Compulsive-like Behaviors in Amyloid-β 1-42-Induced Alzheimer's Disease in Mice Are Associated With Hippocampo-cortical Neural Circuit Dysfunction.

Background: In addition to memory deficits, patients with Alzheimer's disease (AD) experience neuropsychiatric disturbances. Recent studies have suggested the association of obsessive-compulsive disorder with the early stages of AD. However, there is a lack of understanding of the neurobiological underpinnings of compulsive-like behaviors at the neuronal circuit level and their relationship with AD. Methods: We have addressed this issue in an amyloid-β 1-42-induced mouse model of AD by studying compulsive-like behaviors. Next, we compared the hippocampal and medial prefrontal cortex (mPFC) local field potential pattern and coherence between these regions of control and AD mice. We also assessed the expression pattern of acetylcholine and glutamatergic signaling in these regions, using quantitative polymerase chain reaction. Results: Our findings show that AD mice exhibit compulsive-like behaviors, as evidenced by enhanced marble burying, nest building, and burrowing. Furthermore, AD mice exhibited hippocampo-cortical circuit dysfunction demonstrated by decreased power of rhythmic oscillations at the theta (4-12 Hz) and gamma (25-50 Hz) frequencies in the hippocampus and mPFC, two functionally interconnected brain regions involved both in AD and compulsive behaviors. Importantly, coherence between the hippocampus and mPFC in the theta band of AD animals was significantly reduced. Furthermore, we found reduced cholinergic and glutamatergic neurotransmission in the hippocampus and mPFC of AD mice. Conclusions: We conclude that the hippocampo-cortical functional alterations may play a significant role in mediating the compulsive-like behaviors observed in AD mice. These findings may help in understanding the underlying circuit mechanisms of obsessive-compulsive disorder-like phenotypes associated with AD.