Cardiovascular disease (CVD) remains the leading cause of death, and people who remain sedentary are more likely to die from CVD than from other preventable risk factors. High blood pressure is also a risk factor for CVD, and sedentary individuals are more likely to have higher blood pressure than individuals who exercise regularly. Recently, we have identified anatomical and biochemical differences in brainstem regions that control blood pressure in sedentary versus physically active animals. Specifically, neurons in the Rostral Ventrolateral Medulla (RVLM) have greater dendritic branching following sedentary conditions, the latter of which are associated with greater levels of the mature form of Brain-Derived Neurotrophic Factor (mBDNF). However, the link between increased expression of BDNF in the RVLM, increased neuroplasticity, and elevated blood pressure is unknown. The purpose of the present study was to examine the effects of BDNF overexpression in the RVLM on resting blood pressure. We hypothesized that overexpressing BDNF in the RVLM increases resting blood pressure. We used in vivo gene targeting by viral vector-mediated enhancement of BDNF expression in the RVLM of five-week-old, male Sprague-Dawley rats (n=11). Overexpression of BDNF was accomplished by injections of an AAV vector expressing either AAV/rg-CamKII-rBDNF(iso3).MYC-WPRE or AAV/rg-CamKII-EGFP-WPRE (control vector). Under isoflurane anesthesia and aseptic conditions, three 60nL microinjections of the retrograde AAV were injected bilaterally into the intermediolateral cell column of the spinal cord. Following five weeks of recovery, rats injected with the AAV vector to overexpress BDNF had significantly higher systolic blood pressure than those injected with the control viral vector (144±10 n=5 vs 117±3 mmHg n=6, p=0.019). Our results indicate the possibility that BDNF controls blood pressure by expression in the RVLM. Future studies are planned to test if hypertensive rats have overactive BDNF signaling in the RVLM (R01HL161233). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Overactive urinary bladder (OAB) negatively impacts quality of life, and stress is known to play a key role in its development. However, the mechanisms linking stress to OAB are not yet fully understood. This study examined how chronic activation of neuroendocrine stress pathways, independently of environmental or psychological stressors, affects bladder function and the control of micturition. Utilizing the central role of brain-derived-neurotrophic factor (BDNF) in orchestrating the neuroendocrine stress response within the paraventricular nucleus of the hypothalamus (PVN), our novel experimental model subjected 10-week-old male Sprague Dawley rats to bilateral PVN injections of AAV2 viral vectors expressing either BDNF or GFP (for control). Urine voiding behavior was assessed in UroVoid metabolic cages over 14 weeks post-injections. Bladder strip myography, assessment of bladder wall mechanics, and histology were also conducted to determine any BDNF-induced differences in bladder contractility, capacity and morphology. Prolonged activation of neuroendocrine stress mechanisms with BDNF overexpression in the PVN significantly reduced intermicturition intervals and voided volumes, lowered bladder capacity, and induced relative bladder wall hypertrophy but had no effect on bladder wall mechanics or detrusor contractility. These results indicate that chronic activation of neuroendocrine stress pathways, even without additional environmental or psychological influences of stress, lead to a significant OAB phenotype and reduced bladder capacity.

The paraventricular nucleus of the hypothalamus (PVN) receives and integrates afferent information from various central regions to regulate sympathetic tone and cardiovascular function. These neurons are largely inhibited as baseline, but activated in response to stress, relaying excitatory signals to increase blood pressure and heart rate. Neuronal activation induces the expression of brain-derived neurotrophic factor (BDNF), a well-known regulator of neuroplasticity in the central nervous system (CNS). We have previously shown that BDNF modulates glutamatergic, GABAergic, and catecholaminergic mechanisms in the PVN, shifting the excitatory-inhibitory (E/I) synaptic balance towards excitation, promoting hypertensive and tachycardic responses. BDNF activates the mammalian target of rapamycin (mTOR) as part of mTOR complex 1 (mTORC1) with regulatory associated protein of mTOR (Raptor). In the CNS, mTOR sets E/I balance and controls dendritic branching and neuronal size. While hypothalamic mTOR signaling is known to regulate whole-organism energy balance, and components of this pathway are present in the PVN, the effect of mTOR signaling in the PVN on cardiovascular regulation is not known. Here, we hypothesize that PVN mTOR signaling modulates the integration of afferent signals and mediates the effects of BDNF. To test this, male Sprague-Dawley (SD) rats received bilateral PVN injections of AAV2 viral vectors expressing BDNF or shRNA against TSC1 (a mTORC1 repressor) to stimulate mTORC1 or shRNA against Raptor to inhibit mTORC1. Scrambled shRNA/GFP vectors served as controls. Blood pressure (mean arterial pressure, MAP) and heart rate (HR) were monitored via telemetry over 4 