Loss of Brain-Derived Neurotrophic Factor Mediates Inhibition of Hippocampal Long-Term Potentiation by High-Intensity Sound.

Exposure to noise produces cognitive and emotional disorders, and recent studies have shown that auditory stimulation or deprivation affects hippocampal function. Previously, we showed that exposure to high-intensity sound (110 dB, 1 min) strongly inhibits Schaffer-CA1 long-term potentiation (LTP). Here we investigated possible mechanisms involved in this effect. We found that exposure to 110 dB sound activates c-fos expression in hippocampal CA1 and CA3 neurons. Although sound stimulation did not affect glutamatergic or GABAergic neurotransmission in CA1, it did depress the level of brain-derived neurotrophic factor (BDNF), which is involved in promoting hippocampal synaptic plasticity. Moreover, perfusion of slices with BDNF rescued LTP in animals exposed to sound stimulation, whereas BDNF did not affect LTP in sham-stimulated rats. Furthermore, LM22A4, a TrkB receptor agonist, also rescued LTP from sound-stimulated animals. Our results indicate that depression of hippocampal BDNF mediates the inhibition of LTP produced by high-intensity sound stimulation.

Increased lipopolysaccharide-induced hypothermia in neurogenic hypertension is caused by reduced hypothalamic PGE2 production and increased heat loss.

KEY POINTS: The mechanisms involved in hypothermia and fever during systemic inflammation (SI) remain largely unknown. Our data support the contention that brain-mediated mechanisms are different in hypertension during SI. Considering that, clinically, it is not easy to assess all mechanisms involved in cardiovascular and thermoregulatory control during SI, the present study sheds light on these integrated mechanisms that may be triggered simultaneously in septic hypertensive patients. The result obtained demonstrate that, in lipopolysaccharide-induced SI, an increased hypothermia is observed in neurogenic hypertension, which is caused by reduced hypothalamic prostaglandin E2 production and increased heat loss in conscious rats. Therefore, the results of the present study provide useful insight for clinical trials evaluating the thermoregulatory outcomes of septic patients with hypertension. ABSTRACT: Hypertension is a prevalent disease characterized by autonomic-induced elevated and sustained blood pressure levels and abnormal body core temperature (Tb) regulation. The present study aimed to determine the brain-mediated mechanisms involved in the thermoregulatory changes observed during lipopolysaccharide (LPS)-induced systemic inflammation (SI; at a septic-like model) in spontaneously hypertensive rats (SHR). We combined Tb and skin temperature (Tsk) analysis, assessment of prostaglandin (PG) E2 levels (the proximal mediator of fever) in the anteroventral region of the hypothalamus (AVPO; an important site for Tb control), oxygen consumption analysis, cardiovascular recordings, assays of inflammatory markers, and evaluation of oxidative stress in the plasma and brain of male Wistar rats and SHR that had received LPS (1.5 mg kg-1 ) or saline. LPS induced hypothermia followed by fever in Wistar rats, whereas, in SHR, a maintained hypothermia without fever were observed. These thermoregulatory responses were associated with an increased heat loss in SHR compared to Wistar rats. We measured LPS-induced increased PGE2 levels in the AVPO in Wistar rats, but not in SHR. The LPS-induced drop in blood pressure was higher in SHR than in Wistar rats. Furthermore, LPS-induced plasma and brain [regions involved in autonomic control: nucleus tractus solitarius (NTS) and rostral ventrolateral medulla (RVLM)] cytokine surges were blunted, whereas oxidative stress was higher in SHR. LPS-induced SI leads to blunted cytokine surges both systemically (plasma) and centrally (NTS and RVLM) and reduced hypothalamic PGE2 production, which are all associated with increased hypothermia mediated by increased heat loss, but not by heat production, in SHR.

Neuroinflammation in the NTS is associated with changes in cardiovascular reflexes during systemic inflammation.

BACKGROUND: Lipopolysaccharide (LPS)-induced systemic inflammation (SI) is associated with neuroinflammation in the brain, hypotension, tachycardia, and multiple organs dysfunctions. Considering that during SI these important cardiovascular and inflammatory changes take place, we measured the sensitivity of the cardiovascular reflexes baroreflex, chemoreflex, and Bezold-Jarisch that are key regulators of hemodynamic function. We also evaluated neuroinflammation in the nucleus tractus solitarius (NTS), the first synaptic station that integrates peripheral signals arising from the cardiovascular and inflammatory status. METHODS: We combined cardiovascular recordings, immunofluorescence, and assays of inflammatory markers in male Wistar rats that receive iv administration of LPS (1.5 or 2.5 mg kg-1) to investigate putative interactions of the neuroinflammation in the NTS and in the anteroventral preoptic region of the hypothalamus (AVPO) with the short-term regulation of blood pressure and heart rate. RESULTS: LPS induced hypotension, tachycardia, autonomic disbalance, hypothermia followed by fever, and reduction in spontaneous baroreflex gain. On the other hand, during SI, the bradycardic component of Bezold-Jarisch and chemoreflex activation was increased. These changes were associated with a higher number of activated microglia and interleukin (IL)-1ß levels in the NTS. CONCLUSIONS: The present data are consistent with the notion that during SI and neuroinflammation in the NTS, rats have a reduced baroreflex gain, combined with an enhancement of the bradycardic component of Bezold-Jarisch and chemoreflex despite the important cardiovascular impairments (hypotension and tachycardia). These changes in the cardiac component of Bezold-Jarisch and chemoreflex may be beneficial during SI and indicate that the improvement of theses reflexes responsiveness though specific nerve stimulations may be useful in the management of sepsis.

