How dopamine leads to hallucinations

doi:10.1126/science.abh1310

GSTDTAP > 气候变化

DOI	10.1126/science.abh1310
	How dopamine leads to hallucinations
	Miriam Matamales
	2021-04-02
发表期刊	Science
出版年	2021
英文摘要	The ability to detect external stimuli rapidly and accurately by building internal sensory representations is a central computation of the brain that is critical to guide behavior. Such expectations (or priors) may be acquired throughout the lifetime of an individual and are important to influence perception, particularly when incoming sensory signals are ambiguous ([ 1 ][1]). But this process is not exempt from failure. Hallucinations (perceptual experiences without external stimuli) seen in conditions such as schizophrenia are thought to result from giving too much weight to priors, creating an imbalance at the expense of actual sensory evidence ([ 2 ][2], [ 3 ][3]). Sustained high-dopamine tone in the striatum has been proposed to contribute to this imbalance ([ 4 ][4]); however, it has remained unclear how the dopaminergic perturbation leads to the generation of hallucinations. On page 51 of this issue, Schmack et al. ([ 5 ][5]) uncover the neurobiological mechanisms that underlie dopamine-dependent auditory hallucinatory states, with therapeutic implications. In the laboratory, it has been consistently shown that hallucination-like perceptual experiences (percepts) can be experimentally elicited by establishing associations between stimuli ([ 6 ][6]). For example, repeated visual-auditory stimulus pairings lead to auditory percepts when visual stimuli are presented alone, an effect that appears widely across the animal kingdom. On the basis of this effect, Schmack et al. developed a sensory detection task that is conducted under variable levels of perceptual uncertainty to maximize the proportion of hallucination-like percepts in mice. In their task, the animals learned a visual cue (a light) that was presented either with an auditory signal (a tone) that was embedded in background noise or with the background noise alone. After repeated presentations of this set of associations (light and tone above noise versus light and noise), mice could appropriately choose a response according to what was presented. However, when Schmack et al. increased the uncertainty in the task by introducing auditory signals hardly distinguishable from the noise, conditioned hallucinations started to emerge: the light-evoked representation of the tone established early in training biased the mice toward the “tone present” response even when the tone was largely attenuated or completely absent. The bias was even greater when the expectancy of hearing the auditory signal was manipulated by increasing the number of light-tone pairings during training, in line with the idea that learned—perhaps aberrant—associations may seed the establishment of overweight priors that can ultimately distort perception ([ 7 ][7]). A key feature of hallucination-prone individuals is that they show inadequate overconfidence in decision-making tasks, particularly when engaged in an erroneous choice ([ 8 ][8]). Schmack et al. recorded the amount of time an animal is willing to wait for the reward after a response and used this measure as a behavioral proxy for confidence ([ 9 ][9]). On the basis of this postdecision time investment, Schmack et al. found a fraction of false alarm responses (tone choice in the absence of a tone) in which mice had a high conviction that the auditory signal had been presented, and therefore the authors demonstrated that high-confidence hallucination-like percepts (HALIPs) could indeed be modeled in mice (see the figure). In support of the hallucinogenic nature of this response, administering ketamine (a drug that precipitates psychogenic symptoms) specifically increased HALIP rate in mice. Moreover, the behavioral task could be readily translated to nonclinical human participants, whose self-reported auditory hallucinations were positively correlated with HALIPs (false alarm responses in the task). A critical unresolved question is whether dopamine dysregulation at specific striatal loci is at the root of psychotic symptoms. Schmack et al. addressed this by studying the dynamics of dopamine release in the tail of the striatum (TS), an associative region implicated in the perception and memory of auditory signals in which cortico-, thalamoand nigro-striatal projections converge ([ 10 ][10]). The authors found an intriguing sustained increase of dopamine in the TS in no-signal trials that specifically preceded false alarm responses. Optogenetic stimulation of dopamine release in the TS at the onset of the trial mimicked this effect, which led to