Cognitive impairment such as the inability to make advantageous decisions is one of the consequences of persistent pain but the underlying neural mechanisms are not known (NIH PA-06-544). The role of the prefrontal cortex in cognitive function, including decision-making and avoidance of emotion-based risky choices, is well established. Impaired prefrontal cortical function was recently shown in pain patients with cognitive deficits. A major source of input to the mPFC is the basolateral amygdala (BLA), a key element in the emotional-affective amygdala circuitry. Our previous studies showed enhanced synaptic transmission from the BLA to the central nucleus of the amygdala (CeA) in an arthritis pain model. We hypothesize that the BLA is an important structure underlying pain-related emotional-affective behavior (through projections to the CeA) and cognitive deficits (through connections with the mPFC). To determine the role of the BLA-mPFC interaction in cognitive effects of pain, we will use a multidisciplinary approach that combines behavior, systems and cellular electrophysiology and pharmacology. We will continue to use our well-established pain model, the kaolin/carrageenan-induced knee joint arthritis. The following specific hypotheses will be tested: 1. Restoring normal function in the BLA and mPFC improves pain-related decision-making deficits. 2. Pain-related sensitization of BLA projection neurons inhibits mPFC neurons. 3. Pain leads to synaptic plasticity in the BLA and increases inhibitory transmission from the BLA to mPFC neurons.
The Specific Aims are: 1. Determine if restoring normal function in the BLA (deactivation with APS, an NMDA receptor antagonist) and in the mPFC (removing inhibition with bicuculline, a GABAA receptor antagonist) improves pain-related cognitive impairment in a novel behavioral test modeled after a decision-making gambling task in humans. Arthritic and control animals decide between disadvantageous high-risk and advantageous low-risk strategies based on food reward. 2. Analyze the effect of arthritis on BLA and mPFC neurons and determine if inhibiting BLA sensitization (with APS) or disinhibiting the mPFC (with bicuculline) reverse pain-related inhibition of mPFC neurons in anesthetized rats in vivo. 3. Determine the effect of arthritis on excitatory and inhibitory synaptic transmission in the BLA and at the BLA-mPFC synapse in vitro, using whole-cell patch-clamp recordings in brain slices from arthritic and control animals. This translational research project will determine the neurobiological mechanism by which pain produces clinically documented cognitive deficits. If our hypotheses are correct, the proposed studies will be the first to demonstrate that the amygdala impairs mPFC function resulting in pain-related decision-making deficits. The long-term goal of this project is the better understanding of higher brain functions involved in the different pain components to improve pain management strategies and decision making.
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