weeks. Injections were verified, and neuronal morphology and pS6 levels (a marker of mTOR activity) were assessed with immunofluorescence. Activating mTORC1 with TSC1 knockdown increased blood pressure and showed changes in circadian rhythm, leading to significant differences in daytime but not nighttime (daytime MAP: controls: 95.2±0.9, shTSC1: 102.6±1.2 mmHg; nighttime MAP: controls: 102.1±1.4, shTSC1: 105.2±0.9 mmHg). In contrast, BDNF overexpression significantly raised blood pressure and heart rate both during day- (increased MAP by ~32 mmHg and HR by ~68.6 bpm) and nighttime (increased MAP by ~29.4 mmHg and HR by ~2.8 bpm), consistent with our previous findings. Raptor knockdown had no effect alone on either day or nighttime blood pressure but completely abolished BDNF-induced increases in both blood pressure and heart rate. Immunofluorescence analysis showed that soma size and immunoreactivity of pS6 were significantly increased by both TSC1 knockdown and BDNF whereas Raptor knockdown reduced soma size and pS6 intensity relative to controls and counteracted the effects of BDNF. In addition, ongoing patch clamp experiments are conducted on PVN brain slices isolated 4-6 weeks after vector injections to test whether these in vivo changes correlate with altered neuronal and synaptic excitability in PVN neurons. This study demonstrates that PVN mTOR-mediated mechanisms play a significant role in cardiovascular mechanisms and mediate hypertensive responses and neuronal morphological changes induced by BDNF. Supported by R01HL166464. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Stress and hypertension are leading causes for cerebrovascular dysfunction. Astrocytes are a key component of the neurovascular unit and are involved in regulation of both angioplasticity and vascular reactivity. We investigated the hypothesis that centrally induced chronic neuroendocrine stress would lead to changes in astrocyte morphology and altered cerebrovascular architecture. Prolonged upregulation of brain-derived neurotrophic factor (BDNF) in the paraventricular nucleus of the hypothalamus (PVN) has been shown to chronically activate all major stress pathways, including the sympathetic nervous system and the hypothalamus-pituitary-adrenal axis. Taking advantage of this mechanism, we created a novel chronic neuroendocrine stress model by subjecting male Sprague Dawley rats to bilateral PVN injections of AAV2 viral vectors expressing either BDNF or GFP (for control). Cortical and hippocampal vasculature and astrocyte GFAP immunoreactivity were analyzed 14 weeks after vector injections. Fixed coronal brain slabs (2mm) were subjected to iDiSCO tissue transparency protocol and immunolabeling (PECAM: blood vessels; GFAP: astrocytes; and NeuN: neurons). Z-stacks were imaged with a Nikon C2 confocal microscope. IMARIS software was used to generate 3D models of the vasculature and astrocytes. Euclidean distance mapping (EDM) was used to determine distribution of non-labeled space to nearest blood vessels or astrocyte processes. Additionally, in-house 3D image analysis was used to track blood vessel characteristics and density in relation neural layers. IMARIS analysis found no differences in overall cortical or hippocampal vascular and branch point densities and EDM analysis revealed similar spacing characteristics of blood vessels in both regions. However, we found shorter distances between astrocytes in the hippocampus of BDNF rats indicating higher astrocyte density. Our in-house analysis performed in relation to the outer CA neuronal layer showed a reduction in large diameter vessels and larger distances between vessels in the BDNF group, particularly within the region 200-350mm ventral from the CA neuronal layer. In summary, we demonstrated that our novel model of chronic neuroendocrine stress induced glial activation and alterations in cerebrovascular architecture. Interestingly, changes in the vascular network were only detected by using image analysis techniques that took into consideration the laminar nature of neurovascular structures, highlighting the importance of developing such analytic techniques. The observed reduction of larger vascular diameters in certain hippocampal regions may indicate compensatory changes in response to hypertension in our neuroendocrine stress model, whereas the larger gaps between vessels may indicate capillary rarefaction increasing susceptibility to hippocampal hypoperfusion. Funded by R01HL166464 and R03AG072016. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

