NTS

Past social trauma is encoded by a population of stress/threat-responsive brain cells that become hyperactivated during subsequent interaction with non-threatening social targets. As a consequence, previously rewarding social targets are now perceived as social threats, which promotes generalized social avoidance and impaired social reward processing that can contribute to psychiatric disorders. Past social trauma is encoded by a population of stress/threat-responsive brain cells that become hyperactivated during subsequent interaction with non-threatening social targets. As a consequence, previously rewarding social targets are now perceived as social threats, which promotes generalized social avoidance and impaired social reward processing that can contribute to psychiatric disorders, according to a study conducted by researchers at the Brain and Body Research Center at Mount Sinai and published November 30 in Nature. In humans, studies have shown that social trauma impairs brain reward function to the extent that social interaction is no longer rewarding, leading to severe social avoidance. In rodents, chronic social defeat stress, a model of social trauma, has been used to understand the brain circuit mechanisms underlying stress susceptibility versus resilience, yet little is known regarding its impact on social reward. Previous studies have assessed social interaction with an adult mouse similar to those used as aggressors to induce the social trauma. Social avoidance under these circumstances likely reflects fear or submissive behavior, rather than altered social reward. "To better understand how traumatic social experience affects social reward, we tested social interaction and social preference with a same-sex juvenile mouse that, under control conditions, is rewarding," said Long Li, PhD, Instructor of Neuroscience at the Icahn School of Medicine at Mount Sinai and lead author of the study. "We found that, following chronic social defeat stress, a subset of male and female mice termed susceptible avoid social interactions with juvenile mice and do not develop context-dependent social reward following encounters with them." In the study, adult male and female mice underwent chronic social defeat stress, in which they were repeatedly subordinated by aggressive mice, followed by social interaction testing, where an experimental mouse is placed in a cage with a larger aggressive mouse behind a barrier and the amount of time spent interacting is measured. The mice were classified as resilient or susceptible to the stressor based on their social interaction behavior. This was followed by an additional social interaction test called resident-intruder test in which a 4-6-week-old (juvenile) same-sex mouse was introduced into the subjects' homecage and allowed to freely interact. This was then followed by a social conditioned place preference test in which the subject mice were conditioned with the juvenile mice to assess their preference for rewarding social targets. During the resident-intruder test, control and resilient mice exhibited similar social behaviors towards the juvenile, including the amount of active interaction (approach, close following, and sniffing). Mice in these groups rarely withdrew from social contact with the juvenile and freely approached and investigated them. Conversely, stress-susceptible mice exhibited much less active social investigation, a longer delay before the first social bout ("latency"), and significantly more social avoidance. Furthermore, social investigation time, social avoidance, and latency to investigate correlated with social interaction ratios during testing with an aggressive adult mouse. These results show that susceptible mice not only exhibit avoidance towards aggressive adult male mice, but also to non-threatening same-sex juvenile mice. To identify the potential brain regions involved in heightened social threat, advanced histological and imaging techniques were used to identify a population of stress/threat responsive lateral septum neurotensin (NTLS) neurons that are activated by juvenile social interactions only in susceptible mice, but not in resilient or unstressed control mice. Lastly the team used optogenetic and chemogenetic strategies to either activate or inhibit NTLS neurons and their downstream connections. "What was so surprising is that when NTLS neurons were activated in a social threat context, they inhibited centers in the brain that encode information about social rewards," said Scott Russo, PhD, Professor of Neuroscience and Director of the Center for Affective Neuroscience and Brain Body Research Center. "So ultimately we believe that when mice experience social trauma their ability to experience social reward is occluded by these NTLS cells." These findings provide an important foundation for understanding the neural mechanisms underlying post-trauma social reward processing. The Mount Sinai team is planning studies in humans to test the relevance of lateral septum circuitry in mediating social threat perception and reward sensitivity in victims of trauma.

