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William Buchser Neuroscience Journal Club April 28th 2004 Timing of neural responses in cortical organotypic slices Background Timing • Events which occur with timing greater than a few seconds is probably grasped by out frontal cortex – a component of complex thought processing. • Timing in the shorter range (less than a second or two) is thought of as automatic – the brain has a system that deals with it unconsciously. “The neural representation of time.” Ivry RB, Spencer RM Background Ordinal Metric WORD L R Duration Discrimination Parkinson’s Disease “The neural representation of time.” Ivry RB, Spencer RM Timing Examination 400 ms L R L R 200 ms 600 ms 300 ms http://www.neurobio.ucla.edu/~dbuono/InterThr.htm Background • Our temporal resolution in the auditory system is much higher than in other sensory systems • Timing has been studied using psychological, behavioral, and neuro-imaging approaches. • Few in vitro studies exist this paper! • Can we observe a physiological ‘memory trace’ in brain slices? “The neural representation of time.” Ivry RB, Spencer RM This paper uses organotypic slices to try determine if reliably timed ‘late’ responses can be observed in vitro, and what mechanisms lead to their existence. Methods - Adult Sprague Dawley Rats - Remove Brain and make slices - Use coronal slice, 350400μm thick slices containing auditory cortex http://caddlab.rad.unc.edu Organotypic Slices Coronal slices are placed on special membranes used for culture, they are bathed constantly in artificial cerebrospinal fluid. Millipore: Millicell®-CM Recording Paradigm A single pulse was applied every 15-30 s to elicit synaptic responses. Stimulation intensity ranged from 30 to 100 µAmpere. Stimulating Electrode Recording Pipette Dorsal Ventral Lateral Medial Slice from: Redefining the tonotopic core of rat auditory cortex: Physiological evidence for a posterior field Neot N. Doron, Joseph E. Ledoux, Malcolm N. Semple Horizontal Voltage Sweeps Timing of the Late Response -50mV Stimulus Average response of 60 trials below -80mV Figure 1A Timing of the Late Response -30mV -80mV Time (min) Action Potentials Figure 1B Timing of the Late Response • We now know what the ‘late’ response looks like. • A monosynaptic PSP is observed within the first few milliseconds after stimulus. • After more time (between 50 and 400 ms) more EPSPs occur (probably polysynaptic in nature), and are sometimes integrated into action potentials (all of this is the ‘late’ response). Summary - Figure 1 What does mono and polysynaptic mean? Stimulus Latency vs. Accuracy •What is the latency and accuracy of the timed responses? • By examining the mean and the SD for the latency of the first spike, we can make some conclusions about relationships therein. Preface - Figure 2 Mean latency of the first spike versus the SD Correlation r = 0.94 High Variability Long Latency High Accuracy Short Latency Figure 2 Latency vs. Standard Deviation • Strong correlation between the latency and the SD (accuracy) of firing. Summary - Figure 2 Electrode Distance and First Spike Latency • Does the distance from the stimulating electrode correlate to the observed latency? • Others have made the observation that with a monosynaptic connection, distance is highly correlated with latency. •Polysynaptic connections on the other hand, may or may not be correlated with spatial relationships. Preface - Figure 3 Recording Paradigm 650µm 1200µm Stimulating Electrodes Recording Pipette Dorsal Ventral Lateral Medial Figure 3 A cell that fires sooner to more distant stimulation Figure 3B Distance vs. Mono and Poly Response Latency Figure 3A Electrode Distance and First Spike Latency • Distance from stimulating electrode affects the latency of the sub-threshold monosynaptic response. • Distance from the electrode has no simple relationship with the latency in neuron firing (polysynaptic integration leading to response) Summary - Figure 3 The Network nature of the Late Response • The complex nature of the ‘late’ response of a single cell implies polysynaptic network input. • To test this, we will determine the extent that the late response is reliant on NMDA receptors. • We will use the NMDA blocker APV to determine if NMDA receptors play a role in the late response. Preface - Figure 4 Late responses are dependent on NMDA receptors -10mV -80mV Figure 4A Network nature of the Late Response • NMDA receptors are indicated in the late response due to an abolition of polysynaptic potential during APV’s application • Therefore, neurons are likely to get excitatory polysynaptic input which needs to be integrated before a supra-threshold response occurs. Summary - Figure 4 Paired Recordings • To determine whether different cells exhibit similar responses to the same stimulus, we recorded simultaneously from two neurons. Preface - Figure 5 Recording Paradigm 50µm 750µm Stimulating Electrode Recording Pipettes Dorsal Ventral Lateral Medial Figure 5 Different cells respond to same stimulus 750µm 50 Time (min) 350 Figure 5A Average sub-threshold response of two cells Red cell firing elicited an EPSP in blue cell AP Stimulus AP 750µm Figure 5A Two cells compared by correlating their sub-threshold output. Mean = 0.84 Figure 5C Paired recordings and shared input • Figure 5 demonstrates that two different neurons have different responses to the same stimulus • Although the action potentials are different, a lot of the subthreshold response is similar between them, reflecting shared input from the network. • Regardless of shared inputs, there is significant difference such to produce different suprathreshold responses. Summary - Figure 5 Cross-Correlation between two neurons Figure 6A First-spike latency between neurons that fire at different intervals is correlated. Figure 6B Other correlations of paired recordings • The scatter plot indicates that there is a strong correlation between the first spike in the red and green neuron • Activity in the green cell is contributing to the firing of the red cell. Summary - Figure 6 Stimulus intensity and first spike latency • To find if hard-wired ‘delay lines’ exist in the network, we can vary different stimulus parameters and see if the latency changes. • For the final experiment, they test whether intensity has an effect on the latency of the late response Not in Printed Copy Preface - Figure 7 Stimulus intensity and first spike latency -20mV High Low (5-10% below high) -80mV Figure 7A Stimulus intensity and first spike latency Figure 7B Stimulus intensity and first spike latency • Latencies are stimulus-level (intensity) dependent. • Therefore the latency is not hardwired into a particular neuron. • Stimulus intensity may be involved in the mechanism in which timing is learned. Not in Printed Copy Summary - Figure 7 Summary • Action potentials occurring up to 300 ms after stimulus onset are observed in organotypic slices from rat auditory cortex. •These late responses are attributed to dynamics of the neural network •Buonomano hypothesizes that timing in this range could be a local process, reflected in the dynamics of neurons recruited in a task-specific manner. “The neural representation of time.” Ivry RB, Spencer RM