A novel pathway between stress and cognition

In ever faster moving societies, an increasing number of people are becoming affected by the short- and long-term consequences of chronic stress. It is thus not surprising that chronic stress has emerged as a risk factor for both psychiatric and neurodegenerative diseases. Indeed, neurophysiological maladaptation to chronic stress have been found to be highly relevant to the pathogenesis of human diseases such as depression and Alzheimer’s disease, but the precise mechanisms and neuronal circuitry underlying this relationship remains poorly understood.

In a recent study published in PNAS, Johannes Gräff, Assistant Professor at the Brain Mind Institute (EPFL), together with a team of neuroscientists at MIT and Stanford, has shed light on a hitherto unknown pathway governing the deleterious effects of chronic stress on memory impairment. Using state-of-the art optogenetic and pharmaco-genetic tools, several types of chronic behavioral stress were found to impair cognitive functions via a direct neural circuit from the basolateral amygdala to the dorsal, but not the ventral hippocampus. Moreover, the researchers identified one potential molecular mechanism by which behavioral stress is translated to hippocampal dysfunction, namely via an upregulation of the Cdk5 (Cyclin-dependent kinase 5) co-activator p25 – known to be associated with Alzheimer’s disease – and via subsequent HDAC2 (Histone Deacetylase 2)-mediated epigenetic alterations of neuroplasticity-related gene expression, which the team had previously shown to lead to an epigenetic blockade of cognitive functions in the neurodegenerative brain. These findings reveal new insights into the neuromolecular circuitry of stress-induced memory impairments associated with Alzheimer’s disease.