Altering the Stress Response To Reduce Anxiety

Post by Annie Phan

The takeaway

The most common mental health disorders, anxiety and depression, are linked to chronic stress. To design better pharmacological treatments for stress-related disorders, it is important to identify and undo the disruption of chemical interactions in the brain that occur with repeated exposure to stress.

What's the science?

Current medications for anxiety and depressive disorders target related neurotransmitter systems, like serotonin, to yield therapeutic effects. However, they also have side effects that may reflect biological processes unrelated to these disorders. This week in PNAS, Pandey and colleagues used mouse models of chronic stress to investigate signaling pathways that were changed in response to stress manipulation. Then, they attempted to reverse the anxiety behavior by pharmacologically repairing this pathway.

How did they do it?

The researchers used a mouse model of chronic stress where they physically restrained young adult mice for 3 hours daily for 14 consecutive days. They also validated their results with a second mouse model of stress, maternal separation, where young pups from postnatal day 5 to 21 were isolated from their mother for 3 hours daily. To assess the mice for anxiety- and depressive-like behaviours, they used common rodent assays like the elevated plus maze, marble burying test, and forced swim test. To study the molecular events in the brain specifically related to the synapse, they performed biochemical tests to evaluate the amount of relevant proteins and electrophysiological tests to evaluate excitatory and inhibitory transmission. To further investigate the reduction of protein expression, they performed a proteomic screen by co-immunoprecipitation and then mass spectrometry analysis, providing insight into how these proteins interact as part of a signaling pathway.  

What did they find?

First, the researchers found that following the chronic stress protocol, the mice in both chronic stress models showed anxiety and depressive-like behavior, and this was in parallel with the decrease in several inhibitory proteins at the synapse including Neuroligin2 (NL2). When they investigated the decrease in NL2 expression further, they found that upregulation of proteins including Src kinase and calmodulin (CaM) resulted in reduced interaction between MyosinVa (MyoVa) and NL2, indicating this pathway was altered in response to chronic stress. The authors manipulated this pathway by suppressing Src kinase activity via an injection of a Src kinase inhibitor, PP2 for 7 consecutive days after the chronic stress protocol. An inactive analog PP3 was used as a control. They observed a reduction in anxiety-like behavior in mice treated with PP2. Overall, inhibiting the elevated activity of Src kinase in chronically stressed mice re-established the expression of synaptic protein NL2 — which was previously reduced by stress — thereby restoring inhibitory synaptic transmission. 

What's the impact?

The public health burden of anxiety and depression calls for the need to create more effective and well-tolerated medication for these disorders. This study found a novel therapeutic target sensitive to the stress response, the Src-CaM-MyoVA-NL2 pathway, which is related to the GABA system responsible for inhibitory transmission. Targeting this pathway could help reduce anxiety behavior and improve outcomes for those affected. Further research in humans is needed to validate these findings and explore whether therapies targeting this pathway might be effective. 

ccess the original scientific publication here.

Orexin Neurons Mediate the Decision to Exercise Instead of Eating

Post by Shahin Khodaei

The takeaway

When mice are actively deciding between exercise or eating a tasty treat, the activity of a group of neurons in the lateral hypothalamus called orexin neurons plays a role in mice prioritizing exercise.

What's the science?

When given the choice between exercising or eating something, what part of the brain helps make the decision? One possibility is the lateral hypothalamus, an evolutionarily old region of the brain that plays a part in regulating both eating and movement. Specifically, research shows that a group of neurons called hypocretin/orexin neurons (HONs) in the lateral hypothalamus is important for these behaviours. What is not well-known is whether HONs also play a part in the decision between whether to eat or exercise. This week in Nature Neuroscience, Tesmer and colleagues published a study that looked at the role of HONs in this scenario and showed that the activity of these neurons played a part in mice prioritizing exercise over eating a highly palatable food.

How did they do it?

To study their decision-making process, the authors placed mice in the center of a maze with 8 arms. Each arm contained something different, giving the mouse multiple options to choose from (e.g. regular food, a new object, another mouse, etc.) Importantly, one arm contained a running wheel so mice could voluntarily exercise, and another arm was either empty or contained a tasty milkshake treat (the highly palatable food). This setup allowed the researchers to see if the mice chose exercise over the other options, particularly the milkshake.  

To parse out the role of HONs in this decision-making process, the authors either decreased or increased their function. They either injected mice with a pharmacological blocker for orexin receptors or increased the activity of HONs using a technique known as optogenetics. Tesmer and colleagues also used a technique called fiber photometry to indirectly measure the electrical activity of HONs. This let them see how the activity of these neurons changed when mice used the running wheel or ate the milkshake. 

