{"id":58557,"date":"2025-04-28T22:12:08","date_gmt":"2025-04-28T22:12:08","guid":{"rendered":"https:\/\/www.europesays.com\/uk\/58557\/"},"modified":"2025-04-28T22:12:08","modified_gmt":"2025-04-28T22:12:08","slug":"dopamine-signals-teach-the-brain-to-unlearn-fear","status":"publish","type":"post","link":"https:\/\/www.europesays.com\/uk\/58557\/","title":{"rendered":"Dopamine Signals Teach the Brain to Unlearn Fear"},"content":{"rendered":"<p><strong>Summary: <\/strong>A new study reveals that dopamine release along a specific brain circuit helps extinguish fear by activating reward-related neurons in the amygdala. Researchers showed that dopamine from the ventral tegmental area (VTA) drives the brain\u2019s positive learning process during fear extinction, rather than simply suppressing fear.<\/p>\n<p>Disruption of this dopamine-driven pathway impaired the ability to unlearn fear, suggesting critical implications for anxiety and PTSD treatments. The findings highlight a precise neural mechanism that could lead to targeted therapies for fear-related disorders.<\/p>\n<p><strong>Key Facts:<\/strong><\/p>\n<ul class=\"wp-block-list\">\n<li><strong>Teaching Signal:<\/strong> Dopamine release from the VTA activates specific amygdala neurons to drive fear extinction.<\/li>\n<li><strong>Positive Learning:<\/strong> Fear extinction involves a reward-based learning process, not just suppression of fear memories.<\/li>\n<li><strong>Therapeutic Potential:<\/strong> Targeting the pBLA-VTA dopamine pathway could aid treatments for PTSD and anxiety disorders.<\/li>\n<\/ul>\n<p><strong>Source: <\/strong>Picower Institute at MIT<\/p>\n<p><strong>Dangers come but dangers also go and when they do, the brain has an \u201call-clear\u201d signal that teaches it to extinguish its fear. <\/strong><\/p>\n<p>A new study in mice by MIT neuroscientists shows that the signal is the release of dopamine along a specific interregional brain circuit.<\/p>\n<p>  <img fetchpriority=\"high\" decoding=\"async\" width=\"1200\" height=\"799\" src=\"https:\/\/www.europesays.com\/uk\/wp-content\/uploads\/2025\/04\/dopamine-fear-neuroscience.jpg\" alt=\"This shows a brain.\"  \/> Meanwhile in the Rspo2 cells, knocking down receptors reduced the freezing behavior. Credit: Neuroscience News<\/p>\n<p>The research therefore pinpoints a potentially critical mechanism of mental health, restoring calm when it works, but prolonging anxiety or even post-traumatic stress disorder when it doesn\u2019t.<\/p>\n<p>\u201cDopamine is essential to initiate fear extinction,\u201d said Michele Pignatelli di Spinazzola, co-author of the new study from the lab of senior author\u00a0Susumu Tonegawa, Picower Professor of biology and neuroscience at the RIKEN-MIT Laboratory for Neural Circuit Genetics in The Picower Institute for Learning and Memory and an HHMI Investigator.<\/p>\n<p>In 2020\u00a0Tonegawa\u2019s lab showed\u00a0that learning to be afraid, and then learning when that\u2019s no longer necessary, result from a competition between populations of cells in the brain\u2019s amygdala region.<\/p>\n<p>When a mouse learns that a place is \u201cdangerous\u201d (because it gets a little foot shock there), the fear memory is encoded by neurons in the anterior of the basolateral amygdala (aBLA) that express the gene Rspo2.<\/p>\n<p>When the mouse then learns that a place is no longer associated with danger (because they wait there and the zap doesn\u2019t recur), neurons in the posterior basolateral amygdala (pBLA) that express the gene Ppp1r1b encode a new fear extinction memory that overcomes the original dread.<\/p>\n<p>Notably those same neurons encode feelings of reward, helping to explain why it feels so good when we realize that an expected danger has dwindled.<\/p>\n<p>In the new study, the lab, led by former members Xiangyu Zhang and Katelyn Flick, sought to determine what prompts these amygdala neurons to encode these memories.<\/p>\n<p>The rigorous set of experiments the team reports in the\u00a0Proceedings of the National Academy of Sciences\u00a0show that it\u2019s dopamine sent to the different amygdala populations from distinct groups of neurons in the ventral tegmental area (VTA).<\/p>\n<p>\u201cOur study uncovers a precise mechanism by which dopamine helps the brain unlearn fear,\u201d said Zhang, who also led the 2020 study and is now Senior Associate at Orbimed, a healthcare investment firm.<\/p>\n<p>\u201cWe found that dopamine activates specific amygdala neurons tied to reward, which in turn drive fear extinction. We now see that unlearning fear isn\u2019t just about suppressing it\u2014it\u2019s a positive learning process powered by the brain\u2019s reward machinery.