Brain & Behavior Research Foundation announces recipients of NARSAD Investigator Grants

The Brain & Behavior Research Foundation (formerly known as NARSAD, the National Alliance for Research on Schizophrenia and Depression), under the direction of Dr. Jeffrey Borenstein, President & CEO, has announced the latest recipients of its NARSAD Distinguished Investigator Grants. The highly competitive grants provide support for experienced investigators (full professor or equivalent) conducting neurobiological and behavioral research. One-year grants of $100,000 each are provided for established scientists pursuing particularly innovative project ideas in diverse areas of brain and behavior research.

Annual selections were made by members of the Foundation's Scientific Council, a volunteer group of 147 leaders in brain and behavior research. This year's fifteen established investigators, selected from 200 applicants, include a number utilizing new technologies, such as advanced brain imaging, optogenetics and stem cell technology. Others will work toward identifying new targets for next generation therapies, through greater understanding of genetic risk factors and dysregulation in brain circuitry. Yet another novel project aims to collect data on firearms injury and mortality among adults with schizophrenia, bipolar disorder or depression in an effort to spur public policy reform with regard to gun violence among the mentally ill.

"One of the most important set of research awards in all of neuroscience is the NARSAD Distinguished Investigator Grant of the Brain & Behavior Research Foundation," commented Jack Barchas, M.D., of Weill Cornell Medical College, a Scientific Council member and Chair of the Distinguished Investigator Grant Selection Committee. "An exciting aspect of the awards is the degree to which they either attempt to answer an important question or help to identify new potentially game-changing targets for treatment. Even in the best of funding times they have been extremely important …Now they are absolutely essential for seed funding for new directions which would otherwise be impossible."
The 2013 grant recipients and their studies follow:

Deanna M. Barch, Ph.D., Washington University, will integrate state-of-the-art neuroimaging with behavioral approaches to identify the risk trajectory for major depressive disorder in a group of pre-pubertal children with mothers with depression. Maternal depression is a highly predictive risk factor for children. The processes associated with depression likely influence brain development long before clinical signs appear, suggesting early childhood as a unique opportunity for prevention efforts. Dr. Barch uses equipment that allows unprecedented high-resolution imaging of brain circuitry.

Vadim Bolshakov, Ph.D., Harvard University, will combine the technology "optogenetics" with electrophysiological recordings and behavioral testing to address questions about the brain circuits of fear conditioning and fear extinction. Focusing on auditory fear conditioning, the research will investigate whether extinction is associated with synaptic plasticity, the ability of synapses to strengthen or weaken in response to changing conditions. The hypothesis of this research is that fear extinction may involve decreased efficacy in the system regulating transmission of the neurotransmitter glutamate from a region of the medial prefrontal cortex to targets in the amygdala, a brain center critical for processing memory and emotions, including fear.

Fred H. Gage, Ph.D., Salk Institute for Biological Studies, will use stem-cell technology to probe the causes and underlying neuronal pathology of schizophrenia. Induced pluripotent stem cells engineered from non-stem cells obtained from schizophrenia patients and controls will be reprogrammed to become neurons. Applying this method, Dr. Gage and his team previously demonstrated deficits in neural connectivity and neurotransmission in schizophrenia, studies that also highlighted several genes and neuronal processes that may play a central role in the pathophysiology of schizophrenia.

Charles D. Gilbert, M.D., Ph.D., The Rockefeller University, will test a theory of brain-circuit interactions underlying re-entrant processing as a way of understanding behavioral disorders. Re-entry refers to how brain regions interact to interpret stimuli. Dr. Gilbert's theory involves disruption of normal brain interactions; in particular, schizophrenia and autism as disconnection syndromes, whereby re-entrant signals between cortical areas are not operating properly. Instead, internally generated sounds, thoughts or movements, are misidentified as coming from an external source rather than being communicated as self-generated within the brain.

Vivian Hook, Ph.D., University of California, San Diego, will model schizophrenia by means of human induced pluripotent stem cells (hiPSC) differentiated into neurons. Her preliminary data show that schizophrenia hiPSC neurons display changes in amounts of secreted catecholamine neurotransmitters compared to normal controls and also that the antipsychotic loxapine reverses some of these changes. The project will assess the hypothesis that changes in profiles of secreted neurotransmitters occur in schizophrenia compared to controls and will also evaluate the effects of antipsychotic drugs on secreted neurotransmitter profiles.

James L Kennedy, M.D., Centre for Addiction and Mental Health, University of Toronto, will study the proposition that variants in mitochondrial genes increase susceptibility for major psychoses, and that schizophrenia and bipolar disorder may be, at least in part, due to the inability of neuronal mitochondria to keep up with the brain's energy demands. (Mitochondria are the cellular organelles responsible for energy production.) If so, identification of mitochondrial risk factors should help shed light on the causes of psychosis and address the urgent need for new therapeutic targets.

