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. 2020 May 22;41(4):751–763. doi: 10.1007/s10571-020-00881-8

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

Júnia L de Deus 1,2, Mateus R Amorim 2, Aline B Ribeiro 1, Procópio C G Barcellos-Filho 1, César C Ceballos 1, Luiz Guilherme S Branco 2, Alexandra O S Cunha 1, Ricardo M Leão 1,✉
PMCID: PMC11448697  PMID: 32445041

Abstract

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.

Keywords: Hippocampus, BDNF, LTP, High-intensity sound

Introduction

Loud sounds can damage cochlear hair cells and is currently the leading cause of permanent hearing loss and tinnitus (Le et al. 2017). Even prolonged exposure to non-traumatic noise has adverse effects on the auditory processing (Eggermont et al. 2017), and exposure to moderate to high-intensity sound triggers behavioral responses resulting in the avoidance of the sound source (Manohar et al. 2017). Indeed, loud sounds are stressors that lead to the activation of the HPA axis, leading to increased secretion of corticosterone (Helfferich and Palkovits 2003; Burow et al. 2005). Thus, non-auditory areas are affected by the level of auditory input and adjust the animal´s behavior to the acoustic environment.

Additionally, exposure to moderate or loud sounds can produce several systemic and cognitive deficits in humans (Lercher et al. 2003; Stansfeld et al. 2005; Basner et al. 2014). The so-called “sonic attack” to American diplomatic personnel, which produced emotional and cognitive symptoms after the exposure to a high-pitched, loud sound (Hofner et al. 2018; Swanson et al. 2018), is a dramatic example of the harmful effects of exposure to loud sounds.

The hippocampus receives sensory information from several modalities, which are fundamental for its role in spatial navigation, learning, and memory formation (Save et al. 2000; Jeffery 2007; Ravassard et al. 2013). It is connected to the auditory system (Kraus and Canlon 2012; Zhang et al. 2018), and sound stimulation triggers excitatory and inhibitory neurotransmission in hippocampal neurons in vivo (Wang et al. 2017). Also, the hippocampus is related to the formation of auditory memories (Squire et al. 2001), it uses auditory information for the formation of spatial memory (Tamura et al. 1990) and hippocampal place cells can be activated by auditory dimension cues (Aronov et al. 2017). On the other hand, prolonged exposure to loud or even moderate-intensity sounds causes oxidative damage and tau phosphorylation in the hippocampus and impairs spatial memory in mice (Cheng et al. 2011, 2016), whereas high-intensity sound exposure affects hippocampal place cells activity (Goble et al. 2009). Additionally, exposure to moderate to loud sounds can lead to impairment of spatial and associative memory, which seems to be associated with oxidative status imbalance (Uran et al. 2010, 2012; Manikandan et al. 2006). On the other hand, 40-min exposure to mild (80 dB) sounds, increased hippocampal long-term potentiation (LTP), and brain-derived neurotrophic factor (BDNF) expression (Matt et al. 2018). Finally, we have shown that one-minute exposure to a high-intensity (110–120 dB) broadband sound inhibits LTP in the Schaffer-CA1 synapses in the hippocampus of rats for 24 h after exposure (de Deus et al. 2017), an effect not related to corticosterone secretion, and not observed after moderate noise (80 dB) exposure.

Hippocampal LTP is a long-lasting enhancement of synaptic efficacy associated with hippocampal learning and memory (Bliss and Lomo 1973; Bliss and Collingridge 1993). In the Schaffer-CA1 synapse, LTP is dependent on post-synaptic calcium influx via glutamatergic NMDA receptors (for review, see Malenka and Bear 2004; Nicoll 2017). LTP is modulated positively or negatively by several signaling molecules, such as BDNF, a neurotrophic factor that acts on TrkB receptors (Minichielo 2009). Activation of TrkB receptors by BDNF promotes LTP in the Schaffer-CA1 synapse (Minichielo 2009; Edelman et al. 2015; Lin et al. 2018). Heterozygous BDNF (±) knockout mice have a significant deficit in hippocampal LTP (Korte et al. 1995), which can be rescued by exogenous BDNF (Patterson et al. 1996). The secretion of BNDF is promoted by stimulation protocols that develop LTP but not to stimulation patterns that do not lead to LTP (Aicardi et al. 2004). In accordance with the role of BDNF in facilitating the induction of LTP, BDNF can rescue LTP in situations where LTP is inhibited by exogenous conditions, for example, after prolonged periods of chronic intermittent hypoxia (Xie et al. 2010).

Here we investigated the mechanisms of LTP inhibition by a single episode of high-intensity sound stimulation (de Deus et al. 2017). We demonstrated that this treatment does not affect glutamatergic or GABAergic transmission but does reduce the hippocampal levels of BDNF, and LTP could be rescued by exogenous BDNF application.

Materials and Methods

Animals

Experiments were performed on male Wistar rats with 60–70 days old obtained from the Central Animal Facility of the Ribeirão Preto Campus of the University of São Paulo. Rats were kept in Plexiglas cages (2–3 animals per cage) with food and water available ad libitum and a 12-h dark/light cycle (lights on at 7:00 a.m.) and controlled temperature (22 °C). We divided the animals into two experimental groups: sham-stimulated (rats placed in the sound stimulus box without sound stimulus) and rats submitted to a sound stimulus of 110 dB (high-intensity sound).

