The morphology of brain cells in the adult brain is in constant flux due to reorganization of the cytoskeleton. In experimental animals, the mature phenotype of neurons can be lost in the adult brain when trophic factors are withdrawn, and reestablished upon replacement. We have been studying reversible brain changes for over 20 years and recently proposed a model based on neuronal instability to explain these changes. The shape of a cell, whether neuronal or glial, is dependent on the integrity of the cytoskeleton composed mainly of microtubules and microtubule associated proteins (MAPs). MAPs function to sta-bilize the tubulin polymers. When the MAPs are phosphorylated, they can no longer attach to the polymers, and the long strands of tubulin depolymerize. This results in a collapse of the cellular morphology, e.g. dendritic and process retraction. S100b is a soluble glial protein concentrated in neurons, which protects MAPs from phos-phorylation. We have shown that the addition of S100b stabilizes and promotes the extension of dendritic processes.Serotonin, acting on the 5-HT1A high affinity receptor, can stimulate the release of S100b from astrocytes. Glucocorticoids, secreted during stress, can enhance serotonin turnover and adrenalectomy has the opposite effect of reducing serotonin activity. Both adrenalectomy (removing source of glucocorticoids) or depletion of serotonin (by injecting the substituted amphetamines or specific synthesis inhibitors) have been found to reduce dendritic staining and synapse number in hippocampus and cortex. This reduction of mature neuronal morphology is rapidly reversible upon replacement of steroids or serotonin. Others have found similar examples of retraction and expansion manipulating estrogen, dopamine, norepinephrine and NGF. We propose a model of neuronal instability to explain these reversible changes in neuronal shape and connections. Our results obtained in experimental animals may have applicability to brain volumetric and neurophilic changes seen in alcoholism, anorexia nervosa, Alzheimer's and depression. As is evident in the hibernating ground squirrel or cycling female rat, loss of dendrites may represent a normal response of a cell to a changing trophic environment, which could represent healthy plasticity rather than irreversible pathology.