Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting

Abstract

Stressful life events have been implicated clinically in the pathogenesis of mental illness, but the neural substrates that may account for this observation remain poorly understood. Attentional impairments symptomatic of these psychiatric conditions are associated with structural and functional abnormalities in a network of prefrontal cortical structures. Here, we examine whether chronic stress-induced dendritic alterations in the medial prefrontal cortex (mPFC) and orbital frontal cortex (OFC) underlie impairments in the behaviors that they subserve. After 21 d of repeated restraint stress, rats were tested on a perceptual attentional set-shifting task, which yields dissociable measures of reversal learning and attentional set-shifting, functions that are mediated by the OFC and mPFC, respectively. Intracellular iontophoretic injections of Lucifer yellow were performed in a subset of these rats to examine dendritic morphology in layer II/III pyramidal cells of the mPFC and lateral OFC. Chronic stress induced a selective impairment in attentional set-shifting and a corresponding retraction (20%) of apical dendritic arbors in the mPFC. In stressed rats, but not in controls, decreased dendritic arborization in the mPFC predicted impaired attentional set-shifting performance. In contrast, stress was not found to adversely affect reversal learning or dendritic morphology in the lateral OFC. Instead, apical dendritic arborization in the OFC was increased by 43%. This study provides the first direct evidence that dendritic remodeling in the prefrontal cortex may underlie the functional deficits in attentional control that are symptomatic of stress-related mental illnesses.

Figure 1.

A, Coronal hemisection of the prefrontal cortex [bregma 3.20 mm, adapted from Swanson (1992)] depicting ACg and lateral OFC regions of interest. B, C, Dendritic reconstructions of neurons from ACg (B) and lateral OFC (C), with apical dendrites highlighted in blue (controls) and red (stressed). D, A typical pyramidal neuron from lateral OFC, with the apical dendrite (arrow) extending from the soma toward the pial surface at right and the axon (arrowheads) extending to the left. Scale bar, 50 μm.

Figure 2.

Chronic stress induced contrasting effects on apical dendritic arborization in ACg and OFC. A, B, In ACg (A), total apical dendritic material decreased with stress, whereas a stress-related increase in apical dendritic material was observed in OFC (B). C, D, Sholl analyses. Stress effects on apical dendritic arborization were most pronounced at distances of 90–180 μm from the soma in ACg (C). In OFC (D), stress affected more distal aspects of the dendrite, with significant increases at 120–240 μm. Error bars indicate SEM. ^‡p < 0.10; ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.005.

Figure 3.

A, Chronic stress selectively impaired EDS, leaving discrimination learning (SD, CD) and reversal learning (Rev) unaffected. B, Stress-related decreases in ACg apical dendritic material predicted attentional impairments in the EDS phase (r = −0.74; p = 0.09). No association was observed in controls (data not shown). C, Stressed rats and controls were divided into four groups based on median splits of their respective ACg apical dendritic lengths. Stressed rats (gray) with the largest ACg morphologic effects (“low ACg arborization”) showed significant attention shifting impairments, whereas stressed rats with minimal morphologic changes (“high arborization”) performed comparably with controls. No association between ACg arborization and attention shifting was observed in controls. Error bars indicate SEM. ∗p < 0.05; ∗∗∗p < 0.005.