Researchers Isolate Two Brain Regions that Generate Anxiety
As different from a reaction to fear or a real, immediate threat, Anxiety is the anticipation of a threat in the near future. The symptoms of Anxiety disorders and the treatment of those symptoms are fundamentally understood, but the neurology of Anxiety is extremely tricky to study. For instance, researchers are aware that dysregulation of the orbitofrontal and ventrolateral prefrontal cortices are implicated in Anxiety and mood disorders, but the specific contributions of each region are not known.
A group of researchers at the University of Cambridge developed a study to measure the contributions of these regions in the Anxiety responses of marmosets. They have published their findings in the Proceedings of the National Academy of Sciences.
In patients experiencing Anxiety, the fear of negative outcomes has a strong negative influence on decision-making, often resulting in distress, social isolation and adverse health conditions. Sensitivity to threat is vital for the survival of an organism, but hypersensitivity and overestimation of future threats hinder proper cost-benefit decision- making in patients suffering from Anxiety and mood disorders.
Previous studies have suggested that this hypersensitivity is due to dysregulation within the prefrontal cortex, but questions persist regarding how this region affects aversive processing and the effect of negative emotional valence in decision-making.
Knowing that excitotoxic lesions on either the anterior orbitofrontal cortex or ventrolateral prefrontal cortex heighten Anxiety and fear responses in marmosets, the researchers designed an experiment to study the responses of test monkeys with temporary inactivation of these regions.
Marmosets were trained to react to two identical visual stimuli presented on each side of a touchsscreen to earn a reward of banana juice. The visual stimuli were presented on independent but identical variable-interval schedules so that the optimal strategy for maximizing reward delivery would be a relatively equal response to both stimuli.
During the course of the experiment, researchers observed the response biases of individual monkeys; each monkey favored one side of the screen or the other. Once a week, responses on one of the two stimuli would produce delivery of a punishment: an aversive loud noise that was superimposed on the unchanged reward schedule. In order to avoid spatial bias contributing to a punishment-induced bias, the punishment was always introduced on the individual monkey’s “preferred” side.
In lieu of reward, the sound produced a strong aversive response. However, when the punishment and reward were delivered simultaneously, the monkeys did not alter their behavior; the researchers conclude that the banana juice reward was “worth” responding for, despite the possibility of the punishment.
The researchers then conducted the same experiment after the inactivation of either the anterior orbitofrontal cortex or ventrolateral prefrontal cortex with a GABA agonist 20 minutes before test sessions. The inactivation of one of the two regions had no effect on responses when the test produced reward but no punishment; however, when punishment was delivered for responses on one side of the screen, animals with inactivation of the ventrolateral interior prefrontal cortex produced a strong, immediate response was to avoid the punishment.
The researchers observed no delayed or long-lasting effects when those animals were tested the subsequent day with a reward-only session. Bias developed in test animals during the reward-punishment sessions, but did not endure. Control animals that were infused with saline instead of the GABA agonist showed unchanged responses to the test in the presence of both reward and punishment.
Nonetheless, animals with inactivated anterior orbitofrontal cortices showed no effects during reward-punishment sessions, but did show a profound bias away from the previously punished side the next day. Thus, the researchers associate the activity of the vlPFC with cost-benefit analyses and the antOFC with the consolidation of memory for the punishment.
Hypothesizing that the formation of memory in anti-punishment bias was based in the amygdala and hippocampus of the marmosets, the researchers cannulated the amygdalas and anterior hippocampi of the antOFC-cannulated animals. They discovered that the inactivation of either structure eliminated the anti-punishment bias in those animals, confirming those structures as agents for the consolidation of punishment memory.
Disconnecting the amygdala from the hippocampus had the same effect as bilateral inactivations of either structure, indicating that punishment memory formation is subserved by the amygdala-hippocampal circuit.
The researchers propose that in the future, cognitive behavioral therapy for patients troubled by Anxiety disorders could be tailored to correspond with the patient’s ability to make accurate cost-benefit analyses or to form memories that lead to strong anti-punishment biases. Such a determination could also point to either the ventrolateral prefrontal cortex or the anterior orbitofrontal cortex as therapeutic targets.
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