Psilocybin decreases neural responsiveness and increases functional connectivity while preserving pure-tone frequency selectivity in mouse auditory cortex.

Psilocybin is a serotonergic psychedelic believed to have therapeutic potential for neuropsychiatric conditions. Despite well-documented prevalence of perceptual alterations, hallucinations, and synesthesia associated with psychedelic experiences, little is known about how psilocybin affects sensory cortex or alters the activity of neurons in awake animals. To investigate, we conducted two-photon imaging experiments in auditory cortex of awake mice and collected video of free-roaming mouse behavior, both at baseline and during psilocybin treatment. In comparison with pre-dose neural activity, a 2 mg/kg ip dose of psilocybin initially increased the amplitude of neural responses to sound. Thirty minutes post-dose, behavioral activity and neural response amplitudes decreased, yet functional connectivity increased. In contrast, control mice given intraperitoneal saline injections showed no significant changes in either neural or behavioral activity across conditions. Notably, neuronal stimulus selectivity remained stable during psilocybin treatment, for both tonotopic cortical maps and single-cell pure-tone frequency tuning curves. Our results mirror similar findings regarding the effects of serotonergic psychedelics in visual cortex and suggest that psilocybin modulates the balance of intrinsic versus stimulus-driven influences on neural activity in auditory cortex.NEW & NOTEWORTHY Recent studies have shown promising therapeutic potential for psychedelics in treating neuropsychiatric conditions. Musical experience during psilocybin-assisted therapy is predictive of treatment outcome, yet little is known about how psilocybin affects auditory processing. Here, we conducted two-photon imaging experiments in auditory cortex of awake mice that received a dose of psilocybin. Our results suggest that psilocybin modulates the roles of intrinsic neural activity versus stimulus-driven influences on auditory perception.

Partial chemogenetic inhibition of the locus coeruleus due to heterogeneous transduction of noradrenergic neurons preserved auditory salience processing in wild-type rats.

The acoustic startle reflex (ASR) and prepulse inhibition of the ASR (PPI) assess the efficiency of salience processing, a fundamental brain function that is impaired in many psychiatric conditions. Both ASR and PPI depend on noradrenergic transmission, yet the modulatory role of the locus coeruleus (LC) remains controversial. Clonidine (0.05 mg/kg, i.p.), an alpha2-adrenoreceptor agonist, strongly reduced the ASR amplitude. In contrast, chemogenetic LC inhibition only mildly suppressed the ASR and did affect the PPI in virus-transduced rats. The canine adenovirus type 2 (CAV2)-based vector carrying a gene cassette for the expression of inhibitory receptors (hM4Di) and noradrenergic cell-specific promoter (PRSx8) had high cell-type specificity (94.4 ± 3.1%) but resulted in heterogeneous virus transduction of DbH-positive LC neurons (range: 9.2-94.4%). Clozapine-N-oxide (CNO; 1 mg/kg, i.p.), a hM4Di actuator, caused the firing cessation of hM4Di-expressing LC neurons, yet complete inhibition of the entire population of LC neurons was not achieved. Case-based immunohistochemistry revealed that virus injections distal (> 150 µm) to the LC core resulted in partial LC transduction, while proximal (< 50 µm) injections caused neuronal loss due to virus neurotoxicity. Neither the ASR nor PPI differed between the intact and virus-transduced rats. Our results suggest that a residual activity of virus-non-transduced LC neurons might have been sufficient for mediating an unaltered ASR and PPI. Our study highlights the importance of a case-based assessment of the virus efficiency, specificity, and neurotoxicity for targeted cell populations and of considering these factors when interpreting behavioral effects in experiments employing chemogenetic modulation.

Examining the effects of caffeine during an auditory attention task.

