Growth Factor Improves Cognition

PLoS One, May 16, 2009

Researchers in Germany and Sweden have demonstrated that G-CSF improves intelligence - at least in laboratory rats.

Also known as colony-stimulating factor 3 (CSF3), the popular G-CSF (granulocyte-colony stimulating factor) has long been understood to play an important role in a variety of immunological and hematological functions, and to some extent in CNS (central nervous system) functions. Now, however, a new study sheds further light on the important role of G-CSF in maintaining healthy neurological function.

Led by Dr. Kai Diederich of the Department of Neurology at the University of Munster in Germany, and Dr. Nina Hellstrom of the Institute for Clinical Neuroscience in Gothenburg, Sweden, scientists have found that G-CSF improves intellectual function in laboratory rats, when also combined with a challenging environment. More specifically, the researchers were able to demonstrate that G-CSF enhances learning and memory, but only when the G-CSF is combined with cognitive training.

The scientists administered G-CSF to rats who were "engaged in spatial learning in an 8-arm radial maze." The G-CSF was administered to the rats both before and during spatial learning, which was followed by the assessment of memory formation and hippocampal neurogenesis. Using a radial 8-arm maze with food positioned at the distal end of 4 baited arms, while the other 4 arms remained unbaited, the scientists reported that, "Our data show that treatment with the hematopoietic factor G-CSF combined with cognitive training improves long-term spatial memory and promotes the survival of newborn hippocampal neurons." In particular, the scientists were able to demonstrate that G-CSF performs a number of neurological functions which include, among other tasks, facilitating the survival of neuronal precursor cells, recruiting new neurons into the dentate gyrus, and solidifying spatial long-term memory formation when combined with environmental hippocampal stimulation.

In fact, the scientists reported that G-CSF "significantly" improves spatial learning, when combined with the other very important half of the equation, which is, namely, "cognitive training". An enriched and challenging environment, in other words, in which the brain is continuously stimulated to learn, is equally as important as is the G-CSF, on which the authors comment that, "The mechanism whereby learning increases cell survival has not been fully identified yet. A 'use it or lose it' principle is thought to underlie the survival of hippocampal neurons." The authors further add that, "Spatial learning is initially dependent on the hippocampus, which appears to prepare contents for long-term storage in the neocortex. Newborn neurons in the hippocampus could contribute to learning and memory formation. Furthermore, neuronal turnover may provide plasticity for information storage that more differentiated neurons cannot. Consistent with this idea, the survival of young adult-born neurons can be increased by learning and enriched environments."

This study illuminates the many complex properties of G-CSF as one of several peripheral circulating peptides that influence and determine CNS structural morphology and function. As the scientists explain, G-CSF not only has specific receptors in the brain but is also produced by the brain and has been shown to induce neurogenesis, neuroplasticity and neuronal complexity, specifically in the hippocampus - a region of the limbic system which plays a key role in long-term memory and spatial navigation. As the authors further explain, "G-CSF may promote the surviving of newborn cells trough its well-investigated anti-apoptotic effects as well as trough its prominent actions in proliferation and differentiation of neural cells." In this manner, the scientists conclude that, "The finding of the present study suggests that the combination of hippocampus-dependent learning and G-CSF treatment may facilitate the integration of adult-born neurons into existing neural networks and therefore insure their survival."

Simultaneously a hormone, a glycoprotein, a neuropeptide, a cytokine and a hematopoietic growth factor, G-CSF had already been recognized as an important component of many physiological processes, though its role in specific neurophysiological processes had not yet been fully defined. As its name implies, G-CSF was previously understood to stimulate granulocyte (white blood cell) production in the bone marrow, from which the granulocytes migrate into the bloodstream. G-CSF was also known to stimulate stem cell production in the bone marrow, and to enhance the differentiation, proliferation, function and survival of mature neutrophils and neutrophil precursor cells - a particularly predominant type of white blood cell which is an essential component of the immune system. G-CSF is naturally and endogenously produced by a variety of tissue types throughout the human body, although it is also manufactured synthetically and prescribed as a drug.

This new study now allows greater insight into the important role that G-CSF plays in neuronal health, which had been studied to some extent though it was not as well understood as the role of G-CSF in immunological and hematological function. Previously, G-CSF has been studied almost exclusively in animal models of various types of neurological diseases such as stroke, Parkinson's disease, Alzheimer's and amyotrophic lateral sclerosis (Lou Gehrig's disease), in which treatment with G-CSF has been found to ameliorate cognitive deficits, especially in the animal models of Alzheimer's disease and stroke. As the investigators of this study report in their paper, "Although recent studies have begun to explore G-CSF-related mechanisms of action in various disease models, little is known about its function in the healthy brain. A more detailed understanding of the physiological role of G-CSF in the healthy brain may, however, open new insights into disease-relevant mechanisms. We therefore investigated the effect of peripheral administered G-CSF on learning and memory formation and the generation and survival of newborn hippocampal neurons in healthy rats."

As the scientists conclude, "Overall, the findings from the present study support the hypothesis that G-CSF can enhance learning and memory formation. Most importantly because of its easy applicability and its history as a well-tolerated hematological drug, learning enhancement by G-CSF opens up new neurological treatment opportunities in conditions where learning and memory-formation deficits occur."

The article was published in PLoS ONE by the Public Library of Science, an international, peer-reviewed, open access online publication.