Wireless electrocochleography in awake chinchillas: A model to study crossmodal modulations at the peripheral level.

The discovery and development of electrocochleography (ECochG) in animal models has been fundamental for its implementation in clinical audiology and neurotology. In our laboratory, the use of round-window ECochG recordings in chinchillas has allowed a better understanding of auditory efferent functioning. In previous works, we gave evidence of the corticofugal modulation of auditory-nerve and cochlear responses during visual attention and working memory. However, whether these cognitive top-down mechanisms to the most peripheral structures of the auditory pathway are also active during audiovisual crossmodal stimulation is unknown. Here, we introduce a new technique, wireless ECochG to record compound-action potentials of the auditory nerve (CAP), cochlear microphonics (CM), and round-window noise (RWN) in awake chinchillas during a paradigm of crossmodal (visual and auditory) stimulation. We compared ECochG data obtained from four awake chinchillas recorded with a wireless ECochG system with wired ECochG recordings from six anesthetized animals. Although ECochG experiments with the wireless system had a lower signal-to-noise ratio than wired recordings, their quality was sufficient to compare ECochG potentials in awake crossmodal conditions. We found non-significant differences in CAP and CM amplitudes in response to audiovisual stimulation compared to auditory stimulation alone (clicks and tones). On the other hand, spontaneous auditory-nerve activity (RWN) was modulated by visual crossmodal stimulation, suggesting that visual crossmodal simulation can modulate spontaneous but not evoked auditory-nerve activity. However, given the limited sample of 10 animals (4 wireless and 6 wired), these results should be interpreted cautiously. Future experiments are required to substantiate these conclusions. In addition, we introduce the use of wireless ECochG in animal models as a useful tool for translational research.

Cannabinoid receptor type 1 modulates the effects of polyunsaturated fatty acids on memory of stressed rats.

Memory and GABAergic activity in the hippocampus of stressed rats improve after n-3 polyunsaturated fatty acid (PUFA) supplementation. On the other hand, cannabinoid receptor type 1 (CB1) strongly regulates inhibitory neurotransmission in the hippocampus. Speculation about a possible relation between stress, endocannabinoids, and PUFAs. Here, we examined whether the effects of PUFAs on memory of chronically stressed rats depends on pharmacological manipulation of CB1 receptors. Male Sprague-Dawley rats were orally supplemented with n-3 (fish oil) or n-6 (primrose oil) PUFAs during chronic restraint stress (CRS) protocol (6 h/day; 21 days). First, we studied if the expression of CB1 receptors in the hippocampus may be affected by CRS and PUFAs supplementation by real-time PCR and immunofluorescence. CRS up-regulated the CB1 expression compared with the non-stressed rats, while only n-3 PUFAs countered this effect. Memory was evaluated in the Morris water maze. Stressed rats were co-treated with PUFAs and/or modulators of CB1 receptor (AM251, antagonist, 0.3 mg/kg/day; WIN55,212-2, agonist, 0.5 mg/kg/day) by intraperitoneal injections. Memory improved in the stressed rats that were treated with AM251 and/or n-3 PUFAs. Supplementation with n-6 PUFAs did not affect memory of stressed rats, but co-treatment with AM251 improved it, while co-treatment with WIN55,212-2 did not affect memory. Our results demonstrate that activity of the CB1 receptors may modulate the effects of PUFAs on memory of stressed rats. This study suggests that endocannabinoids and PUFAs can both become a singular system by being self-regulated in limbic areas, so they control the effects of stress on the brain.

Impact of Stress on Gamma Oscillations in the Rat Nucleus Accumbens During Spontaneous Social Interaction.

Alteration in social behavior is one of the most debilitating symptoms of major depression, a stress related mental illness. Social behavior is modulated by the reward system, and gamma oscillations in the nucleus accumbens (NAc) seem to be associated with reward processing. In this scenario, the role of gamma oscillations in depression remains unknown. We hypothesized that gamma oscillations in the rat NAc are sensitive to the effects of social distress. One group of male Sprague-Dawley rats were exposed to chronic social defeat stress (CSDS) while the other group was left undisturbed (control group). Afterward, a microelectrode array was implanted in the NAc of all animals. Local field potential (LFP) activity was acquired using a wireless recording system. Each implanted rat was placed in an open field chamber for a non-social interaction condition, followed by introducing another unfamiliar rat, creating a social interaction condition, where the implanted rat interacted freely and continuously with the unfamiliar conspecific in a natural-like manner (see Supplementary Videos). We found that the high-gamma band power in the NAc of non-stressed rats was higher during the social interaction compared to a non-social interaction condition. Conversely, we did not find significant differences at this level in the stressed rats when comparing the social interaction- and non-social interaction condition. These findings suggest that high-gamma oscillations in the NAc are involved in social behavior. Furthermore, alterations at this level could be an electrophysiological signature of the effect of chronic social stress on reward processing.