What did they find?

When the authors placed the mice in the maze for 10 minutes, mice consistently chose to use the running wheel more than any other option, even when the maze contained the milkshake treat. The authors called this temptation-resistant voluntary exercise. They then injected mice with the pharmacological blocker of HON function to see how it impacted the choices mice made. If the milkshake was not in the maze, mice kept choosing exercise over all other options. When the milkshake was present, however, mice that received the blocker no longer chose exercise over milkshake, spending less time on the running wheel and more time eating. On the other hand, when the activity of HONs was increased using optogenetics, the mice spent even less time eating the milkshake.

Tesmer and colleagues then performed more experiments to understand exactly how HONs regulate this decision. Does HON activity make milkshakes inherently less appealing? No – when they blocked HON function in a maze with milkshake but no running wheel, the mice didn’t eat any extra milkshakes. Does HON activity make running inherently more appealing? No – when they blocked HON function in a maze with the wheel but no milkshake, the mice didn’t run any less. Instead, altering HON function only changed behaviour when BOTH the running wheel and milkshake were available as options – meaning that in a situation where mice are actively deciding between exercise and eating something highly palatable, HON activity leads to prioritizing exercise. The fiber photometry experiments support this notion: the activity of the HONs negatively correlated with milkshake eating, and positively correlated with wheel running.

What's the impact?

This study provides compelling evidence that HONs in the lateral hypothalamus play a role in the decision-making process between exercise and highly palatable foods. Of course, there is more work to do to determine if HONs play a similar role in human brains. This study takes a valuable step in understanding the neural foundations of such decisions, which can have important consequences for global health.  

Access the original scientific publication here.

Oxytocin and the Social Brain

Post by Lila Metko

The takeaway

Oxytocin has long been known as a peptide involved in promoting social interactions between individuals, in animals and humans alike. Recently, studies have pointed to the conclusion that oxytocin may not be as involved in human social interaction as was previously believed.

What is oxytocin?

Oxytocin is a neuropeptide that acts in both the central and peripheral nervous system. Before it was known for its role in social cognition, it was primarily known as a homeostatic hormone with some effects on sexual behavior. A 1991 study by Popik and Vetulani changed this view when they showed that antagonists of oxytocin receptors improved social memory while the delivery of oxytocin impaired it. Now, oxytocin is known as a major regulator of the social brain. However, the extent to which oxytocin affects different types of social interactions is not well understood. In this topic overview we explore the current literature about oxytocin and social behaviors.

How does oxytocin impact the parental bond?

Oxytocin has a strong impact on the bond between a parent and their offspring. Human mothers suffering from postpartum depression who were given oxytocin intranasally have shown greater protective responses towards their newborns than before oxytocin administration. Additionally, mothers with irregularities in the gene that codes for the oxytocin receptor have exhibited less sensitive parenting behaviors toward their children. Perhaps the most convincing piece of evidence that oxytocin plays a role in this bond is work showing that oxytocin triggers maternal behavior in rats that had never experienced a pregnancy. Interestingly, this could only occur when the rats were primed with estrogen, and the oxytocin dose was extremely high. However, a 2010 paper by MacBeth and colleagues revealed a surprising twist: mice lacking oxytocin receptors still exhibited typical maternal behavior. Further investigation by the same research group uncovered a more nuanced role for oxytocin: while these mice were indeed capable of displaying typical maternal behaviors, oxytocin's primary function appeared to be lowering the threshold at which maternal behaviors were initiated. More recent work (2022) has added another layer of complexity, demonstrating that maternal behaviors in these oxytocin receptor-deficient mice were specifically diminished after exposure to stressful environments. These findings collectively suggest that while oxytocin plays a significant role in maternal behavior, its influence is part of a more intricate and multifaceted system that regulates parental care in mammals.

How does oxytocin affect bonding in other relationships?

If the conclusions are mixed about oxytocin and the parental bond, what about oxytocin and other social contexts? Research in prairie voles, which form long-lasting partnerships with their mates, has shown that oxytocin infusions can bring about a partner preference even in the absence of mating, and that oxytocin antagonists can abolish partner preference in a mated pair. A human study by Kosfeld and colleagues showed that intranasal oxytocin was able to increase trust in a randomly selected ‘trust game’ partner. However, recently it was found that attempts to replicate the Kosfeld study were unsuccessful. In conclusion, while oxytocin may establish partner preference in the highly social species of prairie voles, it has not yet been shown to translate to human concepts like trust.

