Fibroblast growth factor 9 is a novel modulator of negative affect (depression)

This study used rats and postmortem human hippocampal tissue to show that there are two proteins in inverse relationships to each other that are involved in major depressive disorder (MDD). They are both fibroblast growth factors (FGF) specifically FGF2 and FGF9. FGF2 is decreased (http://www.ncbi.nlm.nih.gov/pubmed/25079902) in postmortem tissue of depressed individuals and FGF9 in increased. Also in rats, the same thing is seen. In rats if FGF9 levels are increased experimentally, they start showing symptoms of depression, and localized blockade of FGF9 reduces depression and anxiety symptoms. Also, “chronic social defeat stress” (an animal model recapitulating some aspects of MDD) in rats increases FGF9 levels.

What are FGF2 and 9? They are growth factors, produced by the cells of the body and the brain. They are involved in the proliferation and differentiation of somatic cells and neurons. They are important and key factors in the growth, differentiation and development of the brain. (The regulation of FGFs expression as well as of their receptors during development presumably plays a critical role in cell-cell signaling among neurons, astrocytes and microglia in the immature human brain: http://www.med.unibs.it/~airc/pdf/fgf%20human%20brain.pdf)

Important in the growth and development and differentiation of the brain, changed in depression, changed when depression is induced, and in normal controls, levels are different than in people with MDD. All good reasons to think of them as good targets for treatment and as markers for MDD.

Original Article: http://www.pnas.org/content/early/2015/09/02/1510456112

Fibroblast growth factor 9 is a novel modulator of negative affect

Molecular mechanisms mediating negative emotion and contributing to major depression remain elusive: here, we present evidence implicating fibroblast growth factor 9 (FGF9) as a key mediator. We use whole-transcriptome studies of postmortem human tissue to demonstrate that FGF9 is elevated in depression. Reverse translation animal studies demonstrate that both endogenous and exogenous FGF9 promotes anxiety- and depression-like behavior. Conversely, localized blockade of endogenous FGF9 expression decreases anxiety behavior. To our knowledge, this paper is the first description of hippocampal FGF9 function and the first evidence implicating FGF9 in negative affect. Thus, FGF9 represents a novel target for treating affective disorders. Moreover, our findings suggest that FGF2 and FGF9 work in functional opposition; we hypothesize that the balance between FGF factors may prove critical for optimal regulation of mood.

Abstract

Both gene expression profiling in postmortem human brain and studies using animal models have implicated the fibroblast growth factor (FGF) family in affect regulation and suggest a potential role in the pathophysiology of major depressive disorder (MDD). FGF2, the most widely characterized family member, is down-regulated in the depressed brain and plays a protective role in rodent models of affective disorders. By contrast, using three microarray analyses followed by quantitative RT-PCR confirmation, we show that FGF9 expression is up-regulated in the hippocampus of individuals with MDD, and that FGF9 expression is inversely related to the expression of FGF2. Because little is known about FGF9’s function in emotion regulation, we used animal models to shed light on its potential role in affective function. We found that chronic social defeat stress, an animal model recapitulating some aspects of MDD, leads to a significant increase in hippocampal FGF9 expression, paralleling the elevations seen in postmortem human brain tissue. Chronic intracerebroventricular administration of FGF9 increased both anxiety- and depression-like behaviors. In contrast, knocking down FGF9 expression in the dentate gyrus of the hippocampus using a lentiviral vector produced a decrease in FGF9 expression and ameliorated anxiety-like behavior. Collectively, these results suggest that high levels of hippocampal FGF9 play an important role in the development or expression of mood and anxiety disorders. We propose that the relative levels of FGF9 in relation to other members of the FGF family may prove key to understanding vulnerability or resilience in affective disorders.

