Beta-adrenergic receptors support attention to extinction learning that occurs in the absence, but not the presence, of a context change

Abstract

The noradrenergic (NA)-system is an important regulator of cognitive function. It contributes to extinction learning (EL), and in disorders where EL is impaired NA-dysfunction has been postulated. We explored whether NA acting on beta-adrenergic-receptors (β-AR), regulates EL that depends on context, but is not fear-associated. We assessed behavior in an “AAA” or “ABA” paradigm: rats were trained for 3 days in a T-maze (context-A) to learn that a reward is consistently found in the goal arm, despite low reward probability. This was followed on day 4 by EL (unrewarded), whereby in the ABA-paradigm, EL was reinforced by a context change (B), and in the AAA-paradigm, no context change occurred. On day 5, re-exposure to the A-context (unrewarded) occurred. Typically, in control “AAA” animals EL occurred on day 4 that progressed further on day 5. In control “ABA” animals, EL also occurred on day 4, followed by renewal of the previously learned (A) behavior on day 5, that was succeeded (on day 5) by extinction of this behavior, as the animals realised that no food reward would be given. Treatment with the β-AR-antagonist, propranolol, prior to EL on day 4, impaired EL in the AAA-paradigm. In the “ABA” paradigm, antagonist treatment on day 4, had no effect on extinction that was reinforced by a context change (B). Furthermore, β-AR-antagonism prior to renewal testing (on day 5) in the ABA-paradigm, resulted in normal renewal behavior, although subsequent extinction of responses during day 5 was prevented by the antagonist. Thus, under both treatment conditions, β-AR-antagonism prevented extinction of the behavior learned in the “A” context. β-AR-blockade during an overt context change did not prevent EL, whereas β-AR were required for EL in an unchanging context. These data suggest that β-AR may support EL by reinforcing attention towards relevant changes in the previously learned experience, and that this process supports extinction learning in constant-context conditions.

Involvement of Dopamine D1/D5 and D2 Receptors in Context-Dependent Extinction Learning and Memory Reinstatement

“…Experiments were conducted in a T-maze that was composed of a starting box (25 × 20 cm) that was separated from the main corridor (100 × 20 cm) by a sliding door and two side corridors (40 × 10 cm) positioned perpendicular to the other end of the main corridor. The maze design and the protocol followed was as described previously (Wiescholleck et al, 2014 ; André et al, 2015a , b ). The context of the maze was changed by exchanging the plastic floor of the maze (zebra stripes, checkered patterns, or geometric lines), odor cues that were placed at the end of the goal arms, and exchanging the extra-maze cue cards that were placed 40 cm above the end of the main corridor (Wiescholleck et al, 2014 ).…”

“…Every day, rats engaged in a learning session that comprised 20 consecutive trials, that were split into two data blocks (1st ten, 2nd ten trials), for analysis purposes (see below, and Wiescholleck et al, 2014 ; André et al, 2015a , b ). The trial commenced when the door to the starting box was opened and the animal entered the maze.…”

“…Extinction learning does not eliminate or erase the original memory, but rather mediates the creation of a new representation that allows the animal to ignore its behavioral responses to the previously learned conditioned stimuli (Rescorla, 2001 ). This process is reinforced by a change of context (Bouton, 2004 ), even under non-aversive (appetitive) conditions (Wiescholleck et al, 2014 ; André et al, 2015a , b ). Reinstatement, or renewal, of the original conditioned response is typically reactivated upon re-exposure to the CS in the original context, or to conditions that are sufficiently dissimilar to the extinction context (Rachman, 1989 ; Bouton, 2004 ; Craske et al, 2008 ).…”

“…Recently, we reported that neurotransmitter receptor manipulations that are known to directly influence hippocampal synaptic plasticity and hippocampus-dependent learning, also modulate context-dependent extinction learning (André et al, 2015a , b ). It has also been shown that the hippocampus contributes to context-dependent extinction learning and renewal of fear memory (Good and Honey, 1991 ; Ji and Maren, 2005 ; Hobin et al, 2006 ; de Carvalho Myskiw et al, 2014 ; Portugal et al, 2014 ; Tan et al, 2014 ).…”

The DA antagonist tiapride impairs context-related extinction learning in a novel context without affecting renewal

“…In consequence, it is conceivable that the renewal effect is dependent on attentional and encoding processes that occur during extinction learning and thus may be mediated by neurotransmitter systems involved in learning and attention, such as the noradrenergic and dopaminergic systems (Lauzon et al, 2009 ). Recent studies in humans and rats meanwhile showed that while stimulation of the noradrenergic system actually enhanced extinction learning, it had no impact upon the strength of the renewal effect (André et al, 2015 ; Lissek et al, 2015 ).…”