The number of animals used in each experimental group was as followed: 6 animals for immunofluorescence experiments (Sham: n = 3 and Stimulated: n = 3). For extracellular records we used 21 rats (Sham: n = 3; Stimulated: n = 4; Sham-BDNF: n = 6; Stimulated-LM22A4: n = 3; Stimulated-BDNF: n = 5). For recordings of GABAergic neurotransmission, we used eight rats (Sham: n = 4; Stimulated: n = 4). For recordings of glutamatergic neurotransmission, we used 12 rats (Sham: n = 5; Stimulated: n = 7). For Elisa assay, we used 15 rats (Sham: n = 8; Stimulated: n = 7).

Sound Stimulation

Rats were placed in an acrylic arena (height: 32 cm, diameter: 30 cm), located inside an acoustically isolated chamber (45 × 45 × 40 cm), with two loudspeakers placed at the top of the arena, in accordance with protocols described previously by de Deus et al. (2017). After one-minute acclimatization, they were submitted to a one-minute duration stimulus of 110 dB, spanning frequencies from 3 to 15 kHz (Romcy-Pereira and Garcia-Cairasco 2003). After stimulation, animals were kept in the arena for one more minute and returned to their boxes where they remained for 2 h until the preparation of the hippocampal slices. Sham-stimulated animals were placed in the same arena for 3 min without any sound stimulus. Our previous report showed that LTP was similar in control and sham-stimulated animals (de Deus et al. 2017). Ambient noise inside the acoustic chamber was 55 dB, and the sound intensity inside the arena was checked and calibrated regularly with a decibel meter (Extech 407730—Sound Level Meter).

c-FOS Immunofluorescence

For labeling, 12 slices (2 per animal) of the dorsal hippocampus were used. Each slice contained the two hippocampi (left and right) with well-defined CA1, CA3, and DG fields. After 90 min of the sound or sham stimulus, rats were anesthetized with isoflurane for transcardial perfusion with 80 ml of phosphate-buffered saline (PBS, 0.1 M, pH 7.4) and afterward with 320 ml of paraformaldehyde at 4% dissolved in PBS. After perfusion, the brains were immediately removed and immersed in 30% sucrose solution in PBS until tissue saturation. Next, tissue blocks were frozen in isopentane for 30 s and stored at − 80 °C until sectioned. Coronal slices of 40 μm were cut in a cryostat. The slices were washed rapidly with glycine (0.1 M) to remove excess paraformaldehyde, permeabilized with 0.1% Triton X-100 for 10 min, and washed with 0.1 M PBS. Nonspecific binding was blocked with PBS containing 1% bovine serum albumin (BSA; Sigma, St. Louis, MO, USA) for 1 h. Subsequently, slices were incubated for 40 h at 4 °C with a polyclonal primary anti-c-FOS antibody produced in rabbit (1: 5000; Santa Cruz Biotechnology, Dallas, TX, USA). The primary antibody was diluted in PBS, containing 0.1% Triton X-100 and 1% BSA. Then, after washing with PBS (5X for 5 min), slices were incubated with goat anti-rabbit IgG conjugated with AlexaFluor 594 (1:1000; Vector Laboratories, Burlingame, CA, USA) for 1 h. Finally, nuclear labeling was done with DAPI (4′, 6-diamidino-2-phenylindole; 1 μg/mL, Sigma-Aldrich) for 10 min at room temperature. Slices were then mounted on slides using Fluoromount G mounting medium (Electron Microscopy Sciences, Hatfield, PA), viewed and photographed under fluorescence microscopy DM 5500B (Leica Microsystems, Wetzlar, Germany). Non-specific binding of the secondary antibody was evaluated in slices processed as described above, except that the primary antibody was omitted. No labeling was observed in these controls.

Preparation of Hippocampal Slices

Two hours after sound or sham stimulus, the animals were anesthetized with isoflurane and decapitated. The brains were rapidly removed and placed in an ice-cold solution containing: 87 NaCl, 2.5 KCl, 25 NaHCO3, 1.25 NaH2PO4, 75 sucrose, 25 Glucose, 0.2 CaCl2, 7 MgCl2, bubbled with 95% O2 and 5% CO2. Brain hemispheres were separated, positioned side by side, fixed with cyanoacrylate glue (SuperBonder®) to a base, and placed in the chamber of a vibratome (1000 plus, Vibratome, USA). Transversal slices containing the dorsal hippocampus (200 μm for whole-cell recordings and 400 μm for extracellular recordings) were cut, and the hippocampus was separated from the cortex using ophthalmic scissors and micro-tweezers. Slices were incubated in artificial cerebrospinal fluid (aCSF) solution containing (mM): 125 NaCl, 2.5 KCl, 1.25 NaH2PO4, 26 NaHCO3, 10 Glucose, 2 CaCl2, 1 MgCl2 for 1 h at 34–35 °C and at least 1 h at room temperature, continuously bubbled with a carbogenic mixture (95% O2 and 5% CO2).

