Journal of Neuroscience最新文献

The promiscuous ligand cannabidiol (CBD) shows promise as an analgesic, but its complex pharmacodynamics has made it difficult to identify its mechanism(s) of action. Numerous putative CBD receptors including cannabinoid receptors CB1 and CB2, as well as Trpv1 and Trpa1-the receptors for capsaicin and mustard-oil (AITC) respectively-have been proposed to contribute to CBD-mediated analgesia. Larval zebrafish have several attributes that lend themselves to inquiries into the biology of nociception. The neural circuits underlying nociception in zebrafish larvae are highly analogous to those found in higher vertebrates. Notably, the small size and optical clarity of zebrafish enable holistic evaluation of analgesic function utilizing behavioral and imaging platforms. Here we report that in larval zebrafish of either sex, CBD serves both anti- and pro-nociceptive functions. Utilizing place aversion assays as a proxy for nociception, we found that low concentrations of CBD inhibit aversion to noxious chemical stimuli including AITC and acetic acid. Counterintuitively, we found that higher concentrations of CBD potentiated nocifensive behavior as measured by enhanced thermal aversion and increased locomotion. Knockdown of Trpa1b eliminated the algogenic effects of CBD while having no effect on its analgesic properties, as it abolished trpa1b+ sensory neuron responses to CBD, CBD-evoked thermal hypersensitivity, and increased locomotion in Trpa1b-null animals. Strikingly, CBD profoundly inhibited thermal aversion to noxious heat in Trpa1b-null animals but not in wildtype animals, indicating that CBD-mediated Trpa1b activation can oppose the analgesic properties of CBD. These studies provide a framework to investigate the genetic and neural substrates of CBD-mediated analgesia and nociception.Significance statement While Cannabis and its component compounds such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have long been used to alleviate pain, little is known about their mechanisms of action. Our study provides a framework for investigating the effects of cannabinoids on nociception in a vertebrate, by utilizing behavioral experiments in combination with neuroimaging and in-vitro studies. Together, these approaches allowed us to define the role of one molecular target, Trpa1b, involved in the effects of CBD upon nociception. Critically, activation of this receptor by CBD masks a separate, analgesic effect upon temperature sensation, which suggests a possible explanation for CBD's inconsistent efficacy across different models of pain.

A fundamental aspect of visual motion processing is the computation of motion direction. In ferrets, as in primates, selectivity for motion direction is found both in early cortical stages like the primary visual cortex (V1) and in higher visual areas like the middle temporal (MT) area in primates and the postero-medial lateral suprasylvian (PMLS) area in ferrets. Little is known about how this critical tuning function develops in higher visual cortex. Here, by studying the development of the ferret's motion pathway, we first reveal the surprising finding that direction selectivity develops earlier in PMLS than in V1, contrary to the areas' hierarchical positions. Our data, collected in animals of either sex, furthermore show that while direction selectivity is sensitive to visual experience in both areas, the sensitivity profile differs between them: Presentation of drifting gratings, containing the full complement of spatial and temporal cues generated by visual motion, can promote direction selectivity development in V1 and PMLS. In contrast, flashing stationary stimuli, which lack the spatial displacement of moving stimuli and only contain temporal changes, induce direction selectivity only in PMLS, not V1. Collectively our findings reveal significant deviations in PMLS development from that in V1, which will be important to account for in models of motion pathway development and of the developmental disorders that affect this pathway. The complex pattern of relative PMLS and V1 development also highlights the need to address interactions between areas in developmental research.Significance Statement While the development of early stages of visual cortex up to primary visual cortex (V1) has received much attention throughout the years, significantly less is known about that of higher visual cortex both on its own as well as in relationship to V1. Here, we focus on a core motion function, direction selectivity, to systematically characterize the coordinated development of multiple stages of the visual motion pathway in ferrets. Crucially, our data show that this coordinated development is surprising complex, and that the developmental status of the higher areas cannot be predicted based on that in lower areas. These findings may also provide clues why motion vision is particularly vulnerable to developmental disorders.

Non-nutritive sweeteners are sugar substitutes that may promote weight management by reducing an individual's calorie intake. It is, however, unclear whether (i) sugar and non-nutritive sweetener elicit distinct orosensory responses in the human brain, and (ii) whether the neural responses to these flavours are modulated by expectancy. Addressing these questions has direct relevance to our understanding of food choice behaviour and how it may be modified in dietary interventions. We screened N=99 healthy adults of either sex to select a sample (N=27, M[SD]_age = 24.25[2.94] years) who reported similar perceptual experiences of sugar and sweetener, thus removing a potential confound of sensory differences, for fMRI scanning. While scanning, they received sugar- and artificially-sweetened beverages in two conditioning paradigms, which manipulated participants' expectation of flavour delivery: first in a probabilistic and second in a deterministic way. Participants' ability to accurately distinguish sugar from non-nutritive sweetener depended largely on their expectations, which also significantly affected the perceived pleasantness of each flavour. Expectation altered brain responses to flavour delivery during the deterministic task only, where the (mistaken) expectation of sugar significantly increased midbrain responses to sweetener compared to when sweetener was expected. Trial-wise confidence and pleasantness ratings differentially scaled with brain responses to sugar and sweetener delivery. These results highlight the importance of expectancy in both the behavioural and neural encoding of sweet flavour, particularly when sensory information is unreliable. The expectation of sugar appears to increase the subjective value of noncaloric sweetener, which may result from flavour-nutrient conditioning that preferentially reinforcers sugar.Significance statement Artificial sweeteners have become common alternatives to sugar-sweetened beverages. The perceived reward from sweet flavour depends not only on the sweetener but also on our expectations of its resulting pleasantness. However, it remains unknown if shared brain circuits encode sugar and non-nutritive sweetener-and our expectations surrounding them. Here, we examined brain responses to sugar- and artificially-sweetened beverages in healthy humans who could not reliably discriminate them, and we manipulated their expectation of flavour delivery. Expectation altered participants' accuracy and perceived pleasantness of each flavour, where the expectation of sugar increased midbrain responses and perceived pleasantness of artificial sweetener. The rewarding effects of sugar appeared to exceed those of sweetener, which may reflect flavour-nutrient conditioning that shapes food choice behaviour.