The paraventricular nucleus of the hypothalamus (PVN) integrates afferent inputs from limbic, medullary and hypothalamic regions to orchestrate cardiovascular stress responses via its medullary and spinal projections. Brain-derived neurotrophic factor (BDNF) is an important pro-hypertensive regulator in the PVN upregulated during stress that transforms the PVN neurocircuitry to facilitate responsiveness to hypertensive stimuli by shifting the balance of excitatory/inhibitory synaptic mechanisms. Mechanistic target of rapamycin (mTOR), as part of mTOR complex-1 (mTORC1), is stimulated by trophic factors, such as BDNF, in other brain regions to induce changes in neuronal morphology and increases in neuronal excitability. We tested the hypothesis that activation of mTORC1 in the PVN by BDNF and acute stress plays a key role in stimulating hypertensive responses. Male Sprague Dawley (SD) rats (n=4/group) received bilateral PVN injections of AAV2 viral vectors expressing myc-tagged BDNF (BDNFmyc), shRNA against TSC1 (a repressor of mTORC1) to stimulate mTORC1, shRNA against Raptor (a key component of the mTORC1) to inhibit mTORC1 or GFP for control. Blood pressure and heart rate were monitored by telemetry for 4 wks, and cardiovascular responses to restraint (60min) and water stress (15 minutes, 1-cm deep, 25°C water) were recorded 4-5 wks after vector injections. Vector injections were confirmed and neuronal morphology as well as pS6 levels (a marker of mTOR activity) were analyzed with immunofluorescence. Activation mTORC1 with TSC1 knock-down significantly increased resting blood pressure compared with control, but inhibition of mTORC1 with Raptor knock-down had no effect. BDNF overexpression significantly elevated blood pressure, as we have shown previously, and these increases were completely abolished by Raptor knock-down (daytime mean arterial pressure: shTSC1: 108.0±1.4*; BDNFmyc: 131.4±2.5*; shRaptor: 101.8±0.9; BDNF+shRaptor: 102.7±2.8 # , GFP: 96.5±1.8 mmHg at week 4, *p<0.05 vs GFP; # p<0.05 vs. BDNFmyc). In addition, mTORC1 inhibition with Raptor knock-down also significantly diminished stress-induced hypertensive responses. Maximum blood pressure increase in shRaptor rats was 30.3±1.3 mmHg during restraint and 26.0±3.4 mmHg during water stress vs 43.8±2.2 and 37.4±2.5 mmHg in control rats (p<0.05). Immunofluorescence of pS6, an indicator of mTOR activity, and neuronal soma size were significantly elevated by both TSC1 knock-down and BDNF overexpression in the PVN, whereas Raptor knock-down reduced pS6 intensity and soma size and completely abolished the effects of BDNF. In summary, we demonstrated that mTOR activation in the PVN significantly increased blood pressure both during baseline conditions and during acute stress, and mediated hypertensive responses and neuronal morphological changes elicited by BDNF. Supported by R01 HL133211. R01 HL133211 (BE), R03 AG072016 (BE) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cerebral small vessel disease and Alzheimer's disease are leading causes of dementia. Psychological/social stress and associated hypertension are important drivers of brain vascular dysfunction and impaired perfusion. We set out to investigate if chronic neuroendocrine stress and hypertension have adverse effects on cerebrovascular architecture of various brain regions in two rodent models: 1) a rat model where HPA axis activation and hypertension were induced by brain derived neurotrophic factor (BDNF) overexpression in the paraventricular nucleus of the hypothalamus (PVN) for 5 wks, and 2) in a mouse model, where blood pressure and/or corticosterone levels were elevated by subcutaneous infusions of angiotensin II (AngII, 1.5mg/kg/day), adrenocorticotropic hormone (ACTH, 30ug/kg/day) or a combination of AngII and ACTH for 4 weeks. Cerebrovasculature was labeled by transcardiac perfusion of a liposome-encapsulated fluorescent DiI dye. Brains were fixed in 4% PFA and transparency was increased with the SeeDB method. Vasculature of the hippocampus (HPC), sensory cortex (CTX), and PVN was evaluated using 2-photon microscopy in 2mm thick coronal brain slices. 3D model of the vasculature was created by Imaris software (Oxford Instruments) yielding parameters such as vascular segment numbers, lengths, diameters, and number of branch points. 3D Euclidean distance mapping (EDM) was used to determine distribution of distances to nearest vessels (DNVs) within the extravascular space as a measure of accessibility to blood supply. We found that vascular densities were markedly elevated in the PVN relative to other brain regions in both rats and mice. In mice, HPC vascular density was significantly lower relative to CTX, whereas in rats, CTX and HPC densities were similar [vascular densities % (rats, mice): PVN:14.6±1.4, 17.0±0.6; CTX: 9.6±0.5, 8.6±0.4; HPC CA: 8.8±0.7, 6.2±0.3; HPC DG: 9.4±0.6, 5.4±0.3]. EDM analysis revealed that the proportion of short (<15μm) vs long DNVs was the highest in the PVN in both rats and mice. Distribution of DNVs shifted to longer distances in the CTX, and the proportion of short vs long DNVs was the lowest in HPC regions indicating an increased vulnerability to hypoperfusion. Interestingly, neuroendocrine stress and hypertension failed to significantly affect vascular densities and DNV statistics in either rats or mice in the analyzed brain regions. However, there was a notable sex difference in distribution of DNVs in HPC CA regions with male rats having a higher proportion of longer distances than females. In addition, analysis of vascular diameter distribution revealed that BDNF treatment decreased vessel diameters in the PVN of both male and female rats, and in the CTX of male, but not female rats. In summary, we found significant region-specific variability in vascular structure, with the PVN demonstrating a uniquely dense vascular network. Cerebrovascular architecture was fairly resilient to treatments resembling chronic stress-induced neuroendocrine and cardiovascular responses, but sex differences in HPC vasculature may promote a higher sensitivity to hypoperfusion in male vs female rats.

