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Figure 1. A Platform for the Patterned Spatiotemporal Stimulation of Neuronal Networks. (A) Schematic of cortical slice interfaced with a chip for whole-cell recording and control via stimulator (left) and live image (right). (B) The system can be interchangeably interfaced to commercial arrays from different vendors, such as MCS (left, with blowup) and MED (right) to enable multi-site stimulation. (C) Chip placed on stage. (D) Stimulator box – or circuit diagram (left) and inside view of *custom* stimulator (right). (E) Example pulse delivered to two pins from the stimulator via multielectrode array. Scale bars: 5 ms and 1 V. (F) Cortical slice integrated with the multielectrode array of different spacings, such as 200 μm (left) and 10 μm (right). (G) Multielectrode array interfaced with healthy pyramidal cells from a cortical slice (left) and a dissociated culture (right). (H) Simultaneous stimulation of 10 randomly selected pins in distinct, random patterns. The stimulator and multi-electrode array can be used together to stimulate each pin individually (I) and in conjunction with other pins at distinct and precise stimulus intensities (J). Figure 2. Precise control over neuronal activity using the spatiotemporal stimulator. (A) A cortical slice is interfaced with a chip, and simultaneous patch-clamp is achieved on a layer 2/3 pyramidal cell, as visualized at 2.5x. Scale bars: 200 μm. Stimulating a pin during current clamp near the patched cell results in single action potentials (B), which are abolished with 1μm TTX (C). Scale bars: 50 ms and 30 mV (B, C). (D) Probability of eliciting an action potential exhibits all or none behavior with stimulus intensity. (E) Action potentials can be elicited by stimulating pins close to the patched cell within an approximate radius determined by stimulus intensity. (F) Maximum effective range of stimulus as a function of stimulus intensity. (G) Spread of activation on a cortical slice bulk loaded with Oregon Green BAPTA 1-AM while stimulating distinct pins. Each square within the 4x4 grid represents the location of the stimulated pin. Action potential response to stimulation is temporally precise (H) and can be elicited in a random pattern (I). Scale bars: 1.5 s and 4 mV (H). Electrical stimuli are indicated by blue arrows. Figure 3. Precise control over synaptic transmission. (A) A cortical slice is interfaced with a chip, and a layer 2/3 pyramidal cell is patched in voltage clamp, as visualized at 2.5x. Scale bars: 200 μm. (B) AMPA-mediated EPSCs can be elicited by stimulating pins away from patched cell at -60 mV in voltage clamp (top) and abolished with 1 μm NBQX (bottom). Scale bars: 80 ms and 50 pA. (C) Synaptic transmission can be engaged to different degrees depending on stimulation intensity. Scale bars: 80 ms and 50 pA. (D) Distinct EPSCs, presumably arising from distinct subpopulations of cells, can be evoked by different stimulus locations. Numbers correspond to the row and column of the pin location. Scale bars: 80ms and 30 pA. (E) Mapped visualization of distinct EPSCs elicited by stimulation of each pin at 4.5 V, indicating heterogeneous responses from across the cortex. Scale bars: 200 μm. Figure 4. Evoked synaptic plasticity at single pathway. (A) A cortical slice is interfaced with a multi-electrode array; a pyramidal cell is patched, and two distinct pins, inputs A and B, are identified that elicit synaptic transmission (3-4 V, 0.5 ms), visualized at 2.5x (A) and recorded at -60 mV in voltage clamp (B). (C) Potentiation can be achieved by applying tetanic to input A (top), and subsequently to input B (bottom). (D) Average EPSC traces before and after LTP. (E) Average EPSC amplitude for each input before and after LTP, indicating a significant increase in EPSC amplitude following tetanic LTP stimulation. Figure 5. Selective association of entrained pathways via spatiotemporal programming. (A) Sample traces elicited in current-clamp from two spatially disparate inputs before and after stimulation in a close temporal sequence. (B) Mapped visualization of all pin responses before and after association of two chosen pins. Change in response is specific to pin targeted by associative programming (far right). (C) Repetition of associative multi-synaptic plasticity across multiple slices. Inputs are mediated by AMPA transmission and abolished by 1 μm NBQX (top right). Figure 6. Sequence “ABCDEFG” learning, by repeated fast-timed activation of nearby cortical regions. A cortical slice is interfaced with a chip, and a pyramidal cell is patched, as visualized at 2.5x (A) and 40x (B), and as a schematic (D). (C) A whole cell recording of the patched cell while a “moving bar” stimulus of 2-4V per pin is delivered to consecutive columns of pins sweeping across the cortex from left to right at 80ms intervals between columns. (E) Response to the bar is measured before and after a higherfrequency repetition of the bar’s movement. Mapped visualization of response to “moving bar” stimulus (F) before and (G) after high-frequency repetition. (H) Average amplitude of response to “moving bar” stimulus before and after high-frequency repetition as a function of left-to-right bar position. Figure 7. Using the multi-electrode array to change dynamics at population level. (A) A system view, illuminating fluorescence using 488 nm light.(B) Layer 2/3 of a cortical slice bulk loaded with Oregon Green BAPTA 1-AM, as visualized at 40x. (C) Actual cortical slice interfaced with a chip, as visualized at 2.5x for experimentation. (D) Cortical slice from (C) has been bulk loaded. Circles, which are areas around each electrode, depict the regions of interest used during image analysis to quantify the magnitude of the calcium response about a given electrode. (E) Sample calcium transient before sequence training (left). Heat maps of responses measured for each given ROI by stimulating each of the 12 pins. Each box within the 2x6 grid represents measurements within a single ROI at that spatial position and is a spatial color map depicting the efficacy of stimulating each site while recording in the box’s ROI (right).(F) Sample calcium transients (left) and heat maps of responses after training (right). Most ROIs show larger responses after training, as seen in blue traces in (E) and (F), and some ROIs even show responses where there previously were none, as seen in green traces in (E) and (F).