Astroglial CB1 Cannabinoid Receptors Mediate CP 55,940-Induced Conditioned Place Aversion Through Cyclooxygenase-2 Signaling in Mice

Cannabinoids (CBs), such as phytocannabinoids, synthetic CBs, and endogenous CBs, can be neuroprotective, rewarding, or aversive. The aversive effects of CBs may hinder their medical and recreational applications. It is unknown which type of CB receptors mediates the direct aversive effects of synthetic CB CP 55,940 which is an analog of Δ9-tetrahydrocannabinol, the major psychoactive component of marijuana. In this study, we address this question by taking the advantage of systematic type 1 CB receptor (CB1R) knockout mice and conditional reinstatement of this receptor only in astrocytes. We show that CP 55,940 at a concentration of 1 mg/kg induces conditioned place aversion (CPA) and the CPA effect of CP 55,940 is mediated by the astroglial CB1Rs. Inhibiting cyclooxygenase-2 (COX-2) eliminates CP 55,940-induced CPA in mice that only express CB1Rs in astrocytes. These findings conclude that CPA effect of CP 55,940 is mediated by the astroglial CB1Rs through COX-2 signaling, suggesting that selective COX-2 inhibition or precise isolation of astroglial CB1R activity may be the strategy for treating aversive response of medical and recreational administrations of marijuana.

Trypsin induces an aversive response in zebrafish by PAR2 activation in keratinocytes

Previously we have shown that trypsin, a protein typically involved in digestion, is released from gills of both fresh and saltwater fishes into surrounding water under stress or injury. We have also shown that each species produces trypsin with different specific activities. In this report, using zebrafish as a model, we identified that trypsin induces an aversive response in zebrafish larvae and adult zebrafish. Since Protease-Activated Receptor 2 (PAR2) responds to trypsin, we tested whether the aversive response is dependent on the activation of PAR2 located on the zebrafish skin cells. Zebrafish larvae treated separately with neomycin and zinc sulfate also showed aversive response indicating neuromast, and olfactory cells are not involved in this aversion. Cultured keratinocytes from zebrafish showed a response to trypsin. Zebrafish larvae subjected to knockdown of par2a also exhibited reduced escape response. Similarly, par2a-deficient mutant larvae displayed no response to trypsin. Since it has been shown that stress activates PAR2 and sends signals to the brain as shown by the increased c-fos expression, we tested c-fos expression in adult zebrafish brains after trypsin treatment of adults and found enhanced c-fos expression by qRT-PCR. Taken together, our results show that the trypsin activates PAR2 on keratinocytes signaling the brain, and this pathway of trypsin-induced escape response will provide a unique communication mechanism in zebrafish. Furthermore, since PAR2 activation also occurs in pain/pruritus sensing, this model might be useful in elucidating components of signaling pathways in pain/pruritus.

What's the Story With Blue Steak? On the Unexpected Popularity of Blue Foods

Is blue food desirable or disgusting? The answer, it would seem, is both, but it really depends on the food in which the color happens to be present. It turns out that the oft-cited aversive response to blue meat may not even have been scientifically validated, despite the fact that blue food coloring is often added to discombobulate diners. In the case of drinks, however, there has been a recent growth of successful new blue product launches in everything from beer to tea, and from wine to gin, arguing that coloring food products blue is more than simply a contemporary fad. In fact, the current interest in blue food coloring builds on the color's earlier appearance in everything from blue curacao to blue-raspberry candyfloss (cotton candy), and thereafter a number of soft drinks. Over the years, the combination of blue coloring with raspberry flavoring has also appeared in everything from bubble-gum to patriotic pop rocks (popping candy in The United States). Ultimately, it is the rarity of naturally-blue foods that is likely what makes this color so special. As such, blue food coloring can both work effectively to attract the visual attention of the shopper while, at the same time, being linked to a range of different flavors (since this is one of the few color-flavor mappings that are essentially arbitrary) depending on the food format in which it happens to appear. Note also that the basic descriptor “blue” covers a wide range of hues having a range of different associations, hence eliciting different reactions (be they positive or negative). While blue was once associated with artificiality, a growing number of natural blue food colorings have come onto the market in recent years thus perhaps changing the dominant associations that many consumers may have with this most unusual of food colors.

Reconceptualising resilience within a translational framework is supported by unique and brain-region specific transcriptional signatures in mice

ABSTRACTChronic social defeat (CSD) in mice has been increasingly employed in experimental resilience research. Particularly, the degree of CSD-induced social avoidance is used to classify animals into resilient (socially non-avoidant) versus susceptible (avoidant). In-spired by human data pointing to threat-safety discrimination and responsiveness to extinction training of aversive memories as characteristics of resilient individuals, we here describe a translationally informed stratification which identified three phenotypic subgroups of mice following CSD: the Discriminating-avoiders, characterised by successful social threat-safety discrimination and successful extinction of social avoidance; the Indis-criminate-avoiders, showing aversive response generalisation, and the Non-avoiders (absence of social avoidance) displaying impaired conditioned learning. Furthermore, and supporting the biological validity of our approach, we uncovered subgroup-specific transcriptional signatures in classical fear conditioning and anxiety-related brain regions. Our reconceptualisation of resilience in mice refines the currently used dichotomous classification and contributes to advancing future translational approaches.