Researchers have discovered the molecule in the brain responsible for associating good or bad feelings with a memory. Their discovery paves the way for a better understanding of why some people are more likely to retain negative emotions than positive ones -- as can occur with anxiety, depression or post-traumatic stress disorder (PTSD). Researchers at the Salk Institute and colleagues have discovered the molecule in the brain responsible for associating good or bad feelings with a memory. Their discovery, published in Nature on July 20, 2022, paves the way for a better understanding of why some people are more likely to retain negative emotions than positive ones -- as can occur with anxiety, depression or post-traumatic stress disorder (PTSD). "We've basically gotten a handle on the fundamental biological process of how you can remember if something is good or bad," says senior author Kay Tye, a professor in Salk's Systems Neurobiology Laboratory and a Howard Hughes Medical Institute Investigator. "This is something that's core to our experience of life, and the notion that it can boil down to a single molecule is incredibly exciting." For a human or animal to learn whether to avoid, or seek out, a particular experience again in the future, their brain must associate a positive or negative feeling, or "valence" with that stimulus. The brain's ability to link these feelings with a memory is called "valence assignment." In 2016, Tye discovered that a group of neurons in the brain's basolateral amygdala (BLA) helps assign valence when mice are learning. One set of BLA neurons was activated with positive valence, as the animals learned to associate a tone with a sweet taste. A separate set of BLA neurons was activated with negative valence, as the animals learned to associate a different tone with a bitter taste. "We found these two pathways -- analogous to railroad tracks -- that were leading to positive and negative valence, but we still didn't know what signal was acting as the switch operator to direct which track should be used at any given time," says Tye, holder of the Wylie Vale Chair. In the new study, the researchers homed in on the importance of the signaling molecule neurotensin to these BLA neurons. They already knew that neurotensin is a neuropeptide produced by the cells associated with valence processing, but so are a few other neurotransmitters. So, they used CRISPR gene editing approaches to selectively remove the gene for neurotensin from the cells -- the first time that CRISPR has been used to isolate specific neurotransmitter function. Without neurotensin signaling in the BLA, mice could no longer assign positive valence and didn't learn to associate the first tone with a positive stimulus. Interestingly, the absence of neurotensin did not block negative valence. The animals instead became even better at negative valence, having a stronger association between the second tone and a negative stimulus. The findings suggest that the brain's default state is to have a bias toward fear -- the neurons associated with negative valence are activated until neurotensin is released, switching on the neurons associated with positive valence. From an evolutionary perspective, Tye says, this makes sense because it helps people avoid potentially dangerous situations -- and it probably resonates with people who tend to find the worst in a situation. In further experiments, Tye and her team showed that high levels of neurotensin promoted reward learning and dampened negative valence, further supporting the idea that neurotensin is responsible for positive valence. "We can actually manipulate this switch to turn on positive or negative learning," says co-first author Hao Li, a postdoctoral fellow in the Tye Lab. "Ultimately, we'd like to try to identify novel therapeutic targets for this pathway." The researchers still have questions about whether levels of neurotensin can be modulated in people's brains to treat anxiety or PTSD. They are also planning future studies to probe what other brain pathways and molecules are responsible for triggering the release of neurotensin. Other authors of the paper were Matilde Borio, Mackenzie Lemieux, Austin Coley, Avraham Libster, Aneesh Bal, Caroline Jia, Jasmin Revanna, Kanha Batra, Kyle Fischer, Laurel Keyes, Nancy Padilla-Coreano and Romy Wichmann of Salk; Praneeth Namburi, Jacob Olson, Anna Beyeler, Gwendolyn Calhoon, Natsuko Hitora-Imamura, Ada Felix-Ortiz, Verónica de la Fuente, Vanessa Barth, Hunter King, Ehsan Izadmehr, Cody Siciliano and Ila Fiete of MIT; Xin Jin, Sourav Choudhury, Xi Shi and Feng Zhang of the Broad Institute of MIT and Harvard; Huan Wang and Yulong Li of Peking University; and Kenneth McCullough and Kerry Ressler of Harvard Medical School. The work was supported by the JPB Foundation, PIIF, PNDRF, JFDP, Alfred P. Sloan Foundation, New York Stem Cell Foundation, Klingenstein Foundation, McKnight Foundation, Clayton Foundation, National Institutes of Health (R01-MH102441, RF1-AG047661, DP2-DK102256, DP1-AT009925, F32 MH115446-01 and K99 DA055111), the Brain and Behavior Research Foundation, MEXT (15K21744, 17H06043), the Uehara Memorial Foundation, Singleton, Leventhal and Whitaker fellowships, a fellowship from the Swiss National Science Foundation and a Fulbright scholarship.

