The way we conduct research at the center can lead to changes in the fields of neuroscience and neurobiology more quickly than usual. While holding ourselves to the highest, most rigorous academic, professional, and medical standards, we speed up our research by sharing ideas and data among our entire team. This brings a variety of disciplinary approaches to bear on each study.
We have quickly become a hub full of hard-working pioneers in neurobiological study and testing with more than 30 expert researchers. Our groundbreaking scholars, innovative physicians, and promising young researchers are investigating more than 80 distinct affective disorders and conditions, and treatments and therapies for affective disorders. Our end goal is to improve the quality of life for individuals with affective disorders.
Ongoing Translational Projects in the Center for Affective Neuroscience
Here are four examples of our research projects, which all show varying scopes of collaboration and integration among departments, specialties, research methods, or the specific disorders or symptoms being studied.
Repurposing FDA-Approved Medication as a Novel Antidepressant
Over the past ten years, Scott Russo, PhD, Ming-Hu Han, PhD, and Eric Nestler, MD, PhD, along with other investigators, have demonstrated a critical role for the brain reward circuit in influencing depression-like behavior in rodent stress models. (PMID: 23064380).
Recently, Dr. Han and colleagues have found that hyperactivity of ventral tegmental area dopamine neurons, driven by the hyperpolarization-activated cation channel current (Ih), played a causal role in depression-like behavior. This pathogenic hyperactivity can be normalized by activating the potassium channel KCNQ to counteract the increased (Ih) current in resilient mice, ultimately preventing depression-like behaviors (PMID: 24744379).
Certain medications, KCNQ-openers, can make a significant difference in alleviating depression. (PMID: 27216573).
These preclinical studies have led to a recent pilot study led by James Murrough, MD, to test antidepressant efficacy of ezogabine, a KCNQ-channel opener that is approved by the U.S. Food and Drug (FDA) for treatment of seizure disorder. Early results show that ezogabine significantly reduces severity of depression symptoms such as anhedonia, loss of interest, and reduced motivation in humans. These data suggest that we might be able to repurpose an existing drug to treat depression. Our collaborative approach has contributed greatly to this undertaking.
Testing Immune-Modulatory Drugs as Novel Antidepressants
Dr. Russo and our team have set out to test whether overactive, unresolved inflammation might ultimately lead to the development of mood disorders. To achieve this goal, Dr. Russo has partnered with a broad team of Mount Sinai specialists including James Murrough, MD, Miriam Merad, MD, PhD, and Zahi Fayad, PhD. By adopting a “reverse translational” approach, they first identified elevations of the inflammatory cytokine IL-6(interleukin-6) in humans with treatment-resistant depression. Our team showed that by neutralizing IL-6in the periphery and preventing it from entering brain reward centers, they could produce antidepressant-like effects in a mouse model of depression (PMID: 25331895).
As a result of this preclinical work, Janssen Pharmaceuticals has initiated a phase II clinical trial to test the safety and efficacy of IL-6 neutralization in treatment of unipolar depression, with a particular focus on individuals with elevated levels of this cytokine; part of the study is being performed at Mount Sinai.
Testing Novel Antidepressants for Patients with Comorbid Pain and Depression
Our team are investigating signal transduction and epigenetic mechanisms underlying responses to chronic stress. We use advanced genetic mouse models and biochemical and molecular approaches to understand the brain’s region-specific and network-specific mechanisms underlying the transition to depressive states. Our group has identified molecules that affect vulnerability to depression and the efficacy of antidepressant medications. We recently identified the intracellular molecule named RGS4 as a key modulator of synaptic plasticity in brain networks that mediate responses to acute and chronic stress. Current studies in the lab are looking at RGS4 complexes in the brain reward pathway to ameliorate maladaptive responses to chronic stress.
Repurposing of FDA-Approved Medication as a Novel Social Cognitive Enhancer
Social cognition, defined broadly as the ability to appropriately detect, interpret, and respond to social cues, is crucial for developing and maintaining social relationships. In many psychiatric disorders, such as spectrum, personality, or mood and anxiety disorders, or schizophrenia, social cognition is impaired, causing significant disability and difficulty with social functions.
Maria de las Mercedes Perez-Rodriguez, MD, PhD, and our team are investigating the brain mechanisms underlying abnormal social cognition, and testing the neuropeptide oxytocin as a new treatment. Oxytocin (pitocin) is a hormone approved by the FDA for the induction of labor, among other uses. Research data suggest that administering oxytocin through a nasal spray may cause changes in social cognition (PMID: 25153535).
Dr. Perez-Rodriguez’s team has shown that people with schizophrenia spectrum disorders experience impaired social cognition and poor social functioning (PMID: 23810511).
Dr. Perez-Rodriguez has teamed up with Prantik Kundu, PhD, and Scott Moeller, PhD, to develop new ways to assess real-life social cognition by combining, for the first time, a naturalistic social cognition experiment with functional brain imaging and eye-tracking technology.
Early results show that in patients with schizophrenia spectrum disorders, oxytocin increases their ability to notice social cues and understand them. These exciting data suggest that oxytocin could be repurposed to improve social cognition in psychiatric disorders.