Context influences how individuals with misophonia respond to sounds

ABSTRACTMisophonia is a newly researched condition in which specific sounds cause an intense, aversive response in individuals, characterized by negative emotions and autonomic arousal. Although virtually any sound can become a misophonic “trigger,” the most common sounds appear to be bodily sounds related to chewing and eating as well as other repetitive sounds. An intriguing aspect of misophonia is the fact that many misophonic individuals report that they are triggered more, or even only, by sounds produced by specific individuals, and less, or not at all, by sounds produced by animals (although there are always exceptions).In general, anecdotal evidence suggests that misophonic triggers involve a combination of sound stimuli and contextual cues. The aversive stimulus is more than just a sound and can be thought of as a Gestalt of features which includes sound as a necessary component as well as additional contextual information. In this study, we explore how contextual information influences misophonic responses to human chewing, as well as sonically similar sounds produced by non-human sources. The current study revealed that the exact same sound can be perceived as being much more or less aversive depending on the contextual information presented alongside the auditory information. The results of this study provide a foundation for potential cognitive based therapies.

Aversive Response Towards Culture Fusion Is Moderated by the Source of Foreign Cultural Inflow

Culture fusion reflects blending of elements from distinct cultures that produces a novel, hybrid cultural representation. Prior research among participants in the USA revealed that fusion of cultural elements from the USA and China could be perceived as contamination of one’s local culture and evokes disgust. It remains unknown whether this aversion to culture fusion generalizes to other samples and is contingent on perceivers’ attitudes toward the source of the foreign culture. Here, we tested these questions across two studies. Participants were exposed to different patterns of culture mixing of their own local culture and two foreign cultures (one relatively favored and one relatively disfavored). Across both studies (Singaporean participants in Study 1 and Hong Kong participants in Study 2), the results replicated prior findings suggesting that culture fusion elicits stronger negative evaluations (e.g., disgust, discomfort) compared to other patterns of culture mixing (i.e., presentation of local and foreign elements side-by-side). Importantly, a Mixing Type × Foreign Source interaction emerged, such that participants in both studies reacted more negatively to culture mixing involving a less favored (China) than a more favored (USA) culture, with negative reactions especially pronounced toward culture fusion. This aversive response was moderated by patriotism in Singapore but not in Hong Kong. These findings demonstrate that response to culture mixing depends on intergroup attitudes toward foreign cultures, and culture fusion is especially aversive when involving cultural inflows from a disfavored out-group. The contribution of geopolitical differences between Singapore and Hong Kong on these findings are also considered.

Acetic acid activates distinct taste pathways in Drosophila to elicit opposing, state-dependent feeding responses

Taste circuits are genetically determined to elicit an innate appetitive or aversive response, ensuring that animals consume nutritious foods and avoid the ingestion of toxins. We have examined the response of Drosophila melanogaster to acetic acid, a tastant that can be a metabolic resource but can also be toxic to the fly. Our data reveal that flies accommodate these conflicting attributes of acetic acid by virtue of a hunger-dependent switch in their behavioral response to this stimulus. Fed flies show taste aversion to acetic acid, whereas starved flies show a robust appetitive response. These opposing responses are mediated by two different classes of taste neurons, the sugar- and bitter-sensing neurons. Hunger shifts the behavioral response from aversion to attraction by enhancing the appetitive sugar pathway as well as suppressing the aversive bitter pathway. Thus a single tastant can drive opposing behaviors by activating distinct taste pathways modulated by internal state.

Dopaminergic Cellular and Circuit Contributions to Kappa Opioid Receptor Mediated Aversion

Neural circuits that enable an organism to protect itself by promoting escape from immediate threat and avoidance of future injury are conceptualized to carry an “aversive” signal. One of the key molecular elements of these circuits is the kappa opioid receptor (KOR) and its endogenous peptide agonist, dynorphin. In many cases, the aversive response to an experimental manipulation can be eliminated by selective blockade of KOR function, indicating its necessity in transmitting this signal. The dopamine system, through its contributions to reinforcement learning, is also involved in processing of aversive stimuli, and KOR control of dopamine in the context of aversive behavioral states has been intensely studied. In this review, we have discussed the multiple ways in which the KORs regulate dopamine dynamics with a central focus on dopamine neurons and projections from the ventral tegmental area. At the neuronal level, KOR agonists inhibit dopamine neurons both in the somatodendritic region as well as at terminal release sites, through various signaling pathways and ion channels, and these effects are specific to different synaptic sites. While the dominant hypotheses are that aversive states are driven by decreases in dopamine and increases in dynorphin, reported exceptions to these patterns indicate these ideas require refinement. This is critical given that KOR is being considered as a target for development of new therapeutics for anxiety, depression, pain, and other psychiatric disorders.

Acetic acid activates distinct taste pathways in Drosophila to elicit opposing, state-dependent feeding responses

ABSTRACTTaste circuits are genetically determined to elicit an innate appetitive or aversive response, ensuring that animals consume nutritious foods and avoid the ingestion of toxins. We have examined the response of the fruit fly Drosophila melanogaster to acetic acid, a tastant that can be a metabolic resource but can also be toxic to the fly. Our data reveal that flies accommodate these conflicting attributes of acetic acid by virtue of a hunger-dependent switch in their behavioral response to this stimulus. Fed flies show taste aversion to acetic acid, likely a response to its potential toxicity, whereas starved flies show a robust appetitive response that may reflect their overriding need for calories. These opposing responses are mediated by two different classes of taste neurons. Acetic acid activates both the sugar and bitter pathways, which have opposing effects on feeding behavior. Hunger shifts the response from aversion to attraction by enhancing the appetitive sugar pathway as well as suppressing the aversive bitter pathway. Thus a single tastant can drive opposing behaviors by activating distinct taste pathways modulated by internal state.