Disruption of Communication Between Two Regions of the Brain Contributes to Symptoms of Psychiatric Illnesses

Basically, when the synaptic transmission between the hippocampus and the prefrontal cortex is disrupted, symptoms of mental illnesses such as schizophrenia are seen. This has been known for a long time. What wasn’t known was how is this communication between the hippocampus and prefrontal cortex disrupted? That is, what are the mechanisms responsible for the disruption of communication between these two regions of the brain? Well, in this paper below, they show over activation of the D2-like Dopamine receptors leads to a decrease in another type of receptor called the NMDA receptor. This leads to a marked disruption of synaptic transmission between the two brain regions. This newly discovered relationship between the Dopamine and NMDA receptors may lead to treatment options for people with mental illnesses like schizophrenia.

“Synaptic transmission between the hippocampus and prefrontal cortex is required for many executive cognitive functions. It is believed that disruption of this communication contributes to symptoms observed in psychiatric disorders including schizophrenia. Hyperdopaminergic tone and hypofunction of NMDA receptor-mediated glutamate transmission are distinctive elements of schizophrenia. Here we demonstrate that activation of low-affinity D2-like dopamine receptors leads to a lasting depression of NMDA receptors at the hippocampal– prefrontal projection of juvenile rats, leading to a marked disruption of synaptic transmission. These data demonstrate a link between dopamine and hypofunction of NMDA receptormediated transmission with potential implications for psychiatric disease.”

http://www.pnas.org/content/early/2015/08/18/1512064112.full.pdf

“New research has identified the mechanisms that trigger disruption in the brain’s communication channels linked to symptoms in psychiatric disorders including schizophrenia. The University of Bristol study, published in the Proceedings of National Academy of Sciences, could have important implications for treating symptoms of brain disorders.

Many of our everyday cognitive functions such as learning and memory rely on normal communication between the two regions of the brain – the hippocampus and prefrontal cortex. While previous studies have identified disruption to communication channels in these two areas of the brain contribute to symptoms in psychiatric disorders, the mechanisms that lead to these disturbances have been largely unknown, until now.

In this study, led by Professor Zafar Bashir from Bristol’s School of Physiology and Pharmacology, the researchers studied the neurotransmitters glutamate and dopamine, which work together in controlling normal transmission between these brain regions by communicating chemical information throughout our brain and are disrupted in schizophrenics.

The team found that subtle changes in the interplay of these transmitters completely altered the flow of information from the hippocampus to prefrontal cortex. Over-activation of the D2 class of dopamine receptors led to suppression of the function of NMDA receptors, which are activated by the neurotransmitter glutamate, at the synaptic connection between hippocampus and prefrontal cortex. This in turn leads to a marked disruption of communication between these brain regions.

Dr Paul Banks, one of the researchers, said: “Our findings demonstrate a mechanism for how dopamine neurotransmission can influence NMDA receptor function at a connection in the brain needed for complex mental tasks which are disrupted in schizophrenic patients. It has been known for some time that dopamine and NMDA receptor function are altered in schizophrenic patients – our data mirror the direction of these changes and therefore might give insight into how these changes come about mechanistically.”

http://www.neuroscientistnews.com/research-news/study-identifies-cause-disruption-brain-linked-psychiatric-disorder

Mindfulness practice leads to increases in regional brain gray matter density

IMG_1661 IMG_3618

Thank you Kitt, (kittomalley.com) for posting this on your FB page! This is big, very big.

Of course it’s known that meditation has tremendous benefits for practitioners. Now, a study called “Mindfulness practice leads to increases in regional brain gray matter density” by Hölzel et al, shows how and why. In this Harvard study, they took participants who did Mindfulness meditation 27 minutes per day, for eight weeks and controls who did not meditate. They then took MRI’s of their brains and looked for differences. In the group that practiced mindfulness meditation, the areas in the hippocampus had a major increase in gray matter. The hippocampus is part of the Limbic system, the region in the brain that regulates emotions. They also saw a decrease in the gray matter of the amygdala, the area in the brain that is responsible for stress and anxiety. Therefore, “The results suggest that participation in MBSR is associated with changes in gray matter concentration in brain regions involved in learning and memory processes, emotion regulation, self-referential processing, and perspective taking.”

So it has now been shown how meditation works! It seems like the perfect thing to do if you have a mood disorder! Will you meditate? Well that’s up to you. For myself, yes. I am starting today.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3004979/