To understand what happens in the brain to cause mental illness
Larry H Bernstein, MD, FCAP, Curator
Leaders in Pharmaceutical Intelligence
Series E. 2; 5.10
https://bbrfoundation.org/research/basic-research
Fernando Sampaio Goes, M.D., a 2008 NARSAD Young Investigator at Johns Hopkins School of Medicine, and his colleagues took an alternative approach to the ongoing genome-wide association studies (GWAS) that hunt for these factors by scouring the complete genomes of tens of thousands of individuals. The team––which included 2005 Young InvestigatorDimitrios Avramopoulos, M.D., Ph.D.; 2000 Young Investigator, 2008 Independent Investigator, and BBRF Scientific Council member James B. Potash, M.D., M.P.H.; and 2004 Young Investigator Peter P. Zandi, Ph.D.––conceived the study to detect rare genetic variations that GWAS are not designed to find.
Rather than scanning entire genomes for depression-associated variations, Goes’s team narrowed its search to a set of genes in which they already suspected alterations might contribute to depression: those that encode proteins found at or near the junctions between neurons, where cell-to-cell communication takes place. Based on previous surveys of these synaptic proteins, the scientists chose 1,742 genes to include in their analysis.
They compared the protein-coding sequences of that set of genes in 259 people with major depression to the same set in 334 unaffected individuals. To increase the chance of finding relevant genetic factors, all the patients with depression were selected based on the criterion of early-onset, recurrent depression, which is suspected by some to be a more heritable form of the illness. (An important component of depression causation is environmental, and reflects the particular life circumstances of those affected, who may or may not be naturally resilient when faced with stress and other environmental factors.)
The team’s analysis pointed to two sets of genes in which variations were linked with major depression. One includes genes that control the growth of dendritic spines (tiny knob-like protrusions from a neuron’s surface that receive inputs from other neurons). Other research has suggested that the size, density, and shape of these structures may be involved in mood disorders and other mental illnesses. The second gene set includes genes linked with the entry of calcium into neurons, which regulates a variety of processes, including the release of message-propagating neurotransmitters. Variations within this gene set have also been linked to autism and epilepsy.
Researchers have identified unique characteristics of emotional processing in young people with post-traumatic stress disorder (PTSD), showing for the first time how that processing might be disrupted at different ages.
Publishing their findings online August 5th in Neuropsychopharmacology, were 2012 NARSAD Young Investigator grantee Ryan J. Herringa, M.D., Ph.D., of the University of Wisconsin School of Medicine and Public Health and Richard C. Wolf, a Ph.D. candidate at the university. Together they looked at brain activity during an emotion-related task in children aged 8 to 18, both with and without PTSD. The children with PTSD had experienced trauma such as sexual abuse, the death of a loved one, a physical accident, or witnessing violence.
The children viewed emotionally “threatening” and “neutral” pictures. During this task, the researchers used imaging to measure activity in brain regions associated in PTSD with an increased fear response and sense of threat. These regions include the amygdala, important for processing emotions; the dorsal anterior cingulate cortex (dACC), which helps to gauge threat levels; and the medial portion of the prefrontal cortex (PFC), crucial for dialing back fear responses and putting perceived threats in context.
The researchers found higher threat-related dACC activity in youths with PTSD, as well as weaker connections between the amygdala and mPFC. The findings suggest these brain regions contribute to the difficulty young people with PTSD have in assessing perceptions of threat. The study also found that amygdala-PFC connections followed a different developmental path for youths with PTSD. Whereas those connections were stronger at older ages in those without PTSD, the same connections grew weaker for children with PTSD as they aged. This may reflect a progressive weakening in the ability of the PFC to reduce fear.
In research reported June 17th in the journal Neuron, scientists have shown that a protein called CPEB3 is critical for the stabilization and storage of long-term memories in mice. Three-timeNARSAD Distinguished Investigator and BBRF Scientific Council member Eric Kandel, M.D., led the research. Also on the team is 2013 NARSAD Young Investigator Pierre Trifilieff, Ph.D.
