Delving into the Dysfunction of Aging Neurons Involved in Impairment of Spatial Memory – Fight Aging!

There are many layers to aging research. There is the function of tissue, the behavior of cells, the pattern of expression of genes, the profile of circulating molecules of various classes. Typically one research program is focused on one layer (and often only in one organ, or a single function of a tissue), with only occasional excursions into another layer (or other organs, or other functions). There are the usual reasons for this, such as different skills and knowledge being required, different expensive equipment being required, the tendency for researchers to specialize into ever narrower niches, and the eternal pressure to do more with less that exists in academia. It does mean that much of the literature is siloed into layers that talk little to one another, and integration of these layers into a bigger picture of cause and effect lags behind.

Today’s open access paper reports on altered behaviors in neurons involved in spatial memory in the aged mouse brain, and connects these changes to the age-related loss of spatial memory. Different forms of memory involve different neural networks and different regions of the brain, and so can be distinctly affected by aging even if the underlying damage and dysfunction contributing to aging is more or less evenly spread across tissues. This research attempts to link two layers of aging in some of the specific neurons involved in spatial memory, the layer of cell behavior and the layer of gene expression. The intent is to provide a foundation for later efforts to find ways to restore these cells to a more youthful pattern of behavior.

Spatial coding dysfunction and network instability in the aging medial entorhinal cortex

Across mammalian species, neural systems in the medial temporal lobe, including the medial entorhinal cortex (MEC) and hippocampus (HPC), are required for spatial memory. The MEC contains grid cells that fire periodically during environmental traversals and have firing fields that hexagonally tile physical space in rodents, non-human primates, and humans. This firing is proposed to provide a map of space that can support path integration. Head direction-, border-, speed-, and object vector-tuned cells have also been identified in MEC, providing information regarding an animal’s movement through the environment and sensory features likely relevant to navigation. Additionally, MEC neurons can change their firing rates or shift where their firing fields are active, phenomena collectively referred to as ‘remapping‘. MEC remapping events often occur in response to changes in task demands and environmental features, potentially facilitating the differentiation of distinct contexts. Such remapping in MEC grid cells is likely complemented by place cells and goal-vector cells in the reciprocally connected HPC, which can also exhibit context-dependent remapping. Collectively, this network of functional cell types across MEC and HPC may provide the necessary neural substrates for an animal to navigate to goals in novel and familiar environments.

Several lines of evidence suggest that MEC-HPC circuit dysfunction contributes to aged spatial memory deficits. It is unclear how aging impacts the quality or stability of tuning to navigational variables across MEC functional cell types, however. The integrity and flexibility of population-level spatial maps in the aged MEC also remain unknown. Since the HPC and MEC are reciprocally connected, one possibility is that spatial coding dysfunction in these regions might interdependently contribute to spatial memory decline in aging. Eventually, rejuvenating aged spatial cognition dependent on MEC-HPC networks will also require a more precise understanding of the molecular mechanisms that drive cellular and circuit dysfunction.

Here, we combined in vivo silicon probe recordings with neuronal bulk sequencing in MEC in the same mice, complemented by single-nucleus RNA sequencing (snRNA-seq), to identify neural and molecular substrates of aged spatial memory function. Advanced electrophysiologic tools permitted the simultaneous recording of hundreds of neurons per day from each mouse. As a result, we could robustly analyze age effects on MEC spatial coding at the animal level. Moreover, we interrogated how aging altered single neuron firing patterns and population-level spatial coding phenomena. Using a virtual-reality (VR) task with two dynamically interleaved contexts and another with invariant cues, we demonstrated how aging impacts the flexibility and stability of MEC spatial coding at both these levels. Finally, by correlating key spatial coding metrics with the expression of neuronal genes differentially expressed across age groups, we identified potential molecular drivers of aging-mediated spatial cognitive decline in MEC.