What are the roles of norepinephrine and the locus coeruleus (LC) in promoting anxiety-like behavior through the basolateral amygdala (BLA)?
The LC regulates arousal and stress reactions, especially by releasing norepinephrine. In the context of anxiety-like behaviors, norepinephrine release from the LC can influence neuronal activity in the BLA.
Our research has demonstrated that norepinephrine can increase the gain of neuronal ensembles in the BLA, which is especially important during times of stress or worry. This modulation effectively makes specific ensembles more sensitive, resulting in the anxiety-like responses we see.
Norepinephrine from the LC functions as a crucial neuromodulator, amplifying the effect of stress on the amygdala, a central center for processing emotional reactions.
Image Credits: luchschenF/Shutterstock.com
How do neurons in the amygdala form ensembles, and what is the significance of neuromodulation in controlling ensemble activity?
Neurons in the amygdala form ensembles that respond to certain stimuli—some respond to positive stimuli like sucrose, while others respond to negative stimuli like quinine. What is remarkable is how these ensembles work in opposition to one another.
For example, quinine can inhibit neurons that have been stimulated by sucrose and vice versa. We believe neuromodulation, particularly norepinephrine from the LC, is critical for controlling the activity of these ensembles.
This dynamic modulation scaling may help balance varying ensemble responses, regulating how an organism responds to both positive and negative stimuli. It could enable the brain to manage emotional reactions and behaviors in a context-dependent manner.
What challenges are associated with imaging and recording neuronal activity in the locus coeruleus, and how were these overcome?
The LC is a difficult region to work with for a variety of reasons. It is located deep in the brain and contains a tiny number of neurons, making imaging and recording difficult. One of the most difficult issues we faced was capturing stable recordings of neural activity while concurrently activating these neurons.
To solve this, we employed multi-photon microscopy in conjunction with advanced lens techniques such as prism lenses to penetrate deep into the brain and record neuronal activity. Combining these technologies has enabled us to both stably record as well as manipulate LC neuron activity in an awake and behaving mouse.
How does stress, such as exposure to predator odor, affect LC neuron activity, and what are the implications for norepinephrine release in the amygdala?
Stressors, such as the odor of a predator odor to a rodent, trigger synchronized activity in the LC, leading to significant norepinephrine release. We believe this synchronized LC activity amplifies the gain of neural ensembles downstream in the amygdala, heightening their sensitivity.
Our findings indicate that the increased norepinephrine release enhances anxiety-like behaviors by intensifying neuronal responses in the amygdala. During stress, the synchronized firing of LC neurons plays a crucial role in generating excessive emotional responses, further promoting an anxious state.
What effect does optogenetic stimulation of the LC-amygdala pathway have on anxiety-like behavior, and how is it modulated by norepinephrine receptors?
Using optogenetics, we were able to directly stimulate the LC-amygdala pathway and study its impact on anxiety-like behavior.
When we engaged in this route, we saw an increase in anxiety-like behaviors, which is consistent with the involvement of norepinephrine in the amygdala. Interestingly, pharmacological blockade of beta-adrenergic receptors caused a shift in how these neurons responded to stress, while a specific genetic knock out of beta-2 adrenergic receptors lead to more active coping behaviors rather than passive anxiety-like responses.
This demonstrates that norepinephrine receptors, particularly beta-adrenergic receptors, play a vital role in how the brain processes stress and anxiety.
How do different neurons in the amygdala respond to stimuli of opposing valence (e.g., sucrose Vs. quinine), and what mechanisms underlie this antagonistic activity?
In the amygdala, neurons respond to both positive and negative stimuli, such as sucrose and quinine. We discovered that these neurons frequently exhibit opposite activity patterns; when one group is activated, the other is suppressed.
For example, when sucrose-responsive neurons are excited, quinine-responsive neurons become inhibited, and vice versa. This mutual inhibition implies a tightly regulated mechanism in which opposing ensembles interact to maintain emotional balance. We suspect that interneurons or other intermediate processes are mediating this antagonistic interaction, although we are actively exploring.
What insights do multi-photon microscopy and optogenetics provide in manipulating specific neuronal ensembles to alter behavior related to valence stimuli?
Multi-photon microscopy and optogenetics enable us to precisely target and control specific neuronal ensembles in the amygdala while also observing how these changes affect behavior.
For example, by stimulating neurons that respond to sucrose or quinine, we were able to manipulate mouse behavior in response to these stimuli. Specifically activating sucrose-responsive neurons enhanced the mice's likelihood of consuming a liquid it previously found unpleasent, whereas activating quinine-responsive neurons reduced positive actions, such as licking for sucrose.
These techniques offer amazing accuracy, allowing us to investigate how single neurons and their connections influence behavior.
How does synchronous activity in LC and amygdala neurons impact behavior, and what is the role of beta-adrenergic receptors in mediating these effects?
Anxiety-like actions are mostly driven by synchronous activity in LC and amygdala neurons. When the LC fires in a very synchronized manner, it causes a coordinated release of norepinephrine, which boosts the responsiveness of amygdale neurons. This increased neuronal synchronization improves emotional reactions, especially during stress.
Beta-adrenergic receptors, particularly the beta-2 subtype, are critical in mediating these actions. In tests where we shut down beta-2 receptors, we saw a decrease in anxiety-like behavior, indicating that these receptors are important in how the brain processes stress and regulates emotional responses.
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About the Speaker
Sean completed his doctoral work in the laboratory of Dr. Susanne Ahmari at the University of Pittsburgh where he used mouse models to study the functional contributions of the orbitofrontal cortex and striatum in compulsive behavior. He is now a BRAIN Initiative K99 funded post-doctoral fellow at the University of Washington working in the laboratory of Dr. Michael Bruchas, where his work has demonstrated the causal relationship between discrete neuronal ensembles in the amygdala and valence-specific behavior.
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