Participants completed two sessions of an auditory attention task and intermittently responded to thought probes asking about their level of mind-wandering. After the first session one group received 200 mg of caffeinated chewing gum (n = 61) and another group received regular (placebo) chewing gum (n = 66). The gum was chewed for 20-minutes and then disposed of before beginning the second session. Participants who received caffeine showed a performance benefit as well as reported being more on task and fewer instances of spontaneous mind-wandering compared to those in the placebo group. Participants who received caffeine also reported greater positive affect and arousal, as well as less feelings of boredom, sleepiness, and mental effort required to stay on task compared to those who received placebo. These results suggest that caffeine may benefit attentional engagement as well as performance during a sustained attention task.

Dexamphetamine increased speech and visual unimodal illusions in healthy participants without affecting temporal binding window.

OBJECTIVE: Stimuli received beyond a very short timeframe, known as temporal binding windows (TBWs), are perceived as separate events. In previous audio-visual multisensory integration (McGurk effect) studies, widening of TBWs has been observed in people with schizophrenia. The present study aimed to determine if dexamphetamine could increase TBWs in unimodal auditory and unimodal visual illusions that may have some validity as experimental models for auditory and visual hallucinations in psychotic disorders. METHODS: A double-blind, placebo-controlled, counter-balanced crossover design with permuted block randomisation for drug order was followed. Dexamphetamine (0.45 mg/kg, PO, q.d.) was administered to healthy participants. Phantom word illusion (speech illusion) and visual-induced flash illusion/VIFI (visual illusion) tests were measured to determine if TBWs were altered as a function of delay between stimuli presentations. Word emotional content for phantom word illusions was also analysed. RESULTS: Dexamphetamine significantly increased the total number of phantom words/speech illusions (p < 0.01) for pooled 220-1100 ms ISIs in kernel density estimation and the number of positive valence words heard (beta = 2.20, 95% CI [1.86, 2.55], t = 12.46, p < 0.001) with a large effect size (std. beta = 1.05, 95% CI [0.89, 1.22]) relative to placebo without affecting the TBWs. For the VIFI test, kernel density estimation for pooled 0-801 ms ISIs showed a significant difference (p < 0.01) in the data distributions of number of target flash (es) perceived by participants after receiving dexamphetamine as compared with placebo. CONCLUSIONS: Overall, healthy participants who were administered dexamphetamine (0.45 mg/kg, PO, q.d.) experienced increases in auditory and visual illusions in both phantom word illusion and VIFI tests without affecting their TBWs.

Degenerate brainstem circuitry after combined physiochemical exposure to jet fuel and noise.

Degenerate neural circuits exhibit "different" circuit properties yet produce similar circuit outcomes (many-to-one) which ensures circuit robustness and complexity. However, neuropathies may hijack degeneracy to yield robust and complex pathological circuits. The aim of the current study was to test the hypothesis that physiochemical exposure to combined jet fuel and noise might induce degeneracy in the brainstem. The auditory brainstem of pigmented rats was used as a model system. The animals were randomized into the following experimental groups: Fuel+Noise, fuel-only, noise-only, and control. Ascending volume conductance from various auditory brainstem regions were evaluated simultaneously with peripheral nervous system (PNS) input to brainstem circuitry. Data demonstrated normal PNS inputs for all groups. However, the Fuel+Noise exposure group produced different caudal brainstem circuit properties while rostral brainstem circuitry initiated outputs that were similar to that of control. This degenerative effect was specific to Fuel+Noise exposure, since neither noise-alone or fuel-alone produced the same result. Degeneracy in the auditory brainstem is consistent with perceptual abnormalities, such as poor speech discrimination (hear but not understand), tinnitus (ringing in the ear), hyperacusis (hypersensitivity to even low-level sound), and loudness intolerance. Therefore, a potential consequence of Fuel+Noise exposure among military and civilian populations may be evidenced as increased rates of super-threshold auditory perceptual abnormalities. This is particularly important because to date, the ototoxic profile of Fuel+Noise exposure has remained unresolved.

Model-based prediction of muscarinic receptor function from auditory mismatch negativity responses.