<\/p>\n<blockquote class=\"wp-block-quote is-layout-flow wp-block-quote-is-layout-flow\">\n<p>\u201cThis opens up new avenues for understanding and potentially treating fear-related disorders like PTSD.\u201d<\/p>\n<\/blockquote>\n<p><strong>Forgetting fear<\/strong><\/p>\n<p>The VTA was the lab\u2019s prime suspect to be the source of the signal because the region is well known for encoding surprising experiences and instructing the brain, with dopamine, to learn from them.<\/p>\n<p>The first set of experiments in the paper used multiple methods for tracing neural circuits to see whether and how cells in the VTA and the amygdala connect.<\/p>\n<p>They found a clear pattern: Rspo2 neurons were targeted by dopaminergic neurons in the anterior and left and right sides of the VTA. Ppp1r1b neurons received dopaminergic input from neurons in the center and posterior sections of the VTA. The density of connections was greater on the Ppp1r1b neurons than for the Rspo2 ones.<\/p>\n<p>The circuit tracing showed that dopamine is available to amygdala neurons that encode fear and its extinction, but do those neurons care about dopamine?<\/p>\n<p>The team showed that indeed they express \u201cD1\u201d receptors for the neuromodulator. Commensurate with the degree of dopamine connectivity, Ppp1r1b cells had more receptors than Rspo2 neurons.<\/p>\n<p>Dopamine does a lot of things, so the next question was whether its activity in the amygdala actually correlated with fear encoding and extinction. Using a method to track and visualize it in the brain, the team watched dopamine in the amygdala as mice underwent a three-day experiment.<\/p>\n<p>On day one they went to an enclosure where they experienced three little zaps on the feet.<\/p>\n<p>On day two they went back to the enclosure for 45 minutes where they didn\u2019t experience any new shocks \u2013at first the mice froze in fear but then relaxed after about 15 minutes.<\/p>\n<p>On day 3 they returned again to test whether they had indeed extinguished the fear they showed at the beginning of day 2.<\/p>\n<p>The dopamine activity tracking revealed that during the shocks on day 1, Rspo2 neurons had the larger response to dopamine, but in the early moments of day 2 when the anticipated shocks didn\u2019t come and the mice eased up on freezing in fear, the Ppp1r1b neurons showed the stronger dopamine activity.<\/p>\n<p>More strikingly, the mice that learned to extinguish their fear most strongly also showed the greatest dopamine signal at those neurons.<\/p>\n<p><strong>Causal connections<\/strong><\/p>\n<p>The final sets of experiments sought to show that dopamine is not just available and associated with fear encoding and extinction, but also actually causes them. In one set, they turned to optogenetics, a technology that enables scientists to activate or quiet neurons with different colors of light.<\/p>\n<p>Sure enough, when they quieted VTA dopaminergic inputs in the pBLA, doing so impaired fear extinction. When they activated those inputs, it accelerated fear extinction.<\/p>\n<p>The researchers were surprised that when they activated VTA dopaminergic inputs into the aBLA they could reinstate fear even without any new foot shocks, impairing fear extinction.<\/p>\n<p>The other way they confirmed a causal role for dopamine in fear encoding and extinction was to manipulate the amygdala neurons\u2019 dopamine receptors. In Ppp1r1b neurons, overexpressing dopamine receptors impaired fear recall and promoted extinction, whereas knocking the receptors down impaired fear extinction. Meanwhile in the Rspo2 cells, knocking down receptors reduced the freezing behavior.<\/p>\n<p>\u201cWe showed that fear extinction requires VTA dopaminergic activity in the pBLA Ppp1r1b neurons by using optogenetic inhibition of VTA terminals and cell-type-specific knockdown of D1 receptors in these neurons,\u201d the authors wrote.<\/p>\n<p>The scientists are careful in the study to note that while they\u2019ve identified the \u201cteaching signal\u201d for fear extinction learning, the broader phenomenon of fear extinction occurs brainwide, rather than in just this single circuit.<\/p>\n<p>But the circuit seems to be a key node to consider as drug developers and psychiatrists work to combat anxiety and PTSD, Pignatelli di Spinazzola said.<\/p>\n<p>\u201cFear learning and fear extinction provide a strong framework to study generalized anxiety and PTSD,\u201d he said.<\/p>\n<p>\u201cOur study investigates the underlying mechanisms suggesting multiple targets for a translational approach such as pBLA and use of dopaminergic modulation.