Affective anxiety is characterized by behavioral inhibition accompanied by cognitive arousal and vigilance, reflecting a future-oriented emotional state. Anxiety is an adaptive response to perceived threat; however, chronic anxiety is debilitating, and anxiety disorders are the most common type of mental illness in the United States. Identification of neural circuits that underlie behavioral responses to threat in animal models is essential for understanding neurobiological mechanisms that contribute to normative and pathological anxiety in humans. Basic and clinical research has emphasized the importance of the central nucleus of the amygdala (CEA) and the anterolateral bed nucleus of stria terminalis (alBST) in regulating affective and physiological components of anxiety. The CEA and alBST are heavily interconnected and share many common sources of input, including input from caudal brainstem neurons that convey sensory feedback from body to brain; this feedback strongly modulates emotional state, including threat responses. The proposed research will test new hypotheses regarding the organization and behavioral role of CEA/alBST-projecting brainstem neurons that express glucagon-like peptide-1 (GLP1). GLP1 neurons are activated to express cFos in rats after acute threat, and GLP1 receptor signaling in the CEA/alBST increases arousal/vigilance and behavioral inhibition/avoidance in rats, akin to anxiety in humans. We recently developed a transgenic Sprague Dawley rat (Gcg-Cre) in which Cre is efficiently and selectively expressed by GLP1 neurons in the caudal nucleus of the solitary tract and intermediate reticular nucleus (i.e., NTS/IRtGLP1 neurons). Using validated viral tools and behavioral assays in this new model organism, we will conduct comparative analyses of the synaptic connectivity and functional role of NTS/IRtGLP1 CEA/alBST circuits in male and female Gcg-Cre rats, including documentation of potential sex differences. Since the distribution of GLP1 neurons in brainstem and GLP1 receptors in limbic forebrain appears similar in rats and humans, results from this basic science project have potential translational relevance for understanding neurobiological bases of normal and pathological symptoms of anxiety in humans.
The proposed basic science research project will reveal the neural circuit connectivity and behavioral function of chemically-identified brainstem neurons that signal to the limbic forebrain to increase threat-induced emotional responses, akin to symptoms of anxiety in humans. For this, a new transgenic rat model will be used to target two specific groups of hindbrain neurons that express glucagon-like peptide 1 (GLP1) and project to the limbic forebrain. Given evidence that brainstem GLP1 neurons and limbic GLP1 receptors are similar in rats and humans, results from this basic science project have potential translational relevance for understanding the neurobiological bases of normal threat responses and pathological anxiety in humans.
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