Pattern dynamics and stochasticity of the brain rhythms.

Our current understanding of brain rhythms is based on quantifying their instantaneous or time-averaged characteristics. What remains unexplored is the actual structure of the waves-their shapes and patterns over finite timescales. Here, we study brain wave patterning in different physiological contexts using two independent approaches: The first is based on quantifying stochasticity relative to the underlying mean behavior, and the second assesses "orderliness" of the waves' features. The corresponding measures capture the waves' characteristics and abnormal behaviors, such as atypical periodicity or excessive clustering, and demonstrate coupling between the patterns' dynamics and the animal's location, speed, and acceleration. Specifically, we studied patterns of θ, γ, and ripple waves recorded in mice hippocampi and observed speed-modulated changes of the wave's cadence, an antiphase relationship between orderliness and acceleration, as well as spatial selectiveness of patterns. Taken together, our results offer a complementary-mesoscale-perspective on brain wave structure, dynamics, and functionality.

Comparing Mouse and Rat Hippocampal Place Cell Activities and Firing Sequences in the Same Environments.

Hippocampal place cells are key to spatial representation and spatial memory processing. They fire at specific locations in a space (place fields) and fire in precise patterns during theta sequences and during ripple-associated replay events. These phenomena have been extensively studied in rats, but to a less extent in mice. The availability of versatile genetic manipulations gives mice an advantage for place cell studies. However, it is unknown how place fields and place cell sequences in the same environment differ between mice and rats. Here, we provide a quantitative comparison in place field properties, as well as theta sequences and replays, between rats and mice as they ran on the same novel track and as they rested afterwards. We found that place cells in mice display less spatial specificity with more but smaller place fields. Theta oscillations, theta phase precession and aspects of theta sequences in mice are similar as those in rats. The ripple-associated replay, however, is relatively rare during stopping on the novel track in mice. The replay is present during resting after the track running, but is weaker in mice than the replay in rats. Our results suggest that place cells in mice and rats are qualitatively similar, but with substantial quantitative differences.

Progressive functional impairments of hippocampal neurons in a tauopathy mouse model.

The age-dependent progression of tau pathology is a major characteristic of tauopathies, including Alzheimer's disease (AD), and plays an important role in the behavioral phenotypes of AD, including memory deficits. Despite extensive molecular and cellular studies on tau pathology, it remains to be determined how it alters the neural circuit functions underlying learning and memory in vivo. In rTg4510 mice, a Tau-P301L tauopathy model, hippocampal place fields that support spatial memories are abnormal at old age (7-9 months) when tau tangles and neurodegeneration are extensive. However, it is unclear how the abnormality in the hippocampal circuit function arises and progresses with the age-dependent progression of tau pathology. Here we show that in young (2-4 months of age) rTg4510 mice, place fields of hippocampal CA1 cells are largely normal, with only subtle differences from those of age-matched wild-type control mice. Second, high-frequency ripple oscillations of local field potentials in the hippocampal CA1 area are significantly reduced in young rTg4510 mice, and even further deteriorated in old rTg4510 mice. The ripple reduction is associated with less bursty firing and altered synchrony of CA1 cells. Together, the data indicate that deficits in ripples and neuronal synchronization occur before overt deficits in place fields in these mice. The results reveal a tau-pathology-induced progression of hippocampal functional changes in vivo.

Rigid firing sequences undermine spatial memory codes in a neurodegenerative mouse model.

Hippocampal neurons encode spatial memories by firing at specific locations. As the animal traverses a spatial trajectory, individual locations along the trajectory activate these neurons in a unique firing sequence, which yields a memory code representing the trajectory. How this type of memory code is altered in dementia-producing neurodegenerative disorders is unknown. Here we show that in transgenic rTg4510 mice, a model of tauopathies including Alzheimer's disease, hippocampal neurons did not fire at specific locations, yet displayed robust firing sequences as animals run along familiar or novel trajectories. The sequences seen on the trajectories also appeared during free exploration of open spaces. The spatially dissociated firing sequences suggest that hippocampal neurons in the transgenic mice are not primarily driven by external space but by internally generated brain activities. We propose that tau pathology and/or neurodegeneration renders hippocampal circuits overwhelmed by internal information and therefore prevents them from encoding spatial memories. DOI:http://dx.doi.org/10.7554/eLife.00647.001.