The neuroendocrine stress response impairs hippocampal vascular function and memory in male and 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.

BDNF shifts excitatory-inhibitory balance in the paraventricular nucleus of the hypothalamus to elevate blood pressure.

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.

BDNF downregulates β-adrenergic receptor-mediated hypotensive mechanisms in the paraventricular nucleus of the hypothalamus.

Brain-derived neurotrophic factor (BDNF) is upregulated in the paraventricular nucleus of the hypothalamus (PVN) in response to hypertensive stimuli such as stress and hyperosmolality, and BDNF acting in the PVN plays a key role in elevating sympathetic activity and blood pressure. However, downstream mechanisms mediating these effects remain unclear. We tested the hypothesis that BDNF increases blood pressure, in part by diminishing inhibitory hypotensive input from nucleus of the solitary tract (NTS) catecholaminergic neurons projecting to the PVN.

Inhibition of BDNF signaling in the paraventricular nucleus of the hypothalamus lowers acute stress-induced pressor responses.

Brain-derived neurotrophic factor (BDNF) expression increases in the paraventricular nucleus of the hypothalamus (PVN) during stress, and our recent studies indicate that BDNF induces sympathoexcitatory and hypertensive responses when injected acutely or overexpressed chronically in the PVN. However, it remained to be investigated whether BDNF is involved in the mediation of stress-induced cardiovascular responses. Here we tested the hypothesis that inhibition of the high-affinity BDNF receptor TrkB in the PVN diminishes acute stress-induced cardiovascular responses.

Effect of High-Salt Diet on Age-Related High Blood Pressure and Hypothalamic Redox Signaling.

Aim: The aim of this study was to investigate the effect of a high salt (HS) diet on age-related changes in blood pressure (BP) and the possible role played by regulatory central mechanisms.

Methods: Young (5 months) and old (27 months) male Fischer 344 × Brown Norway (F344/BN) rats were fed standard chow or 8% HS diet for 12 days. BP and heart rate (HR) were measured by telemetry.

Altered potassium ATP channel signaling in mesenteric arteries of old high salt-fed rats.

Purpose: Both aging and the consumption of a high salt diet are associated with clear changes in the vascular system that can lead to the development of cardiovascular disease; however the mechanisms are not clearly understood. Therefore, we examined whether aging and the consumption of excess salt alters the function of potassium ATP-dependent channel signaling in mesenteric arteries.

Methods: Young (7 months) and old (29 months) Fischer 344 x Brown Norway rats were fed a control or a high salt diet (8% NaCl) for 12 days and mesenteric arteries were utilized for vascular reactivity measurements.

Age Impaired endothelium-dependent vasodilation is improved by resveratrol in rat mesenteric arteries.

Purpose: To determine whether resveratrol improves the adverse effects age on vascular function in mesenteric arteries (MAs), and diminishes the hyperactivity in adrenal gland with age.

Methods: Male F344 x Brown Norway rats were assigned to 6-month control (YC), 6-month resveratrol (YR), 24-month control (OC) and 24-month resveratrol (OR). Resveratrol (15 mg/kg) was provided to resveratrol groups in drinking water for 14 days.

BDNF acting in the hypothalamus induces acute pressor responses under permissive control of angiotensin II.

Brain-derived neurotrophic factor (BDNF) expression increases in the paraventricular nucleus of the hypothalamus (PVN) during hypertensive stimuli including stress and hyperosmolarity, but its role in PVN cardiovascular regulatory mechanisms is unclear. Chronic BDNF overexpression in the PVN has been shown to elevate sympathetic tone and blood pressure in part by modulating central angiotensin (Ang) II mechanisms. However, the cardiovascular effects of short-term increases in PVN levels of BDNF and the mechanisms governing them are unknown.

Novel mechanism within the paraventricular nucleus reduces both blood pressure and hypothalamic pituitary-adrenal axis responses to acute stress.

Macrophage migration inhibitory factor (MIF) counteracts pressor effects of angiotensin II (ANG II) in the paraventricular nucleus of the hypothalamus (PVN) in normotensive rats, but this mechanism is absent in spontaneously hypertensive rats (SHRs) due to a lack of MIF in PVN neurons. Since endogenous ANG II in the PVN modulates stress reactivity, we tested the hypothesis that replacement of MIF in PVN neurons would reduce baseline blood pressure and inhibit stress-induced increases in blood pressure and plasma corticosterone in adult male SHRs. Radiotelemetry transmitters were implanted to measure blood pressure, and then an adeno-associated viral vector expressing either enhanced green fluorescent protein (GFP) or MIF was injected bilaterally into the PVN.

