β-Adrenergic Receptors Regulate the Acquisition and Consolidation Phases of Aversive Memory Formation Through Distinct, Temporally Regulated Signaling Pathways

Abstract

Memory formation requires the temporal coordination of molecular events and cellular processes following a learned event. During Pavlovian threat (fear) conditioning (PTC), sensory and neuromodulatory inputs converge on post-synaptic neurons within the lateral nucleus of the amygdala (LA). By activating an intracellular cascade of signaling molecules, these G-protein-coupled neuromodulatory receptors are capable of recruiting a diverse profile of plasticity-related proteins. Here we report that norepinephrine, through its actions on β-adrenergic receptors (βARs), modulates aversive memory formation following PTC through two molecularly and temporally distinct signaling mechanisms. Specifically, using behavioral pharmacology and biochemistry in adult rats, we determined that βAR activity during, but not after PTC training initiates the activation of two plasticity-related targets: AMPA receptors (AMPARs) for memory acquisition and short-term memory and extracellular regulated kinase (ERK) for consolidating the learned association into a long-term memory. These findings reveal that βAR activity during, but not following PTC sets in motion cascading molecular events for the acquisition (AMPARs) and subsequent consolidation (ERK) of learned associations.

Noradrenergic Regulation of Central Amygdala in Aversive Pavlovian-to-Instrumental Transfer

“…In contrast, although it is well established that noradrenergic (NE) neuromodulation in the amygdala regulates aversive learning (Murchison et al, 2004; Gertner and Thomas, 2006; Bush et al, 2010; Tully and Bolshakov, 2010; Johansen et al, 2011; Ferry and Quirarte, 2012; Sears et al, 2014; Schiff et al, 2016), a role for NE in aversive PIT is not known. …”

A brainstem-central amygdala circuit underlies defensive responses to learned threats

“…Studies using other aversive learning paradigms such as inhibitory avoidance also find an important role for NE activity in amygdala, although there are discrepancies when compared to PTC [29][30][31]48 . For example, NE signaling in the lateral and/or basolateral amygdala is required for memory acquisition in PTC but not for inhibitory avoidance 1,2,[29][30][31]48 . These differences suggest that distinct behavioral and neural processes may underlie each task.…”

“…LC stimulation or noxious stimuli (e.g., footshock) modulate the basolateral region of the amygdala (BLA) 24,25,27 , and studies suggest that this is through direct NE activity at β-adrenergic receptors (β-ARs) 2, [28][29][30][31] . Notably, β-ARs in the LA are critical for initial acquisition (and indirectly for consolidation 2 processes), but not expression of Pavlovian threat memories 1,2 , and in BLA (which includes LA and BA), for conditioned place aversion and anxietylike behaviors 32 . Although much work on the role of NE in the amygdala has focused on the BLA, the CeA also receives significant NE inputs from the LC 33,34,35,36 .…”

Transient global amnesia: The cerebral Takotsubo?

“…Since the locus coeruleus modulates inhibition and facitilation of pain it is conceivable that stress may contribute to the maintenance or enhancement of hyperalgesia [4]. A second argument derives from studies in adult rats undergoing Pavlovian threat (fear) conditioning (PTC) which induces memory formation [5]. After PTC, beta-adrenergic stimulation no longer initiates the activation of AMPA-receptors for memory acquisition and short-term memory and activation of the extracellular regulated kinase (ERK) for consolidating the learned association into a long-term memory [5].…”

“…A second argument derives from studies in adult rats undergoing Pavlovian threat (fear) conditioning (PTC) which induces memory formation [5]. After PTC, beta-adrenergic stimulation no longer initiates the activation of AMPA-receptors for memory acquisition and short-term memory and activation of the extracellular regulated kinase (ERK) for consolidating the learned association into a long-term memory [5]. Furthermore, memory processing in chickens is regulated by noradrenalin and serotonine [6].…”