Dublin, June 23, 2021 (GLOBE NEWSWIRE) -- The "Global Pain Therapeutics Market - Comprehensive Overview of Marketed and Pipeline Products, Opportunities, Challenges, Market Size and Key Players" report has been added to ResearchAndMarkets.com's offering. Pain is a multifaceted disorder that can be classified in a multitude of ways. Pain can be classified based on physiology, intensity, temporal characteristics, type of tissue affected, and syndrome.Innovation in the pain market over the last decade has been limited to new drug delivery systems, new extended-release formulations, and the repositioning of anticonvulsant and antidepressant therapeutics for difficult-to-treat pain conditions.Despite the improvements in symptom relief offered by new treatments and delivery systems, the pain market still has significant unmet needs. Opioids remain the most effective modes of treatment. However, because of their abuse potential, they are typically administered for chronic pain conditions.For the scope of this report, the publisher will use the time course classification, with the main focus on chronic pain.This report assesses: The report combines information obtained from secondary sources and primary research with specialists and physicians.The publisher's Global Pain Therapeutics Market Overview report combines primary research from a cross-specialty panel of experts with in-house analyst expertise to provide an assessment of the development landscape.Key Highlights ScopeComponents of the slide deck include primary and secondary research - Reasons to Buy Key Topics Covered: 1. Preface2. Executive Summary2.1. Key Findings3. Pain Overview4. Trends5. Clinical Trials5.1. Pain Therapeutics in Clinical Trials5.2. Pain Therapeutics Clinical Trials by Region5.3. Pain Therapeutics Clinical Trials by Leading Sponsors5.4. Pain Therapeutics in Clinical Trials - Challenges5.5. Pain Therapeutics in Clinical Trials - Opportunities6. Marketed Products6.1. Marketed Global Pain Products6.2. NSAIDs and COX-2 inhibitors6.3. Opioids6.4. Antidepressants and Anticonvulsants7. Pipeline Products7.1. Global Pain Therapeutics Pipeline Products7.2. Beta Nerve Growth Factor Target7.3. Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Type I Receptor Target7.4. Neurotensin Receptor 1 Target8. Market Analysis8.1. Mixed Pain Market Analysis and Forecast8.2. Neuropathic Pain Market Analysis and Forecast8.3. Nociceptive Pain Market Analysis and Forecast8.4. Top 10 Deals in the Pain Therapeutics Space8.5. H1 2021 Deals in the Pain Therapeutics Space8.6. H2 2020- H1 2021 Mergers and Acquisitions in the Pain Therapeutics Space9. Opportunities, Challenges, and Unmet Needs9.1. Global Pain Therapeutics - Opportunities9.2. Global Pain Therapeutics - Challenges9.3. Global Pain Therapeutics Unmet Needs - Gap Analysis10. Key Players10.1. Pfizer10.2. Eli Lilly10.3. Allergan10.4. Teva10.5. Viatris10.6. Novartis11. Appendix11.1. Bibliography11.2. Primary Research11.3. About the Authors11.4. About the Publisher11.5. Contact the Publisher11.6. DisclaimerFor more information about this report visit