Neural Circuit Mechanisms Underlying the Exacerbation of Alzheimer’s Disease by Chronic Stress

Both epidemiological and animal studies have demonstrated a strong association between Alzheimer’s disease (AD), neuropsychiatric symptoms such as depression and anxiety, and chronic psychological stress. The neurophysiological basis of fear, anxiety, and stress has been well studied and is thought to involve the basolateral amygdala (BLA) – a structure of the anterior temporal lobe, which interprets fearful stimuli and outputs a behavioral fear response. To determine if increased BLA activity could act to accelerate the progression of AD, we manipulated a direct BLA-to-hippocampus circuit using optogenetic (ChR2) and pharmacogenetic (GiDREADD) technologies, and subsequently examined hippocampal AD-related pathology, synaptic density, histone-deacetylase-2 expression, and hippocampus-dependent learning and memory abilities. We found that in wild-type mice, activation of glutamatergic BLA neurons was both necessary and sufficient to produce the molecular and cognitive effects of chronic stress. Terminal photostimulation of direct BLA afferents within the hippocampus was also sufficient. Chronic activation of BLA glutamatergic neurons in the 5xFAD model of AD accelerated the neuropathological and cognitive AD-like phenotype, while chronic BLA inactivation had opposite effects. Overall our results suggest that neuropsychiatric disease and chronic stress may act through enhanced BLA activation to accelerate the progression of AD.