10 August 2006. Understanding how stress alters the brain may hold one key to unlocking the puzzle of genetic and environmental interplay in schizophrenia. In this regard, a new study from Conor Liston, Bruce McEwen, and colleagues at Rockefeller University and Mt. Sinai School of Medicine in New York should be of some interest to schizophrenia researchers. Writing in the July 26 issue of the Journal of Neuroscience, they report that subjecting rats to repeated stress causes dendritic loss in the medial prefrontal cortex, but dendritic growth in the orbitofrontal cortex. These distinct morphologic changes were accompanied by distinctly different effects on facets of executive function subserved by these two areas.
Executive function is of particular interest to researchers in schizophrenia because many patients are impaired on tests of cognitive flexibility—they often learn tasks as readily as control subjects, but then have trouble shifting strategies when the rules change. With evidence pointing to traumatic stress as a possible risk factor in schizophrenia (see SRF related news story), this new study provides a possible link between stress-induced brain alterations and some of the cognitive deficits characteristic of schizophrenia.
Previously, McEwen’s group had shown that repeated stress, provided by restraining rats in a wire mesh restrainer for 6 hours daily over 3 weeks, caused retraction and debranching of dendrites and synapse loss in the medial prefrontal cortex (mPFC) (Radley et al., 2006). In the new study, Liston and colleagues confirm this finding for neurons in the anterior cingulate region (ACg) of the mPFC. But a different area of the frontal cortex showed the opposite result: In the orbital frontal cortex (OFC), stress increased dendritic material and branching by 43 and 36 percent, respectively, as assessed by morphometric analysis of apical dendrites after ionophoric cell loading of Lucifer yellow dye. This is the first report of a stress-related increase in arborization of any region in the frontal cortex, the researchers write.
To look for functional consequences of these contrasting changes, the researchers tested the stressed rats for their ability to pay attention to varying environmental cues in order to locate a food reward. The procedure tests several different forms of executive function, including reversal learning (e.g., an odor that predicted reward no longer does so, and vice versa) and extradimensional attentional set-shifting (features of a stimulus that previously had no predictive value, e.g., texture, now are needed to find reward). Specifically, the rats had to find a sweet treat placed in one of two bowls cued with different odors (for example, cloves vs. nutmeg), or different digging material (e.g., plastic vs. Styrofoam beads).
In simple discrimination tests, the stressed rats learned the cue and performed just as well as control rats. Similarly, when the cues were reversed so that the wrong answer became the correct one (reversal learning, which is known to depend on OFC function), the stressed rats learned just as quickly as controls. The stressed rats were not so mentally agile, however, when the relevant cue switched from odor to texture, or vice versa. The stressed animals had a harder time than control rats learning to shift attention to the tactile cue and ignore the scent cue. Dealing with this type of extradimensional set-shift depends upon the mPFC, and morphologic measurements on individual rats strengthened the link between dendritic loss in this region and learning impairments. Animals with the largest stress-related morphologic changes showed the greatest impairments in attentional shifting, while animals with smaller changes performed like controls.
“Collectively, our results indicate that chronic stress induces contrasting morphologic effects in the lateral OFC and ACg, which in turn predict the severity of stress-related impairments in attention shifting,” the authors write. “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 illness.”
An obvious, and open, question is how stress can have different effects on cells in neighboring cortical areas. In this regard, there is a precedent: pyramidal cells in hippocampus respond to stress with dendritic loss, whereas pyramidal cells of the basolateral amygdala show dendritic growth under the same conditions (see, e.g., Vyas et al., 2002 ). As the authors mention, the intra- and extracellular milieus can differ markedly in different brain regions, as well as patterns of innervation from monoaminergic neurons.—Pat McCaffrey.
Liston C, Miller MM, Goldwater DS, Radley JJ, Rocher AB, Hof PR, Morrison JH, McEwen BS. Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J Neurosci. 2006 Jul 26;26(30):7870-4. Abstract