Chronic psychological stress affects brain regions involved in memory such as the hippocampus and accelerates age-related cognitive decline, including in Alzheimer's disease and vascular dementia. However, little is known about how chronic stress impacts hippocampal vascular function that is critically involved in maintaining neurocognitive health that could contribute to stress-related memory dysfunction. Here, we used a novel experimental rat model that mimics the neuroendocrine and cardiovascular aspects of chronic stress to determine how the neuroendocrine components of the stress response affect hippocampal function. We studied both male and female rats to determine potential sex differences in the susceptibility of the hippocampus and its vasculature to neuroendocrine stress-induced dysfunction. We show that activation of neuroendocrine stress pathways impaired the vasoreactivity of hippocampal arterioles to mediators involved in coupling neuronal activity with local blood flow that was associated with impaired memory function. Interestingly, we found more hippocampal arteriolar dysfunction and scarcer hippocampal microvasculature in male compared to female rats that was associated with greater memory impairment, suggesting the male sex may be at increased risk of neuroendocrine-derived hippocampal dysfunction during chronic stress. Overall, this study revealed the therapeutic potential of targeting hippocampal arterioles to prevent or slow memory decline in the setting of prolonged and/or unavoidable stress.

An overview of recent results obtained at the tokamak ASDEX Upgrade (AUG) is given. A work flow for predictive profile modelling of AUG discharges was established which is able to reproduce experimental H-mode plasma profiles based on engineering parameters only. In the plasma center, theoretical predictions on plasma current redistribution by a dynamo effect were confirmed experimentally. For core transport, the stabilizing effect of fast ion distributions on turbulent transport is shown to be important to explain the core isotope effect and improves the description of hollow low-Z impurity profiles. The L–H power threshold of hydrogen plasmas is not affected by small helium admixtures and it increases continuously from the deuterium to the hydrogen level when the hydrogen concentration is raised from 0 to 100%. One focus of recent campaigns was the search for a fusion relevant integrated plasma scenario without large edge localised modes (ELMs). Results from six different ELM-free confinement regimes are compared with respect to reactor relevance: ELM suppression by magnetic perturbation coils could be attributed to toroidally asymmetric turbulent fluctuations in the vicinity of the separatrix. Stable improved confinement mode plasma phases with a detached inner divertor were obtained using a feedback control of the plasma β. The enhanced D α H-mode regime was extended to higher heating power by feedback controlled radiative cooling with argon. The quasi-coherent exhaust regime was developed into an integrated scenario at high heating power and energy confinement, with a detached divertor and without large ELMs. Small ELMs close to the separatrix lead to peeling-ballooning stability and quasi continuous power exhaust. Helium beam density fluctuation measurements confirm that transport close to the separatrix is important to achieve the different ELM-free regimes. Based on separatrix plasma parameters and interchange-drift-Alfvén turbulence, an analytic model was derived that reproduces the experimentally found important operational boundaries of the density limit and between L- and H-mode confinement. Feedback control for the X-point radiator (XPR) position was established as an important element for divertor detachment control. Stable and detached ELM-free phases with H-mode confinement quality were obtained when the XPR was moved 10 cm above the X-point. Investigations of the plasma in the future flexible snow-flake divertor of AUG by means of first SOLPS-ITER simulations with drifts activated predict beneficial detachment properties and the activation of an additional strike point by the drifts.

