Social Behavior Disorders

Findings May Offer Insight Into Social Disorders Like Autism NEW YORK, Jan. 24, 2024 /PRNewswire/ -- Like humans, mice live in complex social groups, fight over territory and mates, and learn when it is safer to avoid certain opponents. After losing even a brief fight, the defeated animals will flee from the mice that hurt them for weeks afterward, a new study shows. Led by researchers at NYU Grossman School of Medicine, the study reveals that such "retreating behavior" is influenced by a distinct area on the underside of the hypothalamus, a part of the brain that controls hunger, sleep, and levels of many hormones. The team had previously found that this special region, called the anterior ventrolateral part of the ventromedial hypothalamus (aVMHvl), helps rodents defend themselves against bullies' attacks. Here, the authors further identified a central role of the area to drive longer-lasting avoidance after being defeated. The study showed that when rival mice first meet, scent information about opponents is not strong enough to activate aVMHvl cells to prompt a retreat. Once a fight begins, however, pain (such as from getting bitten) triggers the release of the "cuddle hormone" oxytocin. While this signal has long been linked with parenting and attraction, in this case it binds to oxytocin receptors on aVMHvl cells and signals danger. This process links pain signals to the opponent's scent so the next time the aggressor approaches, its smell alone encourages the bullied mouse to stay away, say the study authors. "Our findings provide new insight into how oxytocin within the hypothalamus drives learning from traumatic social experiences," said study lead author Takuya Osakada, PhD. "While the hormone is often associated with positive behaviors like caregiving, our study highlights its key role in social conflict," adds Osakada, a postdoctoral fellow in the Departments of Psychiatry and Neuroscience and Physiology at NYU Langone Health. The study team, while cautioning that mice share a lot of brain chemistry with people but are not the same, says previous research has shown similar "retreat" behavior following social defeat in many species including humans. In addition, past studies in children have linked the experience of being bullied to increased social isolation and school absences. Osakada notes that while previous research had examined rodent behavior over time after experiencing repeated defeats, the new study, publishing online Jan. 24 in the journal Nature, is the first to explore rapid social learning that occurs immediately after losing a fight. For the research, the study team observed hundreds of mice that were exposed to a rival for 10 minutes before being separated. They also measured the animals' brain activity before and after a conflict. The results showed that 24 hours after losing a single fight, social interaction dropped down to just 20% of pre-defeat levels. In addition, the findings revealed that pain prompted the immediate activation of oxytocin-releasing brain cells located right next to the aVMHvl. To further examine the role of the aVMHvl in social avoidance, the researchers prevented receptors on these cells from binding to oxytocin. They found that rodents with blocked oxytocin receptors were less likely to retreat from their aggressor in later encounters. Meanwhile, when the team instead artificially activated aVMHvl cells, animals kept to themselves even if they had not lost a fight. "Now that we have a better understanding of critical forces behind social avoidance, researchers can start exploring ways to harness oxytocin to treat disorders that affect social skills, such as autism, social anxiety, and attention-deficit hyperactivity disorder," said study senior author Dayu Lin, PhD. Lin is a professor in the Departments of Psychiatry and Neuroscience and Physiology at NYU Langone, as well as a member of its Neuroscience Institute. That said, Lin cautions that while the team connected the aVMHvl to social avoidance, they found no such link to another behavior exhibited by defeated mice — freezing up in the face of conflict. As a result, researchers say additional brain systems are likely involved in defeat behavior, and understanding such systems is essential before developing oxytocin-based therapies for human social disorders. The study team next plans to examine whether the newly uncovered aVMHvl mechanism may also be involved in behaviors that rodents use to establish their social hierarchy under more natural conditions, instead of during the contrived scenario from the initial experiment. Funding for the study was provided by National Institutes of Health grants U19NS107616, R01MH101377, R01MH124927, and R01HD092596. Further funding was provided by the Mathers Foundation, the Vulnerable Brain Project, the Uehara Memorial Foundation, the JSPS Overseas Research Fellowship, and the Osamu Hayaishi Memorial Scholarship. In addition to Osakada and Lin, other NYU Langone researchers involved in the study were Rongzhen Yan, PhD; Yiwen Jiang, MS; Dongyu Wei, PhD; Rina Tabuchi; Bing Dai, BS; Xiaohan Wang, PhD; Richard Tsien, PhD; and Adam Mar, PhD. Media Inquiries: Shira Polan Phone: 212-404-4279 [email protected] SOURCE NYU Grossman School of Medicine and NYU Langone Health

