In a groundbreaking new study published in the Proceedings of the National Academy of Sciences, scientists have uncovered a biological pathway in the brain that is highly sensitive to chronic stress and plays a critical role in anxiety-like behaviors. By manipulating this pathway in mice, the team was able to reverse anxiety symptoms, providing a potential new target for therapeutic strategies against anxiety and depression.
Anxiety and depression are among the most common mental health disorders globally, affecting roughly one-third of the population. Despite the availability of treatments like selective serotonin reuptake inhibitors (which increase serotonin levels in the brain) and drugs targeting gamma-aminobutyric acid receptors (which enhance inhibitory neurotransmission), these treatments have significant drawbacks. They can take weeks to become effective, may cause unwanted side effects, and often fail to work for a substantial number of patients.
The researchers sought to find a more targeted approach to treating anxiety by focusing on the specific molecular pathways directly involved in the stress response. Chronic stress is known to cause changes in the brain that contribute to the development of anxiety and depression, but the exact mechanisms have remained elusive. By identifying the precise pathways affected by stress, the researchers hoped to find new ways to intervene and potentially develop more effective treatments.
“Stress and anxiety are among the most prevalent neurological disorders affecting the public, and the recent COVID-19 pandemic has exacerbated this burden, highlighting the need for improved medications,” explained study author Saurabh Pandey, a member of Wei Lu’s Synapse and Neural Circuit Research Lab at the National Institute of Neurological Disorders and Stroke.
To explore this, the researchers employed a series of experiments involving mice that were exposed to chronic stress. They used two different models of stress: one involving restraint stress, where mice were physically restrained for several hours a day over two weeks, and another involving maternal separation, where young mice were separated from their mothers for a few hours daily. Both stress models are known to induce anxiety-like behaviors in mice, making them suitable for studying the effects of chronic stress on the brain.
The researchers then analyzed the brains of these stressed mice, particularly focusing on the hippocampus, a region known to be involved in emotion regulation and stress response. They observed that chronic stress did not change the overall levels of many synaptic proteins but significantly reduced the expression of specific inhibitory synaptic proteins. These proteins are crucial for maintaining the balance of excitation and inhibition in the brain, which is essential for normal emotional functioning.
One of the key findings was that chronic stress led to an increase in the activity of Src kinase, an enzyme that modifies other proteins by adding phosphate groups to them. This increased Src activity, in turn, led to the phosphorylation of calmodulin, a protein that interacts with another protein called MyosinVa. MyosinVa is responsible for transporting proteins like Neuroligin2 (NL2) to the synapses, where they help facilitate inhibitory neurotransmission.
Under stress, the interaction between MyosinVa and NL2 was disrupted, leading to reduced levels of NL2 at the synapses and, consequently, decreased inhibitory transmission. This disruption was closely associated with the development of anxiety-like behaviors in the stressed mice.
To further understand the role of this pathway, the researchers genetically manipulated mice to lack a specific part of the NL2 protein that interacts with MyosinVa. These genetically modified mice exhibited anxiety-like behaviors even without being subjected to stress, underscoring the importance of the MyoVa-NL2 interaction in regulating anxiety. Moreover, when these mice were exposed to chronic stress, their anxiety behaviors did not worsen, suggesting that the disruption of this pathway alone was sufficient to cause high anxiety.
“We discovered that two distinct forms of chronic stress activate a shared signaling pathway in the brain in response to both physical and psychological stress,” Pandey told PsyPost.
In a pivotal experiment, the researchers tested whether they could reverse the stress-induced anxiety by pharmacologically inhibiting Src kinase, thereby reducing the phosphorylation of calmodulin and restoring the MyoVa-NL2 interaction. They administered a drug known as PP2, which inhibits Src kinase, to the chronically stressed mice. The treatment successfully restored the levels of inhibitory synaptic proteins, including NL2, and reversed the anxiety-like behaviors in these mice.
However, when the same drug was administered to the genetically modified mice that lacked the MyoVa-NL2 interaction, the drug had no effect. This finding confirmed that the MyoVa-NL2 interaction is crucial for the regulation of anxiety and that the pathway involving Src kinase, calmodulin, MyoVa, and NL2 is a critical mechanism through which chronic stress induces anxiety.
The implications of this study are significant. It identifies a specific molecular pathway that could be targeted for developing new treatments for anxiety and depression. By focusing on this pathway, future therapies could potentially avoid the broad side effects associated with current treatments that affect a wide range of neurotransmitter systems. This research also opens up new directions for exploring how stress affects the brain and contributes to mental health disorders.
“We have identified a novel molecular pathway that is highly responsive to anxiety and depressive disorders, offering a potential new avenue for therapeutic development,” Pandey said. “This study is significant, as it paves the way for a new line of drug development targeting anxiety and depressive disorders.”
However, the study has its limitations. The experiments were conducted in mice, and while mice are often used as models for human biology, there are always differences between species that must be considered. Additionally, the study focused primarily on the hippocampus, but other brain regions are also likely involved.
“We examined a specific brain region, the hippocampus, but we cannot rule out the possibility that other brain regions are involved or that the signaling pathway we discovered functions similarly in these regions,” Pandey explained. “We aim to extend this study through collaboration with researchers involved in pre-clinical or clinical studies.”
The study, “Reversing anxiety by targeting a stress-responsive signaling pathway,” was authored by Saurabh Pandey, Wenyan Han, Jun Li, Ryan Shepard, Kunwei Wu, David Castellano, Qingjun Tian, Lijin Dong, Yan Li, and Wei Lu.
