Molecular, genetic therapies

Hope for depression research flourishing

 

Cover photo from iStock
 
 
 
Depression killed my father.
 
I still remember the gold plaid skirt I wore to the funeral – looking down at the frozen ground by the gravesite. The numbness of that cold afternoon followed me like a fog to junior high the next day, where I went through the motions of being a 14-year-old girl. But the fog remained when I woke up the next day – and the next day … and the next.
 
No one talked about depression much in those days. And if they did at all, it often led to prescriptions for little green, heart-shaped amphetamines and red capsules of barbiturates –deadly in my dad’s case. The poor man didn’t have a chance.
 
Today, according to the National Institute of Mental Health, there are around 15 million clinically depressed people in the United States at any given time. Most are being treated with an ever-increasing array of antidepressants such as MAO inhibitors or selective serotonin reuptake inhibitors like Prozac. But these drugs may take weeks to start working – and in up to 50 percent of patients, may never work well at all. The drugs can also cause side effects ranging from mild nausea to suicide.
 
Hope for Depression
Determined to change those odds, a team of five scientists in the WSU College of Veterinary Medicine is homing in on the underlying
biochemical and molecular causes of depression.
 
Funded by the New York-based Hope for Depression Research Foundation (HDRF), their work promises advancement in the treatment of depression  that could make today’s antidepressants look as primitive as the speed and downers of yesterday. 
 
Under the visionary leadership of Jaak Panksepp – professor and Baily Endowed Chair of Animal Well-Being Science in the Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology (VCAPP) – depression team members have received more than $500,000 in research grants from the HDRF in the past three years.

                
  
 

 

 

More than low serotonin levels

Over the last decade, there has been a growing awareness that depression stems from more than just a deficiency in brain chemicals like serotonin. Scientists have discovered that the disorder is also tied to malfunctions in brain “circuitry” – the intricate pathways by which neurons communicate in the brain.
 
Panksepp and his team are investigating the dynamics of this circuitry as well as the genetic and epigenetic factors that help regulate the pathways. He believes that depression may be associated with three major brain circuit disorders.
“You can make the case for opioids as well as the dynorphin or glutamate systems,” he said.
The dynorphin system* is of particular interest to Yan Dong,
assistant professor in VCAPP. As a molecular biologist, Dong is studying the circuitry of addiction and drug-withdrawal-induced depression – specifically as it is mediated by the dynorphin system.
 
Dynorphin is a naturally occurring brain opiate related to the endorphins and enkephalins that are responsible for producing “runner’s high.” But instead of promoting euphoria, dynorphin makes people feel dysphoric – crabby and unhappy.
 
Dynorphin receptors are heavily concentrated in a circuit called the “brain reward pathway (BRP)” – which is activated after pleasurable events, “like a good meal,” said Dong.
 
From his studies on heroin and cocaine addiction, Dong hypothesizes that dynorphin “hijacks” the BRP – causing a person to feel unhappy.
 
“Even when an addict has stopped taking drugs, the depression component can remain – and they can’t get back to a normal life,” he said.
 
Taking it down to the cellular level, Dong has shown that dynorphin works by suppressing the nerve’s ability to fire action potentials as well as the driving force that leads up to an action potential.
 
This suppression results in sluggish nerve function in a part of the brain key for controlling emotional states (nucleus accumbens) – triggering depression. 
 

 

Shrinking brain cells
These findings are closely tied to work by Gary Wayman, assistant professor in VCAPP, who recently received a $110,000 grant from the HDRF to investigate structural changes in the brain and nerves during depression.  
 
Wayman has peeled back some of the layers of brain circuitry to identify genes that directly regulate those pathways and contribute to the development of depression.
 
One pathway he is investigating involves brain-derived neurotrophic factor (BDNF) – an important substance for normal brain development.
 
“During major depressive disorder, BDNF levels crash in several areas of the brain – such as the hippocampus, which is important for learning, memory and emotional processing,” said Wayman. 
 
He explained that when BDNF levels decrease, the hippocampus shrinks and nerves change shape structurally. The dendritic processes at the end of nerves  lose their spines and shrivel. This damage impairs the ability of nerves to communicate and transmit impulses through the synapses.
 
He also found that BDNF regulates a protein called CREB which controls thousands of genes including those responsible for nerve growth.
 
Putting it all together, he hypothesizes that BDNF activates CREB which in turn activates the genes that keep nerve cells healthy – preventing the shrinkage and distortion characterized by depression.
 
Wayman already has shown that direct treatment of hippocampal neurons with BDNF stimulates these genes and triggers rejuvenation of nerve cells. His next step is to
see if antidepressant treatments also will enhance the gene expression.
 
(Photo: close-up of dendritic spines on nerve. Courtesy of Gary Wayman.)