Whole-Cell Patch-Clamp Recordings

Whole-cell patch-clamp experiments were performed in slices placed in a chamber continuously perfused with aCSF (1 ml/min) supplemented with picrotoxin (GABAA receptor antagonist: 20 μM, Sigma, USA) except for experiments that measured GABAergic neurotransmission. The temperature was controlled to 34 °C with an inline heater (Scientifica, UK). Pyramidal neurons from the CA1 region were visualized with an Olympus BX51WI microscope through a 40 × water immersion objective and with infrared differential interference contrast (IR-DIC). Pyramidal cells were identified based on morphology (pyramidal shape) and position. Recording electrodes were filled with an internal pipette solution chosen for each set of experiments and fabricated from borosilicate capillaries (BF150-86-10, 15 Sutter Instruments, USA) with tip resistance of 4–5 MΩ. Electrophysiological recordings in whole-cell patch-clamp were performed using a Heka EPC10 amplifier (HEKA Electronik, Germany), low-pass filtered at 3 kHz (Bessel), and sampled at 50 kHz and. Experiments for which series resistance increases more than over 20% during recording, or for which resting membrane potential was more positive than − 60 mV, were discarded. Series resistance (< 20 MΩ) was compensated by around 50–60%. Voltages were corrected offline for a liquid junction potential calculated for each internal solution using Clampfit software (Molecular Devices).

Glutamatergic EPSCs were evoked by stimulation of the Schaffer pathway with a concentric bipolar microelectrode (FHC-Bowdoin, ME, USA) connected to an SD9 Grass voltage stimulator (Natus Medical Incorporated, Warwick, RI, USA). For recordings of AMPA and NMDA EPSCs, the aCSF contained picrotoxin (20 μM), and the internal solution was composed of in mM: 130 CsCl, 10 HEPES, 5 EGTA, 5 phosphocreatine, 4 Mg-ATP, 0.5 Na-GTP, 10 TEA, 5 QX 314, adjusted to pH 7.3 with CsOH and ≈ 290 mOsm/kg H2O. AMPA and NMDA currents were recorded at different potentials ranging from − 70 to + 80 mV with increments of + 30 mV. The stimulus intensity was gradually increased until the amplitude of the synaptic current reached its maximum. We then stimulated Schaffer pathway with the minimum voltage necessary to evoke a maximum post-synaptic current for recording the currents. To obtain NMDA currents, we blocked AMPA/KA currents with DNQX (10 μM, Sigma, USA) for 10 min. AMPA/KA currents were obtained by subtracting the currents before and after DNQX.

Miniature GABAergic IPSCs (mIPSCs) recorded at − 70 mV were isolated by recording in aCSF containing tetrodotoxin (TTX; 0.5 μM, Alomone Lab, Israel) and DNQX (10 μM) using an internal solution consisting of (mM): 145 KCl, 10 HEPES, 0.5 EGTA, 10 phosphocreatine, 4 Mg-ATP, 0.3 Na-GTP, adjusted to pH 7.3 with KOH and ≈290 mOsm/kg H2O.

BDNF Quantification

Mature BNDF was quantified using ELISA. 4 h after sham or sound stimulus, rats were decapitated, and the brains were carefully collected, frozen by submersion in dry ice-cold isopentane, and kept at − 80 °C until the day of the assay. The dorsal hippocampus was cut in a cryostat with a thickness of 1200 μm, and samples of the left and right hippocampus obtained using a punch needle (1.5 mm inner diameter) (Fig. 4a), pooled and stored in plastic tubes at − 80 °C until analysis Samples were homogenized with buffer solution (137 mM NaCl, 20 mM Tris–HCl pH 7.6, 10% glycerol and sodium orthovanadate), supplemented with phosphatase protease inhibitor cocktail (Cell Signaling, Massachusetts, USA) and centrifuged at 13.000 rpm for 20 min at 4 °C. Tissue supernatant was used to estimate mature BDNF (detection limits 7.8–500 pg/ml) by ELISA, according to the manufacturer's instructions. Results from BDNF in hippocampal homogenates were normalized by protein concentrations, which were assessed by the Bradford assay (#5000205, Bio-Rad Laboratories, USA). Total protein concentration was 0.18 ± 0.012 mg/ml for sham rats and 0.22 ± 0.008 mg/ml for stimulated rats.

Fig. 4.

Fig. 4

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Aa Schematic drawing of a transversal slice of the hippocampus. b Representative photo of the bilateral dorsal hippocampus before and after the punch (1200 µm). c BDNF levels in the dorsal hippocampus from sham-stimulated and rats submitted to a sound stimulus of 110 dB. ***P < 0.005