Oxytocin can also impact social cognition — mental actions such as thinking, learning about, or understanding a social interaction. Mice genetically lacking oxytocin have no social memory (could not distinguish familiar and novel mice) but when given oxytocin, social memory was restored. It was later shown that this action occurred through receptors in the amygdala, a brain region involved in emotional memory. Some research in humans suggests that there are sex differences in the effects of oxytocin on social cognition and behavior and that these effects are context-dependent. For example, evidence suggests that the 'prosocial' effects of oxytocin are more prominent in males.

How does oxytocin affect mood?

Interestingly, oxytocin can affect more than just social behaviors, but also social-related phenomena like emotions. In a study of 37 healthy men put into a stressful situation (a mock job interview), it was shown that intranasal oxytocin had anxiety-relieving effects. In a mouse model of hormone-induced postpartum depression, it was found that oxytocin receptor levels were low in certain brain regions. Additionally, intranasal oxytocin can affect the mood of women with postpartum depression, although how it affects mood is unclear. Some studies show that oxytocin improves mood in postpartum women, while another study showed that oxytocin exacerbated depressive symptoms.

What can we conclude from these findings?

In the current literature on oxytocin’s impact on the social brain, there is a large amount of variation in outcomes. However, it is clear that oxytocin affects social pathways in the brains of both humans and animals. The extent to which these animal studies can translate to humans needs to be explored further.

We are undeniably a social society, and social interactions make up a large part of many people’s daily lives. Additionally, the symptom profiles of multiple mental health disorders, such as schizophrenia and autism spectrum disorder, include deficits in social cognition. Therefore, from a treatment-focused perspective, understanding the role of oxytocin and its impact on social behavior is crucial.

References +

Leng, G., Leng, R. I., & Ludwig, M. (2022). Oxytocin-a social peptide? Deconstructing the evidence. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 377(1858), 20210055. https://doi.org/10.1098/rstb.2021.0055

Popik, P., & Vetulani, J. (1991). Opposite action of oxytocin and its peptide antagonists on social memory in rats. Neuropeptides, 18(1), 23–27. https://doi.org/10.1016/0143-4179(91)90159-g

Zhu, J., Jin, J., & Tang, J. (2023). Oxytocin and Women Postpartum Depression: A Systematic Review of Randomized Controlled Trials. Neuropsychiatric disease and treatment, 19, 939–947. https://doi.org/10.2147/NDT.S393499

Bakermans-Kranenburg, M. J., & van Ijzendoorn, M. H. (2008). Oxytocin receptor (OXTR) and serotonin transporter (5-HTT) genes associated with observed parenting. Social cognitive and affective neuroscience, 3(2), 128–134. https://doi.org/10.1093/scan/nsn004

Macbeth, A. H., Stepp, J. E., Lee, H.-J., Young, W. S. III, & Caldwell, H. K. (2010). Normal maternal behavior, but increased pup mortality, in conditional oxytocin receptor knockout females. Behavioral Neuroscience, 124(5), 677–685. https://doi.org/10.1037/a0020799

Rich, M. E., deCardenas, E. J., Lee, H., & Caldwell, H. K. (2014). Impairments in the Initiation of Maternal Behavior in Oxytocin Receptor Knockout Mice. Plus ONE. 9(6), e99839. https://doi:10.1371/journal.pone.0098839

Tsuneoka, Y., Yoshihara, C., Ohnishi, R., Yoshida, S., Miyazawa, E., Yamada, M., Horiguchi, K., Young, W.S., Nishimori, K., Kato, T., Kuroda, K.O. (2022). Oxytocin Facilitates Allomaternal Behavior under Stress in Laboratory Mice. eNeuro, 9(1), 0405-21. https://doi: 10.1523/ENEURO.0405-21.2022

Kosfeld, M., Heinrichs, M., Zak, P. J., Fischbacher, U., & Fehr, E. (2005). Oxytocin increases trust in humans. Nature, 435 (7042), 673–676. https://doi.org/10.1038/nature03701

Heinrichs, M., Baumgartner, T., Kirschbaum, C., & Ehlert, U. (2003). Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biological psychiatry, 54(12), 1389–1398. https://doi.org/10.1016/s0006-3223(03)00465-7

Zhu, J., & Tang, J. (2020). LncRNA Gm14205 induces astrocytic NLRP3 inflammasome activation via inhibiting oxytocin receptor in postpartum depression. Bioscience reports, 40(8), BSR20200672. https://doi.org/10.1042/BSR20200672