Abstract
Hippocampal-cortical dialogue, during which hippocampal ripple oscillations support information transfer, is necessary for long-term consolidation of spatial memories. Whereas a vast amount of work has been carried out to understand the cellular and molecular mechanisms involved in the impairments of memory formation in Alzheimer’s disease (AD), far less work has been accomplished to understand these memory deficiencies at the network-level interaction that may underlie memory processing. We recently demonstrated that freely moving 8 to 9-month-old APP/PS1 mice, a model of AD, are able to learn a spatial reference memory task despite a major deficit in Sharp-Wave Ripples (SWRs), the integrity of which is considered to be crucial for spatial memory formation. In order to test whether reconfiguration of hippocampal-cortical dialogue could be responsible for the maintenance of this ability for memory formation, we undertook a study to identify causal relations between hippocampal and cortical circuits in epochs when SWRs are generated in hippocampus. We analyzed the data set obtained from multielectrode intracranial recording of transgenic and wild-type mice undergoing consolidation of spatial memory reported in our previous study. We applied Directed Transfer Function, a connectivity measure based on Granger causality, in order to determine effective coupling between distributed circuits which express oscillatory activity in multiple frequency bands. Our results showed that hippocampal-cortical coupling in epochs containing SWRs was expressed in the two frequency ranges corresponding to ripple (130–180 Hz) and slow gamma (20–60 Hz) band. The general features of connectivity patterns were similar in the 8 to 9-month-old APP/PS1 and wild-type animals except that the coupling in the slow gamma range was stronger and spread to more cortical sites in APP/PS1 mice than in the wild-type group. During the occurrence of SWRs, the strength of effective coupling from the cortex to hippocampus (CA1) in the ripple band undergoes sharp increase, involving cortical areas that were different in the two groups of animals. In the wild-type group, retrosplenial cortex and posterior cingulate cortex interacted with the hippocampus most strongly, whereas in the APP/PS1 group more anterior structures interacted with the hippocampus, that is, anterior cingulate cortex and prefrontal cortex. This reconfiguration of cortical-hippocampal interaction pattern may be an adaptive mechanism responsible for supporting spatial memory consolidation in AD mice model.
Highlights
Since the pioneering work of Alois Alzheimer in 1906, a substantial body of work has shown how Alzheimer’s disease (AD) alters cognitive functions such as working memory and semantic and episodic memories formation [1, 2]
We applied Directed Transfer Function (DTF), a connectivity measure based on Granger causality [23], to determine the magnitudes of effective coupling between remote neuronal circuits that are involved in the generation of signals in a given frequency band; we evaluated if and how this coupling changes during the occurrence of Sharp-Wave Ripples (SWRs)
Since these findings suggested a reconfiguration of networks involved in SWRs-dependent memory formation, we applied direct DTF (dDTF), a connectivity measure based on Granger causality, in order to compare the interaction of hippocampal and cortical circuits in epochs containing SWRs in the WT and amyloid precursor protein (APP)/PS1 mice
Summary
Since the pioneering work of Alois Alzheimer in 1906, a substantial body of work has shown how Alzheimer’s disease (AD) alters cognitive functions such as working memory and semantic and episodic memories formation [1, 2]. Research has primarily focused on deciphering the cellular and molecular mechanisms involved in AD memory impairments. Memory impairment in AD has been associated with the presence of soluble amyloid-β proteins (Aβ), which alter cellular and synaptic physiology in different parts of the brain [3,4,5,6]. Accumulation of Aβ has been extensively studied in transgenic APP/PS1 mice that overexpress mutant human genes for amyloid precursor protein (APP) and presenilin (PS1) [7] and develop memory deficits correlated with Aβ deposition [8]. The physiopathology of the networks involved in memory processing has received far less consideration
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