Chronic stress alters neural activity in medial prefrontal cortex during retrieval of extinction

Abstract

Chronic restraint stress produces morphological changes in medial prefrontal cortex and disrupts a prefrontally mediated behavior, retrieval of extinction. To assess potential physiological correlates of these alterations, we compared neural activity in infralimbic and prelimbic cortex of unstressed versus stressed rats during fear conditioning and extinction. After implantation of microwire bundles into infralimbic or prelimbic cortex, rats were either unstressed or stressed via placement in a plastic restrainer (3 h/day for 1 week). Rats then underwent fear conditioning and extinction while activity of neurons in infralimbic or prelimbic cortex was recorded. Percent freezing and neural activity were assessed during all phases of training. Chronic stress enhanced freezing during acquisition of conditioned fear, and altered both prelimbic and infralimbic activity during this phase. Stress did not alter initial extinction or conditioned stimulus (CS)-related activity during this phase. However, stress impaired retrieval of extinction assessed 24 h later, and this was accompanied by alterations in neuronal activity in both prelimbic and infralimbic cortex. In prelimbic cortex, unstressed rats showed decreased activity in response to CS presentation, whereas stressed rats showed no change. In infralimbic cortex, neurons in unstressed rats exhibited increased firing in response to the CS, whereas stressed rats showed no increase in infralimbic firing during the tone. Finally, CS-related firing in infralimbic but not prelimbic cortex was correlated with extinction retrieval. Thus, the stress-induced alteration of neuronal activity in infralimbic cortex may be responsible for the stress-induced deficit in retrieval of extinction.

Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction

“…In vivo recordings have demonstrated that activity within the PL cortex, the region of the mPFC where we studied LTD, is correlated with freezing behavior during fear extinction (32,(38)(39)(40). During states of high fear and freezing, neurons within the PL will display robust firing in response to fear cues, such as a tone CS.…”

Single prolonged stress disrupts retention of extinguished fear in rats

“…Exposure to other kinds of stressors also induces deficits in extinction retention. These include brief uncontrollable stress (Izquierdo et al 2006), chronic stress (Miracle et al 2006;Garcia et al 2008;Baran et al 2009;Wilber et al 2011), and footshock stress (Rau et al 2005;Maren and Chang 2006). Also, animals that are vulnerable to the effects of stress show extinction retention deficits (Goswami et al 2010).…”

“…Exposing animals to brief uncontrollable and chronic stress prior to fear conditioning, or conducting fear conditioning in animals that are vulnerable to stress, enhances cued conditioned responding during fear conditioning and/or fear extinction (Izquierdo et al 2006;Miracle et al 2006;Goswami et al 2010;Wilber et al 2011), which suggests that stress-induced changes in fear memory may contribute to changes in extinction retention. This interpretation is also supported by the observation that, when the cue and the footshock presentations are not explicitly paired during fear conditioning (i.e., pseudoconditioning), chronic stress pre-exposure has no effect on extinction retention (Baran et al 2009;Wilber et al 2011). SPS exposure prior to fear conditioning disrupted extinction retention without having any effects on acquisition or expression of conditioned fear.…”

“…Studies that have specifically focused on the neurobiology of stress-induced extinction retention deficits also suggested that stress-induced changes in IL cortical function may underlie stress-induced extinction retention deficits (Izquierdo et al 2006;Baran et al 2009;Wilber et al 2011). For example, stressinduced retraction of apical dendrites in the IL is associated with extinction retention deficits (Izquierdo et al 2006;Miracle et al 2006), and rats exposed to chronic stress show deficits in extinction retention and fail to show an enhancement in single unit activity in the IL cortex during extinction retention testing (Wilber et al 2011).…”

“…For example, stressinduced retraction of apical dendrites in the IL is associated with extinction retention deficits (Izquierdo et al 2006;Miracle et al 2006), and rats exposed to chronic stress show deficits in extinction retention and fail to show an enhancement in single unit activity in the IL cortex during extinction retention testing (Wilber et al 2011). On the molecular level, repeated stress exposure enhances corticosterone-glucocorticoid receptor (GR) binding (Meaney et al 1985;Xu et al 1998;Liu and Aghajanian 2008;Gourley et al 2009) and excitatory neurotransmitter release (Moghaddam 1993;Martin and Wellman 2011), which then can disrupt IL function (McEwen 2001;Miracle et al 2006;Liu and Aghajanian 2008;Wilber et al 2011). While there are clearly differences between repeated stress exposure within chronic stress procedures and SPS, there may yet be intermediate outcomes (e.g., enhanced GR signaling), by which chronic stress and SPS induce extinction retention deficits.…”