The Cellular Phase of Alzheimer’s Disease

Sharp wave ripples (SPW-Rs) represent the most synchronous population pattern in the mammalian brain. Their excitatory output affects a wide area of the cortex and several subcortical nuclei. SPW-Rs occur during "off-line" states of the brain, associated with consummatory behaviors and non-REM sleep, and are influenced by numerous neurotransmitters and neuromodulators. They arise from the excitatory recurrent system of the CA3 region and the SPW-induced excitation brings about a fast network oscillation (ripple) in CA1. The spike content of SPW-Rs is temporally and spatially coordinated by a consortium of interneurons to replay fragments of waking neuronal sequences in a compressed format. SPW-Rs assist in transferring this compressed hippocampal representation to distributed circuits to support memory consolidation; selective disruption of SPW-Rs interferes with memory. Recently acquired and pre-existing information are combined during SPW-R replay to influence decisions, plan actions and, potentially, allow for creative thoughts. In addition to the widely studied contribution to memory, SPW-Rs may also affect endocrine function via activation of hypothalamic circuits. Alteration of the physiological mechanisms supporting SPW-Rs leads to their pathological conversion, "p-ripples," which are a marker of epileptogenic tissue and can be observed in rodent models of schizophrenia and Alzheimer's Disease. Mechanisms for SPW-R genesis and function are discussed in this review.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/hipo.22488

Hippocampal sharp wave‐ripple: A cognitive biomarker for episodic memory and planning

Recent studies have revealed the existence of hippocampal neurons that fire at successive moments in temporally structured experiences. Several studies have shown that such temporal coding is not attributable to external events, specific behaviours or spatial dimensions of an experience. Instead, these cells represent the flow of time in specific memories and have therefore been dubbed 'time cells'. The firing properties of time cells parallel those of hippocampal place cells; time cells thus provide an additional dimension that is integrated with spatial mapping. The robust representation of both time and space in the hippocampus suggests a fundamental mechanism for organizing the elements of experience into coherent memories.

/pdf/time-cells-in-the-hippocampus-a-new-dimension-for-mapping-3ixz9ohy17.pdf

Time cells in the hippocampus: a new dimension for mapping memories

Alzheimer's disease is a progressive loss of memory and cognition, for which there is no cure. Although genetic studies initially suggested a primary role for amyloid-in Alzheimer's disease, treatment strategies targeted at reducing amyloid-have failed to reverse cognitive symptoms. These clinical findings suggest that cognitive decline is the result of a complex pathophysiology and that targeting amyloid-alone may not be sufficient to treat Alzheimer's disease. Instead, a broad outlook on neural-circuit-damaging processes may yield insights into new therapeutic strategies for curing memory loss in the disease.

The road to restoring neural circuits for the treatment of Alzheimer's disease

On the Integration of Space, Time, and Memory

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.

/pdf/rigid-firing-sequences-undermine-spatial-memory-codes-in-a-94y4kxs9fr.pdf

Rigid firing sequences undermine spatial memory codes in a neurodegenerative 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

https://www.jneurosci.org/content/jneuro/35/21/8118.full.pdf

Progressive Functional Impairments of Hippocampal Neurons in a Tauopathy Mouse Model

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.

/pdf/comparing-mouse-and-rat-hippocampal-place-cell-activities-bsb3oldpan.pdf

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

Accurate measurements of soil water content are important to land activities, especially those involving agriculture, forestry, hydrology, and engineering. In this paper, a theoretical and experimental study of the microwave moisture measurement sensors is conducted. 
A phase-based moisture sensor system using a transmission line sensor is designed. The amplitude of the transmission measurement is a strong function of the conductivity (loss of the media) and the imaginary part of the dielectric constant, and the phase is mainly a strong function of the real part of the dielectric constant. One can obtain the soil moisture information from measuring the phase shift of the transmitted waves. Microstrip resonator sensors are also studied and fabricated. The effective permittivity will change if a dielectric material is present near the substrate of the resonator, which causes the shift of the resonant frequency. The measured data show that both sensors are sensitive and accurate.

Jingheng Cheng

Papers

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

Progressive Functional Impairments of Hippocampal Neurons in a Tauopathy Mouse Model

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

Development of the RF soil moisture sensors