  
  
 

 

The protective power of play
Pharmaceuticals are not the only option for reversing brain degeneration associated with depression. Studies show that exercise, for example, can in some cases be as effective for reducing depression as medication.
 
“When you enrich (a rat’s) environment with play, interaction and toys, the neurons in the hippocampus bloom and generate more synapses. The rats become smarter and learn more quickly. BDNF levels increase too,” said Wayman.
 
Toward this end, he and Panksepp are using  play as a model to determine if play experiences early in life can help protect against depression later on.
 
“The orchestra in the cortex is dramatically affected by play,” said Panksepp. “Play is the most positive social activity there is.”
 
Their work is based on the findings of Sylvie Cloutier, research assistant professor in the VCAPP Center for Animal Well-Being, who, in 2006, developed a model for depression using the strongly social and family-oriented rodent, the degu.

 

 

 

Epigenetics of depression

In support of this work, Panksepp – also co-director of research of the HDRF – recently was awarded a $110,000 grant specifically earmarked for investigating the epigenetics of depression.
 
Together with Dan Guerra, research associate professor in VCAPP, he has whittled down thousands of genes in the degu’s “genetic library” to a small number identified as playing a role in positive emotions. Theoretically, activating those genes through various therapies could help prevent depression.
 
One of their discoveries is a gene that produces “insulin-like growth factor.”
 
“No one has looked at this one before in an emotional study – it’s a brand new target,” said Panksepp. “Our studies show that the more an animal has (of this factor) the more resilient it is to depression.”
 
“It is possible that if this gene is methylated – and we could find a way to demethylate it, a person could have some resistance to depression from a genetic perspective,” he said.
 
Methylation refers to one type of “epigenetic change” that takes place in malleable proteins that surround DNA. In Greek, ‘epi’ means upon, near or over – so, simply speaking, the epigenome is a second layer of information enfolding the DNA of the genome.
 
These epigenetic proteins respond to environmental conditions – such as famine or stress – to control which genes are turned off or on in a particular situation. There is mounting evidence that changes in the epigenome play a significant role in the development of cancer and emotional disorders such as depression. Epigenetic changes also may be passed on to offspring – for better or worse.
 
New treatments on the horizon
For the future, Panksepp hopes all of the team’s hard work pays off.
 
“If everything works out, we may find new genetic targets for the development of antidepressive maneuvers – both environmental and pharmacological.”
 
Indeed, Panksepp and a group at Northwestern University have a molecule ready for preclinical testing. Known as “glyxins,” this family of molecules can tune down the glutamate system in the brain – a key chemical pathway that becomes hyperactive during depression.
 
In animal models, glyxins promote better hippocampal function and rapid reversal of depression.
 
“We have FDA approval for the drug trial – we are just waiting for venture capital to proceed,” said Panksepp.
 
 
*There has been additional work in this area by Brendan Walker, assistant professor in the Department of Psychology, who has led preliminary investigations into the role of dynorphin systems in alcohol dependence.

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Child abuse causes sensitivity to stress  

Jaak Panksepp recently was quoted in the New York Times concerning research at McGill University in Montreal where it was proven, for the first time, that people who were abused or neglected as children showed epigenetic changes making them more biologically sensitive to stress. The study showed that people with traumatic childhoods who went on to commit suicide had significantly fewer cortisol receptors in their brains than those who had gentler childhoods.

Cortisol is a hormone produced when the body is under stress – preparing it for “fight or flight.” Too much cortisol can cause anxiety and fear, so the body clears the hormone through specialized receptors in the brain. Children who were abused showed 40 percent fewer cortisol receptors than normal, leaving them more vulnerable to distress than children who had not been traumatized.

 “The study extends the animal work on the regulation of stress to humans in a dramatic way,” said Panksepp. “It suggests pathways that have promoted the psychic pain that makes life intolerable.”

 
 
 
 
 

Finding balance after childbirth   

Rebecca Craft is investigating a distinctly feminine side of depression. As a professor in the department of psychology, Craft is one of a few researchers in the nation developing animal models detailing post-partum depression.
 
It is estimated that around 75 percent of women experience a mild form of depression after childbirth – often called “baby blues.” Up to 15 percent of new mothers may go on to develop a more debilitating major depression – while less than one percent experience the rare and dangerous post-partum psychosis.
 
It has been speculated that the sudden drop in estrogen and progesterone after birth is the cause of post-partum depression, but Craft believes it is more about the balance of “positive mood and negative mood” hormones. “Prolactin and oxytocin are hormones that normally rise at the end of pregnancy and are shown to have positive mood effects,” said Craft. “The levels may stay up depending on other factors – such as breastfeeding … and the presence of the father.”
 
To validate her hypothesis, Craft is initially looking at each of the hormones separately. Eventually, she plans to study them all together – with the intention of countering the depressive effect of estrogen withdrawal through supplementation with oxytocin and prolactin.