Field Potential Recordings and LTP Induction

Extracellular electrophysiological recordings were performed with a Multiclamp 700B amplifier (Molecular Devices, USA) connected to a Digidata 1440 A AC/DC interface (Molecular Devices, USA). Slices were placed in the recording chamber with continuous superfusion of aCSF (1 mL/min) bubbled with a carbogenic mixture and the temperature-controlled (32–34 °C) using an inline temperature heater (Warner Instruments, USA). To stimulate Schaffer/collateral fibers, we used a stainless steel bipolar concentric microelectrode (FHC-Bowdoin, Maine, USA) connected to a Master-9 voltage stimulator (A.M.P.I., Israel). Field excitatory post-synaptic potentials (fEPSPs) were recorded at CA1 stratum radiatum with borosilicate glass microelectrodes (G85150T, Warner Instruments, USA) filled with aCSF with tip resistances of 1–2 MΩ. For LTP induction, first, we performed an input–output curve, where the voltage was gradually increased by 10 V increments until population spikes were observed in the fEPSP. From the maximum stimulus, we choose the stimulus intensity that produced an fEPSP equivalent to approximately 50% of the maximum response. Subsequently, 50 fEPSPs were recorded at this intensity for 25 min (30 s interval between stimuli). After baseline recording, LTP was induced on Schaffer-collateral fibers using three trains of high-frequency stimulation (HFS) at 100 Hz, 1-s duration (inter-train interval of 3 s). After applying the LTP protocol, fEPSPs were recorded for 80 min. When used, BDNF (recombinant human, 25 ng / ml, Alomone Labs, Israel) and (LM22A4: 5 μM, Cayman Chemicals, Ann Arbor, MI, USA) were perfused during the last 5 min of the baseline recording and in the first 5 min post-LTP. Signals filtered at 3 kHz (Bessel, 8-pole) and acquired at 100 kHz, with pClamp 10.2 software (Molecular Devices, USA).

Data Analysis and Statistics

For analysis of c-FOS labeling, we used in total 36 hippocampi sections (2 sections of CA1, 2 of CA3, and 2 of DG, per animal). For the quantitative analysis of cells positive for c-FOS, the experimenter was blind to the experimental group. Two consecutive sections containing the hippocampus were taken from each animal. A square (same size for all slices) was manually drawn around the area of CA1, CA3, and dentate gyrus to define regions of interest. In each section, the number of c-Fos-positive cells was counted bilaterally using an automated cell counting procedure by ImageJ software (National Institute of Health, Bethesda, MA). The image was converted to grayscale using the thresholding feature, to highlight and standardize the shape parameters of the immunoreactive particles to teach the program how to detect a cell. Threshold settings and light intensity were the same across all sections and during photo acquisition. The thresholded FOS-stained cells for the area were averaged and are presented as Fos-positive nuclei/section for each brain area.

AMPA and NMDA EPSCs slope conductances were determined as the slope of linear functions of the linear part of the IV relationships. mIPSCs were analyzed using Mini Analysis software (Synaptosoft 6.0.3, Fort Lee, NJ, USA) and EPSCs with custom-written routines in IgorPro (Wavemetrics, Portland, OR, USA) and Matlab (MathWorks, Natick, MA, USA). The peaks of the EPSCs were used to build IV relationships to calculate the reversal potential. We measured rise times from baseline to peak and decay times from peak to baseline. mIPSCs were recorded for 10 min at − 70 mV after the application of TTX to block action potentials and were selected manually, and only currents with good signal to noise ratio which could be easily identified as mIPSCs were chosen. Histograms for inter-event (IEI) intervals, amplitudes, and rise times were built with the same fixed bins for different groups of cells and. Analysis of the decay kinetics for inhibitory currents was performed by Mini Analysis group analysis with individual currents fitted with double exponential functions. Fast and slow time constants were presented as the average and compared between groups.

Field potentials were analyzed with Clampfit 10.2. Traces were low-pass filtered offline (500 Hz), and the slopes of the fEPSPs were fitted with a standard linear function. Data from each experiment were normalized relative to its baseline. LTP was quantified as the average of the fEPSP slopes in the last 20 min from the 80 min post-induction recording period.

The results are presented as means ± SE, and statistical significance was determined using unpaired Student's t-test and one-way ANOVA as required, cumulative frequency distributions were tested for significance with Kolmogorov–Smirnov (KS) test. We used a significance level of 5% (P ≤ 0.05).

Results

High-Intensity Sound Exposure Increases c-fos Expression in Hippocampal Neurons

Because high-intensity sound affects the hippocampus in several ways (de Deus et al. 2017; Cunha et al. 2019), we tested if our protocol of high-intensity sound stimulation was able to activate hippocampal cells through of c-FOS expression. c-fos is an immediate early gene (IEG) which expression is driven by calcium entry by NMDA receptor activation and voltage-dependent calcium channels, during intense action potential firing, and it is used as a marker of neuronal activation (Dragunow and Faull 1989; Hudson 2018). Immunostaining for c-FOS in stimulated rats showed a high level of c-FOS expression in CA1 neurons in the pyramidal layer (192.0 ± 16.71 cells/section; n = 3 animals) compared to sham-stimulated (142.0 ± 3.041 cells/section; n = 3 animals; P = 0.04, Fig. 1a). We also observed that pyramidal layer CA3 neurons presented higher c-FOS expression in stimulated (154.8 ± 12.74 cells/section; n = 3 animals) when compared sham-stimulated rats (88.50 ± 5.074 cells/section; n = 3 animals; P = 0.008, Fig. 1b). In contrast, c-FOS expression was similar in neurons of the dentate gyrus, in sham and stimulated rats (P ≥ 0.05, Fig. 1c). These findings indicate that high-intensity sound excites hippocampal neurons and induce c-FOS expression in hippocampal neurons.

Fig. 1.