Drugs affecting neuromodulation, for example by dopamine or acetylcholine, take centre stage among therapeutic strategies in psychiatry. These neuromodulators can change both neuronal gain and synaptic plasticity and therefore affect electrophysiological measures. An important goal for clinical diagnostics is to exploit this effect in the reverse direction, i.e., to infer the status of specific neuromodulatory systems from electrophysiological measures. In this study, we provide proof-of-concept that the functional status of cholinergic (specifically muscarinic) receptors can be inferred from electrophysiological data using generative (dynamic causal) models. To this end, we used epidural EEG recordings over two auditory cortical regions during a mismatch negativity (MMN) paradigm in rats. All animals were treated, across sessions, with muscarinic receptor agonists and antagonists at different doses. Together with a placebo condition, this resulted in five levels of muscarinic receptor status. Using a dynamic causal model - embodying a small network of coupled cortical microcircuits - we estimated synaptic parameters and their change across pharmacological conditions. The ensuing parameter estimates associated with (the neuromodulation of) synaptic efficacy showed both graded muscarinic effects and predictive validity between agonistic and antagonistic pharmacological conditions. This finding illustrates the potential utility of generative models of electrophysiological data as computational assays of muscarinic function. In application to EEG data of patients from heterogeneous spectrum diseases, e.g. schizophrenia, such models might help identify subgroups of patients that respond differentially to cholinergic treatments. SIGNIFICANCE STATEMENT: In psychiatry, the vast majority of pharmacological treatments affect actions of neuromodulatory transmitters, e.g. dopamine or acetylcholine. As treatment is largely trial-and-error based, one of the goals for computational psychiatry is to construct mathematical models that can serve as "computational assays" and infer the status of specific neuromodulatory systems in individual patients. This translational neuromodeling strategy has great promise for electrophysiological data in particular but requires careful validation. The present study demonstrates that the functional status of cholinergic (muscarinic) receptors can be inferred from electrophysiological data using dynamic causal models of neural circuits. While accuracy needs to be enhanced and our results must be replicated in larger samples, our current results provide proof-of-concept for computational assays of muscarinic function using EEG.

Ketamine-xylazine anesthesia depth affects auditory neuronal responses in the lateral superior olive complex of the gerbil.

Studies of in vivo neuronal responses to auditory inputs in the superior olive complex (SOC) are usually done under anesthesia. However, little attention has been paid to the effect of anesthesia itself on response properties. Here, we assessed the effect of anesthesia depth under ketamine-xylazine anesthetics on auditory evoked response properties of lateral SOC neurons. Anesthesia depth was tracked by monitoring EEG spectral peak frequencies. An increase in anesthesia depth led to a decrease of spontaneous discharge activities and an elevated response threshold. The temporal responses to suprathreshold tones were also affected, with adapted responses reduced but peak responses unaffected. Deepening the anesthesia depth also increased first spike latency. However, spike jitter was not affected. Auditory brainstem responses to clicks confirmed that ketamine-xylazine anesthesia depth affects auditory neuronal activities and the effect on spike rate and spike timing persists through the auditory pathway. We concluded from those observations that ketamine-xylazine affects lateral SOC response properties depending on the anesthesia depth.NEW & NOTEWORTHY We studied how the depth of ketamine-xylazine anesthesia altered response properties of lateral superior olive complex neurons, and auditory brainstem evoked responses. Our results provide direct evidence that anesthesia depth affects auditory neuronal responses and reinforce the notion that both the anesthetics and the anesthesia depth should be considered when interpreting/comparing in vivo neuronal recordings.

Disruption of Long-Term Depression Potentiates Latent Inhibition: Key Role for Central Nucleus of the Amygdala.

