Fear in nonthreatening contexts is a hallmark of anxiety disorders. The hippocampus' plays a critical role in recognizing a context as a previously experienced dangerous one or a safe one. We will study the ability to differentiate such contexts in rats. Rats have proven to be an excellent model of human anxiety disorders. Rats need a period to explore a context in order to learn that it is dangerous. Our data indicate that a period just long enough to support robust fear learning results in generalizing that fear to any similar context. They need a longer period to learn a specific fear that allows them to distinguish between danger and safety. We will study the biology of this type of learning. We will examine how a particular neuromodulator, acetylcholine (ACh), influences the ability for this learning and have discovered that stimulating this neuromodulatory system enhances the learning. Anxiety disorders are much more prevalent in women and we will test the hypothesis that at certain times during the female cycle, when metabolites of progesterone are high, they act to dampen the brain's response to this neuromodulator. This results in a state where fear learning will be more nonspecific and generalize to safe situations. To study this we will use optogenetics to selectively stimulate ACh and measure release of this neuromodulator with a novel biosensor implanted in a brain region responsible for learning. We will also measure the rhythms of brain activity produced by the neuromodulator, the ability to learn fear and to differentiate safe and dangerous environments. We will compare male and female rats and also compare females in different stages of their cycle. This will provide a deeper understanding of why anxiety disorders develop and why they are more prevalent in women.
In the United States, it is estimated that the lifetime prevalence of anxiety disorders in almost 30%, with a 60% greater incidence in woman than men. This high prevalence is likely caused by evaluation favoring strategies that lead us to treat ambiguous situations as threatening resulting in fear in safe environments. Therefore this grant examines the biological mechanisms that allow us to classify situations as dangerous or safe.
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