Inhaled molecular hydrogen attenuates intense acute exercise-induced hippocampal inflammation in sedentary rats.

Physical exercise-induced inflammation may be beneficial when exercise is regular but it may be harmful when exercise is intense and performed by unaccustomed individuals/rats. Molecular hydrogen (H2) has recently emerged as a powerful anti-inflammatory, antioxidant and anti-apoptotic molecule in a number of pathological conditions, but little is known about its putative role under physiological conditions such as physical exercise. Therefore, we tested the hypothesis that H2 decreases intense acute exercise-induced inflammation in the hippocampus, since it is a brain region particularly susceptible to inflammation. Moreover, we also assessed hippocampus oxidative status. Rats ran on a sealed treadmill inhaling either the H2 (2% H2, 21% O2, balanced with N2) or the control gas (0% H2, 21% O2, balanced with N2) and hippocampal samples were collected immediately or 3 h after exercise. We measured hippocampal levels of cytokines [tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6 and IL-10] and oxidative markers [superoxide dismutase (SOD), thiobarbituric acid reactive species (TBARS) and nitrite/nitrate (NOx)]. Exercise increased TNF-α, IL-6 and IL-10 immediately after the session, whereas no change in IL-1ß levels was observed. Conversely, exercise did not cause any change in SOD activity, TBARS and NOx levels. H2 inhibited the exercise-induced surges in TNF-α and IL-6, and potentiated the IL-10 surge, immediately after the exercise. Moreover, no change in IL1-ß levels of rats inhaling H2 was observed. Regarding the oxidative stress markers, H2 failed to cause any change in SOD activity, TBARS and NOx levels. No significant change was observed in any of the assessed parameters 3 h after the exercise bout. These data are consistent with the notion that H2 acts as a powerful anti-inflammatory agent not only down-modulating pro-inflammatory cytokines (TNF-α and IL-6) but also upregulating an anti-inflammatory cytokine (IL-10) production without affecting the local oxidative stress status. These data indicate that H2 effectively decreases exercise-induced inflammation in the hippocampus, despite the fact that this region is particularly prone to inflammatory insults.

Author Correction: Baroreceptor denervation reduces inflammatory status but worsens cardiovascular collapse during systemic inflammation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Baroreceptor denervation reduces inflammatory status but worsens cardiovascular collapse during systemic inflammation.

Beyond the regulation of cardiovascular function, baroreceptor afferents play polymodal roles in health and disease. Sepsis is a life-threatening condition characterized by systemic inflammation (SI) and hemodynamic dysfunction. We hypothesized that baroreceptor denervation worsens lipopolysaccharide (LPS) induced-hemodynamic collapse and SI in conscious rats. We combined: (a) hemodynamic and thermoregulatory recordings after LPS administration at a septic-like non-lethal dose (b) analysis of the cardiovascular complexity, (c) evaluation of vascular function in mesenteric resistance vessels, and (d) measurements of inflammatory cytokines (plasma and spleen). LPS-induced drop in blood pressure was higher in sino-aortic denervated (SAD) rats. LPS-induced hemodynamic collapse was associated with SAD-dependent autonomic disbalance. LPS-induced vascular dysfunction was not affected by SAD. Surprisingly, SAD blunted LPS-induced surges of plasma and spleen cytokines. These data indicate that baroreceptor afferents are key to alleviate LPS-induced hemodynamic collapse, affecting the autonomic control of cardiovascular function, without affecting resistance blood vessels. Moreover, baroreflex modulation of the LPS-induced SI and hemodynamic collapse are not dependent of each other given that baroreceptor denervation worsened hypotension and reduced SI.

Increased hippocampal GABAergic inhibition after long-term high-intensity sound exposure.

Exposure to loud sounds is related to harmful mental and systemic effects. The hippocampal function can be affected to either high-intensity sound exposure or long-term sound deprivation. We previously showed that hippocampal long-term potentiation (LTP) is inhibited after ten days of daily exposure to 2 minutes of high-intensity noise (110 dB), in the hippocampi of Wistar rats. Here we investigated how the glutamatergic and GABAergic neurotransmission mediated by ionotropic receptors is affected by the same protocol of high-intensity sound exposure. We found that while the glutamatergic transmission both by AMPA/kainate and NMDA receptors in the Schaffer-CA1 synapses is unaffected by long-term exposure to high-intensity sound, the amplitude of the inhibitory GABAergic currents is potentiated, but not the frequency of both spontaneous and miniature currents. We conclude that after prolonged exposure to short periods of high-intensity sound, GABAergic transmission is potentiated in the hippocampal CA1 pyramidal neurons. This effect could be an essential factor for the reduced LTP in the hippocampi of these animals after high-intensity sound exposure. We conclude that prolonged exposure to high- intensity sound could affect hippocampal inhibitory transmission and consequently, its function.