Activation of PVN neurons projecting to the rostral ventrolateral medulla and spinal cord increases sympathetic activity and blood pressure (BP). Elevated expression of BDNF in the PVN is known to increase BP and heart rate (HR) and it is a key mechanism mediating stress-induced cardiovascular responses. However, the underlying mechanisms are not fully understood. BDNF is a neurotrophic factor known to enhance excitatory activity and reduce inhibitory activity broadly in the central nervous system. Further, changes in the excitatory/inhibitory balance in the PVN have been demonstrated to elevate BP and sympathetic activity chronically in various hypertensive models. Here, we tested the hypothesis that increased BDNF expression in the PVN elevates BP in part by increasing the expression of excitatory signaling components and decreasing the expression of inhibitory signaling components in the PVN. Sprague Dawley (SD) rats received bilateral PVN injections of AAV2 viral vectors expressing GFP or myc-conjugated BDNF (BDNFmyc). Three weeks later, the animals were deeply anesthetized and perfused with PBS and 4% paraformaldehyde. PVN expression of NMDAR1, GABAA-alpha1, GAD67, KCC2 and synapsin 1a/b were assessed using immunofluorescence, confocal microscopy and image analysis. In a second group of AAV2-GFP or BDNFmyc-treated SD rats, BP and HR responses to PVN injections of AP5 (10 mM), an NMDA receptor antagonist, NMDA (100 µM), gabazine (2 mM), a GABAA antagonist, and muscimol (10 mM), a GABAA agonist, were recorded under alpha chloralose-urethane anesthesia. Our results showed that NMDAR1 protein expression in the PVN was significantly elevated in the BDNF compared to the GFP group (p<0.001). Conversely, GABAA-alpha1 protein expression in the PVN was significantly higher in the GFP compared to the BDNF group (p<0.01), while KCC2 protein expression was significantly elevated in the BDNF compared to the GFP group (p<0.001). In contrast, GAD67 and synapsin 1a/b expression was unaffected by BDNF treatment. NMDA inhibition led to peak average decreases in BP and HR of -17±5 mmHg and -61±18 BPM in the BDNF group, compared with -2±7 mmHg (p<0.05) and -6±1 BPM (p<0.05) in the GFP group. NMDA activation led to peak average increases in BP and decreases in HR of 5±1 mmHg and -94±23 BPM in the BDNF group, compared with 8±2 mmHg (n=0.31, n.s.) and -40±13 BPM (p<0.05) in the GFP group. GABAA inhibition led to peak average increases in BP and HR of 34±7 mmHg and 97±26 BPM in the BDNF group, compared with 70±12 mmHg (p<0.05) and 155±22 BPM (p=0.12, n.s.) in the GFP group. GABAA activation led to peak average decreases in BP and HR of -15±2 mmHg and -27±8 BPM in the BDNF group, compared with -26±5 mmHg (p<0.05) and -48±9 BPM (p<0.05) in the GFP group. In summary, BDNF enhances NMDA receptor-mediated excitatory synaptic transmission and diminishes GABAA-mediated inhibitory synaptic transmission in the PVN to elevate BP.

The hippocampus is a deep brain structure critically involved in learning and memory that is highly susceptible to hypoxic/ischemic injury. Hypertension and psychological stress are major risk factors of dementia; however, their effects on the vasculature of the cognition-centric hippocampus remain unclear. This study investigated hippocampal vascular function and memory in a novel model of neuroendocrine-derived stress and hypertension. This model is induced via vector mediated brain-derived neurotrophic factor (BDNF) overexpression in the paraventricular nucleus of the hypothalamus (PVN) that causes chronic stimulation of the major hypothalamic stress pathways (e.g. hypothalamic-pituitary-adrenal axis), leading to significant long-term elevation of blood pressure. We hypothesized that function of the arterioles supplying the hippocampus and memory would be impaired in this BDNF-PVN model of chronic stress and hypertension. Potential sex differences in the susceptibility of the hippocampus to dysfunction were also investigated. Male and female Sprague Dawley rats received bilateral PVN injections of AAV2 vectors expressing BDNF or GFP for control (n=6-8/group) at 8 weeks of age. Four weeks later, an object recognition task was used to quantify the percent of time spent investigating a novel object as a measure of hippocampal-dependent long-term memory function. Hippocampal arterioles (HAs) from the same rats were then studied isolated and pressurized in an arteriograph chamber. Vasodilator responses of HAs to mediators of functional hyperemia were measured, including small- and intermediate-conductance calcium-activated potassium (SK/IK) channel activation via NS309, and activation of inward rectifier potassium (KIR) channels by increasing extracellular K+ from 3-15mM. Memory function was significantly impaired by PVN-BDNF treatment (two-way ANOVA, Tukey's post hoc test, F1,22=16.53; p=0.001), but sex had no effect (F1,22=1.16; p=0.29). Object recognition was lower in both male and female PVN-BDNF rats that spent 49±3% and 52±6% of the time with the novel object, compared to control male and female rats that spent 66±3% and 72±4% of the time investigating the novel object. HAs from male and female PVN-BDNF rats dilated significantly less to NS309 than controls (F1,20=12.35; p=0.002), suggesting endothelial damage. Surprisingly, activation of KIR channels with 15mM K+ caused a 3-5% vasoconstriction of HAs from both male and female PVN-BDNF rats that was in striking contrast to the 20-30% vasodilation that occurred in response to KIR channel activation in HAs from control rats (F1,19=24.90; p<0.0001). These data show that chronic neuroendocrine stress and hypertension caused hippocampal vascular dysfunction and impaired memory similarly in male and female rats. The blunted vasodilation of HAs from PVN-BDNF rats suggests functional hyperemia may be impaired in the hippocampus that could lead to neuronal dysfunction, memory loss and dementia.

