as regulation of cerebral blood flow plays a critical role in chronic diseases such as sleep apnea, hypertension and cognitive decline (Willie et al., 2014), having a method to measure sympathetic (and local microvascular) control mechanisms of cerebral vascular bed is likely to provide important indices of cerebral microvascular function (Willie et al., 2012(Willie et al., , 2014. ...
Sympathetic nervous system dysregulation and vascular impairment in neuronal tissue beds are hallmarks of prominent cardiorespiratory diseases. However, an accurate and convenient method of assessing SNA and local vascular regulation is lacking, hindering routine clinical and research assessments. To address this, we investigated whether spectral domain optical coherence tomography (OCT), that allows investigation of retina and choroid vascular responsiveness, reflects sympathetic activity in order to develop a quick, easy and non-invasive sympathetic index. Here, we compare choroid and retina vascular perfusion density (VPD) acquired with OCT and heart rate variability (HRV) to microneurography. We recruited 6 healthy males (26 ± 3 years) and 5 healthy females (23 ± 1 year) and instrumented them for respiratory parameters, ECG, blood pressure and muscle sympathetic nerve microneurography. Choroid VPD decreases with the cold pressor test, inhaled hypoxia and breath-hold, and increases with hyperoxia and hyperpnea suggesting that sympathetic activity dominates choroid responses. In contrast, retina VPD was unaffected by the cold pressor test, increased with hypoxia and breath hold and decreases with hyperoxia and hyperpnea, suggesting metabolic vascular regulation dominates the retina. With regards to integrated muscle sympathetic nerve activity, HRV had low predictive power whereas choroid VPD was strongly (inversely) correlated with integrated muscle sympathetic nerve activity (R = −0.76; p < 0.0001). These data suggest that Functional-OCT may provide a novel approach to assess sympathetic activity and intrinsic vascular responsiveness (i.e., autoregulation). Given that sympathetic nervous system activity is the main determinant of autonomic function, sympathetic excitation is associated with severe cardiovascular/cardiorespiratory diseases and autoregulation is critical for brain health, we suggest that the use of our new Functional-OCT technique will be of broad interest to clinicians and researchers.
... This is mainly attributed to the differential changes in sympathetic outflow to end-organs, i.e., the SNS activity is increased to the kidney in congestive heart failure, whereas it is not altered to the gut or liver (Kaye and Esler 2005). These region-specific changes in SNA are referred to as Bsympathetic signature^which is seen in a variety of conditions including, but not limited to, aging and obesity (Osborn and Kuroki 2012;Subramanian and Mueller 2016). In this review, we have discussed the remarkable similarities in aging and obesity with respect to SNS dysregulation in cardiovascular diseases with a specific focus on hypertension. ...
... Further, the neuronal population within the RVLM is not homogenous in nature with respect to generation of SNA to peripheral tissues. The topographical organization and neuroplasticity of sub-population of neurons within the RVLM have been attributed to differential responses in SNA to end organs contributing to the sympathetic signature in disease conditions (Ootsuka andTerui 1997, Subramanian andMueller 2016). Several key and emerging central mechanisms by which overactivity of the SNS could contribute to end-organ damage in obesity and aging are discussed in the following sections. ...
Chronic sympathetic nervous system overactivity is a hallmark of aging and obesity and contributes to the development of cardiovascular diseases including hypertension and heart failure. The cause of this chronic sympathoexcitation in aging and obesity is multifactorial and centrally mediated. In this mini-review, we have provided an overview of the key and emerging central mechanisms contributing to the pathogenesis of sympathoexcitation in obesity and healthy aging, specifically focusing on hypertension. A clear understanding of these mechanisms will pave way for targeting the sympathetic nervous system for the treatment of cardiovascular diseases in obesity and aging.
... [10][11][12][13] Related to the latter, sedentary conditions have also been shown to produce a regionally dependent neuroplasticity in the RVLM, such that more rostrally located neurons exhibit greater dendritic branching and responsive- ness to direct excitation by glutamate microinjection. 14,15 As cardiovascular disease remains the leading cause of death in the USA, it is imperative to understand the central nervous system mechanisms by which these pathophysiological states develop and progress over time. 10,12,13,16 In animal studies, the activity of RVLM neurons has been assessed using techniques developed in both conscious and anesthetized prepara- tions, including single unit recordings [17][18][19][20] and Fos immunohistochemistry. [21][22][23][24] In humans, blood oxygen level-dependent (BOLD) imaging has also been used recently to identify tonically active regions of the brainstem, which include the RVLM. ...
