electrical activity

Multi-modal Micro Electrode Fluidic Array (MEFA) Shells for Brain Organoids

Abstract Brain organoids (BOs) derived from human stem cells bridge the gap between monolayer cell culture studies and animal models, which have well-documented limitations. Monolayer cell culture models fail to accurately replicate the 3D interconnectivity in the brain; animal models, while helpful, are limited due to interspecies differences, with most research focusing on rather phenotypical rather than mechanistic aspects. Concurrent with the advancement of BO models is the urgent need to develop 3D micro instrumentation supporting these organoids to investigate brain development and disease in their accurate physiological environment. Conventional microelectrode arrays (MEAs) used for neuronal cell culture studies are planar, which limits recording access to a small fraction of cells on the bottom side of the organoid. Also, conventional microfluidics is inherently planar, and while recent advances in 3D MEAs and 3D microfluidics have enabled electrical and chemical interrogation in 3D, combining both features with tunability and precision to allow independent and simultaneous control is challenging. Recently, we reported new 3D micro instrumentation in the form of 3D shell MEAs and demonstrated its applicability for electrical recording from BOs. They feature lithographically patterned and chip-integrated electrodes and self-folding polymer shells that can be triggered to wrap around BOs to measure electrical activity from the entire organoid surface. The 3D MEA shell system is modeled on and resembles a miniaturized electroencephalography (EEG) cap; the process used to make them is size-scalable, chip-integrated, and mass- producible. In the research, we aim to develop and validate 3D Micro Electrode Fluidic Array (MEFA) shells with multi-modal electrical recording and biochemical control capabilities, offering high spatiotemporal resolution, tunability, and scalability. Since 3D spatiotemporal patterns of neurochemicals play a critical role in molecular and cellular events of neural development and disease, we propose to apply and validate the MEFA shells in two studies that mimic neurodevelopment and monitor the spatiotemporal effects in neurological disorders and their treatments in vitro. We anticipate that the proposed 3D MEFAs would revolutionize brain sciences by permitting real-time, in-situ studies of electrical and chemical stimulation and interrogation of BOs in a high- throughput manner. The proposed 3D scalable, reproducible, and tunable 3D micro instrumentation for BOs has broad relevance to understanding brain development in utero and the development of anatomically accurate drug and toxicity screening platforms for brain sciences and neurological disorders.

The circadian clock and neural circuits maintaining body fluid homeostasis

Neurons in the suprachiasmatic nucleus (SCN, the brain’s master circadian clock) display a 24 hour cycle in the their rate of action potential discharge whereby firing rates are high during the light phase and lower during the dark phase. Although it is generally agreed that this cycle of activity is a key mediator of the clock’s neural and humoral output, surprisingly little is known about how changes in clock electrical activity can mediate scheduled physiological changes at different times of day. Using opto- and chemogenetic approaches in mice we have shown that the onset of electrical activity in vasopressin releasing SCN neurons near Zeitgeber time 22 (ZT22) activates glutamatergic thirst-promoting neurons in the OVLT (organum vasculosum lamina terminalis) to promote water intake prior to sleep. This effect is mediated by activity-dependent release of vasopressin from the axon terminals of SCN neurons which acts as a neurotransmitter on OVLT neurons. More recently we found that the clock receives excitatory input from a different subset of sodium sensing neurons in the OVLT. Activation of these neurons by a systemic salt load delivered at ZT19 stimulated the electrical activity of SCN neurons which are normally silent at this time. Remarkably, this effect induced an acute reduction in non-shivering thermogenesis and body temperature, which is an adaptive response to the salt load. These findings provide information regarding the mechanisms by which the SCN promotes scheduled physiological rhythms and indicates that the clock’s output circuitry can also be recruited to mediate an unscheduled homeostatic response.

Neural coding in the auditory cortex - "Emergent Scientists Seminar Series

Dr Jennifer Lawlor Title: Tracking changes in complex auditory scenes along the cortical pathway Complex acoustic environments, such as a busy street, are characterised by their everchanging dynamics. Despite their complexity, listeners can readily tease apart relevant changes from irrelevant variations. This requires continuously tracking the appropriate sensory evidence while discarding noisy acoustic variations. Despite the apparent simplicity of this perceptual phenomenon, the neural basis of the extraction of relevant information in complex continuous streams for goal-directed behavior is currently not well understood. As a minimalistic model for change detection in complex auditory environments, we designed broad-range tone clouds whose first-order statistics change at a random time. Subjects (humans or ferrets) were trained to detect these changes.They were faced with the dual-task of estimating the baseline statistics and detecting a potential change in those statistics at any moment. To characterize the extraction and encoding of relevant sensory information along the cortical hierarchy, we first recorded the brain electrical activity of human subjects engaged in this task using electroencephalography. Human performance and reaction times improved with longer pre-change exposure, consistent with improved estimation of baseline statistics. Change-locked and decision-related EEG responses were found in a centro-parietal scalp location, whose slope depended on change size, consistent with sensory evidence accumulation. To further this investigation, we performed a series of electrophysiological recordings in the primary auditory cortex (A1), secondary auditory cortex (PEG) and frontal cortex (FC) of the fully trained behaving ferret. A1 neurons exhibited strong onset responses and change-related discharges specific to neuronal tuning. PEG population showed reduced onset-related responses, but more categorical change-related modulations. Finally, a subset of FC neurons (dlPFC/premotor) presented a generalized response to all change-related events only during behavior. We show using a Generalized Linear Model (GLM) that the same subpopulation in FC encodes sensory and decision signals, suggesting that FC neurons could operate conversion of sensory evidence to perceptual decision. All together, these area-specific responses suggest a behavior-dependent mechanism of sensory extraction and generalization of task-relevant event. Aleksandar Ivanov Title: How does the auditory system adapt to different environments: A song of echoes and adaptation

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COSYNE 2025

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