Research JBRF Finds Interesting

Published research articles and pilot studies by other research investigators that JBRF finds interesting.

How ketamine works to treat depression

How ketamine works to treat depression

Shots – Health Blog: NPR
– Andrew Prince


Traditional antidepressants like Prozac work on a group of chemical messengers in the brain called the serotonin system. Researchers once thought that a lack of serotonin was the cause of depression, and that these drugs worked simply by boosting serotonin levels.

Recent research suggests a more complicated explanation. Serotonin drugs work by stimulating the birth of new neurons, which eventually form new connections in the brain. But creating new neurons takes time — a few weeks, at least — which is thought to explain the delay in responding to antidepressant medications.

Ketamine, in contrast, activates a different chemical system in the brain — the glutamate system. Researcher Ron Duman at Yale thinks ketamine rapidly increases the communication among existing neurons by creating new connections. This is a quicker process than waiting for new neurons to form and accomplishes the same goal of enhancing brain circuit activity.

To study how ketamine might work, Duman turned to rats. The first image below shows the neuron of a rat that has received no ketamine treatment. The small bumps and spots on the side of the neuron are budding connections between neurons.

A rat neuron prior to ketamine treatment. Ronald Duman/Yale University

Just hours after giving the rats doses of ketamine, Duman saw a dramatic increase in the number of new connections between brain cells. This increase in neuronal connectivity is thought to relieve depression.


A rat neuron after ketamine treatment. Ronald Duman/Yale University

via I Wanted To Live: New Depression Drugs Offer Hope For Toughest Cases : Shots – Health Blog : NPR.

Patients getting experimental doses of ketamine report astoundingly fast relief from symptoms

Click here to read the NPR article.

Lithium Impacts on the Amplitude and Period of the Molecular Circadian Clockwork

Lithium Impacts on the Amplitude and Period of the Molecular Circadian Clockwork

The findings of the study presented below are in line with the data recorded in the study conducted by JBRF researchers: Sleep, Activity Patterns and Temperature Study. JBRF will continue to explore the role of thermoregulation in the biological basis of the Fear-of-Harm type of juvenile bipolar disorder.

Lithium salt has been widely used in treatment of Bipolar Disorder, a mental disturbance associated with circadian rhythm disruptions. Lithium mildly but consistently lengthens circadian period of behavioural rhythms in multiple organisms. To systematically address the impacts of lithium on circadian pacemaking and the underlying mechanisms, we measured locomotor activity in mice in vivo following chronic lithium treatment, and also tracked clock protein dynamics (PER2::Luciferase) in vitro in lithium-treated tissue slices/cells. Lithium lengthens period of both the locomotor activity rhythms, as well as the molecular oscillations in the suprachiasmatic nucleus, lung tissues and fibroblast cells. In addition, we also identified significantly elevated PER2::LUC expression and oscillation amplitude in both central and peripheral pacemakers. Elevation of PER2::LUC by lithium was not associated with changes in protein stabilities of PER2, but instead with increased transcription of Per2 gene. Although lithium and GSK3 inhibition showed opposing effects on clock period, they acted in a similar fashion to up-regulate PER2 expression and oscillation amplitude. Collectively, our data have identified a novel amplitude-enhancing effect of lithium on the PER2 protein rhythms in the central and peripheral circadian clockwork, which may involve a GSK3-mediated signalling pathway. These findings may advance our understanding of the therapeutic actions of lithium in Bipolar Disorder or other psychiatric diseases that involve circadian rhythm disruptions.

Lithium lengthens period for behavioral rhythms and alters molecular oscillations in the suprachiasmatic nucleus

Click here to read the peer-reviewed research article in its entirety.

Jian Li1, Wei-Qun Lu2, Stephen Beesley1, Andrew S. I. Loudon1*, Qing-Jun Meng1*
1 Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom,   2Faculty of Fisheries and Life Sciences, Shanghai Ocean University, Shanghai, China


What is the suprachiasmatic nucleus?

In mammals, the controlling clock component that generates a 24-hour rhythm is the suprachiasmatic nucleus (SCN), located in a part of the brain called the hypothalamus. The SCN produces a signal that can keep the rest of the body on an approximately 24-hour schedule.  Click here to watch an animated illustration of the human SCN created by the Howard Hughes Medical Institute1.

