β-adrenergic receptors set a molecular context for threat learning

Associative learning for threat conditioning relies on convergent information about the conditioned stimulus (CS-an auditory tone) and unconditioned stimulus (US-a mild footshock) relayed to lateral amygdala neurons. This strengthens CS synapses and results in a stronger behavioral response to the CS. Learning theory states that the strength of the memory for the CS is determined by the intensity of the US. Behavioral experiments support these theoretical predictions such that training with a weak US produces a weak memory, indicated by modest levels of freezing to later presentations of the CS alone; training with a strong US produces a strong memory. Little is known about how the brain regulates the strength of a conditioned memory. I pursued this question using pharmacological strengthening of memory to a weakly trained US and examining the molecular processes supporting the formation of different strengths of memory. I report that, within a certain range, memory strength can be scaled up and down by manipulations to the β-adrenergic receptor (βAR) similar to manipulating the strength of the US itself. These data support the notion that βARs contribute to memory formation by signaling information about the strength of the US. To that end, memory formation for strong threat conditioning is impaired when βARs in the lateral amygdala are blocked with the antagonist, propranolol. Conversely, activating βARs in the lateral amygdala with the agonist, isoproterenol, enhances weak memory. Activation of βARs in the lateral amygdala initiates at least two molecular signaling pathways. One results in the phosphorylation of the GluA1 subunit of AMPA receptors at the PKA site, ser845. Phosphorylation at this site is required for AMPA receptor insertion into the synaptic membrane—a process required for memory formation. The second pathway recruits extracellular signal regulated kinase (ERK). ERK activation is also required for memory formation for threat conditioning by regulating protein synthesis and gene expression. These are the first studies to show that βAR activation recruits GluA1 and ERK in the lateral amygdala with an effect on learning. Together they indicate that βAR activation, GluA1, and ERK set a molecular context in which strong learning can occur. I report that, within a certain range, strength of memory can be scaled up and down by manipulations to the adrenergic system, particularly the β-subtype of adrenergic receptor (βAR) in a manner that resembles the scaling of memory strength through manipulations to the strength of the US itself. These data, together with the knowledge that noradrenaline is released into the amygdala by footshocks, support the notion that βARs contribute to memory formation by signaling information about the strength of the US. To that end, memory formation for strong threat conditioning is impaired when βARs in the lateral amygdala are blocked with the antagonist, propranolol, specifically when it is administered before training. Conversely, activating βARs in the lateral amygdala with the agonist, isoproterenol (ISO), enhances weak memory when it is administered before training. The molecular mechanism underlying this effect was also explored. ISO administration to the lateral amygdala to activate βARs initiates at least two molecular signaling pathways. One results in the phosphorylation of the GluA1 subunit of AMPA receptors at the PKA site, ser845. Phosphorylation at this site has, in previous studies, been shown to be required for AMPA receptor insertion into the synaptic membrane--a process required for normal memory formation. The second pathway recruits extracellular signal regulated kinase (ERK). ERK activation is also required for normal memory formation for threat conditioning by regulating protein synthesis and gene expression. Together these data indicate that βAR activation, GluA1, and ERK set a molecular context in which strong learning can occur. These are the first studies to show that βAR activation recruits GluA1 and ERK in the lateral amygdala and that these actions have behavioral consequences