27 This finding illustrates a role for GRs acting upon the genome in a task that is known to depend on the hippocampus. Interestingly, other actions of glucocorticoids via GRs are known to involve the protein–protein interactions that are not prevented in mice carrying the GR defective in the DNA binding domain.28 Other evidence for glucocorticoid actions supports an inverted U-shaped dose–response curve in which low to moderate levels of adrenal steroids enhance acquisition of tasks that involve the hippocampus, whereas high levels of glucocorticoids disrupt task acquisition.22,29-31 Adrenal steroids have biphasic

effects upon excitability of hippocampal neurons, which may underlie their biphasic Inhibitors,research,lifescience,medical actions on memory and recall.30,32,34 Adaptive structural plasticity One of the ways that stress hormones modulate function within the brain is by changing the structure of neurons. Within the hippocampus, the input from the entorhinal cortex to the DG is ramified by the connections between the DG and the CA3 pyramidal neurons. One granule neuron innervates, Inhibitors,research,lifescience,medical on average, 12 CA3 neurons; Inhibitors,research,lifescience,medical and each CA3 neuron innervates, on the average, 50 other CA3 neurons via axon collaterals, as well as 25 inhibitory cells via other axon collaterals (Figure 2).35 The net result is a 600-fold amplification of excitation as well as a 300-fold amplification of inhibition, which

provide some degree of control of the system. As to why this JIB-04 solubility dmso system exists, the DG-CA3 system is believed to play a role in the Inhibitors,research,lifescience,medical memory of sequences of events, although long-term storage of memory occurs in other brain regions.36,37 Figure 2. Why is the CA3 so vulnerable? Feed-forward excitability serves memory functions but increases vulnerability for excitotoxicity. Inhibitors,research,lifescience,medical DG, dentate gyrus. Neurogenesis in the DG There is structural plasticity within the DG-CA3 system, in that new neurons continue to be produced in the DG throughout adult life38 and CA3 pyramidal

cells undergo remodeling of their dendrites,2 as will be discussed further below.39 The subgranular layer of the DG contains cells that have properties of astrocytes (eg, expression of glial fibrillary acidic Non-specific serine/threonine protein kinase protein) and give rise to granule neurons.40 After administration of bromodcoxyuridine (BrdU) to label DNA of dividing cells, these newly born cells appear as clusters in the inner part of the granule cell layer, where a substantial number of them will go on to differentiate into granule neurons within as little as 7 days. The new granule neurons appear to be quite excitable and capable of participating in long-term potentiation. In the adult rat, 9000 new neurons are born per day and survive with a half-life of 28 days.41 There are many hormonal and neurochemical modulators of neurogenesis and cell survival in the DG.15,38,42-44 Neurogenesis in the adult DG is enhanced by the hormone insulin-like growth factor–1 (IGF-1) and by serotonin and a number of antidepressant drugs.