Preclinical studies of stress, extinction, and prefrontal cortex: intriguing leads and pressing questions
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Stress is associated with cognitive and emotional dysfunction, and increases risk for a variety of psychological disorders, including depression and posttraumatic stress disorder. Prefrontal cortex is critical for executive function and emotion regulation, is a target for stress hormones, and is implicated in many stress-influenced psychological disorders. Extinction of conditioned fear provides an excellent model system for examining how stress-induced changes in corticolimbic structure and function are related to stress-induced changes in neural function and behavior, as the neural circuitry underlying this behavior is well characterized.
This review examines how acute and chronic stress influences extinction and describes how stress alters the structure and function of the medial prefrontal cortex, a potential neural substrate for these effects. In addition, we identify important unanswered questions about how stress-induced change in prefrontal cortex may mediate extinction deficits and avenues for future research.
A substantial body of work demonstrates deficits in extinction after either acute or chronic stress. A separate and substantial literature demonstrates stress-induced neuronal remodeling in medial prefrontal cortex, along with several key neurohormonal contributors to this remodeling, and there is substantial overlap in prefrontal mechanisms underlying extinction and the mechanisms implicated in stress-induced dysfunction of—and neuronal remodeling in—medial prefrontal cortex. However, data directly examining the contribution of changes in prefrontal structure and function to stress-induced extinction deficits is currently lacking.
Understanding how stress influences extinction and its neural substrates as well as individual differences in this effect will elucidate potential avenues for novel interventions for stress-sensitive disorders characterized by deficits in extinction.
KeywordsChronic stress Infralimbic cortex Prelimbic cortex Extinction
This work was supported in part by National Institute of Health Award Number T32MH103213, National Institute of Health Award Number T32HD049336, and National Institute of Health Award Number UL1TR001108.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- Ball KT, Stone E, Best O, Collins T, Edson H, Hagan E, Nardini S, Neuciler P, Smolinsky M, Tosh L, Woodlen K (2018) Chronic restraint stress during withdrawal increases vulnerability to drug priming-induced cocaine seeking via a dopamine D1-like receptor-mediated mechanism. Drug Alcohol Depend 187:327–334PubMedGoogle Scholar
- Bouton ME, Ricker ST (1994) Renewal of extinguished responding in a second context. Anim Learn Behav 22:317–324Google Scholar
- Calabrese F, Molteni R, Racagni G, Riva MA (2009) Neuronal plasticity: a link between stress and mood disorders. Psychoneuroendocrinol 34. Supplement 1:S208–S216Google Scholar
- Chiba S, Numakawa T, Ninomiya M, Richards MC, Wakabayashi C, Kunugi H (2012) Chronic restraint stress causes anxiety- and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brain-derived neurotrophic factor in the prefrontal cortex. Prog Neuro-Psychopharmacol Biol Psychiatry 39:112–119Google Scholar
- Godar SC, Bortolato M, Richards SE, Li FG, Chen K, Wellman CL, Shih JC (2015) Monoamine oxidase a is required for rapid dendritic remodeling in response to stress. Int J Neuropsychopharmacol 18:1–12Google Scholar
- Grillo CA, Risher M, Macht VA, Bumgardner AL, Hang A, Gabriel C, Mocaër E, Piroli GG, Fadel JR, Reagan LP (2015) Repeated restraint stress-induced atrophy of glutamatergic pyramidal neurons and decreases in glutamatergic efflux in the rat amygdala are prevented by the antidepressant agomelatine. Neuroscience 284:430–443PubMedGoogle Scholar
- Lechin F, Van der Dijs B, Benaim M (1996) Stress versus depression. Prog Neuro-Psychopharmacol Biol Psychiatry 20:899–950Google Scholar
- Li N, Liu R-J, Dwyer JM, Banasr M, Lee B, Son H, Li X-Y, Aghajanian G, Duman RS (2011) Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 59:754–761Google Scholar
- Lin GL, Borders CB, Lundewall LJ, Wellman CL (2015) D1 receptors regulate dendritic morphology in normal and stressed prelimbic cortex. Psychoneuroendocrinol 51:101–111Google Scholar
- Maren S, Holmes A (2016) Stress and fear extinction. Neuropsychopharmacol Rev 41:58–79Google Scholar
- McEwen BS (2017) Allostasis and the epigenetics of brain and body health over the life course: the brain on stress. JAMA Psychiatr 74:551–552Google Scholar
- McKlveen JM, Morano RL, Fitzgerald M, Zoubovsky S, Cassella SN, Scheimann JR, Ghosal S, Mahbod P, Packard BA, Myers B, Baccei ML, Herman JP (2016) Chronic stress increases prefrontal inhibition: a mechanism for stress-induced prefrontal dysfunction. Biol Psychiatry 80:754–764PubMedPubMedCentralGoogle Scholar
- Milad MR, Quirk GJ (2002) Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420:70–74Google Scholar
- Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates, 6th edn. Academic Press, LondonGoogle Scholar
- Popoli M, Yan Z, McEwen BS, Sanacora G (2012) The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci 13:22–37Google Scholar
- Quirk GJ, Russo GK, Barron JK, Lebron K (2000) The role of ventromedial prefrontal cortex in the recovery of extinguished fear. J Neurosci 20:6225–6231Google Scholar
- Risch N, Herrell R, Lehner T, Liang KY, Eaves L, Hoh J, Griem A, Kovacs M, Ott J, Merikangas KR (2009) Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression a meta-analysis. J Am Med Assoc 301:2462–2471Google Scholar
- Rosenkranz JA, Grace AA (2001) Dopamine attenuates prefrontal cortical suppression of sensory inputs to the basolateral amygdala of rats. J Neurosci 21:4090–4103Google Scholar
- Sinclair D, Purves-Tyson T, Allen K, Weickert C (2014) Impacts of stress and sex hormones on dopamine neurotransmission in the adolescent brain. Psychopharmacol 231:1581–1599Google Scholar
- Sotres-Bayon F, Bush DEA, LeDoux JE (2004) Emotional perseveration: an update on prefrontal-amygdala interactions in fear extinction. Learn Mem 11:525–535Google Scholar
- Vyas A, Mitra R, Shankaranarayana Rao BS, Chattarji S (2002) Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J Neurosci 22:6810–6818Google Scholar
- Wellman CL (2001) Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration. J Neurobiol 49:245–253Google Scholar