Brain-derived neurotrophic factor modulates angiotensin signaling in the hypothalamus to increase blood pressure in rats.

Brain-derived neurotrophic factor (BDNF) expression increases in the paraventricular nucleus of the hypothalamus (PVN) in response to hypertensive stimuli including stress and hyperosmolarity. However, it is unclear whether BDNF in the PVN contributes to increases in blood pressure (BP). We tested the hypothesis that increased BDNF levels within the PVN would elevate baseline BP and heart rate (HR) and cardiovascular stress responses by altering central angiotensin signaling.

Overpressure blast-wave induced brain injury elevates oxidative stress in the hypothalamus and catecholamine biosynthesis in the rat adrenal medulla.

Explosive overpressure brain injury (OBI) impacts the lives of both military and civilian population. We hypothesize that a single exposure to OBI results in increased hypothalamic expression of oxidative stress and activation of the sympatho-adrenal medullary axis. Since a key component of blast-induced organ injury is the primary overpressure wave, we assessed selective biochemical markers of autonomic function and oxidative stress in male Sprague Dawley rats subjected to head-directed overpressure insult.

Nucleus of the solitary tract catecholaminergic neurons modulate the cardiovascular response to psychological stress in rats.

Catecholaminergic neurons within the central nervous system are an integral part of stress-related neurocircuitry, and the nucleus of the solitary tract (NTS) plays a critical role in cardiovascular regulation. We tested the hypothesis that NTS catecholaminergic neurons attenuate psychological stress-induced increases in blood pressure and promote neuroendocrine activation in response to psychological stress.Anti-dopamine-β-hydroxylase antibody conjugated to the neurotoxin saporin (DSAP) or saline vehicle was microinjected into the NTS to lesion catecholaminergic neurons in male Sprague-Dawley rats, and 17 days later the rats were subjected to 60 min of restraint stress for five consecutive days.

Effect of age on high-fat diet-induced hypertension.

Aging and obesity both have a significant impact on central blood pressure (BP) regulation, and previous studies indicated that changes in central redox signaling with age may affect high-fat (HF) diet-induced cardiovascular responses. Therefore, we investigated the effects of 60% HF feeding on BP regulation in young adult (5 mo) and old (26 mo) Fischer-344 × Brown-Norway rats. Radiotelemetric transmitters were implanted to measure BP, heart rate (HR), locomotor activity, and spontaneous baroreflex sensitivity.

Lifelong caloric restriction prevents age-induced oxidative stress in the sympathoadrenal system of Fischer 344 x Brown Norway rats.

Aging is associated with oxidative damage and an imbalance in redox signaling in a variety of tissues, yet little is known about the extent of age-induced oxidative stress in the sympathoadrenal system. Lifelong caloric restriction has been shown to lower levels of oxidative stress and slow the aging process. Therefore, the aims of this study were twofold: (1) to investigate the effect of aging on oxidative stress in the adrenal medulla and hypothalamus and (2) determine if lifelong 40% caloric restriction (CR) reverses the adverse effects of age-induced oxidative stress in the sympathetic adrenomedullary system.

Hypertensive effects of central angiotensin II infusion and restraint stress are reduced with age.

Objective: We investigated the effect of age on cardiovascular responses mediated by central angiotensin II (AngII) after intracerebroventricular infusion of AngII, and during restraint stress.

Methods: Blood pressure (BP) and heart rate (HR) of young (5-month-old) and old (27-month-old) male Fischer-344 x Brown-Norway rats were measured using radiotelemetry. AngII was infused intracerebroventricularly using osmotic minipumps (10 ng/0.

Effect of high-fat diet feeding on hypothalamic redox signaling and central blood pressure regulation.

We examined the effect of high-fat (HF) feeding on blood pressure (BP) regulation, including hypothalamic redox signaling, as well as the changes in diurnal patterns and responses to restraint stress. Furthermore, we investigated whether HF feeding affects catecholamine and neuropeptide Y (NPY) biosynthesis in the adrenal medulla. Male obesity-prone Sprague-Dawley rats were fed with standard rat chow or 60% HF diet for 6 months.

Nigrostriatal rAAV-mediated GDNF overexpression induces robust weight loss in a rat model of age-related obesity.