Presympathetic neurons in the paraventricular nucleus of the hypothalamus (PVN) play a key role in cardiovascular regulation. We have previously shown that brain-derived neurotrophic factor (BDNF), acting in the PVN, increases sympathetic activity and blood pressure and serves as a key regulator of stress-induced hypertensive responses. BDNF is known to alter glutamatergic and GABA-ergic signaling broadly in the central nervous system, but whether BDNF has similar actions in the PVN remains to be investigated. Here, we tested the hypothesis that increased BDNF expression in the PVN elevates blood pressure by enhancing N-methyl-d-aspartate (NMDA) receptor (NMDAR)- and inhibiting GABAA receptor (GABAAR)-mediated signaling. Sprague-Dawley rats received bilateral PVN injections of AAV2 viral vectors expressing green fluorescent protein (GFP) or BDNF. Three weeks later, cardiovascular responses to PVN injections of NMDAR and GABAAR agonists and antagonists were recorded under α-chloralose-urethane anesthesia. In addition, expressions of excitatory and inhibitory signaling components in the PVN were assessed using immunofluorescence. Our results showed that NMDAR inhibition led to a greater decrease in blood pressure in the BDNF vs. GFP group, while GABAAR inhibition led to greater increases in blood pressure in the GFP group compared to BDNF. Conversely, GABAAR activation decreased blood pressure significantly more in GFP vs. BDNF rats. In addition, immunoreactivity of NMDAR1 was upregulated, while GABAAR-α1 and K+/Cl- cotransporter 2 were downregulated by BDNF overexpression in the PVN. In summary, our findings indicate that hypertensive actions of BDNF within the PVN are mediated, at least in part, by augmented NMDAR and reduced GABAAR signaling.NEW & NOTEWORTHY We have shown that BDNF, acting in the PVN, elevates blood pressure in part by augmenting NMDA receptor-mediated excitatory input and by diminishing GABAA receptor-mediated inhibitory input to PVN neurons. In addition, we demonstrate that elevated BDNF expression in the PVN upregulates NMDA receptor immunoreactivity and downregulates GABAA receptor as well as KCC2 transporter immunoreactivity.

PVN presympathetic neurons, projecting to the rostral ventrolateral medulla (RVLM) or the spinal cord, play a critical role in the regulation of blood pressure. BDNF is a neurotrophic factor known to be upregulated in the PVN in response to hypertensive stimuli such as stress. However, the mechanisms by which BDNF modulates cardiovascular regulation in the PVN remains unclear. BDNF alters glutamatergic and GABAergic signaling, as well as neuronal morphology broadly in the central nervous system. Within the PVN, glutamatergic synaptic input and NMDA‐signaling are elevated, while GABAergic inhibition is reduced in hypertensive models. We tested the hypothesis that increased BDNF expression in the PVN elevates blood pressure by enhancing NMDA‐signaling, diminishing GABAA‐signaling and altering morphology of RVLM‐projecting PVN neurons. To simulate stress‐related upregulation of BDNF in the PVN, an AAV2 viral vector expressing BDNF was bilaterally injected into the PVN of Sprague Dawley rats, while control rats received AAV2‐GFP injections. Three weeks later, blood pressure and heart rate responses to PVN injections of NMDA and GABAA agonists and antagonists were recorded under anesthesia. Our results showed that inhibition of NMDA receptors with AP5 induced significantly larger decreases in blood pressure and heart rate in the BDNF group (−23±4 mmHg and −56±17 BPM) compared with the GFP group [5±1 mmHg (p<0.01) and −5±1 BPM (p<0.05)]. In contrast, activation of NMDA receptors with NMDA induced similar cardiovascular responses in GFP and BDNF animals. Inhibition of GABAA receptors with gabazine induced significantly smaller blood pressure increases in the BDNF group (32±6 mmHg) compared to GFP (61±11 mmHg, p<0.05), but heart rate responses were similar in the two groups. Activation of GABAA receptors with muscimol caused significantly reduced hypotensive responses in the BDNF group (−14±2 mmHg) compared to GFP (−23±4 mmHg, p<0.05), while changes in heart rate were similar. Quantitative RT‐PCR from PVN brain punches indicated that expression of NMDAR1 or GABAA‐Δ was unaffected by BDNF overexpression. However, immunofluorescence imaging in PVN brain sections demonstrated that BDNF significantly increased the soma size of RVLM‐projecting PVN neurons. In summary, our findings indicate that BDNF augments glutamate signaling in the PVN, primarily by increasing presynaptic glutamate release, and reduces GABA inhibition possibly through postsynaptic mechanisms. Finally, BDNF may also affect the balance of excitatory/inhibitory synaptic balance and regulation of blood pressure by increasing the soma size of PVN‐RVLM neurons.Support or Funding InformationR01 HL133211‐01A1.