a heightened trend to report hearing nonexistent auditory signals. ![Figure][11] Hallucinations in mice Mice learn to discriminate between different categories of stimuli (tone versus no tone) and to respond appropriately. A sustained elevation of dopamine (DA) in the tail of the striatum (blue) is required to robustly virtualize a cortical representation of the tone (red) in the absence of a real input, biasing perception and producing hallucinations. GRAPHIC: KELLIE HOLOSKI/ SCIENCE Moving away from a corticocentric view of sensory processing, the study of Schmack et al. adds support to the idea that “lower-order” brain areas such as the striatum functionally interact with “higher-order” ones such as the auditory cortex to influence perceptual inference ([ 11 ][12]). Although previous human neuroimaging studies have established how sound percepts are represented in the auditory cortex during hallucinatory states ([ 3 ][3]), whether this auditory-related striatal region underpins such cortical representations is yet to be answered. Future deep-brain calcium imaging studies of large populations of cortical and striatal neurons in animal models of hallucinations, such as the one established by Schmack et al. , should help to clarify these complex, brainwide neural dynamics. Although much remains to be explored in these circuits, the findings of Schmack et al. add to a growing body of literature indicating that beyond striatal dopamine's function in reinforcement learning and decision-making, it also plays a key role in the neuromodulation of perception. A local disproportionate increase of dopamine in the TS may alter the encoding of auditory experiences, which by means of distorted striato-thalamo-cortical feedback could ultimately provoke representations of overweight priors in the cortex ([ 12 ][13]). The study of Schmack et al. opens the door to a promising treatment strategy for silencing auditory hallucinations. In support of this idea, electrical stimulation of an auditory-associated area of the human striatum through deep brain stimulation in patients with subjective tinnitus (hearing noises that are not there, such as ringing or hissing) led to loudness modulation of existing tinnitus percepts, and lesioning of this area resulted in enduring tinnitus loudness suppression ([ 13 ][14]). Although Schmack et al. successfully rescued dopamine-elicited HALIPs by systemically administering the antipsychotic drug haloperidol, whether silencing of neurons located in the TS is sufficient to prevent hallucinatory experiences is an important unanswered issue. Nevertheless, it is starting to become clear that elegantly designed behavioral neuroscience experiments can effectively bridge the gap between complex psychiatric disorders and the neural systems that underpin them. 1. [↵][15]1. F. Picard, 2. K. Friston , Neurology 83, 1112 (2014). [OpenUrl][16][CrossRef][17] 2. [↵][18]1. A. R. Powers et al ., Science 357, 596 (2017). [OpenUrl][19][Abstract/FREE Full Text][20] 3. [↵][21]1. P. R. Corlett et al ., Trends Cogn. Sci. 23, 114 (2019). [OpenUrl][22][CrossRef][23][PubMed][24] 4. [↵][25]1. S. Kapur , Am. J. Psychiatry 160, 13 (2003). [OpenUrl][26][CrossRef][27][PubMed][28][Web of Science][29] 5. [↵][30]1. K. Schmack et al ., Science 372, eabf4740 (2021). [OpenUrl][31][Abstract/FREE Full Text][32] 6. [↵][33]1. M. T. Koh, 2. M. Gallagher , Neurobiol. Learn. Mem. 175, 107319 (2020). [OpenUrl][34] 7. [↵][35]1. S. Denève, 2. R. Jardri , Curr. Opin. Behav. Sci. 11, 40 (2016). [OpenUrl][36] 8. [↵][37]1. S. Moritz et al ., Schizophr. Res. Cogn. 1, 165 (2014). [OpenUrl][38] 9. [↵][39]1. A. Kepecs, 2. Z. F. Mainen , Philos. Trans. R. Soc. Lond. B Biol. Sci. 367, 1322 (2012). [OpenUrl][40][CrossRef][41][PubMed][42] 10. [↵][43]1. E. Valjent, 2. G. Gangarossa , Trends Neurosci. 44, 203 (2021). [OpenUrl][44] 11. [↵][45]1. J. McFadyen et al ., Nat. Rev. Neurosci. 21, 264 (2020). [OpenUrl][46] 12. [↵][47]1. M. Avram, 2. F. Brandl, 3. J. Bäuml, 4. C. Sorg , Neuropsychopharmacology 43, 2239 (2018). [OpenUrl][48] 13. [↵][49]1. P. S. Larson, 2. S. W. Cheung , J. Neurosurg. 118, 192 (2013). [OpenUrl][50] Acknowledgments: This work was supported by grants from the Australian Research Council (DP190102511 and DP210102700) and by the National Health and Medical Research Council (APP1165990). [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4 [5]: #ref-5 [6]: #ref-6 [7]: #ref-7 [8]: #ref-8 [9]: #ref-9 [10]: #ref-10 [11]: pending:yes [12]: #ref-11 [13]: #ref-12 [14]: #ref-13 [15]: #xref-ref-1-1 "View reference 1 in text" [16]: {openurl}?query=rft.jtitle%253DNeurology%26rft.volume%253D83%26rft.spage%253D1112%26rft_id%253Dinfo%253Adoi%252F10.1212%252FWNL.0000000000000798%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [17]: /lookup/external-ref?access_num=10.1212/WNL.0000000000000798&link_type=DOI [18]: #xref-ref-2-1 "View reference 2 in text" [19]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.aulast%253DPowers%26rft.auinit1%253DA.