BACKGROUND: Latent inhibition (LI) reflects an adaptive form of learning impaired in certain forms of mental illness. Glutamate receptor activity is linked to LI, but the potential role of synaptic plasticity remains unspecified. METHODS: Accordingly, the present study examined the possible role of long-term depression (LTD) in LI induced by prior exposure of rats to an auditory stimulus used subsequently as a conditional stimulus to signal a pending footshock. We employed 2 mechanistically distinct LTD inhibitors, the Tat-GluA23Y peptide that blocks endocytosis of the GluA2-containing glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, or the selective glutamate n-methyl-d-aspartate receptor 2B antagonist, Ro25-6981, administered prior to the acquisition of 2-way conditioned avoidance with or without tone pre-exposure. RESULTS: Systemic LTD blockade with the Tat-GluA23Y peptide strengthened the LI effect by further impairing acquisition of conditioned avoidance in conditional stimulus-preexposed rats compared with normal conditioning in non-preexposed controls. Systemic Ro25-6981 had no significant effects. Brain region-specific microinjections of the Tat-GluA23Y peptide into the nucleus accumbens, medial prefrontal cortex, or central or basolateral amygdala demonstrated that disruption of glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor endocytosis in the central amygdala also potentiated the LI effect. CONCLUSIONS: These data revealed a previously unknown role for central amygdala LTD in LI as a key mediator of cognitive flexibility required to respond to previously irrelevant stimuli that acquire significance through reinforcement. The findings may have relevance both for our mechanistic understanding of LI and its alteration in disease states such as schizophrenia, while further elucidating the role of LTD in learning and memory.

Exogenous testosterone decreases men's sensitivity to vocal cues of male dominance.

Assessing dominance is important for effective social interactions, and prior research suggests that testosterone is associated with men's dominance perceptions. The present study tested for a causal effect of exogenous testosterone on men's sensitivity to vocal cues of other men's dominance, an important parameter in male-male competition across species. One hundred and thirty-nine Chinese men received a single dose (150 mg) of testosterone or placebo gel in a double-blind, placebo-controlled, between-participant design. Participants reported their own dominance and judged other men's dominance from voices. Men's dominance sensitivity was significantly weaker in the testosterone group compared to those in the placebo group. Moreover, men's dominance sensitivity was negatively associated with their self-reported dominance in our Chinese sample, consistent with findings from Western populations. These results indicate that exogenous testosterone has a causal effect in decreasing men's dominance sensitivity, consistent with the Challenge Hypothesis, suggesting that the fluctuation of testosterone concentration mediates individuals' behaviors. Additionally, the present study could motivate further work on vocal assessment in the context of competition in humans and other species.

Precise memory for pure tones is predicted by measures of learning-induced sensory system neurophysiological plasticity at cortical and subcortical levels.

Despite identical learning experiences, individuals differ in the memory formed of those experiences. Molecular mechanisms that control the neurophysiological bases of long-term memory formation might control how precisely the memory formed reflects the actually perceived experience. Memory formed with sensory specificity determines its utility for selectively cueing subsequent behavior, even in novel situations. Here, a rodent model of auditory learning capitalized on individual differences in learning-induced auditory neuroplasticity to identify and characterize neural substrates for sound-specific (vs. general) memory of the training signal's acoustic frequency. Animals that behaviorally revealed a naturally induced signal-"specific" memory exhibited long-lasting signal-specific neurophysiological plasticity in auditory cortical and subcortical evoked responses. Animals with "general" memories did not exhibit learning-induced changes in these same measures. Manipulating a histone deacetylase during memory consolidation biased animals to have more signal-specific memory. Individual differences validated this brain-behavior relationship in both natural and manipulated memory formation, such that the degree of change in sensory cortical and subcortical neurophysiological responses could be used to predict the behavioral precision of memory.

Modeling an auditory stimulated brain under altered states of consciousness using the generalized Ising model.

