The Role of the Medial Prefrontal Cortex in the Conditioning and Extinction of Fear

Abstract

Once acquired, a fearful memory can persist for a lifetime. Although learned fear can be extinguished, extinction memories are fragile. The resilience of fear memories to extinction may contribute to the maintenance of disorders of fear and anxiety, including post-traumatic stress disorder (PTSD). As such, considerable effort has been placed on understanding the neural circuitry underlying the acquisition, expression, and extinction of emotional memories in rodent models as well as in humans. A triad of brain regions, including the prefrontal cortex, hippocampus, and amygdala, form an essential brain circuit involved in fear conditioning and extinction. Within this circuit, the prefrontal cortex is thought to exert top-down control over subcortical structures to regulate appropriate behavioral responses. Importantly, a division of labor has been proposed in which the prelimbic (PL) and infralimbic (IL) subdivisions of the medial prefrontal cortex (mPFC) regulate the expression and suppression of fear in rodents, respectively. Here, we critically review the anatomical and physiological evidence that has led to this proposed dichotomy of function within mPFC. We propose that under some conditions, the PL and IL act in concert, exhibiting similar patterns of neural activity in response to aversive conditioned stimuli and during the expression or inhibition of conditioned fear. This may stem from common synaptic inputs, parallel downstream outputs, or cortico-cortical interactions. Despite this functional covariation, these mPFC subdivisions may still be coding for largely opposing behavioral outcomes, with PL biased towards fear expression and IL towards suppression.

Acute exercise enhances the consolidation of fear extinction memory and reduces conditioned fear relapse in a sex-dependent manner

“…Indeed, acute increases in each of these factors can enhance fear extinction (for review, see Fitzgerald et al 2014;Myskiw et al 2014;Singewald et al 2015), although in some cases the effects on fear relapse is not well established. The prefrontal cortex (mPFC), particularly the infralimbic region, is well known to be involved in fear extinction learning and memory (Do-Monte et al 2015;Giustino and Maren 2015), and it is possible that exercise facilitates prefrontal mechanisms underlying extinction. Plasticity factors such as BDNF (Neeper et al 1995) and mammalian target of rapamycin (Lloyd et al 2017) are increased in the mPFC following at least a few days of wheel running, although whether a few hours of wheel running is enough to up-regulate plasticity factors in the mPFC is unknown.…”

Recovery from Posttraumatic Stress Requires Dynamic and Sequential Shifts in Amygdalar Connectivities

“…Maladaptive processing of fear memory can entail excessive anxiety (Shin and Liberzon, 2010;Pitman et al, 2012;Giustino and Maren, 2015;Admon et al, 2013;Yehuda and LeDoux, 2007), which may lead to the development of anxiety disorders, such as posttraumatic stress disorder (PTSD).…”

Ethanol Increases Mechanical Pain Sensitivity in Rats via Activation of GABAA Receptors in Medial Prefrontal Cortex

“…Some human neuroimaging studies have suggested that alcohol-dependence and chronic pain may also share mechanisms through amygdala-medial prefrontal cortex (mPFC) interactions [2]. The mPFC, a cortical structure that includes the prelimbic (PrLC), infralimbic (ILC), and anterior cingulate cortex (ACC) [4][5][6], has been demonstrated to be involved in pain processing [7][8][9][10][11][12][13][14]. More recently, we also demonstrated that the mPFC is involved in the mediation of empathy for pain in rats, a phenomenon in which the mechanical pain sensitivity and spinal nociceptive responses of rats are dramatically increased after social interaction with a cagemate (but not a non-cagemate) in pain [15].…”