CPEB3 is a “prion-like” protein. Prions––infectious, misshapen proteins best known for the devastation they cause––clump together and lead to brain damage in people and animals with mad cow disease and related conditions. Similar protein-clumping mechanisms may also contribute to neurodegenerative diseases including Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis. (Curiously, certain proteins with prion-like properties have an important role in the healthy brain.)
The new finding extends previous work showing that prion-like proteins are vital for the stabilization of long-term term memory in sea slugs and fruit flies. Although further work is needed to understand whether the same mechanism is at work in humans, humans do produce a protein similar to the mouse protein CPEB3.
Memories are stored in the connections between neurons, and proteins play a role in the long-term storage of the information. But since proteins degrade over time, scientists had wondered how a memory can persist long after a new experience triggers neurons to make memory-specific proteins. Prion-like proteins, which are self-perpetuating because they can convert normal proteins to their own misshapen form, appear to be the answer.
Genetic studies have recently yielded large numbers of “hits” for genes that subtly increase or decrease risk for disorders, including for schizophrenia. However, there have been no hits for major depression, perhaps because the studies are not yet large enough or because depression is less heritable. Estimates put the heritability of major depression at around 50%, with the remaining contribution coming from environmental and experiential causes.
However, a new approach has paid off: a study published online July 15th at the journal Natureidentifies two genomic regions that harbor genes that increase risk of major depression. A multinational collaboration employed a strategy of narrowing the pool of subjects to women in China with the most severe and stubborn form of depression, with the hope that a more homogenous population would yield results.
In an accompanying News and Views, 2014 Lieber Prizewinner for Outstanding Achievement in Schizophrenia Research,Patrick Sullivan, M.D., of the University of North Carolina, writes, “This first identification of replicable, significant genome-wide associations for MDD is exceptional.”
Qi Xu, Ph.D., of Peking Union Medical College and Jun Wang, Ph.D., of BGI-Shenzhen, who led the China components of the study, along with Foundation Scientific Council Member Kenneth Kendler, M.D., of Virginia Commonwealth University and 2007 NARSAD Distinguished Investigator Grantee Jonathan Flint, M.D., of the University of Oxford in the United Kingdom focused exclusively on women with severe, recurrent depression (an average of more than five episodes), building a sample of 5,303 cases and 5,337 controls. The results were replicated in a separate group of 3,231 Chinese women with major depression and 3,186 mixed male/female controls.
“I think this paper is groundbreaking because it really demonstrates that we can make progress in reducing genetic heterogeneity by paying attention to key clinical indicators,” said three-time NARSAD Grantee, Francis McMahon, M.D., of the National Institute of Mental Health (NIMH), who was not an author on the paper.
A team based at the University of Edinburgh analyzed data from thousands of Scottish adults to see whether they had genetic mutations either linked with obesity or major depressive disorder. They tested for relationships between those genetic profiles, the presence of depression or other psychological distress, and body mass index, a measure used to determine obesity. A genetic predisposition for obesity more strongly predicted actual obesity among those adults who were also depressed.
The findings were reported June 30th in Translational Psychiatry by a team including 2008NARSAD Distinguished Investigator Grantee David J. Porteous, Ph.D., and 2010 Independent Investigator Andrew M. McIntosh, Ph.D.
The study results show people becoming obese in part because of their depression, rather than becoming depressed because they are already obese. The experience of depression may drive disordered eating habits. It may also trigger chemical responses in the body (such as the release of the stress hormone cortisol) that promote weight gain, the researchers hypothesize.
The team also found some degree of association between a genetic profile linked to obesity and current psychological distress, even among individuals who were not obese. Obesity-linked genes also more closely predicted actual obesity among people experiencing distress even if they were not diagnosed with depression. This indicates that psychological strain, and not just depression per se, contributes to obesity.
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