New research on depression biology and treatment highlights the rapid increase in knowledge in this area in the last decade. In this post we will summarize some of these research findings briefly.
This brief tour will take us to a newly discovered protein that may be a vital link between stress and depression. A genome wide search for changes associated with ketamine or imipramine infusion provides insight into the biological processes the underly resilience to stress. Finally, two studies published in Biological Psychiatry suggest that another new protein, Netrin 1, which is involved in cell growth in certain cancers, may also play a key role in risk for depression and stress susceptibility.
In an editorial accompanying several of these articles, Steven Hyman suggests that these studies represent “A New Hope for Biological Insights into Depression.”
JNK May Link Stress and Depression
The newly discovered protein, JNK, is activated in response to stress and inhibits brain cell formation (neurogenesis) in the hippocampus. In a mouse study, blocking JNK led to a rapid reduction in symptoms of anxiety and depression in mice exposed to uncontrolled stress.
The ventral hippocampus is the hub of limbic and cortical brain structures involved in response to stress and fear – the amygdala and prefrontal cortex – and it plays a key role in regulating stress responses throughout the body.
In addition, it has long been known that high levels of the stress hormone cortisol inhibit neurogenesis in the hippocampus, which may be way depression and anxiety is associated with memory impairment.
This study suggests that JNK may be the molecule that regulates these effects. Thus drugs that block JNK might treat or prevent depression and anxiety induced by stress.
Mohammad H, Marchisella F, Ortega-Martinez S, et al. JNK1 controls adult hippocampal neurogenesis and imposes cell-autonomous control of anxiety behaviour from the neurogenic niche. Molecular Psychiatry. 2016 November 15;[Epub ahead of print].
Ketamine and Imipramine Share Effects on Prefrontal Cortex Linked to Increased Resilience
This study looked at patterns of RNA transcription in parts of the brain involved in defeat and learned helplessness in mice.
In the experiment a mouse is exposed to another more aggressive mouse. After experiencing defeat, the mouse continues to be exposed to the mouse through an invisible partition.
Some of the mice in this experiment become passive and withdrawn (looking for all the world like depressed mice) and some do not.
In this study, those mice who were vulnerable to defeat were subsequently treated with either imipramine or ketamine infusion.
Again, some of those treated responded by acting the same as resilient mice (treatment responders) and some did not.
Ketamine responders showed a normalization of protein transcription in the hippocampus and prefrontal cortex. Imipramine responders showed a normalization of protein transcription in the amygdala and nucleus accumbens and the prefrontal cortex.
The effects of both drugs on the prefrontal cortex appeared to be central to their antidepressant effects.
As you can see in the picture to the right, these brain structures, as well as the ventral tegmental area (VTA) are intimately connected and involved in the effects of fear and reward on activity.
Bagot RC, Cates HM, Purushothaman I, Vialou V, Heller EA, Yieh L, LaBonté B, Peña CJ, Shen L, Wittenberg GM, Nestler EJ. Ketamine and Imipramine Reverse Transcriptional Signatures of Susceptibility and Induce Resilience-Specific Gene Expression Profiles. Biol Psychiatry. 2017 Feb 15;81(4):285-295. doi: 10.1016/j.biopsych.2016.06.012. PubMed PMID: 27569543; PubMed Central PMCID: PMC5164982.
DCC Confers Susceptibility to Depression-like Behaviors in Humans and Mice and Is Regulated by miR-218
Levels of expression of the protein DCC (deleted in colorectal cancer) are linked to either resilience or susceptibility to psychopathologies involving prefrontal cortex (PFC) dysfunction such as depression and anxiety. In this study the authors looked at human and mice brains and identified a common pathway for the regulation of DCC expression involving micro-RNA.
MicroRNAs (miRNAs) are noncoding RNAs (~22 nucleotides) that regulate gene expression at a posttranscriptional level. See the picture to the right.
The authors summarize the implications and findings of this study in the conclusion…
An understanding of the pathophysiology of stress-related disorders, including MDD, is necessary for developing novel preventive strategies and overcoming the lack of effectiveness of current treatments. One way to advance this knowledge is to identify candidate molecular determinants of vulnerability and of resiliency using postmortem human brain tissue of subjects who manifest such conditions. Another strategy is to take advantage of preclinical models to characterize the enduring plastic alterations occurring in the brain caused by stress. In this study we combined these two approaches and demonstrated that increased DCC expression in PFC neurons causes susceptibility to stress-induced depressive-like behaviors, whereas dampened DCC expression is protective. These findings are in line with our idea that DCC receptors mediate detrimental, enduring effects of environmental risk factors, but they are also involved in conferring resilience ( 4, 5 and 36). Therefore, the expression of DCC or of its molecular regulators or both could serve as a biomarker of vulnerability to MDD.
In this study we identified miR-218 as a repressor of DCC gene expression and found a significant reduction in miR-218 expression in the PFC of 1) adult mice that are susceptible to chronic stress-induced social avoidance and 2) adult nonmedicated humans with MDD who died by suicide. In fact, the expression of miR-218 and DCC in the PFC are negatively correlated in MDD. These findings indicate that miR-218 could potentially serve as both a noninvasive biomarker of DCC function and a target of therapeutic interventions. miRNAs can be measured in blood with the advantage of being stable and resistant to changes in temperature.
Torres-Berrío A, Lopez JP, Bagot RC, Nouel D, Dal Bo G, Cuesta S, Zhu L, Manitt C, Eng C, Cooper HM, Storch KF, Turecki G, Nestler EJ, Flores C. DCC Confers Susceptibility to Depression-like Behaviors in Humans and Mice and Is Regulated by miR-218. Biol Psychiatry. 2017 Feb 15;81(4):306-315. doi: 10.1016/j.biopsych.2016.08.017. PubMed PMID: 27773352; PubMed Central PMCID: PMC5239724.