%2BR.%26rft.volume%253D357%26rft.issue%253D6351%26rft.spage%253D596%26rft.epage%253D600%26rft.atitle%253DPavlovian%2Bconditioning-induced%2Bhallucinations%2Bresult%2Bfrom%2Boverweighting%2Bof%2Bperceptual%2Bpriors%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.aan3458%26rft_id%253Dinfo%253Apmid%252F28798131%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [20]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEyOiIzNTcvNjM1MS81OTYiO3M6NDoiYXRvbSI7czoyMToiL3NjaS8zNzIvNjUzNy8zMy5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30= [21]: #xref-ref-3-1 "View reference 3 in text" [22]: {openurl}?query=rft.jtitle%253DTrends%2BCogn.%2BSci.%26rft.volume%253D23%26rft.spage%253D114%26rft_id%253Dinfo%253Adoi%252F10.1162%252FNECO_a_00864%26rft_id%253Dinfo%253Apmid%252F27391683%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [23]: /lookup/external-ref?access_num=10.1162/NECO_a_00864&link_type=DOI [24]: /lookup/external-ref?access_num=27391683&link_type=MED&atom=%2Fsci%2F372%2F6537%2F33.atom [25]: #xref-ref-4-1 "View reference 4 in text" [26]: {openurl}?query=rft.jtitle%253DAmerican%2BJournal%2Bof%2BPsychiatry%26rft.stitle%253DAm.%2BJ.%2BPsychiatry%26rft.aulast%253DKapur%26rft.auinit1%253DS.%26rft.volume%253D160%26rft.issue%253D1%26rft.spage%253D13%26rft.epage%253D23%26rft.atitle%253DPsychosis%2Bas%2Ba%2BState%2Bof%2BAberrant%2BSalience%253A%2BA%2BFramework%2BLinking%2BBiology%252C%2BPhenomenology%252C%2Band%2BPharmacology%2Bin%2BSchizophrenia%26rft_id%253Dinfo%253Adoi%252F10.1176%252Fappi.ajp.160.1.13%26rft_id%253Dinfo%253Apmid%252F12505794%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [27]: /lookup/external-ref?access_num=10.1176/appi.ajp.160.1.13&link_type=DOI [28]: /lookup/external-ref?access_num=12505794&link_type=MED&atom=%2Fsci%2F372%2F6537%2F33.atom [29]: /lookup/external-ref?access_num=000180195400003&link_type=ISI [30]: #xref-ref-5-1 "View reference 5 in text" [31]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.aulast%253DSchmack%26rft.auinit1%253DK.%26rft.volume%253D372%26rft.issue%253D6537%26rft.spage%253Deabf4740%26rft.epage%253Deabf4740%26rft.atitle%253DStriatal%2Bdopamine%2Bmediates%2Bhallucination-like%2Bperception%2Bin%2Bmice%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.abf4740%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [32]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjE3OiIzNzIvNjUzNy9lYWJmNDc0MCI7czo0OiJhdG9tIjtzOjIxOiIvc2NpLzM3Mi82NTM3LzMzLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ== [33]: #xref-ref-6-1 "View reference 6 in text" [34]: {openurl}?query=rft.jtitle%253DNeurobiol.%2BLearn.%2BMem.%26rft.volume%253D175%26rft.spage%253D107319%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [35]: #xref-ref-7-1 "View reference 7 in text" [36]: {openurl}?query=rft.jtitle%253DCurr.%2BOpin.%2BBehav.%2BSci.%26rft.volume%253D11%26rft.spage%253D40%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [37]: #xref-ref-8-1 "View reference 8 in text" [38]: {openurl}?query=rft.jtitle%253DSchizophr.%2BRes.%2BCogn.%26rft.volume%253D1%26rft.spage%253D165%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [39]: #xref-ref-9-1 "View reference 9 in text" [40]: {openurl}?query=rft.jtitle%253DPhilos.%2BTrans.%2BR.%2BSoc.%2BLond.%2BB%2BBiol.%2BSci.%26rft_id%253Dinfo%253Adoi%252F10.1098%252Frstb.2012.0037%26rft_id%253Dinfo%253Apmid%252F22492750%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [41]: /lookup/external-ref?access_num=10.1098/rstb.2012.0037&link_type=DOI [42]: /lookup/external-ref?access_num=22492750&link_type=MED&atom=%2Fsci%2F372%2F6537%2F33.atom [43]: #xref-ref-10-1 "View reference 10 in text" [44]: {openurl}?query=rft.jtitle%253DTrends%2BNeurosci.%26rft.volume%253D44%26rft.spage%253D203%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [45]: #xref-ref-11-1 "View reference 11 in text" [46]: {openurl}?query=rft.jtitle%253DNat.%2BRev.%2BNeurosci.%26rft.volume%253D21%26rft.spage%253D264%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [47]: #xref-ref-12-1 "View reference 12 in text" [48]: 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领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/321126
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Miriam Matamales. How dopamine leads to hallucinations[J]. Science,2021.
APA	Miriam Matamales.(2021).How dopamine leads to hallucinations.Science.
MLA	Miriam Matamales."How dopamine leads to hallucinations".Science (2021).