Cognitive Flexibility Training Improves Extinction Retention Memory and Enhances Cortical Dopamine With and Without Traumatic Stress Exposure

Abstract

Stress exposure can cause lasting changes in cognition, but certain individual traits, such as cognitive flexibility, have been shown to reduce the degree, duration, or severity of cognitive changes following stress. Both stress and cognitive flexibility training affect decision making by modulating monoamine signaling. Here, we test the role cognitive flexibility training, and high vs. low cognitive flexibility at the individual level, in attenuating stress-induced changes in memory and monoamine levels using the single prolonged stress (SPS) rodent model of traumatic stress in male Sprague-Dawley rats. Exposure to SPS can heighten fear responses to conditioned cues (i.e., freezing) after a fear association has been extinguished, referred to as a deficit in extinction retention. This deficit is thought to reflect an impairment in context processing that is characteristic of posttraumatic stress disorder (PTSD). During a cognitive flexibility training we assessed individual variability in cognitive skills and conditioned rats to discriminately use cues in their environment. We found that cognitive flexibility training, alone or followed by SPS exposure, accelerated extinction learning and decreased fear responses over time during extinction retention testing, compared with rats not given cognitive flexibility training. These findings suggest that cognitive flexibility training may improve context processing in individuals with and without traumatic stress exposure. Individual performance during the reversal phase of the cognitive flexibility training predicted subsequent context processing; individuals with high reversal performance exhibited a faster decrease in freezing responses during extinction retention testing. Thus, high reversal performance predicted enhanced retention of extinction learning over time and suggests that cognitive flexibility training may be a strategy to promote context processing. In a brain region vital for maintaining cognitive flexibility and fear suppression, the prelimbic cortex (PLC), cognitive flexibility training also lastingly enhanced dopamine (DA) and norepinephrine (NE) levels, in animals with and without traumatic stress exposure. In contrast, cognitive flexibility training prior to traumatic stress exposure decreased levels of DA and its metabolites in the striatum, a region mediating reflexive decision making. Overall, our results suggest that cognitive flexibility training can provide lasting benefits by enhancing extinction retention, a hallmark cognitive effect of trauma, and prelimbic DA, which can maintain flexibility across changing contexts.

Cognitive training increases dendritic arborization in the dorsal hippocampal CA1 and CA3 neurons of female and male Long–Evans rats

“…We promoted CT through learning and memory tasks in tandem. CT is a process associated with rearrangements of synaptic connectivity at brain sites specific to memory that occur as a result of dendritic spine changes in response to stimuli (Ammassari‐Teule, ); this process possibly increases cognitive flexibility, defined as the capacity to shift behavioral strategies in a changing environment (Chaby, Karavidha, Lisieski, Perrine, & Liberzon, ).…”

Assessment of Stress Effects on Cognitive Flexibility using an Operant Strategy Shifting Paradigm

“…Researchers can choose to manipulate these neural substrates at different timepoints in conjunction with stress or strategy shifting, or alternatively measure neural substrates after exposure to these behavioral paradigms. This modified operant strategy shifting task has clear advantages over other cognitive flexibility paradigms used in the stress literature (i.e., the digging task [12][13][14][15] ), which require more time and effort by the experimenter to train rodents. This procedure requires minimal oversight by the experimenter and allows multiple rats to be tested simultaneously.…”

“…The operant strategy shifting paradigm does have certain limitations. One limitation is that it can only test two stimulus dimensions (e.g., left or right lever vs. light cue), whereas the digging task [12][13][14][15] can test a third stimulus dimension (e.g., digging media vs. odor vs. texture). However, the task described in this protocol still allows for testing of the rat's ability to shift to different rules, which allows testing of the cognitive flexibility constructs.…”

Repeated stress exposure in mid-adolescence attenuates behavioral, noradrenergic, and epigenetic effects of trauma-like stress in early adult male rats

“…SPS can induce an extinction retention deficit, in which fear is enhanced after a fear association has been extinguished, indicating the dominance of fear memory over extinction memory 44,65,67 . To test extinction retention, rats were trained on the 8th day following SPS to associate a tone with a shock across five shock-tone pairings in a fear conditioning chamber (day 1: fear conditioning; shock features: 1 s, 1 mA; tone: 10 s, 1 kHz, 80 dB, 60 s inter-trial-interval 65,69 ). Freezing responses were quantified as a proxy of fear 44,70 .…”

“…On the 9th day after SPS, rats were presented with the same tone 30 times without the shock to extinguish fear responses in a second context (day 2: fear extinction). The second context was differentiated by novel auditory, visual, tactile, and olfactory cues 65,69 . Finally, rats were returned to the extinction context on the 10th day after SPS and were re-exposed to the tone without the shock for 10 presentations (day 3: extinction retention).…”