Anxiety-like behavior induced by salicylate depends on age and can be prevented by a single dose of 5-MeO-DMT

Abstract

Salicylate intoxication is a cause of tinnitus and comorbidly associated with anxiety in humans. In a previous work, we showed that salicylate induces anxiety-like behavior and hippocampal type 2 theta oscillations (theta2) in mice. Here we investigate if the anxiogenic effect of salicylate is dependent on age and previous tinnitus experience. We also tested whether a single dose of DMT can prevent this effect. Using microwire electrode arrays, we recorded local field potential in young (4-5-month-old) and old (11-13-month-old) mice to study the electrophysiological effect of tinnitus in the ventral hippocampus (vHipp) and medial prefrontal cortex (mPFC) in an open field arena and elevated plus maze 1 h after salicylate (300 mg/kg) injection. We found that anxietylike behavior and increase in theta2 oscillations (4-6 Hz), following salicylate pre-treatment, only occurs in young (normal hearing) mice. We also show that theta2 and slow gamma oscillations increase in the vHipp and mPFC in a complementary manner during anxiety tests in the presence of salicylate. Finally, we show that pretreating mice with a single dose of the hallucinogenic 5-MeO-DMT prevents anxiety-like behavior and the increase in theta2 and slow gamma oscillations after salicylate injection in normal hearing young mice. This work further support the hypothesis that anxiety-like behavior after salicylate injection is triggered by tinnitus and require normal hearing. Moreover, our results show that hallucinogenic compounds can be effective in treating tinnitus-related anxiety.

Loud noise exposure differentially affects subpopulations of auditory cortex pyramidal cells

“…Interestingly, the lack of distinct sag, ADP and AHP for type B PCs does not appear related to the age/resting potential. Hence, noise trauma experiments in C57 mice should fall within an age window in which cells are mature but before the early onset of age related hearing loss (Winne et al, 2020).…”

“…However, both human and animal studies have shown tinnitus without hearing loss (Langers et al, 2012;Longenecker and Galazyuk, 2016), but few studies separate the two conditions. We have used a tinnitus triggering noise that does not significantly change hearing thresholds (Winne et al, 2020) to show that PCs in the auditory cortex alter their input/output function. Our results further demonstrate that in the absence of underlying cochlear pathology, plastic alterations in higher auditory areas could sustain tinnitus.…”

“…Tinnitus is a prevalent disorder affecting about 15% of the world population (Shargorodsky et al, 2010) and is highly correlated to mood disorders (Langguth et al, 2011;Malouff et al, 2011;Winne et al, 2019). We recently showed that anxiety is prominent in animal models of tinnitus without hearing loss and that tinnitus affect limbic regions related to anxiety/depression (Winne et al, 2020). However, little is known about the after effect of loud noise exposure in auditory cortex neurons.…”

“…Moreover, type A are known to express prominent h-current (Ih) and project subcortically, while type B PCs are thin-tufted, have little Ih and connect contralaterally or to the striatum (Lee et al, 2014). Using patch clamp recordings and principal component analysis, we examine the primary auditory cortex to see if noise exposure of tinnitus-causing noise (Winne et al, 2020) alters membrane or firing properties of type A and type B PCs.…”

Chemogenetically decreasing activity of the dorsal cochlear nucleus can ameliorate noise-induced tinnitus in mice

“…Mice were acclimatized and habituated to the test equipment before subjected to GPIAS (Figure 1A) testing the capability of detecting a short (40ms) silence in background noise (60dBSPL) 100ms prior to a loud startle pulse (105dBSPL, 50ms duration), thereby suppressing the acoustic startle reflex by at least 30% (Li et al, 2013 1A) for adequate hM4Di expression in CaMKIIα expressing cells, comprising both excitatory and some inhibitory cell populations (Malfatti et al, 2021). Hearing threshold was evaluated by recording auditory brainstem responses (ABRs, Figure 1B-C) three days prior to noise exposure (1h, 90dBSPL, 9-11kHz filtered uniform white noise, followed by 2h in silence) under anesthesia in order to induce tinnitus-like behavior (Winne et al, 2020).…”