Propofol is a short-acting medication that results in decreased levels of consciousness and is used for general anesthesia. Although it is the most commonly used anesthetic in the world, much remains unknown about the mechanisms by which it induces a loss of consciousness. Characterizing anesthesia-induced alterations to brain network activity might provide a powerful framework for understanding the neural mechanisms of unconsciousness. The aim of this work was to model brain activity in healthy brains during various stages of consciousness, as induced by propofol, in the auditory paradigm. We used the generalized Ising model (GIM) to fit the empirical fMRI data of healthy subjects while they listened to an audio clip from a movie. The external stimulus (audio clip) is believed to be at least partially driving a synchronization process of the brain activity and provides a similar conscious experience in different subjects. In order to observe the common synchronization among the subjects, a novel technique called the inter subject correlation (ISC) was implemented. We showed that the GIM-modified to incorporate the naturalistic external field-was able to fit the empirical task fMRI data in the awake state, in mild sedation, in deep sedation, and in recovery, at a temperature T* which is well above the critical temperature. To our knowledge this is the first study that captures human brain activity in response to real-life external stimuli at different levels of conscious awareness using mathematical modeling. This study might be helpful in the future to assess the level of consciousness of patients with disorders of consciousness and help in regaining their consciousness.

GABAA receptors contribute more to rate than temporal coding in the IC of awake mice.

Speech is our most important form of communication, yet we have a poor understanding of how communication sounds are processed by the brain. Mice make great model organisms to study neural processing of communication sounds because of their rich repertoire of social vocalizations and because they have brain structures analogous to humans, such as the auditory midbrain nucleus inferior colliculus (IC). Although the combined roles of GABAergic and glycinergic inhibition on vocalization selectivity in the IC have been studied to a limited degree, the discrete contributions of GABAergic inhibition have only rarely been examined. In this study, we examined how GABAergic inhibition contributes to shaping responses to pure tones as well as selectivity to complex sounds in the IC of awake mice. In our set of long-latency neurons, we found that GABAergic inhibition extends the evoked firing rate range of IC neurons by lowering the baseline firing rate but maintaining the highest probability of firing rate. GABAergic inhibition also prevented IC neurons from bursting in a spontaneous state. Finally, we found that although GABAergic inhibition shaped the spectrotemporal response to vocalizations in a nonlinear fashion, it did not affect the neural code needed to discriminate vocalizations, based either on spiking patterns or on firing rate. Overall, our results emphasize that even if GABAergic inhibition generally decreases the firing rate, it does so while maintaining or extending the abilities of neurons in the IC to code the wide variety of sounds that mammals are exposed to in their daily lives.NEW & NOTEWORTHY GABAergic inhibition adds nonlinearity to neuronal response curves. This increases the neuronal range of evoked firing rate by reducing baseline firing. GABAergic inhibition prevents bursting responses from neurons in a spontaneous state, reducing noise in the temporal coding of the neuron. This could result in improved signal transmission to the cortex.

Acute pharmacological inhibition of matrix metalloproteinase-9 activity during development restores perineuronal net formation and normalizes auditory processing in Fmr1 KO mice.

Individuals with Fragile X Syndrome (FXS) and autism spectrum disorder (ASD) exhibit cognitive impairments, social deficits, increased anxiety, and sensory hyperexcitability. Previously, we showed that elevated levels of matrix metalloproteinase-9 (MMP-9) may contribute to abnormal development of parvalbumin (PV) interneurons and perineuronal nets (PNNs) in the developing auditory cortex (AC) of Fmr1 knock-out (KO) mice, which likely underlie auditory hypersensitivity. Thus, MMP-9 may serve as a potential target for treatment of auditory hypersensitivity in FXS. Here, we used the MMP-2/9 inhibitor, SB-3CT, to pharmacologically inhibit MMP-9 activity during a specific developmental period and to test whether inhibition of MMP-9 activity reverses neural oscillation deficits and behavioral impairments by enhancing PNN formation around PV cells in Fmr1 KO mice. Electroencephalography (EEG) was used to measure resting state and sound-evoked electrocortical activity in auditory and frontal cortices of postnatal day (P)22-23 male mice before and one-day after treatment with SB-3CT (25 mg/kg) or vehicle. At P27-28, animal behaviors were tested to measure the effects of the treatment on anxiety and hyperactivity. Results show that acute inhibition of MMP-9 activity improved evoked synchronization to auditory stimuli and ameliorated mouse behavioral deficits. MMP-9 inhibition enhanced PNN formation, increased PV levels and TrkB phosphorylation yet reduced Akt phosphorylation in the AC of Fmr1 KO mice. Our results show that MMP-9 inhibition during early postnatal development is beneficial in reducing some auditory processing deficits in the FXS mouse model and may serve as a candidate therapeutic for reversing sensory hypersensitivity in FXS and possibly other ASDs.