Intraventricular administration of glial cell line-derived neurotrophic factor (GDNF) in primate and humans to study Parkinson's disease (PD) has revealed the potential for GDNF to induce weight loss. Our previous data indicate that bilateral continuous hypothalamic GDNF overexpression via recombinant adeno-associated virus (rAAV) results in significant failure to gain weight in young rats and weight loss in aged rats. Based on these previous results, we hypothesized that because the nigrostriatal tract passes through the lateral hypothalamus, motor hyperactivity mediated by nigrostriatal dopamine (DA) may have been responsible for the previously observed effect on body weight.

Effect of age on angiotensin II-mediated downregulation of adrenomedullary catecholamine biosynthetic enzymes.

Expression of catecholamine biosynthesizing enzymes, tyrosine hydroxylase (TH) and dopamine beta hydroxylase (DbetaH) increase with age in the adrenal medulla, however, the underlying mechanisms are unclear. In the present study, we examined the effect of peripheral angiotensin II (AngII) on the expression of TH and DbetaH, in the adrenal medulla of young (6 mo) and old (23 mo) Fischer-344 rats. Saline or AngII (230 ng/kg/min sc) was infused for 3 days using osmotic minipumps.

Leptin antagonist reverses hypertension caused by leptin overexpression, but fails to normalize obesity-related hypertension.

Objective: The present study employed a rat leptin antagonist to evaluate the role of elevated leptin in obesity-associated hypertension.

Methods: First, leptin was overexpressed in the hypothalamus of lean rats for 155 days through the administration of a recombinant adeno-associated viral-mediated central vector-encoding leptin. Then a leptin antagonist was infused intracerebroventricularly for 14 days.

Effects of life-long caloric restriction and voluntary exercise on age-related changes in levels of catecholamine biosynthetic enzymes and angiotensin II receptors in the rat adrenal medulla and hypothalamus.

We examined if life-long mild caloric restriction (CR) alone or with voluntary exercise prevents the age-related changes in catecholamine biosynthetic enzyme levels in the adrenal medulla and hypothalamus. Ten-week-old Fisher-344 rats were assigned to: sedentary; sedentary+8% CR; or 8% CR+wheel running. Rats were euthanized at 6 or 24 months of age.

Somatosensory pain does not affect total cerebral blood volume.

The effect of somatosensory pain on the total cerebral blood volume was investigated in anesthetized rats. Our results show for the first time that total cerebral blood volume remains unaltered in both brain hemispheres during 2.5 min noxious stimulation of the sensory C-fibres of the sciatic nerve.

Adverse effects of reactive oxygen species on vascular reactivity in insulin resistance.

Insulin resistance (IR) has adverse effects on the reactivity of arteries and arterioles and promotes arterial hypertension and vascular occlusive diseases. Altered reactivity of resistance vessels occurs at both the endothelium and smooth-muscle levels. One major mechanism of vascular dysfunction with IR involves the augmented generation, availability, and/or actions of reactive oxygen species (ROS).

Acute pressor effect of central angiotensin II is mediated by NAD(P)H-oxidase-dependent production of superoxide in the hypothalamic cardiovascular regulatory nuclei.

Background: Centrally applied angiotensin II (Ang II) increases sympathetic nervous activity and mean arterial blood pressure (MAP), but the mediation of these effects is not fully understood.

Objective: To test the hypothesis that central effects of Ang II are mediated by reduced nicotinamide adenine dinucleotide phosphate [NAD(P)H]-oxidase-dependent production of superoxide in the hypothalamus.

Methods: Under isoflurane anesthesia, male Sprague-Dawley rats were given an intracerebroventricular infusion of either artificial cerebrospinal fluid or apocynin (4 microg/kg per min), a selective inhibitor for NAD(P)H oxidase, for 30 min, followed by Ang II (20 ng) or carbachol (200 ng), while MAP and heart rate were measured at the femoral artery.

Rosuvastatin improves cerebrovascular function in Zucker obese rats by inhibiting NAD(P)H oxidase-dependent superoxide production.

Insulin-resistance induces cerebrovascular dysfunction and increases the risk for stroke. We investigated whether rosuvastatin (RSV), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, can reverse reduced cerebrovascular responsiveness in insulin-resistant rats. Dilator responses of the basilar artery (BA) were examined after 1-day or 4-wk RSV (2 mg.

Blood-brain barrier changes during compensated and decompensated hemorrhagic shock.

Dysfunction of the blood-brain barrier (BBB) can be associated with a large number of central nervous system and systemic disorders. The aim of the present study was to determine BBB changes during different phases of hemorrhagic shock. The experiments were carried out on male Wistar rats anaesthetized with urethane.