Fig. 1

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Photomicrographs illustrating c-FOS-positive nuclei labeling (red), and cell nuclei stained with DAPI (blue) in sections of CA1 (a), CA3 (b), and dentate gyrus (c). Left panel, representative images from an animal exposed to sham stimulation, and an animal exposed to 110 dB sound stimulation (× 10). Inset: squared area at higher magnification (× 20). Right panel, the number of c-FOS-positive nuclei staining/section for CA1 (A1), CA3 (B1), and dentate gyrus (C1). *P < 0.05

High-Intensity Sound Exposure Does Not Affect Glutamatergic Neurotransmission In The Schaffer-CA1 Synapses

LTP is dependent on the activation of NMDA receptors in the synapses of the Schaffer-CA1 pathway with pyramidal neurons of the hippocampus (Collingridge and Bliss 1987; Tang et al. 1999; Tsien et al. 1996). The inhibition of LTP induced high-intensity sound-induced previously shown by our group (de Deus et al. 2017) could be due to an inhibition of NMDA-mediated currents or to a decreased AMPA/Kainate (AMPA/KA) receptor activation. Therefore, we investigated if acute high-intensity sound stimulus alters glutamatergic synaptic neurotransmission. In these experiments, we recorded AMPA/KA (DNQX-sensitive) and NMDA (DNQX-resistant) receptor-mediated EPSCs from Schaffer-CA1 synapses from sham and stimulated animals (Fig. 2a). Both IV relationships of the AMPA/KA and NMDA receptor-mediated EPSCs were similar between the sham and stimulated groups (Fig. 2b and c). The calculated slope conductances of the currents were not significant different between sham and stimulated groups (AMPA/KA, sham: 8.4 ± 0.6 nS; stimulated: 8.4 ± 0.7 nS, P = 0.9; NMDA, sham: 3.8 ± 0.3 nS; stimulated: 4.0 ± 0.4 nS, P = 0.6). The amplitudes of AMPA/KA receptor-mediated EPSCs at − 80 mV in sham (-616.4 ± 101.7 pA; n = 9) and stimulated animals (− 657.2 ± 108.2 pA; n = 16) were not significantly different (P = 0.80; Fig. 2d). Also NMDA-mediated EPSCs at + 70 mV, were not significantly different between sham (310.2 ± 56.6 pA; n = 9) and stimulated groups (370.7 ± 71.4 pA; n = 11; P = 0.5; Fig. 2e). Our data show that a sound stimulus of 110 dB of 1-min duration did not alter fast hippocampal glutamatergic neurotransmission; thus, LTP inhibition was not caused by a change in the glutamatergic receptor-mediated currents in pyramidal neurons of the CA1 region.

Fig. 2.

Fig. 2

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Glutamatergic neurotransmission evoked by AMPA/KA and NMDA receptors. a Representative traces of AMPA/KA currents (DNQX-sensitive) at − 80 mV and NMDA currents (DNQX-resistant) at + 70 mV, respectively. AMPA/KA (b) and NMDA (c) peak currents at different voltages. Mean peak currents of AMPA/KA (d) at − 80 mV and NMDA at + 70 mV (e)

High-Intensity Sound Exposure Does Not Substantially Affect GABAergic Transmission in CA1 Pyramidal Neurons

Previous results from our group showed that a long-term protocol of high-intensity sound stimulation which inhibits LTP in the Schaffer-CA1 synapse (2 episodes a day, for ten days; Cunha et al. 2015) potentiates GABAergic transmission on pyramidal CA1 hippocampal neurons (Cunha et al. 2019) by increasing the amplitude of the GABAergic currents. We then tested if a single episode of high-intensity sound could potentiate the GABAergic neurotransmission in the CA1 pyramidal neurons.

However, different from what we observed with the 10-day protocol, we did not observe changes in GABAergic transmission in the hippocampus of animals subjected to one minute of high-intensity sound (Fig. 3a). Moreover, we did not find differences in the amplitude of the mIPSCs: (sham-stimulated: 76.8 ± 6.1 pA, n = 8; stimulated: 70.0 ± 3.52 pA, n = 8; P = 0.39, Fig. 3b, c). We found a smaller, but not significant reduction in the frequency of the mIPSCs in neurons from stimulated animals (sham: 2.05 ± 0.48 Hz, n = 8, stimulated: 1.15 ± 0.16 Hz, n = 9, P = 0.08, Fig. 3d, e). However, we found that mIPSCs from stimulated animals had faster decay times than the mIPSCs from control animals (fast decay time constant: sham: 2.9 ± 0.1 ms; n = 8; stimulated: 2.4 ± 0.2 ms; n = 9; P = 0.04, Fig. 3f; slow decay time constant: sham: 25.0 ± 1.2 ms, n = 8 and stimulated: 20.4 ± 0.9 ms, n = 9; P = 0.003, Fig. 3g). The relative proportion of the two components (fast/slow) was similar in both groups (sham: 53%; stimulated: 48%). We conclude that, contrary to the observed after the long-term stimulation with high-intensity sound, the GABAergic inhibitory neurotransmission was not potentiated by a short stimulus with high-intensity sound, but a similar change in current kinetics was observed.

Fig. 3.