P300-mediated modulations in self-other processing under psychedelic psilocybin are related to connectedness and changed meaning: A window into the self-other overlap.

The concept of self and self-referential processing has a growing explanatory value in psychiatry and neuroscience, referring to the cognitive organization and perceptual differentiation of self-stimuli in health and disease. Conditions in which selfhood loses its natural coherence offer a unique opportunity for elucidating the mechanisms underlying self-disturbances. We assessed the psychoactive effects of psilocybin (230 µg/kg p.o.), a preferential 5-HT1A/2A agonist known to induce shifts in self-perception. Our placebo-controlled, double-blind, within-subject crossover experiment (n = 17) implemented a verbal self-monitoring task involving vocalizations and participant identification of real-time auditory source- (self/other) and pitch-modulating feedback. Subjective experience and task performance were analyzed, with time-point-by-time-point assumption-free multivariate randomization statistics applied to the spatiotemporal dynamics of event-related potentials. Psilocybin-modulated self-experience, interacted with source to affect task accuracy, and altered the late phase of self-stimuli encoding by abolishing the distinctiveness of self- and other-related electric field configurations during the P300 timeframe. This last effect was driven by current source density changes within the supragenual anterior cingulate and right insular cortex. The extent of the P300 effect was associated with the intensity of psilocybin-induced feelings of unity and changed meaning of percepts. Modulations of late encoding and their underlying neural generators in self-referential processing networks via 5-HT signaling may be key for understanding self-disorders. This mechanism may reflect a neural instantiation of altered self-other and relational meaning processing in a stimulus-locked time domain. The study elucidates the neuropharmacological foundation of subjectivity, with implications for therapy, underscoring the concept of connectedness.

Auditory DUM neurons in a bush-cricket: inhibited inhibitors.

Thoracic ganglia of many hearing insects house the first level of auditory processing. In bush-crickets, the largest population of local auditory neurons in the prothoracic processing centre are dorsal unpaired median (DUM) neurons. It has been suggested that DUM neurons are inhibitory using γ-aminobutyric acid (GABA) as transmitter. Immunohistochemistry reveals a population of about 35-50 GABA-positive somata in the posterior medial cluster of the prothoracic ganglion. Only very few small somata in this cluster remain unstained. At least 10 neurites from 10 neurons can be identified. Intracellularly stained auditory DUM neurons have their soma in the cluster of median GABA positive cells and most of them exhibit GABA-immunoreactivity. Responses of certain DUM neurons show obvious signs of inhibition. Application of picrotoxin (PTX), a chloride-channel blocker in insects, changes the responses of many DUM neurons. They become broader in frequency tuning and broader or narrower in temporal pattern tuning. Furthermore, inhibitory postsynaptic potentials (IPSPs) may be replaced by excitatory postsynaptic potentials. Loss of an IPSP in the rising graded potential after PTX-application leads to a significant reduction of first-spike latency. Therefore, auditory DUM neurons receive effective inhibition and are the best candidates for inhibition in DUM neurons and other auditory interneurons.

Auditory Predictive Coding across Awareness States under Anesthesia: An Intracranial Electrophysiology Study.

