New information triggers prospective codes to adapt for flexible navigation.

Navigating a dynamic world requires rapidly updating choices by integrating past experiences with new information. In hippocampus and prefrontal cortex, neural activity representing future goals is theorized to support planning. However, it remains unknown how prospective goal representations incorporate new, pivotal information. Accordingly, we designed a novel task that precisely introduces new information using virtual reality, and we recorded neural activity as mice flexibly adapted their planned destinations. We found that new information triggered increased hippocampal prospective representations of both possible goals; while in prefrontal cortex, new information caused prospective representations of choices to rapidly shift to the new choice. When mice did not flexibly adapt, prefrontal choice codes failed to switch, despite relatively intact hippocampal goal representations. Prospective code updating depended on the commitment to the initial choice and degree of adaptation needed. Thus, we show how prospective codes update with new information to flexibly adapt ongoing navigational plans.

Goal discrimination in hippocampal nonplace cells when place information is ambiguous.

SignificanceGoal-directed spatial navigation has been found to rely on hippocampal neurons that are spatially modulated. We show that "nonplace" cells without significant spatial modulation play a role in discriminating goals when environmental cues for goals are ambiguous. This nonplace cell activity is performance-dependent and is modulated by gamma oscillations. Finally, nonplace cell goal discrimination coding fails in a mouse model of Alzheimer's disease (AD). Together, these results show that nonplace cell firing can signal unique task-relevant information when spatial information is ambiguous; these signals depend on performance and are absent in a mouse model of AD.

Alzheimer's pathology causes impaired inhibitory connections and reactivation of spatial codes during spatial navigation.

Synapse loss and altered synaptic strength are thought to underlie cognitive impairment in Alzheimer's disease (AD) by disrupting neural activity essential for memory. While synaptic dysfunction in AD has been well characterized in anesthetized animals and in vitro, it remains unknown how synaptic transmission is altered during behavior. By measuring synaptic efficacy as mice navigate in a virtual reality task, we find deficits in interneuron connection strength onto pyramidal cells in hippocampal CA1 in the 5XFAD mouse model of AD. These inhibitory synaptic deficits are most pronounced during sharp-wave ripples, network oscillations important for memory that require inhibition. Indeed, 5XFAD mice exhibit fewer and shorter sharp-wave ripples with impaired place cell reactivation. By showing inhibitory synaptic dysfunction in 5XFAD mice during spatial navigation behavior and suggesting a synaptic mechanism underlying deficits in network activity essential for memory, this work bridges the gap between synaptic and neural activity deficits in AD.

Multi-sensory Gamma Stimulation Ameliorates Alzheimer's-Associated Pathology and Improves Cognition.

We previously reported that inducing gamma oscillations with a non-invasive light flicker (gamma entrainment using sensory stimulus or GENUS) impacted pathology in the visual cortex of Alzheimer's disease mouse models. Here, we designed auditory tone stimulation that drove gamma frequency neural activity in auditory cortex (AC) and hippocampal CA1. Seven days of auditory GENUS improved spatial and recognition memory and reduced amyloid in AC and hippocampus of 5XFAD mice. Changes in activation responses were evident in microglia, astrocytes, and vasculature. Auditory GENUS also reduced phosphorylated tau in the P301S tauopathy model. Furthermore, combined auditory and visual GENUS, but not either alone, produced microglial-clustering responses, and decreased amyloid in medial prefrontal cortex. Whole brain analysis using SHIELD revealed widespread reduction of amyloid plaques throughout neocortex after multi-sensory GENUS. Thus, GENUS can be achieved through multiple sensory modalities with wide-ranging effects across multiple brain areas to improve cognitive function.