Fig. 3

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Miniature GABAergic currents. a Representative traces of inhibitory currents from sham-stimulated rats (black trace) and rats submitted to a sound stimulus of 110 dB (red trace). b Mean amplitude of events detected and c cumulative fraction of amplitudes per group. d Mean rise time of mIPSC. e Mean frequency and f Cumulative fraction of IEI of mIPSC. g Mean half-widths. h Mean fast and i slow decay time constants. j The ratio between Afast and Aslow shown as a percentage. *P < 0.05; **P < 0.01

High-Intensity Sound Exposure Decreases BDNF Levels in the Dorsal Hippocampus, and the Inhibition of LTP is Reverted by the Application of BDNF or Its Receptor Agonist

Given that we observed no changes in the glutamatergic and inhibitory currents, we tested if another factor could account for the reduction in hippocampal LTP in these animals. Because of the strong effect of BDNF in facilitating hippocampal LTP, we hypothesized that high-intensity sound exposure could affect BDNF production or secretion in the hippocampus. Indeed, we found that BDNF levels in the dorsal hippocampus were decreased significantly in stimulated (1732 ± 76.87 pg.mg protein−1; n = 7) in comparison with sham rats (2344 ± 89.06 pg mg protein−1, n = 8; P = 0.0002) (Fig. 4). Thus, our results showed that high-intensity sound decreases secretion or production of BDNF in the hippocampus.

We then decided to test if perfusion of BDNF to the hippocampal slices of rats exposed to high-intensity sound could revert the inhibition of LTP, similar to observed in the hippocampi of animals submitted to chronic intermittent hypoxia (Xie et al. 2010). First we reproduced our original observation (de Deus et al. 2017) that exposure to 110 B sound for one minute inhibits the LTP in the Schaffer-CA1 synapse (Fig. 5a–c; sham: 1.41 ± 0.11; n = 4; sound exposed: 1.04 ± 0.06; n = 5; P = 0.01). Perfusion of BDNF (25 ng/ml) previously to the induction of LTP in the Schaffer-CA1 synapse in slices from sham animals did not change the magnitude of LTP (1.43 ± 0.07; n = 7. P = 0.90. Figure 5d, e) showing that supplementation of BDNF to the hippocampus of sham animals does not further potentiate LTP. However, when we perfused the slices of rats submitted to one minute of 110 dB sound with BDNF, we observed a recovery of LTP (1.55 ± 0.12; n = 6; P = 0.01 when compared to sound exposed group), to the same level of the sham group (P = 0.47, Fig. 5f). Additionally, we tested if the Trk-B agonist LM22A4 could restore hippocampal LTP in slices of sound exposed rats. Indeed, perfusion of LM22A4 (5 μM) rescued hippocampal LTP from slices from sound exposed rats (1.62 ± 0.17; n = 5; P = 0.02 compared with the sound exposed group) to the same level to the LTP observed in slices from sham rats; P = 0.38; Fig. 5g, h). These results indicate that Trk-B receptor activation by BDNF reverts the LTP inhibition caused by exposure to high-intensity sound. Together with the reduced levels of BDNF in the hippocampus of these animals, these results suggest that exposition to on minute of high-intensity sound decreases BDNF levels in the hippocampal CA1 region resulting in inhibition of LTP induction.

Fig. 5.

Fig. 5

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LTP from the Schaffer-CA1 synapse of sham- stimulated rats (a) and animals submitted 110 dB sound exposure (b). Normalized fEPSP slopes before and after HFS (arrow) from the Schaffer-CA1 synapse of slices of sham animals and stimulated rats. c Bar graphs showing the summary of LTP for sham-stimulated and stimulated rats. d Normalized fEPSP slopes before and after HFS (arrow) from the Schaffer-CA1 synapse of slices treated with BDNF (bar-10 min) from sham-stimulated rats. e Bar graph showing the summary of LTP for sham-stimulated and stimulated rats. f Normalized fEPSP slopes before and after HFS (arrow) from the Schaffer-CA1 synapses of slices treated with BDNF (bar-10 min) from stimulated rats. g Normalized fEPSP slopes before and after HFS (arrow) from the Schaffer-CA1 synapse of slices treated with LM22A4 (bar-10 min) from stimulated rats. Bar graph showing the summary of LTP from control slices and slices treated with BDNF and LM22A4 from stimulated rats. Representative recordings are shown above each graph. *P < 0.05

Discussion

Several lines of evidence show that auditory stimulation has effects beyond the auditory processing areas (Lercher et al. 2003; Stansfeld et al. 2005; Uran et al. 2010, 2012; Kraus and Canlon 2012; Basner et al. 2014), and several cognitive and emotional deficits are associated to prolonged and acute noise exposure in humans (Lercher et al. 2003; Stansfeld et al. 2005; Basner et al. 2014; Hoffer et al. 2018; Swanson et al. 2018).

Our previous findings showed that intense auditory stimulation strongly depressed long-term potentiation in the hippocampal Schaffer-CA1 synapse (Cunha et al. 2015; de Deus et al. 2017). Our first observation was that a 10-day long protocol of two daily episodes of 120 dB sound exposure for 1 min each, was able to inhibit the LTP in the hippocampal Schaffer-CA1 synapse of Wistar rats (Cunha et al. 2015 We later found that a single one-minute episode of 110 dB sound was able to inhibit LTP in the Schaffer-CA1 synapse (de Deus et al. 2017), showing that exposure to high-intensity sound even for a brief period can impact hippocampal LTP.