\u201d<\/p>\n<p>Marianna Rizzo is also a co-author of the study. Support for the research came from the RIKEN Center for Brain Science, the Howard Hughes Medical Institute, the Freedom Together Foundation and The Picower Institute for Learning and Memory.<\/p>\n<p>About this dopamine and PTSD research news<\/p>\n<p class=\"has-background\" style=\"background-color:#ffffe8\"><strong>Author: <\/strong><a href=\"http:\/\/neurosciencenews.com\/cdn-cgi\/l\/email-protection#096d687f606d63664964607d276c6d7c\" target=\"_blank\" rel=\"noreferrer noopener\">David Orenstein<\/a><br \/><strong>Source: <\/strong><a href=\"https:\/\/mit.edu\" target=\"_blank\" rel=\"noreferrer noopener\">Picower Institute at MIT<\/a><br \/><strong>Contact: <\/strong>David Orenstein \u2013 Picower Institute at MIT<br \/><strong>Image: <\/strong>The image is credited to Neuroscience News<\/p>\n<p class=\"has-background\" style=\"background-color:#ffffe8\"><strong>Original Research: <\/strong>Open access.<br \/>\u201c<a href=\"https:\/\/dx.doi.org\/10.1073\/pnas.2501331122\" target=\"_blank\" rel=\"noreferrer noopener\">Dopamine induces fear extinction by activating the reward-responding amygdala neurons<\/a>\u201d by Susumu Tonegawa et al. PNAS<\/p>\n<p><strong>Abstract<\/strong><\/p>\n<p><strong>Dopamine induces fear extinction by activating the reward-responding amygdala neurons<\/strong><\/p>\n<p>The extinction of conditioned fear responses is crucial for adaptive behavior, and its impairment is a hallmark of anxiety disorders such as posttraumatic stress disorder.<\/p>\n<p>Fear extinction takes place when animals form a new memory that suppresses the original fear memory.<\/p>\n<p>In the case of context-dependent fear memory, the new memory is formed within the reward-responding posterior subset of basolateral amygdala (BLA) that is genetically marked by\u00a0Ppp1r1b+\u00a0neurons.<\/p>\n<p>These memory engram cells suppress the activity of the original fear-responding\u00a0Rspo2+\u00a0engram cells present in the anterior BLA, hence fear extinction. However, the neurological nature of the teaching signal that instructs the formation of fear extinction memory in the\u00a0Ppp1r1b+\u00a0neurons is unknown.<\/p>\n<p>Here, we demonstrate that ventral tegmental area (VTA) dopaminergic signaling drives fear extinction in distinct BLA neuronal populations.<\/p>\n<p>We show that BLA fear and extinction neuronal populations receive topographically divergent inputs from VTA dopaminergic neurons via differentially expressed dopamine receptors.<\/p>\n<p>Fiber photometry recordings of dopaminergic activity in the BLA reveal that dopamine (DA) activity is time-locked to freezing cessation in BLA fear extinction neurons, but not BLA fear neurons.<\/p>\n<p>Furthermore, this dopaminergic activity in BLA fear extinction neurons correlates with extinction learning.<\/p>\n<p>Finally, using projection-specific optogenetic manipulation, we find that activation of the VTA DA projections to BLA reward and fear neurons accelerated or impaired fear extinction, respectively.<\/p>\n<p>Together, this work demonstrates that dopaminergic activity bidirectionally controls fear extinction by distinct patterns of activity at BLA fear and extinction neurons.<\/p>\n","protected":false},"excerpt":{"rendered":"Summary: A new study reveals that dopamine release along a specific brain circuit helps extinguish fear by activating&hellip;\n","protected":false},"author":2,"featured_media":58558,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[11],"tags":[215,17839,776,105,218,219,220,28600,223,16,15],"class_list":{"0":"post-58557","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-health","8":"tag-brain-research","9":"tag-dopamine","10":"tag-fear","11":"tag-health","12":"tag-mental-health","13":"tag-neurobiology","14":"tag-neuroscience","15":"tag-picower-institute-at-mit","16":"tag-ptsd","17":"tag-uk","18":"tag-united-kingdom"},"share_on_mastodon":{"url":"https:\/\/pubeurope.com\/@uk\/114417889782978236","error":""},"_links":{"self":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/posts\/58557","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/comments?post=58557"}],"version-history":[{"count":0,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/posts\/58557\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/media\/58558"}],"wp:attachment":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/media?parent=58557"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/categories?post=58557"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/tags?post=58557"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}