The FDA requested an additional study before it could reconsider Sage Therapeutics' application in major depressive disorder. Sage Therapeutics is preparing to reduce its head count and pipeline in response to the FDA’s rejection of a Biogen-partnered drug as a treatment for major depressive disorder (MDD). It wasn’t all bad news, with Sage’s management saying they were “delighted” that zuranolone, which will be marketed as Zurzuvae, had been approved by the regulator as “the first-and-only oral treatment specifically indicated for adults with postpartum depression [PPD].” Sage is due to receive a $75 million milestone payment from Biogen upon the first sale of zuranolone for PPD. But in the far more commercially lucrative indication of MDD, zuranolone wasn’t as lucky. In a complete response letter, the FDA told the two companies they hadn’t provided “substantial evidence of effectiveness to support the approval of zuranolone for the treatment of MDD and that an additional study or studies will be needed,” according to Sage. “Sage and Biogen are reviewing the feedback from the FDA and are evaluating next steps,” the biotech added in a second-quarter earnings report Monday.  The company’s stock plummeted 48% to $18.71 as the markets opened Monday from a Friday close of $36.10. The failure of the MDD application also sent Sage into defensive mode, warning layoffs and a pipeline refocus could be coming down the tracks. “While we believe we are well capitalized, given the impact of the CRL for zuranolone in MDD on our plans, we are currently evaluating resource allocation, including pipeline prioritization and a workforce reorganization with a goal of extending our cash runway,” Sage CEO Barry Greene said in the release. Sage’s lead neuropsychiatric drug candidate SAGE-718 has a slate of readouts scheduled from next year, which should offer some distraction from the MDD rejection. SAGE-718 is a NMDA receptor positive allosteric modulator in development for various cognitive disorders including Huntington’s, Parkinson’s and Alzheimer’s diseases. Then there’s SAGE-324, the biotech’s lead neurology program, which is in development for movement disorders like essential tremor, epilepsy and Parkinson’s. Enrollment in a phase 2 trial in essential tremor is set to complete this year. Coming up behind it is SAGE-689, a GABAA receptor positive allosteric modulator in phase 1 development for disorders associated with GABA hypofunction. Also in phase 1 is SAGE-319, another GABAA receptor positive allosteric modulator Sage intends to study for social interaction disorders. “With a right-sized organization and portfolio, we believe we have an opportunity to emerge as an even stronger company,” Greene added in the release. “We plan to provide greater detail and next steps before the end of the third quarter.” On the surface, Sage hardly seems short of funds. The biotech ended June with $1 billion in cash and equivalents, which is expected to last into 2025. But in a hint of what’s to come, the company added elsewhere in the earnings release that as a result of the upcoming workforce and pipeline changes, Sage assumes its “operating expenses will decrease in 2024.” On a second-quarter earnings call with analysts Monday morning, Greene stuck close to his script, deflecting questions about whether Sage would be conducting further trials of zuranolone in MDD and the company's continuing working relationship with Biogen. “We don't agree with the FDA's view. We are evaluating the CRL and as soon as we can provide more clarity we will on what the next steps are,” the CEO said on the call. “We really do believe that zuranolone should be available to treat patients with MDD. But we've got to get there and until we're there we'll be solely focused on marketing Zurzuvae to treat women with PDD.” Chief Financial Officer Kimi Iguchi added that “when it comes to looking at the pipeline [and] workforce reorganization … we expect our evaluation of our resource allocation will incorporate the feedback from the FDA.” Zuranolone was designed to be a 14-day, fast-acting treatment—which stands in contrast to commonly approved depression therapies that can take weeks to kick in. But while investors have seen huge potential in the drug for both indications, they were “spooked … by the dearth of focus on the potential zuranolone approval in MDD/PPD in Biogen's earnings call,” Mizhuo analysts noted last month. Adding to the uneasiness has been Biogen’s own cost reductions, which included shaving off $700 million in operating expenses and another 1,000 employees cut from the roster. With all that going on, analysts had wondered at the time whether Biogen would still be committed to a big commercial launch for zuranolone. Reflecting on zuranolone’s MDD rejection by the FDA, Mizuho analysts pointed out that the depressive disorder was the “meaningfully larger opportunity” of the two indications Sage had requested, with potentially around an estimated $1.3 billion in 2030 sales for MDD compared to closer to $200 million for PPD. After zuranolone failed in the phase 3 MOUNTAIN trial in 2019, Sage increased the dose to 50 mg to ensure it passed the WATERFALL study. “Based on the MOUNTAIN/WATERFALL trials, it looks like increasing dose moderately doesn't appear to improve the treatment effect meaningfully and going significantly higher could lead to an undesirably higher sedation rate,” Mizuho analysts pointed out in a note Sunday. “As such, it's not clear what Biogen/Sage could do if they choose to run additional clinical trials,” the analysts concluded.