Prefrontal impairment with stress- NE receptor subtype mechanisms.

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Abstract- The dorsolateral prefrontal cortex (dlPFC) mediates working memory and top-down control, but is impaired by acute or chronic stress, and is dysfunctional in most mental disorders. Stress exposure increases norepinephrine (NE) release, which strengthens amygdala emotional responses via (β-AR and α1-AR, but weakens the dlPFC via α1-AR, while the role(s) of β-AR are unknown. Based on this work, the general α1-AR antagonist, prazosin, and β-AR antagonist, propranolol, are used to treat Post-Traumatic Stress Disorder (PTSD). However, prazosin and propranolol are not always effective, and findings suggest that some subtypes of α1-AR and β-AR may benefit PFC, and thus antagonists that block all subtypes may be counterproductive. The proposed research will perform the first study of α1-AR (α1A-AR, α1B-AR, α1D-AR) and β-AR (β1-AR, β2- AR, β3-AR) subtype actions in rhesus monkey dlPFC, using multiple label immunofluorescence to localize α1- AR and β-AR subtypes on pyramidal cells, GABAergic interneurons, astrocytes and microglia, and immunoEM to reveal ultrastructural locations, e.g. at pre-synaptic release sites or on dendritic spines in layer III dlPFC. We will use iontophoresis coupled with single unit recordings of dlPFC neurons in monkeys performing a working memory task to determine how stimulation of α1-AR and β-AR subtypes alters task-related neuronal firing, and their second messenger actions. We will also use systemic administration of α1-AR and β-AR subtype selective antagonists to block stress-induced working memory deficits, and test whether selective agent(s) are more potent and efficacious than the currently used, nonselective agents, prazosin or propranolol, and whether low doses of more selective antagonists can restore cognition with fewer side effects. Aim 1 will characterize the roles of α1-AR subtypes, examining their localization (Aim 1A), physiological actions in dlPFC (Aim 1B), and effects on working memory performance during a mild, acute stressor (Aim 1C). Preliminary data indicate that the α1A-AR subtype markedly reduces working memory-related dlPFC neuronal firing, and that a selective α1A-AR antagonist potently blocks stress-induced cognitive deficits, suggesting a superior strategy for therapeutics. Aim 2 will characterize β-AR subtypes, examining their localization (Aim 2A), physiological actions in dlPFC (Aim 2B), and effects on working memory performance during a mild, acute stressor (Aim 2C). Preliminary data indicate that the β1-AR subtype markedly reduces working memory-related dlPFC neuronal firing, and that a selective β1-AR antagonist blocks stress-induced cognitive deficits. In heart muscle, the “fight or flight” stress response is mediated by β1-AR opening of voltage-gated Cav1.2 Ca2+ channels (encoded by CACNA1C), and our preliminary data indicate that detrimental β1-AR actions in primate dlPFC involve similar actions, helping to explain why gain-of-function mutations in CACNA1C increase risk of mental disorders with impaired dlPFC function, including PTSD. Identifying the subtypes of α1-AR and β-AR that impair dlPFC function will help the design of more effective therapies for stress-related mental disorders.