Posts Tagged somatostatin

[WEB SITE] Understanding the Anxious Brain

Post by D. Chloe Chung
“I was so anxious to do what is right that I forgot to do what is right.” – Jane Austin

What’s the deal with anxiety?

You’re giving an important presentation tomorrow for work in front of a big crowd. You know you’re well-prepared, but when you imagine yourself standing at the podium, facing strangers whose eyes are fixed on you, you start to feel nauseated – your palms sweat and your heart hammers in your chest. You’re experiencing acute anxiety, a state of negative emotions and heightened arousal, often accompanied by increased alertness. This definition may sound similar to that of ‘fear’, which is produced as an acute response to immediate threats. There is considerable overlap between the brain circuitry regulating anxiety and fear, but anxiety is distinct from fear because it can be internally triggered or anticipatory – just like when you were merely imagining that presentation for work. Much of our understanding of anxiety stems from what we have learned about how the brain processes and learns fear responses.

What’s going on in your brain when you’re feeling anxious?  

Recent research efforts have emphasized the importance of communication between multiple brain areas in evoking anxiety. One of the established models of the neural circuitry of anxiety proposes that anxiety arises due to active neural communication between brain regions, including the amygdala, a brain structure involved in fear learning. The amygdala (the central extended amygdala [CeA]) sends projections to the bed nucleus of the stria terminalis (BNST), a cluster of nuclei involved in threat monitoring. The amygdala and the BNST also communicate with other brain regions such as the ventral hippocampus (vHPC) and the prefrontal cortex (PFC). According to this model, these four regions are connected by neural projections and work with one another in an orchestrated manner to evaluate whether or not a situation is threatening. The brain activity in this group of regions that we’ll refer to as the ‘anxiety detection’ regions can be either anxiogenic or anxiolytic, meaning they can perpetuate or reduce anxiety, respectively.


Downstream, the motor cortex, regions of the brainstem, and the neuroendocrine system receive, interpret, and evaluate possible anxiety signals from the brain regions involved in anxiety detection. These downstream regions then initiate anxiety responses by triggering defensive and risk-avoiding behaviors and altering biological functions such as heart and respiration rate. Excessive anxiety can occur when the brain’s anxiety pathways misinterpret incoming signals. For instance, repeated exposure to ‘threatening’ situations may cause anxiogenic pathways to become abnormally hyperactive, and therefore more sensitive to threatening stimuli. This can cause an imbalance in the neural circuitry that processes anxiety, shaping the brain to become more reactive and susceptible to experiencing anxiety.

What’s new in anxiety research?

While we know the amygdala (specifically the CeA) is particularly important for anxiety regulation, the exact mechanisms are difficult to disentangle. Recent research has helped to shed light on some of the specific circuitry involved. A recent study in the Journal of Neuroscience used a novel rat model and deleted a gene called ErbB4 –  implicated in various neurological disorders  in a group of amygdala neurons that release somatostatin, a peptide implicated in fear responses. In behavioral tests, rats without this gene exhibited higher anxiety levels, due to increased somatostatin levels in the amygdala. The abnormal activity of somatostatin neurons in the CeA also disrupted the inhibition of somatostatin neurons in the BNST, rendering these neurons hyperactive and ultimately causing heightened anxiety. A peptide called dynorphin has been identified as a key molecular player in this amygdala-BNST anxiety circuit. The authors demonstrated that the amount of dynorphin produced by somatostatin neurons in the amygdala was increased, and led to disinhibition of the BNST, contributing to the induction of anxiety-related behaviors. In other words, both somatostatin and dynorphin work together to play an important role in increased anxiety in mice without ErbB4. The good news is that dynorphin could be a potential target for anxiety treatment.

Another area of anxiety research concerns the stress neuropeptide, corticotropin-releasing factor. It’s known to regulate the BNST’s ability to elicit anxiety, but it was unclear where the corticotropin-releasing factor was coming from until recently. A study published by Pomrenze et al. showed that corticotropin-releasing factor is majorly produced and released by a group of neurons located in the lateral amygdala and the dorsolateral BNST. Using designer drugs that can either inhibit or activate neurons expressing the corresponding receptors via viral transduction, the authors found that neurons that project from the lateral amygdala to the BNST and release corticotropin-releasing factor are critical in mediating anxiety. Removal of these neurons reduced anxiety behaviors, confirming the importance of corticotropin-releasing factor in evoking anxiety responses.