Regulating cerebral blood flow to supply oxygen and nutrients and remove waste products is of utmost importance for neuronal health. The brain’s capillary network responds to acute local increases of neuronal activity with vasodilation of upstream arterioles (neurovascular coupling, NVC). NVC mechanisms are impaired in a number of neurodegenerative and cardiovascular diseases. A compounding factor in these diseases is the remodelling of capillary networks. A reduced density of capillaries and/or changes in the arrangement of capillaries so that the parenchyma is not adequately supplied can exacerbate these conditions. We set out to develop novel tools to analyse the architecture of cerebral microvascular networks and assess neuronal‐glial‐vascular plasticity in rodent models of hypertension, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and impaired endothelial Ca2+ signalling (TRPV4‐KO).Animals (mice or rats) were transcardially perfused with a liposome‐encapsulated fluorescent dye (DiI) and brains were harvested and fixed in 4 % paraformaldehyde. Transparency of the tissue was increased using the SeeDB protocol and the microvasculature was imaged in 2 mm thick coronal brain slabs using 2‐photon microscopy. Subsequently, slabs were cryopreserved, re‐sectioned at 80 μm thickness and processed for immunofluorescence (glial fibrillary astrocytic protein, Gfap). Slices were imaged using scanning confocal microscopy. Imaging volumes were taken in the rostro‐caudal axis to a depth of ~1 mm. They were deconvolved, attenuation‐corrected and scaled to equal length voxels. Then, fluorescent structures were converted into 3D objects (Volumetry G9 ‐ GWH) and non‐vessel particulates were filtered. Then, expanding boundary shells were used at every voxel in parenchymal space. Once the expanding boundary shells collided with a vessel, the distance (radius) was converted to a color and a new imaging volume containing the distance mapping results was created. The proportion of parenchymal voxels located at different distances from their closest blood vessel was calculated.We found that in both mice and rats, overall vessel density was the highest in the paraventricular nucleus of the hypothalamus (10–20 % of voxels), followed by cortex (~ 10 %) and hippocampus (~ 5 %). 90 % of the parenchymal volume in the cortex was within 26 μm of a blood vessel compared to > 34 μm in the hippocampus. Interestingly, Gfap staining was intense in the hippocampus but not in the cortex. In disease models, we found that aged mice (CADASIL, CADASIL control and TRPV4‐KO) had a lower vessel density than younger animals especially in cortex and PVN. In contrast, it was hippocampal vessel density in the dentate gyrus that was lower in spontaneously hypertensive rats than in controls.In summary, we describe a simple, yet powerful method to assess the relationship of capillary networks and parenchymal volume and show that rodent models of cardiovascular diseases are associated with plasticity of the neuro‐glia‐vascular unit.Support or Funding InformationR01 HL133211

The aim of this paper is to present a signal processing algorithm that, applied to the raw Locked Mode signal, allows us to obtain a disruption indicator in principle exploitable on different tokamaks. A common definition of such an indicator for different machines would facilitate the development of portable systems for disruption prediction, which is becoming of increasingly importance for the next tokamak generations. Moreover, the indicator allows us to overcome some intrinsic problems in the diagnostic system such as drift and offset. The behavior of the proposed indicator as disruption predictor, based on crossing optimized thresholds of the signal amplitude, has been analyzed using data of both JET and ASDEX Upgrade experiments. A thorough analysis of the disruption prediction performance shows how the indicator is able to recover some missed and tardy detections of the raw signal. Moreover, it intervenes and corrects premature or even wrong alarms due to, e.g., drifts and/or offsets.

