Inside Science: Scientists Consider New Ways to Diagnose, Treat Depression
Depression affects hundreds of millions of people worldwide, yet treatment options are limited and basic questions about the root cause of the disease remain.
During a press conference at Neuroscience 2013, a team of scientists described recent studies pointing to differences in the brains and bodies of individuals with depression, and possible interventions to treat the disease and related mood disorders. The event was moderated by Lisa Monteggia of the University of Texas Southwestern Medical Center.
Manipulating Immune Response Changes Response to Stress
Although numerous studies suggest stress precipitates depression, individual response to stress can vary greatly. Understanding the molecular basis of susceptibility and resilience to stress may offer key insights into the pathology of depression.
Interested in how molecules in the body differ in those more and less susceptible to stress, press conference presenter Georgia Hodes of Icahn School of Medicine at Mt. Sinai in New York exposed mice to a social defeat test. In this test, a small mouse is repeatedly placed into the home cage of a larger, more aggressive mouse, where it is quickly defeated. After repeated exposure to this test, some mice begin to display depressive-like behaviors. Analysis of blood collected at the beginning of the study showed that the mice displaying depressive-like behaviors after social stress (stress-susceptible) had more circulating white blood cells (WBCs) than the unaffected (stress-resilient) mice even before the social stress test. Their WBCs also released more of the pro-inflammatory cytokine interleukin 6 (IL-6) when stimulated with lipopolysaccharide.
Hodes and her colleagues then irradiated the peripheral immune system of naive mice, destroying the animals’ immune cells, and replaced them with immune cells from stress-susceptible or control donors via a bone marrow transplant. The bone marrow from susceptible mice elevated the animals’ WBCs and, after exposure to a stress paradigm, led the animals to develop depressive-like behaviors. Conversely, mice that received a bone marrow transplant containing immune cells lacking IL-6 showed resistance to stress when exposed to the social defeat stress.
“These findings show that the peripheral immune system can actually predate and predict depression-associated behaviors,” Hodes said.
MicroRNAs Change after Stressful Events
Press conference presenter Karen Scott, a postdoctoral fellow in the laboratory of John Cryan at University College Cork in Ireland, is also interested in stress sensitivity and stress resistance. Scott described her work tracking molecular changes following a stressful event.
Scott measured changes in microRNA (miRNA) levels in the hippocampus of two strains of mice (stress-sensitive BALB/c and stress-resistant C57BL/6J) following 10 days of exposure to the social defeat test. miRNA are tiny snippets of messenger RNA that block or degrade other RNA messages. Following stress, expression of miR-16 — which has been implicated in the development of depression — was elevated in BALB/c mice. Conversely, C57BL/6J showed higher levels of miR-34c.
“These studies show that there is a correlation between behavioral and physiological responses to social defeat,” Scott said. However, she noted, future studies will need to explore whether manipulating miRNAs in the brain can alter symptoms of depression.
Nicotinic Receptor Could Provide Target for Antidepressant Treatment
To better understand the brain changes associated with depression and ways to alleviate symptoms of the disease, some scientists are interested in the overlap between depression and other chronic disorders. Press conference presenter Yann Mineur of Yale University described his work exploring the relationship between depression and chronic tobacco use.
Previous studies show that blocking a subtype of nicotinic acetylcholine receptors (nAChRs) called β2 nAChRs has an antidepressant-like effect on behavior and decreases the activity of neurons in the amygdala. Mineur wanted to know if reducing β2 nAChRs expression in the amygdala alone would be enough to produce antidepressant properties.
Compared with control mice, the animals with reduced β2 nAChR expression in the amygdala displayed less depressive-like behaviors and increased stress resilience in the social defeat test. Decreasing β2 nAChRs expression in the prefrontal cortex and hippocampus led to limited behavioral differences, suggesting that this receptor plays an important role specifically in the amygdala.
Identifying Circuits Involved in Anxiety
Nearly 60 percent of people with depression also have anxiety disorders. While previous human and animal studies show a correlation between hyperexcitability of amygdala neurons and anxiety, the circuits involved in anxiety have been unclear, explained press conference presenter Ada Felix-Ortiz of Kay Tye’s laboratory at Massachusetts Institute of Technology.
Felix-Ortiz used optogenetic technology to study the functional brain connections in freely-moving mice. The researchers used optogenetics to stimulate or inhibit basolateral amygdala (BLA) neurons projecting to the ventral hippocampus as mice navigated an elevated-plus maze. When BLA neurons were inhibited, the mice spent more time exploring the open arms of the maze, a behavior indicative of reduced anxiety. Conversely, when these neurons were activated, the mice spent more time in the closed, protected maze arms of the maze, indicating an increase in anxiety.
“This is the just the first step to dissecting … the causal relationship between behaviors and functional connections” in the brain, Felix-Ortiz said.
Deep Brain Stimulation Prevents Return of Aversive Memory in Non-Human Primates
Manipulating the activity of cells in the amygdala and prefrontal cortex may help prevent the return of an aversive memory, which can contribute to anxiety disorders, explained press conference presenter Rony Paz of the Weizmann Institute in Israel. Paz and his colleagues used electrophysiology in non-human primates and fMRI in people to observe activity in the amygdala and the cingulate cortex of people after exposure to a surprising aversive stimulus. The researchers found that synchronous activity of the amygdala and the cingulate cortex predicted how hard it would be for study participants to forget the aversive memory.
The cingulate cortex has been shown to excite the amygdala, promoting anxiety and fear. Paz and colleagues hypothesized that reducing the excitability of this region would make traumatic memories more susceptible to extinction. To test this hypothesis, the researchers delivered low frequency deep-brain stimulation (DBS) to the cingulate cortex of non-human primates after the animals were exposed to an aversive stimulus. Animals that received the low-frequency stimulation in combination with behavioral therapy showed no signs of preserving the traumatic memory compared with animals that only received behavioral therapy. According to Paz, the findings suggest that DBS may improve the effects of behavioral therapy.
Although the group of panelists expressed excitement over their work and other recent advances in the field of depression research, they also noted the challenges that lie ahead, including the need to better understand the heterogeneity of depression and related mood disorders between and within individuals.
In closing, moderator Lisa Monteggia added, “Depression is a complex disorder. It’s only going to be through talking about mental illness and asking questions that trigger more research that we’re going to make clinical advances.”