The mechanisms of the inhibition of LTP by the prolonged exposure to high-intensity sound might be related, at least partially, to an increase in membrane resistance and decrease in action potential threshold, by a reduction in the expression of Ih in CA1 pyramidal neurons (Cunha et al. 2018) and potentiation of GABAergic transmission (Cunha et al. 2019). However, in the animals subjected to one minute of high-intensity sound, we did not find differences in the intrinsic properties of CA1 pyramidal neurons (Cunha et al. 2018), showing that the impact of high-intensity sound in the hippocampus is dependent on the length of sound exposure.

In this work, we continued the investigation of the mechanisms of LTP inhibition after one-minute exposure to a 110 dB sound. We found, like observed after prolonged exposure to one-minute episodes of 110 dB sound (Cunha et al. 2019), that the glutamatergic transmission both via AMPA/kainate and NMDA receptors is not affected by a one minute 110 dB sound exposure. However, no potentiated GABAergic transmission was observed after a single episode of 110 dB sound, differently to the potentiated GABAergic transmission after ten days of stimulation (Cunha et al. 2019), suggesting that the potentiated GABAergic transmission is a late response to high-intensity sound stimulation. This effect probably compensates for the late increased excitability of CA1 pyramidal neurons observed after the prolonged exposure to high-intensity sound (Cunha et al. 2018). Interestingly, a similar change in the decay time of the IPSCs was observed in both single and prolonged high-intensity sound exposure, suggesting a fast post-synaptic change in GABAA receptors induced by high-intensity sound. These results indicate that the effects of high-intensity sound are distinct in both models of high-intensity sound exposure.

The hippocampus is implicated in the formation of long-term auditory and auditory-spatial memories and fear conditioning (Squire et al. 2001; Tamura et al. 1990; Aronov et al. 2017). Recently a new pathway was identified from the cochlear nucleus to the entorhinal cortex involving the pontine reticular nucleus, pontine central gray, and medial septum, with a higher threshold than the canonical pathway via inferior colliculus, and related to fear conditioning (Zhang et al. 2018). The higher threshold for sound activation of this pathway suggests a role in response to high-intensity sounds. Moreover, retrograde tracing experiments suggested a direct connection between the auditory cortex and the CA1 region (Zhao et al. 2018). Accordingly to the connections between the auditory system and the hippocampus, we showed that c-FOS expression was increased in the pyramidal cell layer of both CA1 and CA3 regions. C-FOS expression is induced by strong increases in intracellular calcium trough NMDA receptors and voltage-dependent calcium channels, which activates MAPK pathway leading to the phosphorylation of the transcription factors CREB and Elk-1, that bind to the c-fos promoter (Chung 2015; Hudson 2018). The expressed FOS protein dimerizes with the protein JUN to form the AP-1 complex that regulates the expression of several genes that could be involved in the inhibitory effect of high-intensity sound on LTP. Because c-fos expression needs strong calcium influx induced by synaptic activity, we hypothesize that high-intensity sound stimulation induces a hyperexcitation of hippocampal neurons during the exposure to sound. We found increased c-fos expression in the pyramidal layer, were the glutamatergic pyramidal neurons are located. However, we cannot discard the activation of GABAergic interneurons located in the pyramidal layer or adjacent to it. Interestingly, in vivo, hippocampal recordings showed that sound exposure evokes inhibitory currents on pyramidal neurons, according to the activation of hippocampal inhibitory interneurons (Wang et al. 2017).

Based on the critical role of BDNF over hippocampal LTP (Minichielo 2009; Edelmann et al. 2015; Lin et al. 2018), we tested the hypothesis that a lack of BDNF could be related to the LTP impairment after high-intensity sound exposure. We found that the expression of the mature form of BDNF was reduced in the hippocampus of rats exposed to high-intensity sound. It has been shown that in the Schaffer-CA1 synapse, presynaptic BDNF is released during tetanic activity and contributes to LTP (Zakharenko et al. 2003). Thus a possible explanation of the decrease in hippocampal BDNF is that there is a decrease in the cellular BDNF caused by firing of hippocampal neurons during sound stimulation (which is evidenced by c-FOS expression). We then demonstrated that exogenous application of BDNF was able to rescue the LTP from the Schaffer-CA1 synapses from rats exposed to high-intensity sound. Because BDNF did not increase the magnitude of LTP from the Schaffer-CA1 synapses from sham rats, the increase in the magnitude of LTP in sound exposed animals was not caused by facilitation of LTP by exogenous BDNF, but we believe it represented a replenishment of reduced BDNF levels in the hippocampus of these animals. Additionally, the agonist of the Trk-B receptor LM22A4 also rescued the LTP from sound-stimulated animals, confirming that the hippocampal BDNF/ Trk-B pathway is affected by high-intensity sound exposure. However, the efficacy of LM22A4 and other small molecule agonists of Trk-B receptors has been recently questioned (Boltaev et al. 2017). Thus, we conclude that a decrease in BNDF levels in the hippocampus of rats submitted to one minute of high-intensity sound impairs the expression of LTP in the Schaffer-CA1 synapse.

