Background: In Alzheimer’s disease (AD), synaptic dysfunction is thought to occur many years before the onset of cognitive decline. Objective: Detecting synaptic dysfunctions at the earliest stage of AD would be desirable in both clinic and research settings. Methods: Population voltage imaging allows monitoring of synaptic depolarizations, to which calcium imaging is relatively blind. We developed an AD mouse model (APPswe/PS1dE9 background) expressing a genetically-encoded voltage indicator (GEVI) in the neocortex. GEVI was restricted to the excitatory pyramidal neurons (unlike the voltage-sensitive dyes). Results: Expression of GEVI did not disrupt AD model formation of amyloid plaques. GEVI expression was stable in both AD model mice and Control (healthy) littermates (CTRL) over 247 days postnatal. Brain slices were stimulated in layer 2/3. From the evoked voltage waveforms, we extracted several parameters for comparison AD versus CTRL. Some parameters (e.g., temporal summation, refractoriness, and peak latency) were weak predictors, while other parameters (e.g., signal amplitude, attenuation with distance, and duration (half-width) of the evoked transients) were stronger predictors of the AD condition. Around postnatal age 150 days (P150) and especially at P200, synaptically-evoked voltage signals in brain slices were weaker in the AD groups versus the age- and sex-matched CTRL groups, suggesting an AD-mediated synaptic weakening that coincides with the accumulation of plaques. However, at the youngest ages examined, P40 and P80, the AD groups showed differentially stronger signals, suggesting “hyperexcitability” prior to the formation of plaques. Conclusion: Our results indicate bidirectional alterations in cortical physiology in AD model mice; occurring both prior (P40-80), and after (P150-200) the amyloid deposition.

In a typical electrophysiology experiment, synaptic stimulus is delivered in a cortical layer (1–6) and neuronal responses are recorded intracellularly in individual neurons. We recreated this standard electrophysiological paradigm in brain slices of mice expressing genetically encoded voltage indicators (GEVIs). This allowed us to monitor membrane voltages in the target pyramidal neurons (whole-cell), and population voltages in the surrounding neuropil (optical imaging), simultaneously. Pyramidal neurons have complex dendritic trees that span multiple cortical layers. GEVI imaging revealed areas of the brain slice that experienced the strongest depolarization on a specific synaptic stimulus (location and intensity), thus identifying cortical layers that contribute the most afferent activity to the recorded somatic voltage waveform. By combining whole-cell with GEVI imaging, we obtained a crude distribution of activated synaptic afferents in respect to the dendritic tree of a pyramidal cell. Synaptically evoked voltage waves propagating through the cortical neuropil (dendrites and axons) were not static but rather they changed on a millisecond scale. Voltage imaging can identify areas of brain slices in which the neuropil was in a sustained depolarization (plateau), long after the stimulus onset. Upon a barrage of synaptic inputs, a cortical pyramidal neuron experiences: (a) weak temporal summation of evoked voltage transients (EPSPs); and (b) afterhyperpolarization (intracellular recording), which are not represented in the GEVI population imaging signal (optical signal). To explain these findings [(a) and (b)], we used four voltage indicators (ArcLightD, chi-VSFP, Archon1, and di-4-ANEPPS) with different optical sensitivity, optical response speed, labeling strategy, and a target neuron type. All four imaging methods were used in an identical experimental paradigm: layer 1 (L1) synaptic stimulation, to allow direct comparisons. The population voltage signal showed paired-pulse facilitation, caused in part by additional recruitment of new neurons and dendrites. “Synaptic stimulation” delivered in L1 depolarizes almost an entire cortical column to some degree.

Tissue chip technology has revolutionized biomedical applications and the medical science field for the past few decades. Currently, tissue chips are one of the most powerful research tools aiding in in vitro work to accurately predict the outcome of studies when compared to monolayer two-dimensional (2D) cell cultures. While 2D cell cultures held prominence for a long time, their lack of biomimicry has resulted in a transition to 3D cell cultures, including tissue chips technology, to overcome the discrepancies often seen in in vitro studies. Due to their wide range of applications, different organ systems have been studied over the years, one of which is the blood brain barrier (BBB) which is discussed in this review. The BBB is an incredible protective unit of the body, keeping out pathogens from entering the brain through vasculature. However, there are some microbes and certain diseases that disrupt the function of this barrier which can lead to detrimental outcomes. Over the past few years, various designs of the BBB have been proposed and modeled to study drug delivery and disease modeling on Earth. More recently, researchers have started to utilize tissue chips in space to study the effects of microgravity on human health. BBB tissue chips in space can be a tool to understand function mechanisms and therapeutics. This review addresses the limitations of monolayer cell culture which could be overcome with utilizing tissue chips technology. Current BBB models on Earth and how they are fabricated as well as what influences the BBB cell culture in tissue chips are discussed. Then, this article reviews how application of these technologies together with incorporating biosensors in space would be beneficial to help in predicting a more accurate physiological response in specific tissue or organ chips. Finally, the current platforms used in space and some solutions to overcome some shortcomings for future BBB tissue chip research are also discussed.