Remodeling of projections from ventral hippocampus to prefrontal cortex in Alzheimer's mice

Emotional dysregulation often accompanies cognitive deficits in Alzheimer's disease (AD). The hippocampus, most notably damaged by AD pathology, is classified into the cognition-bound posterior and emotion-bound anterior hippocampi. Since the anterior hippocampus or its rodent counterpart, the ventral hippocampus (VH), sends dense afferents to the prefrontal cortex (PFC) and the basolateral amygdala (BLA), the two structures implicated in fear responses, we investigated whether these afferents are modified in 3xTg AD model mice. An anterograde dextrin tracer injected into VH revealed that axons in PFC were more ramified in 3xTg than wild-type (WT) mice, with the synaptic density reduced. The VH projections to BLA were not affected. Intracellular accumulation of amyloid β (Aβ) or Aβ-like immunoreactivity was found in PFC and BLA neurons alike. Behaviorally, in the 2-way active avoidance test, the frequency of chamber change was higher, with the test performance better, in 3xTg than WT mice, suggesting a distorted contextual fear in the 3xTg group. Given the essential involvement of parts of PFC in contextual fear responses and that of BLA in fear responses in general, the observed remodeling of VH-to-PFC afferents and the accumulation of intracellular Aβ in BLA and PFC pyramidal cells might exercise critical influences on enhanced avoidance behavior in 3xTg mice.