What happens when anxiety interferes with daily life?

Modern life is full of stressors and many people are prone to experiencing intense anxiety at some point in their lives. In fact, anxiety is a part of a normal emotional spectrum and can even be beneficial at times, increasing our vigilance and enabling our survival. However, chronic anxiety can severely interfere with day-to-day living and become pathological, resulting in generalized anxiety disorder (GAD) or other anxiety-related disorders. Anxiety disorders like GAD are common, impacting one in every five adults. Considering how many individuals are affected by pathological anxiety, there is a need for highly effective anti-anxiety drugs or behavioral interventions. It is critical to understand the brain circuitry underlying anxiety to develop effective treatment options for chronic anxiety disorders.

Since anxiety results in heightened arousal, many anxiety medications manipulate neurotransmitters to slow the nervous system down, decreasing arousal. Medications such as selective serotonin reuptake inhibitors (SSRIs) and Buspirone work to increase serotonin in the nervous system, which can, in turn, decrease arousal. Medication options for phobias such as social anxiety tend to decrease the effect of norepinephrine, a neurotransmitter connected to the ‘fight or flight’ fear response. Cognitive-behavioral therapy (CBT) and consulting with certified therapists can also improve anxiety. CBT is a popular and effective strategy that guides individuals to replace anxiety-provoking interpretations of situations with benign ones. For individuals with less severe anxiety symptoms, CBT can sometimes work as well as some medications, depending on the person and the extent of their anxiety. CBT can also be combined with other therapeutic approaches to effectively treat anxiety depending on the severity of symptoms. Regular physical exercise and breathing exercises can also be effective in reducing anxiety symptoms.

Things to remember about anxiety

To manage acute daily anxieties, remembering how the brain circuitry of anxiety works might be helpful – the anxiety regions of the brain first assess whether the situation is threatening or not, and then subsequently trigger the anxiety response. This means that we can practice psychological tricks to aid the brain in better assessing non-threatening situations as just that – non-threatening. Similar to CBT, by taking a step back and evaluating the situation, we can develop habits that lead to new responses and potentially avoid an unnecessary anxiety response in the future. Making an effort to be aware of our anxious thoughts or worries and replacing them with more realistic ones can also be beneficial in helping our brain to relearn our responses to potentially threatening situations. Since the human brain is plastic (i.e. it adapts to changes in our internal and external environments), conscious efforts can result in a shift in the anxiety circuitry. Another key factor in mitigating anxiety is an awareness of the surrounding environment. Anxiety-inducing neural circuitry can be over-activated when we’re repeatedly exposed to certain stressors in our environment, resulting in feelings of anxiety in situations that are not immediately threatening. Hence, eliminating or minimizing such stressors in our environment can help.
Calhoon GG, Tye KM. Resolving the neural circuits of anxiety. Nature Neuroscience (2015) 18(10): 1394-404. DOI: 10.1038/nn.4101.

Ahrens S, Wu MV, Furlan A, Hwang GR, Paik R, Li H, Penzo MA, Tollkuhn J and Li B. A central extended amygdala circuit that modulates anxietyJournal of Neuroscience (2018) 38(24): 5567-5583. DOI: 10.1523/JNEUROSCI.0705-18.2018

Pomrenze MB, Tovar-Diaz J, Blasio A, Maiya R, Giovanetti SM, Lei K, Morikawa H, Hopf FW and Messing RO. A corticotropin releasing factor network in the extended amygdala for anxiety. Journal of Neuroscience (2019) 39(6): 1030-1043. DOI: 10.1523/JNEUROSCI.2143-18.2018

Hofmann SG, Asnaani A, Vonk IJJ, Sawyer AT, and Fang A. The Efficacy of Cognitive Behavioral Therapy: A Review of Meta-analyses. Cognitive Therapy and Research (2012) 36(5): 427-440. DOI: 10.1007/s10608-012-9476-1

Kaczkurkin AN, Foa EB. Cognitive-behavioral therapy for anxiety disorders: an update on the empirical evidence. Dialogues in Cinical Neuroscience (2015) 17(3):337-46. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4610618/

via BrainPost Life: Understanding the Anxious Brain

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