Stress Effects on Structure and Function of Hippocampus

The hippocampus is a vulnerable and yet resilient brain region, and excitatory amino acids play an important role in normal plasticity as well as in damage produced by ischemia, seizures and head trauma. Stress also has important effects on the hippocampus via adrenal steroids and excitatory amino acids. We found receptors for adrenal steroids in hippocampal neurons, and the actions of so-called "stress hormones" has been investigated with increasing intensity over the past several decades. The amygdala is another target of stress and shows structural plasticity in stress that is sometimes opposite to that seen in hippocampus - that is, when stress causes hippocampal neurons to retract it causes amygdala neurons to grow. Accompanying these changes are decreases in hippocampal-dependent memory functions and increases in fear and aggression that are related to the amygdala. There are also changes in neuronal excitability that are regulated acutely by adrenal steroids and chronically by repeated stress. The prefrontal cortex is another important target of chronic stress and also circadian disruption and shows atrophy of dendrites and loss of spines in the medial prefrontal cortex and expansion of dendrites (as in basolateral amygala) in the orbitofrontal region, along with disruption of cognitive flexibility. Aging is associated with a persistence of stress-induced remodeling of mPFC dendrites but with a failure of recovery after the stressor has ceased.

Besides dendritic remodeling, stress also influences the replacement of neurons in the dentate gyrus of the hippocampus. In the adult brain, proliferation of neural stem cells continues in the subventricular zone, providing new neurons for the olfactory bulb and the neocortex, and in the dentate gyrus. Proliferating precursor cells reside in the subgranular zone of the dentate gyrus. The newly born cells express markers of immature neurons and extend axonal processes toward the CA3 region of the hippocampus. As they differentiate, these cells express mature neuronal markers and begin to migrate into the granule cell layer. Neurogenesis and survival are regulated positively by growth factors and certain hormones such as IGF-1 and estrogens and negatively by glucocorticoids, excitatory amino acids and opioids. Chronic restraint stress not only induces atrophy of apical dendrites in CA3 pyramidal neurons, it also suppresses neurogenesis. After 6 weeks it results in a 6% smaller dentate gyrus with 13% fewer granule neurons. Studies of fear conditioning show a specific suppression of neurogenesis associated with pairing of a tone and a shock.

Relevant Publications

  • Sapolsky, R.M., Krey, L.C., McEwen, B.S. The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocr. Rev. 7:284-301 (1986).
  • McEwen, B.S. Stress and hippocampal plasticity. Ann. Rev. Neurosci. 22:105-122 (1999).
  • Pham, K., Nacher, J., Hof, P.R., and McEwen, B.S. Repeated restraint suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus. Eur. J. Neurosci. 17:1-8 (2003).
  • Liston, C., Miller, M.M., Goldwater, D.S., Radley, J.J., Rocher, A.B., Hof, P.R., Morrison, J.H., and McEwen, B.S. Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J. Neurosci. 26:7870-7874 (2006).
  • Roozendaal, B., McEwen, B.S. and Chattarji, S. Stress, memory and the amygdala. Nature Rev. Neurosci. 10:423-433 (2009).
  • Lupien, S.J., McEwen, B.S., Gunnar, M.R. and Heim, C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat. Rev. Neurosci. 10:434-445 (2009).
  • Magarinos, A.M., Li, C.J., Gal Toth, J., Bath, K.G., Jing, D., Lee, F.S., and McEwen, B.S. Effect of brain-derived neurotrophic factor haploinsufficiency on stress-induced remodeling of hippocampal neurons. Hippocampus (2010).
  • Bloss, E.B., Janssen, W.G., McEwen, B.S., and Morrison, J.H. Interactive effects of stress and aging on structural plasticity in the prefrontal cortex. J. Neurosci. 30:6726-6731 (2010).
  • McEwen, B.S. and Gianaros, P.J. Stress- and allostasis-induced brain plasticity. Annu. Rev. Med. 62:5.1-5.15 (2011).

Current Grant Support:

Stress, Adrenal Steroids and the Brain (NIH.NIMH)