... 14 They also corroborate our more recent finding of enhanced resting splanchnic sympathetic nerve activity, as well as augmented responses to direct stimulation, of more rostral regions of the RVLM in sedentary, but not physically active, rats. 15 We contend that increased dendritic arborization probably promotes enhanced resting neuronal activity and reactivity to glutamate in more rostral regions of the RVLM, resulting in enhanced resting and stimulated sympathetic nerve activity reported in our previous studies. 6,37 Certainly confirmation of these speculations requires direct comparison of Mn 2+ enhancement in the RVLM of sedentary versus physically active animals, studies which are currently ongoing in our laboratory. ...
Spinally projecting neurons in the rostral ventrolateral medulla (RVLM) are believed to contribute to pathophysiological alterations in sympathetic nerve activity and the development of cardiovascular disease. The ability to identify changes in the activity of RVLM neurons in conscious animals and humans, especially longitudinally, would represent a clinically important advancement in our understanding of the contribution of the RVLM to cardiovascular disease. To this end, we describe the initial development of manganese-enhanced magnetic resonance imaging (MEMRI) for the rat RVLM. Manganese (Mn2+) has been used to estimate in vivo neuronal activity in other brain regions because of both its paramagnetic properties and its entry into and accumulation in active neurons. In this initial study, our three goals were as follows: (1) to validate that Mn2+ enhancement occurs in functionally and anatomically localized images of the rat RVLM; (2) to quantify the dose and time course dependence of Mn2+ enhancement in the RVLM after one systemic injection in conscious rats (66 or 33 mg/kg, intraperitoneally); and (3) to compare Mn2+ enhancement in the RVLM with other regions to determine an appropriate method of normalization of T1-weighted images. In our proof-of-concept and proof-of-principle studies, Mn2+ was identified by MRI in the rat RVLM after direct microinjection or via retrograde transport following spinal cord injections, respectively. Systemic injections in conscious rats produced significant Mn2+ enhancement at 24 h (p < 0.05). Injections of 66 mg/kg produced greater enhancement than 33 mg/kg in the RVLM and paraventricular nucleus of the hypothalamus (p < 0.05 for both), but only when normalized to baseline scans without Mn2+ injection. Consistent with findings from our previous functional and anatomical studies demonstrating subregional neuroplasticity, Mn2+ enhancement was higher in the rostral regions of the RVLM (p < 0.05). Together with important technical considerations, our studies support the development of MEMRI as a potential method to examine RVLM activity over time in conscious animal subjects.
Recent evidence indicates that sex-based differences in cardiovascular disease (CVD) begin early in life, particularly when associated with risks factors such as a sedentary lifestyle. CVD is associated with elevated sympathetic nerve activity (SNA), quantified as increased SNA bursting activity in humans. Whether burst characteristics are influenced by sex- and (in)activity at younger ages is unknown. The purpose of our study is to compare SNA bursts in active and sedentary female and male rats at ages including pre-puberty into young adulthood. We hypothesized that burst characteristics and blood pressure are higher under sedentary conditions and lower in female rats compared to males. We analyzed splanchnic SNA recordings from Inactin-anesthetized male and female rats at 4-, 8-, and 16-weeks of age. Physically active and sedentary rats were each housed in separate, environmentally-controlled chambers where physically active rats had free access to an in-cage running wheel. Sympathetic bursts were obtained by rectifying and integrating the raw SSNA signal. Burst frequency, burst height, and burst width were calculated using the Peak Parameters extension in LabChart. Our results showed that sedentary conditions produced a greater burst width in 8-and 16-week-old rats compared to 4-week-old rats in both males and female (p<0.001 for both). Burst frequency and incidence were both higher in 16-week-old males compared to 16-week-old females (p<0.001 for both). Our results suggest that there are (in)activity- and sex-related mechanisms, which impact sympathetic regulation of blood pressure at ages that include pre-puberty into young adulthood.
Cardiovascular and metabolic complications associated with excess adiposity are linked to chronic activation of the sympathetic nervous system, resulting in a high risk of mortality among obese individuals. Obesity-related positive energy balance underlies the progression of hypertension, end-organ damage, and insulin resistance, driven by increased sympathetic tone throughout the body. It is, therefore, important to understand the central network that drives and maintains sustained activation of the sympathetic nervous system in the obese state. Experimental and clinical studies have identified structural changes and altered dynamics in both grey and white matter regions in obesity. Aberrant activation in certain brain regions has been associated with altered reward circuitry and metabolic pathways including leptin and insulin signaling along with adiposity-driven systemic and central inflammation. The impact of these pathways on the brain via overactivity of the sympathetic nervous system has gained interest in the past decade. Primarily, the brainstem, hypothalamus, amygdala, hippocampus, and cortical structures including the insular, orbitofrontal, temporal, cingulate and prefrontal cortices have been identified in this context. Although the central network involving these structures is much more intricate, this review highlights recent evidence identifying these regions in sympathetic overactivity in obesity.
