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The medial prefrontal cortex (mPFC) is involved in a variety of important functions including emotional regulation, HPA axis regulation, and working memory. It also demonstrates remarkable plasticity in an experience-dependent manner. There is extensive evidence that stressful experiences can produce profound changes in the morphology of neurons within mPFC with a variety of behavioral consequences. The deleterious behavioral outcomes associated with mPFC dysfunction have been implicated in multiple psychopathologies, including post-traumatic stress disorder (PTSD). Given the prevalence of these disorders, a deeper understanding of the cellular mechanisms underlying stress-induced morphological changes in mPFC is critical, and could lead to improved therapeutic treatments. Here we give a brief review of recent studies examining the mechanisms underlying changes in mPFC pyramidal neuron dendritic spines - the primary sites of excitatory input in cortical pyramidal neurons. We begin with an overview of the effects of chronic stress on mPFC dendritic spine density and morphology followed by proposed mechanisms for these changes. We then discuss the time course of stress effects on mPFC as well as potential intercellular influences. Given that many psychopathologies, including PTSD, have different prevalence rates among men and women, we end with a discussion of the sex differences that have been observed in morphological changes in mPFC. Future directions and implications for PTSD are discussed throughout., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Neonatal maternal separation impairs adult eyeblink conditioning. This impairment is correlated with increases in adult glucocorticoid receptor (GR) expression in the posterior interpositus nucleus [A.A. Wilber, C. Southwood, G. Sokoloff, J.E. Steinmetz, C.L. Wellman, Neonatal maternal separation alters adult eyeblink conditioning and glucocorticoid receptor expression in the interpositus nucleus of the cerebellum, Developmental Neurobiology 67 (2007) 1751-1764], a key structure in the neural circuitry controlling eyeblink conditioning. To further localize this effect, we assessed adult eyeblink conditioning and GR expression in projection versus interneurons in the interpositus of rats that had undergone standard rearing or maternal separation (1h/day) on postnatal days 2-14. At 3 months of age, interpositus neurons were labeled with the retrograde tracer biotinylated dextran amine (BDA). After delay eyeblink conditioning, brains were processed immunohistochemically for GR and BDA labeling of interpositus neurons. GR expression was quantified in BDA-labeled and unlabeled neurons. Neonatal maternal separation impaired adult eyeblink conditioning. Control rats had significantly less GR expression in posterior interpositus BDA-unlabeled versus BDA-labeled neurons, but this difference was absent in maternally separated rats. While neonatal separation significantly increased GR expression in BDA-labeled and unlabeled posterior interpositus neurons, only GR expression in non-BDA-labeled neurons was associated with eyeblink conditioning. Thus, neonatal maternal separation may alter interneuronal modulation of interpositus output neurons, producing deficits in adult eyeblink conditioning.

The NMDA subtype of glutamate receptors mediates a variety of neuronal processes involved in the development of dendritic morphology. For example, NMDA receptor antagonism during the early postnatal period attenuates dendritic growth in spinal motoneurons. NMDA receptors are present in high levels in the spinal cord early in the postnatal period and decline during development, a period of extensive dendritic plasticity in the spinal cord. Previous studies have suggested that an adult pattern of distribution of NMDA receptors is established as early as postnatal day (P)21 (day of birth = P1). However, given that dendritic growth in spinal motoneurons is not complete by this age and that NMDA receptor activation is necessary for dendritic growth, we assessed NMDA receptor binding in specific spinal motor nuclei during normal development. NMDA receptors were labeled with [3H]MK-801 at P7, P14, P28, P49, and in adult male rats. Receptor binding in the spinal nucleus of the bulbocavernosus (SNB), dorsolateral nucleus (DLN) and retrodorsolateral nucleus (RDLN) was measured using in vitro quantitative autoradiography. NMDA receptor binding over the SNB, DLN and RDLN in intact males was initially high, and declined to adult levels. However, the time course of the decline differed across nuclei. The local decline in NMDA receptor binding observed in the SNB and DLN is coincident with the periods of dendritic growth in these nuclei, further supporting a role for NMDA receptors in the development of motoneuron dendritic morphology.

Apical dendrites of pyramidal neurons in medial prefrontal cortex are reorganized after chronic corticosterone treatment. In this study, we assessed the effects of chronic corticosterone administration on dendritic spines. Adult male rats received sc injections of either corticosterone or vehicle daily for 3 weeks or were left untreated. Layer II-III neurons in medial prefrontal cortex were stained using a Golgi-Cox procedure and spines were counted on the portions of apical dendrites where maximal corticosterone-induced dendritic changes occur. In vehicle- and corticosterone-treated rats, spine density proximal to the soma was increased relative to untreated rats, while spine density in the distal portion of the apical arbor was unchanged, suggesting that daily handling alone altered spine density. This stress-induced change in spine density likely reflects important functional changes in excitatory synaptic inputs in prefrontal cortex.