The systems-level mechanisms underlying loss of consciousness (LOC) under anesthesia remain unclear. General anesthetics suppress sensory responses within higher-order cortex and feedback connections, both critical elements of predictive coding hypotheses of conscious perception. Responses to auditory novelty may offer promise as biomarkers for consciousness. This study examined anesthesia-induced changes in auditory novelty responses over short (local deviant [LD]) and long (global deviant [GD]) time scales, envisioned to engage preattentive and conscious levels of processing, respectively. Electrocorticographic recordings were obtained in human neurosurgical patients (3 male, 3 female) from four hierarchical processing levels: core auditory cortex, non-core auditory cortex, auditory-related, and PFC. Stimuli were vowel patterns incorporating deviants within and across stimuli (LD and GD). Subjects were presented with stimuli while awake, and during sedation (responsive) and following LOC (unresponsive) under propofol anesthesia. LD and GD effects were assayed as the averaged evoked potential and high gamma (70-150 Hz) activity. In the awake state, LD and GD effects were present in all recorded regions, with averaged evoked potential effects more broadly distributed than high gamma activity. Under sedation, LD effects were preserved in all regions, except PFC. LOC was accompanied by loss of LD effects outside of auditory cortex. By contrast, GD effects were markedly suppressed under sedation in all regions and were absent following LOC. Thus, although the presence of GD effects is indicative of being awake, its absence is not indicative of LOC. Loss of LD effects in higher-order cortical areas may constitute an alternative biomarker of LOC.SIGNIFICANCE STATEMENT Development of a biomarker that indexes changes in the brain upon loss of consciousness (LOC) under general anesthesia has broad implications for elucidating the neural basis of awareness and clinical relevance to mechanisms of sleep, coma, and disorders of consciousness. Using intracranial recordings from neurosurgery patients, we investigated changes in the activation of cortical networks involved in auditory novelty detection over short (local deviance) and long (global deviance) time scales associated with sedation and LOC under propofol anesthesia. Our results indicate that, whereas the presence of global deviance effects can index awareness, their loss cannot serve as a biomarker for LOC. The dramatic reduction of local deviance effects in areas beyond auditory cortex may constitute an alternative biomarker of LOC.

Serotonin 2A Receptor Signaling Underlies LSD-induced Alteration of the Neural Response to Dynamic Changes in Music.

Classic psychedelic drugs (serotonin 2A, or 5HT2A, receptor agonists) have notable effects on music listening. In the current report, blood oxygen level-dependent (BOLD) signal was collected during music listening in 25 healthy adults after administration of placebo, lysergic acid diethylamide (LSD), and LSD pretreated with the 5HT2A antagonist ketanserin, to investigate the role of 5HT2A receptor signaling in the neural response to the time-varying tonal structure of music. Tonality-tracking analysis of BOLD data revealed that 5HT2A receptor signaling alters the neural response to music in brain regions supporting basic and higher-level musical and auditory processing, and areas involved in memory, emotion, and self-referential processing. This suggests a critical role of 5HT2A receptor signaling in supporting the neural tracking of dynamic tonal structure in music, as well as in supporting the associated increases in emotionality, connectedness, and meaningfulness in response to music that are commonly observed after the administration of LSD and other psychedelics. Together, these findings inform the neuropsychopharmacology of music perception and cognition, meaningful music listening experiences, and altered perception of music during psychedelic experiences.

Sodium salicylate alters temporal integration measured through increasing stimulus presentation rates.

OBJECTIVE: High doses of sodium salicylate (SS) are known to induce tinnitus, general hyperexcitability in the central auditory system, and to cause mild hearing loss. We used the auditory brainstem response (ABR) to assess the effects of SS on auditory sensitivity and temporal processing in the auditory nerve and brainstem. ABRs were evoked using tone burst stimuli varying in frequency and intensity with presentation rates from 11/s to 81/s. DESIGN: ABRs were recorded and analysed prior to and after SS treatment in each animal, and peak 1 and peak 4 amplitudes and latencies were determined along with minimal response threshold. STUDY SAMPLE: Nine young adult CBA/CaJ mice were used in a longitudinal within-subject design. RESULTS: No measurable effects of presentation rate were found on ABR threshold prior to SS; however, following SS administration increasing stimulus rates lowered ABR thresholds by as much as 10 dB and compressed the peak amplitude by intensity level functions. CONCLUSIONS: These results suggest that SS alters temporal integration and compressive nonlinearity, and that varying the stimulus rate of the ABR may prove to be a useful diagnostic tool in the study of hearing disorders that involve hyperexcitability.

