(L) New research sheds light on connection between dopamine and depression symptoms (2012)

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New research sheds light on connection between dopamine and depression symptoms

 A team of researchers at Stanford have successfully induced and relieved depression-like deficiencies in both pleasure and motivation in mice by controlling a region of the brain known as the ventral tegmental area. That part of the brain is a source of dopamine and a central player in the brain’s internal motivation and reward systems.

This is a significant advance in our understanding of the biological underpinnings of depression and related behaviors, with promising implications for future research

More details on the study are offered in a release:

[Researchers were] able to both induce and relieve multiple depression-like symptoms in laboratory mice by genetically modifying the dopamine neurons in the VTA to be sensitive to light. Using fiber optic cables inserted in rodents’ brains, they could then instantaneously produce and inhibit the depression-like symptoms by turning the light on and off. This research technique, developed by Deisseroth at Stanford in 2005, is known as optogenetics.

The team examined mice in a depressed-like, low-motivation state induced by mild stressors whose VTA neurons had been optogenetically modified. “When given light stimulation to the VTA dopamine neurons, these mice showed a robust increase in escape-related behavior. They immediately tried harder to get out of challenging situations — reversing back to normal levels of effort from the depressed-like state they were in,” explained Deisseroth.

Stanford bioengineer and senior author of the study Karl Deisseroth, MD, PhD, commented on the significance of the findings, saying, “These results directly implicated a single class of neuron in a single brain region — ventral tegmental dopamine neurons — in both producing and relieving very different depression-related symptoms, addressing a mystery in disease pathophysiology.”

While the results (subscription required) are notable, Deisseroth cautioned that depression and other mental illnesses are complex, multidimensional conditions that vary among patients. But, he said,

…the VTA dopamine circuitry we studied is very similar in both rodents and humans. And we have shown that the neurons in this circuit specifically cause, correct and encode diverse symptoms of depression. This is a significant advance in our understanding of the biological underpinnings of depression and related behaviors, with promising implications for future research.

Previously: Using light to better understand mental illness


Scientists induce and relieve depression using light in mice

Researchers from Stanford University have, for the first time, successfully used light stimulation of an area of the brain in mice to induce and then relieve depression-like symptoms of lack of pleasure and lack of motivation. The results are published in the Dec. 12 issue of the prestigious science journal Nature.

Among those who suffer from depression, the dual inabilities to experience enjoyment in things once pleasurable and to physically motivate oneself — to meet challenges, or even to get out of bed in the morning — have been documented for decades, though it has been mysterious why these very different kinds of symptoms show up together, and also disappear together when depression is successfully treated.

It has been suspected that the brain chemical dopamine could be a key player in the illness. And yet, in the long history of the study of depression, no one has been able to clearly tie these key concepts together, until now.

The research sheds light on some of the possible mechanisms behind seasonal affective disorder, more commonly known by its acronym of SAD, which is prevalent in areas which experience a severe or protracted winter season.

Researchers at Stanford University have successfully induced and relieved depression-like deficiencies in both pleasure and motivation in mice by controlling just a single area of the brain known as the ventral tegmental area. It is the first time that well-defined types of neurons within a specific brain region have been directly tied to the control of myriad symptoms of major depressive illness.

The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://mednews.stanford.edu. The medical school is part of Stanford Medicine, which includes Stanford Hospital & Clinics and Lucile Packard Children's Hospital.

Stanford bioengineer Karl Deisseroth, MD, PhD, and a team including postdoctoral scholars Kay Tye, PhD, and Melissa Warden, PhD, and research assistant Julie Mirzabekov have used a technique known as optogenetics to pinpoint a specific brain location that produces multiple depression-like symptoms.

The Stanford School of Engineering has been at forefront of innovation for nearly a century, creating pivotal technologies and businesses that have transformed the worlds of technology, medicine, energy and communications and laid the foundation for Silicon Valley. The school advances modern science and engineering through teaching and research. The school is home to nine departments, 245 faculty and more than 4,000 students, tackling the world's most pressing problems in areas like human health and environmental sustainability.

The region in question is the ventral tegmental area, or VTA, a source of dopamine and a central player in the brain's internal motivation and reward systems.

"We have for the first time directly tied dopamine neurons in the VTA to controlling and relieving these very different and diverse symptoms,"

said Deisseroth, the study's senior author and a professor of bioengineering and of psychiatry and behavioral sciences.

