Bruce S. McEwen, Ph.D.
Alfred E. Mirsky Professor
Harold and Margaret Milliken Hatch
Laboratory of Neuroendocrinology
The Rockefeller University
May 10, 2010

Sex, Stress and the Brain: Hormone Action above the Hypothalamus via Novel Mechanisms

 

Just as the most successful social networks are fluid and flexible, so too are the connections that make up the mammalian brain. Like social networks, the neural networks that make up the brain are shaped, for better or worse, by their surroundings. The McEwen Lab looks at the effects of sex, stress and metabolic hormones on shaping neural networks and subsequent behavior. Understanding how the brain remains flexible in order to respond to changing environmental conditions may help to explain how the environment impacts the development of cognitive disorders, as well as mood/anxiety disorders, and cognitive decline later in life.

The McEwen lab studies how stress and sex hormones act on the brain. The adult brain is much more resilient and adaptable than previously believed, and “adaptive structural plasticity” involves growth and shrinkage of dendritic trees, turnover of synapses and limited amounts of neurogenesis (cell birth) in the dentate gyrus of the hippocampal formation. Neural activity resulting from physical activity and experiences, including those that are threatening and stressful, result in structural, as well as neurochemical, changes in the brain. Sex, stress and metabolic hormones play a significant role in many forms of adaptive plasticity.

Stress and sex hormones help to mediate such plasticity, which has been extensively investigated in the hippocampus, as well as, to a lesser extent, in the prefrontal cortex and the amygdala, all of which are brain regions that are involved in cognitive and emotional functions. Stress and sex hormones exert their effects on brain structural remodeling through non-genomic, indirect genomic, and both classical genomic and non-genomic mechanisms, and they do so synergistically with neurotransmitters and other intra- and extracellular mediators. Estrogen, for example, has been shown to play a role in synapse formation in the hippocampus, and in stress-induced remodeling of dendrites and synapses in the hippocampus, amygdala and prefrontal cortex of the brain.

There is a cyclic variation in spine synapse density on CA1 pyramidal neurons during the estrous cycle of female rats that is caused by the increase in estradiol levels during the first phase of the cycle. This increase is then reversed by the progesterone surge at the time of ovulation. A similar cyclicity is seen in mouse and rhesus monkey and in prefrontal cortex, as well as hippocampus, with a recent report also showing such variation of spine synapse density in the primary sensorimotor cortex. Based upon extensive studies in rat and mouse hippocampus, a predominant mechanism for synapse formation, turnover and maturation involves non-genomic actions of estrogen and progestin receptors in dendrites and presynaptic nerve terminals.

As far as stress and stress hormones, the brain is the key organ of the response to stress because it determines what is threatening and, therefore, stressful, as well as the physiological and behavioral responses that can be either protective or damaging. The hippocampus was the first brain region besides hypothalamus to be recognized as a target of glucocorticoids. The amygdala is important in fear and strong emotions, while the prefrontal cortex is involved in attention, executive function and working memory. Hippocampal and medial prefrontal cortical neurons become shorter and less branched, and dentate gyrus neurogenesis is suppressed by repeated stress, whereas amygdala and orbitoprefrontal cortical neurons show signs of hypertrophy after repeated stress. This promotes impairment of hippocampal-dependent memory and enhances fear and aggression, as well as impairing attention set shifting, a form of executive function that indicates cognitive flexibility.

Dr. McEwen ended his talk by addressing the fact that there are several translational studies on the human brain showing that the effects seen in animal models have relevance to normal and abnormal human brain structure and function. Indeed, restrictions of adaptive plasticity, i.e., a loss of resilience, may be a key aspect of mood, anxiety and cognitive disorders as well as age-related cognitive decline.