1Human SCN Anatomy Credits – Director: Dennis Liu, Ph.D. ~ Scientific Direction: Joseph Takahashi, Ph.D. ~ Scientific Content: Donna Messersmith, Ph.D. ~ Animator: Eric Keller




Mental illness suspect genes are among the most environmentally responsive

NIMH: Press Release • February 02, 2012

Gene Regulator in Brain’s Executive Hub Tracked Across Lifespan – NIH study

For the first time, scientists have tracked the activity, across the lifespan, of an environmentally responsive regulatory mechanism that turns genes on and off in the brain’s executive hub. Among key findings of the study by National Institutes of Health scientists: genes implicated in schizophrenia and autism turn out to be members of a select club of genes in which regulatory activity peaks during an environmentally-sensitive critical period in development. The mechanism, called DNA methylation, abruptly switches from off to on within the human brain’s prefrontal cortex during this pivotal transition from fetal to postnatal life. As methylation increases, gene expression slows down after birth.

Epigenetic mechanisms like methylation leave chemical instructions that tell genes what proteins to make – what kind of tissue to produce or what functions to activate. Although not part of our DNA, these instructions are inherited from our parents. But they are also influenced by environmental factors, allowing for change throughout the lifespan.

“Developmental brain disorders may be traceable to altered methylation of genes early in life,” explained Barbara Lipska, Ph.D., a scientist in the NIH’s National Institute of Mental Health (NIMH) and lead author of the study. “For example, genes that code for the enzymes that carry out methylation have been implicated in schizophrenia. In the prenatal brain, these genes help to shape developing circuitry for learning, memory and other executive functions which become disturbed in the disorders. Our study reveals that methylation in a family of these genes changes dramatically during the transition from fetal to postnatal life – and that this process is influenced by methylation itself, as well as genetic variability. Regulation of these genes may be particularly sensitive to environmental influences during this critical early life period.”

Lipska and colleagues report on the ebb and flow of the human prefrontal cortex’s (PFC) epigenome across the lifespan, February 2, 2012, online in the American Journal of Human Genetics.

“This new study reminds us that genetic sequence is only part of the story of development. Epigenetics links nurture and nature, showing us when and where the environment can influence how the genetic sequence is read,” said NIMH director Thomas R. Insel, M.D.

In a companion study published last October, the NIMH researchers traced expression of gene products in the PFC across the lifespan. The current study instead examined methylation at 27,000 sites within PFC genes that regulate such expression. Both studies examined post-mortem brains of non-psychiatrically impaired individuals ranging in age from two weeks after conception to 80 years old.

In most cases, when chemicals called methyl groups attach to regulatory regions of genes, they silence them. Usually, the more methylation, the less gene expression. Lipska’s team found that the overall level of PFC methylation is low prenatally when gene expression is highest and then switches direction at birth, increasing as gene expression plummets in early childhood. It then levels off as we grow older. But methylation in some genes shows an opposite trajectory. The study found that methylation is strongly influenced by gender, age and genetic variation.

For example, methylation levels differed between males and females in 85 percent of X chromosome sites examined, which may help to explain sex differences in disorders like autism and schizophrenia.

Different genes – and subsets of genes – methylate at different ages. Some of the suspect genes found to peak in methylation around birth code for enzymes, called methytransferases, that are over-expressed in people with schizophrenia and bipolar disorder. This process is influenced, in turn, by methylation in other genes, as well as by genetic variation. So genes associated with risk for such psychiatric disorders may influence gene expression through methylation in addition to inherited DNA.

Scientists worldwide can now mine a newly created online database of PFC lifespan DNA methylation from the study. The data are accessible to qualified researchers at: BrainCloud, a web browser application developed by NIMH to interrogate the study data, can be downloaded at

lifespan PFC methylation trajectoriesTwo representative genes show strikingly opposite trajectories of PFC methylation across the lifespan. Each dot represents a different brain. Usually, the more methylation, the less gene expression.
Source: Barbara Lipska, Ph.D., NIMH Clinical Brain Disorders Branch
lifespan methylation by genderA representative gene showing how sex can influence levels of methylation across the lifespan. Each dot represents a different brain.
Source: Barbara Lipska, Ph.D., NIMH Clinical Brain Disorders Branch


DNA methylation signatures in development and aging of the human prefrontal cortex. Numata S, Ye T, Hyde TM, Guitart-Navarro X, Tao R, Wininger M, Colantuoni C, Weinberger DR, Kleinman JE, Lipska BK. Am J Hum Genet. 2012 Feb 10;90(2):260-72. Epub 2012 Feb 2. PMID: 22305529.


The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure.

Antidepressant-induced mania studies

Antidepressant-induced mania studies

The relationship between use of antidepressants and resource utilization among patients with manic or mixed bipolar disorder episodes: Findings from a managed care setting

Self-Reported History of Manic/Hypomanic Switch Associated with Antidepressant Use: Data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)

A Pilot Study of Antidepressant-Induced Mania in Pediatric Bipolar Disorder: Characteristics, Risk Factors, and the Serotonin Transporter Gene

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