Eric Klann, Ph.D., New York University, will test the hypothesis that exaggerated protein synthesis affecting a subpopulation of nerve cells called medium spiny neurons (MSNs) may lead to autism spectrum disorder (ASD) by causing synaptic dysfunction in the striatum region of the brain. Using mice models of ASD, the research will determine the subtype of MSNs that exhibit altered synaptic plasticity and identify their dysregulated proteins. The experiments should provide new insight into the molecular mechanisms whereby dysregulated protein synthesis in the striatum may result in the aberrant behavior of autism.

Joel E. Kleinman, M.D., Ph.D., Lieber Institute for Brain Development, will further his study of postmortem human brains, including fetal brains, in the search for the molecular biology of increased risk for schizophrenia. One hypothesis about the molecular biology mechanisms by which genetic variation increases risk for schizophrenia involves expression of specific alternative transcripts critical for early brain development. Most of these alternative transcripts are common variants found widely throughout the population, making it possible for initial studies to be conducted in normal postmortem human brains so as to then help pinpoint transcript changes that lead to schizophrenia.

Douglas F. Levinson, M.D., Stanford University, will conduct studies of synaptic function in induced pluripotent cell lines (iPSCs) created from cells taken from three schizophrenia patients with deletions in the neurexin-1 (NRXN1) gene and from matched controls. The aim is to characterize the phenotype, or specific traits, associated with NRXN1 deletions (loss of some of the genetic material) and schizophrenia. NRXN1deletions are the only known single-gene mutation with a large effect on schizophrenia risk. The research should produce a profile of synaptic dysfunction in NRXN1 deletion carriers with schizophrenia.

Stuart A. Lipton, M.D., Ph.D., Sanford Burnham Medical Research Center, will follow up evidence from his lab that some cases of autism spectrum disorder (ASD) may result from interaction of genetic and toxic environmental factors. Previously, the lab reported that a process that mediates nitric oxide called S-nitrosylation can regulate the activity of specific proteins that contribute to neurodegenerative conditions such as Parkinson's disease. The current goal is to determine whether many sporadic cases of ASD result in part from environmental factors that induce protein S-nitrosylation which mimics a relatively rare genetic mutation believed to cause ASD.

Andrew A. Nierenberg, M.D., Harvard University, will conduct a trial of a treatment for bipolar disorder based on a newer concept of bipolar pathophysiology. This concept proposes that bipolar disorder results from dysregulation of mitochondria, the structures in cells responsible for cellular energy production. Bezafibrate, a widely used anticholesterol medication, targets mitochondrial master switches called peroxisome proliferator-activated receptors (PPARs). The trial will assess the safety and tolerability of bezafibrate added to lithium for bipolar depression, especially with regard to worsening manic symptoms and suicidal ideation.

Steven G. Potkin, M.D., University of California, Irvine, aims to achieve a more integrated understanding of schizophrenia by combining already collected data from brain imaging, cognitive and clinical examination and DNA sequencing with gene expression data from 180 schizophrenia patients and 180 healthy controls. In addition, he and his colleagues will investigate the role of the miR-137 locus, or gene site, and its genetic variant, which is believed to be involved in schizophrenia, in order to determine miR-137's functional role in the disorder.

Jeffrey Wallace Swanson, Ph.D., Duke University, has as his goal to provide concrete information to spur public policy reform with regard to gun violence among the mentally ill. His team will collect data on firearms injury and mortality, including firearms-related suicide and violence, among 23,000 adults with schizophrenia, bipolar disorder or depression, who received services in Florida's healthcare system between 2002 and 2012. Gun-disqualifying mental health adjudications and criminal disqualification from firearms will also be examined, as well as patterns of psychiatric hospitalization and outpatient mental health services and their effectiveness.

Danny G. Winder, Ph.D., Vanderbilt University, seeks to determine how the medication ketamine produces its rapid, long-lasting antidepressant effect. NMDARs are receptors for the neurotransmitter glutamate. GluN2B is an NMDAR subunit. GluN2B-containing NMDARs in a brain region called BNST appear to be key sites for ketamine's antidepressant action. Studies also suggest an important role in depression for the stress-related chemical corticotropin-releasing factor (CRF) in the BNST region. Dr. Winder will use optogenetic brain mapping in mice models to test whether ketamine produces antidepressant actions by GluN2B-dependent suppression of BNST CRF signaling, which would suggest new therapeutic targets.

Jon-Kar Zubieta, M.D., Ph.D., University of Michigan, will examine the neurobiology of the placebo effect in the treatment of depression. Recent research into the effect in pain treatment has shown the endocannabinoid system to be among the brain systems involved, as reflected by the concentration of cannabinoid receptors (CBR1) in response to placebo. Hypothesizing that this response could cross diagnostic boundaries, Dr. Zubieta proposes to determine CBR1 involvement in antidepressant response in a trial of placebo with a sample of un-medicated patients with major depressive disorder.

 Sourece: Brain & Behavior Research Foundation