Effects of stress on the auditory system: an approach to study a common origin for mood disorders and dementia.

The concept of stress is a fundamental piece to understand how organisms can adapt to the demands produced by a continuously changing environment. However, modern lifestyle subjects humans to high levels of negative stress or distress, which increases the prevalence of mental illnesses. Definitely, stress has become the pandemic of the 21st century, a fact that demands a great intellectual effort from scientists to understand the neurobiology of stress. This review proposes an innovative point of view to understand that mood disorders and dementia have a common etiology in a stressful environment. We propose that distress produces sensory deprivation, and this interferes with the connection between the brain and the environment in which the subject lives. The auditory system can serve as an example to understand this idea. In this sense, distress impairs the auditory system and induces hearing loss or presbycusis at an early age; this can increase the cognitive load in stressed people, which can stimulate the development of dementia in them. On the other hand, distress impairs the auditory system and increases the excitability of the amygdala, a limbic structure involved in the emotional processing of sounds. A consequence of these alterations could be the increase in the persistence of auditory fear memory, which could increase the development of mood disorders. Finally, it is important to emphasize that stress is an evolutionary issue that is necessary to understand the mental health of humans in these modern times. This article is a contribution to this discussion and will provide insights into the origin of stress-related neuropsychiatric disorders.

Reboxetine Improves Auditory Attention and Increases Norepinephrine Levels in the Auditory Cortex of Chronically Stressed Rats.

Chronic stress impairs auditory attention in rats and monoamines regulate neurotransmission in the primary auditory cortex (A1), a brain area that modulates auditory attention. In this context, we hypothesized that norepinephrine (NE) levels in A1 correlate with the auditory attention performance of chronically stressed rats. The first objective of this research was to evaluate whether chronic stress affects monoamines levels in A1. Male Sprague-Dawley rats were subjected to chronic stress (restraint stress) and monoamines levels were measured by high performance liquid chromatographer (HPLC)-electrochemical detection. Chronically stressed rats had lower levels of NE in A1 than did controls, while chronic stress did not affect serotonin (5-HT) and dopamine (DA) levels. The second aim was to determine the effects of reboxetine (a selective inhibitor of NE reuptake) on auditory attention and NE levels in A1. Rats were trained to discriminate between two tones of different frequencies in a two-alternative choice task (2-ACT), a behavioral paradigm to study auditory attention in rats. Trained animals that reached a performance of ≥80% correct trials in the 2-ACT were randomly assigned to control and stress experimental groups. To analyze the effects of chronic stress on the auditory task, trained rats of both groups were subjected to 50 2-ACT trials 1 day before and 1 day after of the chronic stress period. A difference score (DS) was determined by subtracting the number of correct trials after the chronic stress protocol from those before. An unexpected result was that vehicle-treated control rats and vehicle-treated chronically stressed rats had similar performances in the attentional task, suggesting that repeated injections with vehicle were stressful for control animals and deteriorated their auditory attention. In this regard, both auditory attention and NE levels in A1 were higher in chronically stressed rats treated with reboxetine than in vehicle-treated animals. These results indicate that NE has a key role in A1 and attention of stressed rats during tone discrimination.

Repeated restraint stress impairs auditory attention and GABAergic synaptic efficacy in the rat auditory cortex.

Chronic stress induces dendritic atrophy in the rat primary auditory cortex (A1), a key brain area for auditory attention. The aim of this study was to determine whether repeated restraint stress affects auditory attention and synaptic transmission in A1. Male Sprague-Dawley rats were trained in a two-alternative choice task (2-ACT), a behavioral paradigm to study auditory attention in rats. Trained animals that reached a performance over 80% of correct trials in the 2-ACT were randomly assigned to control and restraint stress experimental groups. To analyze the effects of restraint stress on the auditory attention, trained rats of both groups were subjected to 50 2-ACT trials one day before and one day after of the stress period. A difference score was determined by subtracting the number of correct trials after from those before the stress protocol. Another set of rats was used to study the synaptic transmission in A1. Restraint stress decreased the number of correct trials by 28% compared to the performance of control animals (p < 0.001). Furthermore, stress reduced the frequency of spontaneous inhibitory postsynaptic currents (sIPSC) and miniature IPSC in A1, whereas glutamatergic efficacy was not affected. Our results demonstrate that restraint stress decreased auditory attention and GABAergic synaptic efficacy in A1.