In ITER and DEMO, various control objectives related to plasma control must be simultaneously achieved by the plasma control system (PCS), in both normal operation as well as off-normal conditions. The PCS must act on off-normal events and deviations from the target scenario, since certain sequences (chains) of events can precede disruptions. It is important that these decisions are made while maintaining a coherent prioritization between the real-time control tasks to ensure high-performance operation. In this paper, a generic architecture for task-based integrated plasma control is proposed. The architecture is characterized by the separation of state estimation, event detection, decisions and task execution among different algorithms, with standardized signal interfaces. Central to the architecture are a plasma state monitor and supervisory controller. In the plasma state monitor, discrete events in the continuous-valued plasma state are modeled using finite state machines. This provides a high-level representation of the plasma state. The supervisory controller coordinates the execution of multiple plasma control tasks by assigning task priorities, based on the finite states of the plasma and the pulse schedule. These algorithms were implemented on the TCV digital control system and integrated with actuator resource management and existing state estimation algorithms and controllers. The plasma state monitor on TCV can track a multitude of plasma events, related to plasma current, rotating and locked neoclassical tearing modes, and position displacements. In TCV experiments on simultaneous control of plasma pressure, safety factor profile and NTMs using electron cyclotron heating (ECH) and current drive (ECCD), the supervisory controller assigns priorities to the relevant control tasks. The tasks are then executed by feedback controllers and actuator allocation management. This work forms a significant step forward in the ongoing integration of control capabilities in experiments on TCV, in support of tokamak reactor operation.

In this paper we validate the finite element code RAPLICASOL, which models radiofrequency wave propagation in edge plasmas near ICRF antennas, against calculations with the TOPICA code. We compare the output of both codes for the ASDEX Upgrade 2-strap antenna, and for a 4-strap WEST-like antenna. Although RAPLICASOL requires considerably fewer computational resources than TOPICA, we find that the predicted quantities of experimental interest (including reflection coefficients, coupling resistances, - and -matrix entries, optimal matching settings, and even radiofrequency electric fields) are in good agreement provided we are careful to use the same geometry in both codes.

The ASDEX Upgrade (AUG) programme, jointly run with the EUROfusion MST1 task force, continues to significantly enhance the physics base of ITER and DEMO. Here, the full tungsten wall is a key asset for extrapolating to future devices. The high overall heating power, flexible heating mix and comprehensive diagnostic set allows studies ranging from mimicking the scrape-off-layer and divertor conditions of ITER and DEMO at high density to fully non-inductive operation (q(95) = 5.5, beta(N) <= 2.8) at low density. Higher installed electron cyclotron resonance heating power <= 6 MW, new diagnostics and improved analysis techniques have further enhanced the capabilities of AUG. Stable high-density H-modes with P-sep/R <= 11 MW m(-1) with fully detached strike-points have been demonstrated. The ballooning instability close to the separatrix has been identified as a potential cause leading to the H-mode density limit and is also found to play an important role for the access to small edge-localized modes (ELMs). Density limit disruptions have been successfully avoided using a path-oriented approach to disruption handling and progress has been made in understanding the dissipation and avoidance of runaway electron beams. ELM suppression with resonant magnetic perturbations is now routinely achieved reaching transiently H-H98(y,H-2) <= 1.1. This gives new insight into the field penetration physics, in particular with respect to plasma flows. Modelling agrees well with plasma response measurements and a helically localised ballooning structure observed prior to the ELM is evidence for the changed edge stability due to the magnetic perturbations. The impact of 3D perturbations on heat load patterns and fast-ion losses have been further elaborated. Progress has also been made in understanding the ELM cycle itself. Here, new fast measurements of T-i and E-r allow for inter ELM transport analysis confirming that E-r is dominated by the diamagnetic term even for fast timescales. New analysis techniques allow detailed comparison of the ELM crash and are in good agreement with nonlinear MHD modelling. The observation of accelerated ions during the ELM crash can be seen as evidence for the reconnection during the ELM. As type-I ELMs (even mitigated) are likely not a viable operational regime in DEMO studies of 'natural' no ELM regimes have been extended. Stable I-modes up to n/n(GW) <= 0.7 have been characterised using beta-feedback. Core physics has been advanced by more detailed characterisation of the turbulence with new measurements such as the eddy tilt angle-measured for the first time-or the cross-phase angle of T-e and n(e) fluctuations. These new data put strong constraints on gyro-kinetic turbulence modelling. In addition, carefully executed studies in different main species (H, D and He) and with different heating mixes highlight the importance of the collisional energy exchange for interpreting energy confinement. A new regime with a hollow T-e profile now gives access to regimes mimicking aspects of burning plasma conditions and lead to nonlinear interactions of energetic particle modes despite the sub-Alfvenic beam energy. This will help to validate the fast-ion codes for predicting ITER and DEMO.