ReviewStress and anxiety: Structural plasticity and epigenetic regulation as a consequence of stress
Highlights
► Structural plasticity in the hippocampus, amygdala and prefrontal cortex of adult rodents. ► Role of glucocorticoids, excitatory amino acids and brain derived neurotrophic factor. ► How histone modifications change with chronicity of stress in the dentate gyrus. ► Individual differences in anxiety in rodent populations in the laboratory. ► Maternal separation alters hippocampal development and exacerbates stress-induced anxiety.
Introduction
The brain is the central organ of stress and adaptation to stress because it perceives and determines what is threatening, as well as the behavioral and physiological responses to the stressor. The adult, as well as developing brain, possess a remarkable ability to adapt and change with stressful, and other experiences. Structural changes – neuronal replacement, dendritic remodeling, and synapse turnover – are a feature of the adult brain’s response to the environment. Nowhere is this better illustrated in the mammalian brain than in the hippocampus, where all three types of structural plasticity have been recognized and investigated using a combination of morphological, molecular, pharmacological, electrophysiological and behavioral approaches. At the same time, new data on the amygdala and the prefrontal cortex, brain regions involved in anxiety and fear, mood, cognitive function and behavioral control, have demonstrated that the adult brain is indeed a malleable and adaptable structure capable of reversible structural plasticity. Steroid hormones play an important role, acting via both genomic and non-genomic mechanisms. In addition, other intracellular mediators and neurotransmitter systems participate in structural plasticity.
The theme of this review is that stress causes an imbalance of neural circuitry subserving cognition, decision making, anxiety and mood that can increase or decrease expression of those behaviors and behavioral states. In the short term, such as for increased fearful vigilance and anxiety in a threatening environment, these changes may be adaptive; but, if the danger passes and the behavioral state persists along with the changes in neural circuitry, such maladaptation may need intervention with a combination of pharmacological and behavioral therapies, as is the case for chronic or mood anxiety disorders.
Besides reviewing cellular and molecular mechanisms, we shall discuss recent work on individual differences in anxiety-like behavior in the animals that we and others study, as well as possible developmental influences that may underlie those differences and bias how the brain responds to stressors. Finally, we shall note that multiple brain regions are involved and that investigations on amygdala, prefrontal cortex and hippocampus that have been very productive, need to be extended to other brain areas that are also involved in anxiety and mood.
Section snippets
Hippocampus
Stress hormones modulate function within the brain by changing the structure of neurons. The hippocampus is one of the most sensitive and malleable regions of the brain. Within the hippocampus, the input from the entorhinal cortex to the dentate gyrus is ramified by the connections between the dentate gyrus and the CA3 pyramidal neurons. One granule neuron innervates, on the average, 12 CA3 neurons, and each CA3 neuron innervates, on the average, 50 other CA3 neurons via axon collaterals, as
Adrenal steroids
Because the hippocampus was the first higher brain center that was recognized as a target of stress hormones (McEwen et al., 1968), both the hippocampus and adrenal steroids have figured prominently in our understanding of how stress impacts brain structure and behavior. The hippocampus expresses both Type I mineralocorticoid, MR and Type II glucocorticoid, GR receptors, and these receptors mediate a biphasic response to adrenal steroids in the CA1 region, although not in the dentate gyrus (
Acute vs chronic stress effects
Responses to acute and chronic stress in both the amygdala and the prefrontal cortex present challenges to our understanding of the cellular and molecular mechanisms. In the amygdala, while chronic stress causes dendrites in the basolateral amygdala to increase in length along with increased spine density on dendrites (Vyas et al., 2002), a single acute stress to a naïve rat causes increased spine density without increased dendritic branching or length after a 10d interval (Mitra et al., 2005).
Epigenetic involvement in alterations due to stress
Adrenal steroids bind to MR and GR and end up in the cell nucleus (McEwen and Plapinger, 1970), and thus the regulation of gene expression is a key aspect of their action, referred to now under the rubric of “epigenetic” influences. The subject of epigenetic influences on the function of the nervous system has been the subject of much recent research (Jiang et al., 2008). Epigenetics are of interest with regard to disorders, such as anxiety and depression, because epigenetic change is a means
Individual differences in anxiety and their possible implications and origins
Whereas the amygdala and hippocampus have each provided challenging new information about the role of multiple mediators in acute and chronic stress effects upon neuronal structure and function, the prefrontal cortex has provided its own challenges when it comes to individual differences in anxiety related behavior. It is clear that the quite homogenous populations of laboratory rats show individual differences in anxiety related behaviors that can also influence lifespan, with more anxious
Developmental effects on stress responsiveness and behavior
A contributing factor to individual differences in anxiety-related behaviors may be early life experiences that effect development of key brain structures. The quality and quantity of maternal care determines anxiety profiles via epigenetic mechanisms (Meaney and Szyf, 2005) that can be transmitted across generations (Francis et al., 1999). The consistency of maternal care is also important and exposure to novelty with good maternal care also improves cognitive and social development (Akers
Interactions among brain regions
Although there has been a major emphasis on brain regions such as the hippocampus, amygdala and, more recently, the prefrontal cortex, that have led to many new insights into brain involvement in stress and adaptation to stress, as well as pathophysiology, it is important to further understand the network of interactions in the whole brain. The prefrontal cortex, amygdala and hippocampus are interconnected and influence each other via direct and indirect neural activity (Petrovich et al., 2001,
Conclusion: stress and brain plasticity over the life course
The brain responds to experiences with structural, as well as functional plasticity, and hormones play a role, along with neurotransmitters and other mediators via a complex collaborative network. Multiple brain regions are involved, including the amygdala, hippocampus, prefrontal cortex and nucleus accumbens; this list of brain regions needs to be expanded to include other parts of the brain, such as the periaqueductal gray matter and other components of the “separation distress circuit” (
Acknowledgements
Supported by research grants R01 MH41256 and P50 MH58911 to BMc.
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