"While depression is a complex disease with still many unknowns, this knowledge may help launch new kinds of investigation into the pathways of depression in the brain, and develop concepts to help people suffering from depression."

Deisseroth's team was able to both induce and relieve multiple depression-like symptoms in laboratory mice by genetically modifying the dopamine neurons in the VTA to be sensitive to light. Using fiber optic cables inserted in rodents' brains, they could then instantaneously produce and inhibit the depression-like symptoms by turning the light on and off. This research technique, developed by Deisseroth at Stanford in 2005, is known as optogenetics.

The team examined mice in a depressed-like, low-motivation state induced by mild stressors whose VTA neurons had been optogenetically modified.

"When given light stimulation to the VTA dopamine neurons, these mice showed a robust increase in escape-related behavior. They immediately tried harder to get out of challenging situations — reversing back to normal levels of effort from the depressed-like state they were in,"

explained Deisseroth.

Similarly, he said, when offered the choice of sugar water over plain, the mice that had been in a depressed-like state chose the sugar water with much greater frequency when their VTA dopamine neurons were stimulated by illumination. They opted to experience pleasure — back to normal levels.

Finally, and remarkably, Deisseroth noted, optogenetically inhibiting the VTA dopamine neurons instead of stimulating them caused, rather than corrected, both kinds of depression symptoms — instantaneously and reversibly.

"These results directly implicated a single class of neuron in a single brain region — ventral tegmental dopamine neurons — in both producing and relieving very different depression-related symptoms, addressing a mystery in disease pathophysiology," said Deisseroth.

And yet, another key question still remained: What are the VTA dopamine neurons doing to downstream circuits? In other words, how are the depression-related control signals read out?

To answer these questions, the researchers next took the work a step further by mapping the effects of dopamine neuron activity in the VTA on the nucleus accumbens, a brain center thought to influence diverse functions of pleasure, and likely the site of action for addictive drugs as well as natural rewards. Seeing a change in the nucleus accumbens would provide information on the mechanism for how VTA dopamine neuron effects are manifested in the brain.

"Indeed, we established that electrophysiological representation of action in the nucleus accumbens is in fact fundamentally altered by VTA dopamine neuron activation. If we activate the VTA dopamine neurons, it influences the nucleus accumbens' encoding of physical, motivated action,"

emphasized Deisseroth. Together, these results represented a long-sought circuit-level insight into the causes and nature of depression-related behavior.

While the results are significant, Deisseroth, who is also a practicing psychiatrist, cautioned that depression and other mental illnesses are complex, multidimensional and vary from patient to patient. The symptoms of depression are certainly influenced by many neural circuits, he said.

"Nonetheless, the VTA dopamine circuitry we studied is very similar in both rodents and humans. And we have shown that the neurons in this circuit specifically cause, correct and encode diverse symptoms of depression. This is a significant advance in our understanding of the biological underpinnings of depression and related behaviors, with promising implications for future research,"

said Deisseroth.

A recent study, published last week by researchers at the University of Queensland in Australia found the mechanism behind why physical exercise increases the number of stem cells that are actively generating new nerve cells in the brain which reverses the decline normally observed as animals age.

“We have found that Growth Hormone (GH) originally discovered as a potent stimulator of animal growth is increased in the brain of running animals and this stimulates the activation of new neural stem cells,”

QBI scientist Dr Daniel Blackmore said.

The study was carried out in older mice, which show the same cognitive decline as humans.

If you want to improve your cognitive abilities, have a healthy brain and improve the way you feel about life, as well as reducing PCOS symptoms by improving insulin sensitivity, the answer, therefore, lies in getting out into the sunshine and doing some exercise!

Sources:

Chaudhury, Dipesh. (2012-12-12) Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature, 351. DOI: 10.1038/nature11713

Tye, Kay M. (2012-12-12) Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature, 2877. DOI: 10.1038/nature11740

http://www.eurekalert.org/pub_releases/2012-12/sumc-rir121112.php

Blackmore DG, Vukovic J, Waters MJ, & Bartlett PF. (2012) GH Mediates Exercise-Dependent Activation of SVZ Neural Precursor Cells in Aged Mice. PloS one, 7(11). PMID: 23209615