Auditory aversive generalization learning prompts threat-specific changes in alpha-band activity.

Pairing a neutral stimulus with aversive outcomes prompts neurophysiological and autonomic changes in response to the conditioned stimulus (CS+), compared to cues that signal safety (CS-). One of these changes-selective amplitude reduction of parietal alpha-band oscillations-has been reliably linked to processing of visual CS+. It is, however, unclear to what extent auditory conditioned cues prompt similar changes, how these changes evolve as learning progresses, and how alpha reduction in the auditory domain generalizes to similar stimuli. To address these questions, 55 participants listened to three sine wave tones, with either the highest or lowest pitch (CS+) being associated with a noxious white noise burst. A threat-specific (CS+) reduction in occipital-parietal alpha-band power was observed similar to changes expected for visual stimuli. No evidence for aversive generalization to the tone most similar to the CS+ was observed in terms of alpha-band power changes, aversiveness ratings, or pupil dilation. By-trial analyses found that selective alpha-band changes continued to increase as aversive conditioning continued, beyond when participants reported awareness of the contingencies. The results support a theoretical model in which selective alpha power represents a cross-modal index of continuous aversive learning, accompanied by sustained sensory discrimination of conditioned threat from safety cues.

A VTA to Basal Amygdala Dopamine Projection Contributes to Signal Salient Somatosensory Events during Fear Learning.

The amygdala is a brain area critical for the formation of fear memories. However, the nature of the teaching signal(s) that drive plasticity in the amygdala are still under debate. Here, we use optogenetic methods to investigate the contribution of ventral tegmental area (VTA) dopamine neurons to auditory-cued fear learning in male mice. Using anterograde and retrograde labeling, we found that a sparse and relatively evenly distributed population of VTA neurons projects to the basal amygdala (BA). In vivo optrode recordings in behaving mice showed that many VTA neurons, among them putative dopamine neurons, are excited by footshocks, and acquire a response to auditory stimuli during fear learning. Combined cfos imaging and retrograde labeling in dopamine transporter (DAT) Cre mice revealed that a large majority of BA projectors (>95%) are dopamine neurons, and that BA projectors become activated by the tone-footshock pairing of fear learning protocols. Finally, silencing VTA dopamine neurons, or their axon terminals in the BA during the footshock, reduced the strength of fear memory as tested 1 d later, whereas silencing the VTA-central amygdala (CeA) projection had no effect. Thus, VTA dopamine neurons projecting to the BA contribute to fear memory formation, by coding for the saliency of the footshock event and by signaling such events to the basal amygdala.SIGNIFICANCE STATEMENT Powerful mechanisms of fear learning have evolved in animals and humans to enable survival. During fear conditioning, a sensory cue, such as a tone (the conditioned stimulus), comes to predict an innately aversive stimulus, such as a mild footshock (the unconditioned stimulus). A brain representation of the unconditioned stimulus must act as a teaching signal to instruct plasticity of the conditioned stimulus representation in fear-related brain areas. Here we show that dopamine neurons in the VTA that project to the basal amygdala contribute to such a teaching signal for plasticity, thereby facilitating the formation of fear memories. Knowledge about the role of dopamine in aversively motivated plasticity might allow further insights into maladaptive plasticities that underlie anxiety and post-traumatic stress disorders in humans.

The Relationship Between Self-Reported Misophonia Symptoms and Auditory Aversive Generalization Leaning: A Preliminary Report.

Misophonia is characterized by excessive aversive reactions to specific "trigger" sounds. Although this disorder is increasingly recognized in the literature, its etiological mechanisms and maintaining factors are currently unclear. Several etiological models propose a role of Pavlovian conditioning, an associative learning process heavily researched in similar fear and anxiety-related disorders. In addition, generalization of learned associations has been noted as a potential causal or contributory factor. Building upon this framework, we hypothesized that Misophonia symptoms arise as a consequence of overgeneralized associative learning, in which aversive responses to a noxious event also occur in response to similar events. Alternatively, heightened discrimination between conditioned threat and safety cues may be present in participants high in Misophonia symptoms, as predicted by associative learning models of Misophonia. This preliminary report (n = 34) examines auditory generalization learning using self-reported behavioral (i.e., valence and arousal ratings) and EEG alpha power reduction. Participants listened to three sine tones differing in pitch, with one pitch (i.e., CS+) paired with an aversive loud white noise blast, prompting aversive Pavlovian generalization learning. We assessed the extent to which overgeneralization versus heightened discrimination learning is associated with self-reported Misophonia symptoms, by comparing aversive responses to the CS+ and other tones similar in pitch. Behaviorally, all participants learned the contingencies between CS+ and noxious noise, with individuals endorsing elevated Misophonia showing heightened aversive sensitivity to all stimuli, regardless of conditioning and independent of hyperacusis status. Across participants, parieto-occipital EEG alpha-band power reduction was most pronounced in response to the CS+ tone, and this difference was greater in those with self-reported Misophonia symptoms. The current preliminary findings do not support the notion that overgeneralization is a feature of self-reported emotional experience in Misophonia, but that heightened sensitivity and discrimination learning may be present at the neural level.

A Modified Two-Way Active Avoidance Test for Combined Contextual and Auditory Instrumental Conditioning.

Available two-way active avoidance paradigms do not provide contextual testing, likely due to challenges in performing repetitive trials of context exposure. To incorporate contextual conditioning in the two-way shuttle box, we contextually modified one of the chambers of a standard two-chamber rat shuttle box with visual cues consisting of objects and black and white stripe patterns. During the 5 training days, electrical foot shocks were delivered every 10 s in the contextually modified chamber but were signaled by a tone in the plain chamber. Shuttling between chambers prevented an incoming foot shock (avoidance) or aborted an ongoing one (escape). During contextual retention testing, rats were allowed to freely roam in the box. During auditory retention testing, visual cues were removed, and tone-signaled shocks were delivered in both chambers. Avoidance gradually replaced escape or freezing behaviors reaching 80% on the last training day in both chambers. Rats spent twice more time in the plain chamber during contextual retention testing and had 90% avoidance rates during auditory retention testing. Our modified test successfully assesses both auditory and contextual two-way active avoidance. By efficiently expanding its array of outcomes, our novel test will complement standard two-way active avoidance in mechanistic studies and will improve its applications in translational research.