A complex mTOR response in habituation paradigms for a social signal in adult songbirds.

Nonassociative learning is considered simple because it depends on presentation of a single stimulus, but it likely reflects complex molecular signaling. To advance understanding of the molecular mechanisms of one form of nonassociative learning, habituation, for ethologically relevant signals we examined song recognition learning in adult zebra finches. These colonial songbirds learn the unique song of individuals, which helps establish and maintain mate and other social bonds, and informs appropriate behavioral interactions with specific birds. We leveraged prior work demonstrating behavioral habituation for individual songs, and extended the molecular framework correlated with this behavior by investigating the mechanistic Target of Rapamycin (mTOR) signaling cascade. We hypothesized that mTOR may contribute to habituation because it integrates a variety of upstream signals and enhances associative learning, and it crosstalks with another cascade previously associated with habituation, ERK/ZENK. To begin probing for a possible role for mTOR in song recognition learning, we used a combination of song playback paradigms and bidirectional dysregulation of mTORC1 activation. We found that mTOR demonstrates the molecular signatures of a habituation mechanism, and that its manipulation reveals the complexity of processes that may be invoked during nonassociative learning. These results thus expand the molecular targets for habituation studies and raise new questions about neural processing of complex natural signals.

Topography and Lateralized Effect of Acute Aromatase Inhibition on Auditory Processing in a Seasonal Songbird.

It is increasingly recognized that brain-derived estrogens (neuroestrogens) can regulate brain physiology and behavior much faster than what was previously known from the transcriptional action of estrogens on nuclear receptors. One of the best examples of such neuromodulation by neuroestrogens concerns the acute regulation of sensory coding by the auditory cortex as demonstrated by electrophysiological studies of selected neurons in zebra finches. Yet, the spatial extent of such modulation by neuroestrogens is not known. Using functional magnetic resonance imaging, we demonstrate here that acute estrogen depletion alters within minutes auditory processing in male European starlings. These effects are confined to very specific but large areas of the auditory cortex. They are also specifically lateralized to the left hemisphere. Interestingly, the modulation of auditory responses by estrogens was much larger (both in amplitude and in topography) in March than in December or May/June. This effect was presumably independent from changes in circulating testosterone concentrations since levels of the steroid were controlled by subcutaneous implants, thus suggesting actions related to other aspects of the seasonal cycle or photoperiodic manipulations. Finally, we also show that estrogen production specifically modulates selectivity for behaviorally relevant vocalizations in a specific part of the caudomedial nidopallium. These findings confirm and extend previous conclusions that had been obtained by electrophysiological techniques. This approach provides a new very powerful tool to investigate auditory responsiveness in songbirds and its fast modulation by sex steroids.SIGNIFICANCE STATEMENT Neuroestrogens can acutely modulate sensory processing in a manner similar to neuromodulators. We report that acute estrogen depletion rapidly disrupts auditory processing in large areas of the male starling brain. Effects were larger in March than in December or May/June, lateralized to the left hemisphere and specific to behaviorally relevant stimuli. These findings confirm and extend previous data that identified an acute regulation of auditory neurons in zebra finches by (1) delineating the extent of the brain region affected, (2) confirming its lateralization, and (3) demonstrating that a large part of the auditory brain regions are acutely affected by estrogens. These findings provide a very powerful tool to investigate auditory responsiveness in songbirds and its fast modulation by sex steroids.