Caffeine alters proliferation of neuronal precursors in the adult hippocampus.

Neurogenesis continues through adulthood in the hippocampus and olfactory bulb of mammals. Adult neurogenesis has been implicated in learning and memory, and linked with depression. Hippocampal neurogenesis is increased in response to a number of stimuli, including exposure to an enriched environment, increased locomotor activity, and administration of antidepressants. Adult neurogenesis is depressed in response to aging, stress and sleep deprivation. Intriguingly, caffeine modulates a number of these same stimuli in a dose dependent manner. We examined the dose and duration dependent effects of caffeine on the proliferation, differentiation, and survival of newly generated hippocampal neurons in adult mice. Extended, 7 day caffeine administration, alters the proliferation of adult hippocampal precursors in the mouse in a dose dependent manner; moderate to high doses (20-30 mg/kg per day) of caffeine depress proliferation while supraphysiological doses (60 mg/kg per day) increase proliferation of neuronal precursors. Acute, 1 day administration had no affect on proliferation. Caffeine administration does not affect the expression of early or late markers of neuronal differentiation, or rates of long-term survival. However, neurons induced in response to supraphysiological levels of caffeine have a lower survival rate than control cells; increased proliferation does not yield an increase in long-term neurogenesis. These results demonstrate that physiologically relevant doses of caffeine can significantly depress adult hippocampal neurogenesis.