The mechanisms of BDNF induction of LTP can be diverse, both pre-and post-synaptic (Blum and Konnerth 2005). In the Schaffer-CA1 synapse, activation of TrKb receptors by BDNF activates MAP kinase (MAPK) and phosphotidylinositol-3 kinase (PI3-K), which attenuates synaptic fatigue at the Schaffer-CA1 synapse during the tetanic stimulation used to induce LTP (Figurov et al. 1996; Gottschalk et al. 1999). The deletion of the TrKb receptor in the CA1 pyramidal neurons reduces the presynaptic release of glutamate during tetanic stimulation, without affecting post-synaptic glutamatergic receptors, suggesting a presynaptic action of BDNF at this synapse (Xu et al. 2000). Although we did not find any change in basal glutamatergic neurotransmission or paired-pulse depression (de Deus et al. 2017) after high-intensity sound, we did not investigate the effect on the synaptic depression during intense stimulation as used to induce LTP.

Exposure to intense sounds is often associated with deficits in hippocampal function. For instance, acute traumatic noise (106–115 dB, 30–60 min) alters place cell activity in the hippocampus and increases arc expression, an immediate early gene related to synaptic plasticity, in the hippocampi of rats (Goble et al. 2009; Kapolowicz and Thompson 2016). Prenatal exposure to loud sounds has a deleterious effect on the hippocampal LTP hippocampal-dependent learning and memory in rats (Barzegar et al. 2015). In contrast with our results, Matt et al. (2018) found that prolonged exposure to traumatic noise (120 dB, 6 h per day for 21 days) in anesthetized rats did not alter LTP and BDNF expression. This result suggests that BDNF is affected differently by short-term and prolonged sound exposure. Interestingly, general anesthesia inhibits the sound-induced synaptic currents in the hippocampus (Wang et al. 2017). We do not know, however, if the same decrease in BDNF levels occurs in the hippocampus of animals subjected to our 10-days long sound exposure protocol (Cunha et al. 2015).

Prolonged moderate sound exposure also affects hippocampal function in several ways. For instance, prolonged (2 h/ day for 3–6 weeks) moderate (80 dB) sound exposure impairs spatial memory in mice and increases oxidative damage and hippocampal tau phosphorylation (Cheng et al. 2011, 2016). On the other hand, daily exposure to music at moderated intensity levels (60 dB, 6 h per day for 21 days) enhanced learning performance and increased BDNF expression in the hippocampus (Angelucci et al. 2007). Similarly, exposure to an 80 dB sound at 10 kHz for 40 min in anesthetized rats, increased BDNF expression, hippocampal LTP magnitude, and improved performance in the Morris water maze (Matt et al. 2018). Moreover, prolonged exposure (7 to 21 days) to intermittent periods of environmental noise (ranging from 80 to 105 dB) increased c-fos expression in the hippocampus and plasmatic pro-BDNF (Fernandez-Quesada et al. 2019). It appears that the effect of moderate noise is related to the type of noise, and it seems to be contradictory in different reports.

Interestingly, sound deprivation also impacts hippocampal function. Zhao et al. (2018) showed that temporary conductive hearing loss in young rats reduced LTP, NMDA currents, dendritic spine density and resulted in impaired performance in the Morris water maze 30 days later when the hearing was restored. Other reports showed that mice with noise-induced hearing loss had impaired spatial memory, hippocampal neurogenesis and hippocampal c-fos expression induced by the Morris Water Maze test (Tao et al. 2015; Liu et al. 2016, 2018).

Thus, the results presented here and in other reports from our group, in combination with other reports, show that the auditory environment influences the hippocampus strongly and that the BDNF is an important mediator of these effects. Interestingly, despite this strong effect in inhibiting LTP we did not find any deficit in spatial navigation and memory in the animals subjected to our protocols of high-intensity sound exposure (Cunha et al. 2015; de Deus et al. 2017), showing that despite inhibiting hippocampal LTP, exposure to high-intensity sound does not affect basic spatial learning and memory processes. Thus, the impact of the reduced LTP in response to high-intensity sound in the hippocampal function is still unknown.

Acknowledgements

We thank the technical assistance of Mr. J. Fernando Aguiar and Mr. Rubens F. de Melo, and Dr. Christopher Kushmerick for reviewing the manuscript.

Author Contributions

Conceptualization [RML, AOSC, JLD]; Investigation: [JLD, MRA, ABR, PCGB-F); Data Analysis: [JLD, MRA, ABR, PCGB-F, CCC]; Software [CCC]; Writing—original draft preparation: [RML, JLD, ABR]; Writing—review and editing: [RML, JLD, ABR, AOSC]; Funding acquisition: [RML, AOSC, LGSB]; Supervision: [RML, LGSB].

Funding

Work supported by São Paulo State Research Foundation (FAPESP) Grants 2015/22327-7, 2016/01607-4 and 2016/17681-9.

Compliance with Ethical Standards

Conflict of interest

The authors declare no conflict of interest.

Ethical Approval

All experimental procedures involving animals were elaborated according to the rules of research in the National Council for Control of Animal Experimentation and approved by the Committee on Ethics in Animal Use of the Ribeirão Preto Medical School of the University of São Paulo, (protocol # 006/2-2015).

Informed Consent

This article does not contain any studies with human participants performed by any of the authors.

Footnotes

A non-peer reviewed version of the manuscript was published as a preprint (https://www.biorxiv.org/content/10.1101/850214v1.abstract).

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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