Yang Ming Lectures on Neuroscience Feburary 13, 2014 Neural Plasticity: From Synapse to Cognition Mu-ming Poo Neural Plasticity The ability of the nervous system to adopt a new functional or structural state in response to extrinsic and intrinsic factors. Homeostasis vs. Plasticity Electrical activity (sensory/motor/cognitive experience) Neuronal and synaptic modifications (plasticity) Learning/memory and changes in cognition & behaviors A Physiological Postulate on Neural Plasticity “When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A’s efficiency, as one of the cells firing B, is increased.” Donald O. Hebb The Organization of Behavior (1949) Discovery of LTP and LTD Bliss T.V and Lomo M. Journal of Physiology 232:331-56 (1973) Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following high-frequency (100 Hz) stimulation of the perforant path. M. Ito and M. Kano Neuroscience Letters 13;33:253-8 (1982) Long-lasting depression of parallel fiber-Purkinje cell transmission induced by conjunctive stimulation (at 4 Hz) of parallel fibers and climbing fibers in the cerebellar cortex Changes in EPSP Amplitude Long-term potentiation (LTP) and Long-term depression (LTD) (min) 100 Hz stim. (1 sec) 高频刺激 (1秒) (min) 1 Hz stim. (a few min) Time (minutes) Formation of new spines after LTP-inducing high-frequency stimulation in hippocampal slice cultures Engert and Bonhoeffer, Nature (1999) Spine shrinkage after LTD-inducing low-frequency stimulation in acute hippocampal slices Zhou et al. Neuron (2004) In vivo two-photon imaging of YFP-H mice 100 µm Hebb’s Learning Rule 1. Correlated pre- and postsynaptic activities cause synapse strengthening / stabilization 2. Uncorrelated pre- and postsynaptic activities cause synapse weakening / elimination (G. Stent) “Cells that fire together wire together” Development of Retinotectal Projections T N Retina (EphA3) C R Tectum (Ephrin-A2) development activity ganglion cell tectal cell In vivo whole-cell recording in developing Xenopus tectum input 1 R Input 1+input 2 S2 Measured 1+2 (nA) T FB S1 input 2 0.4 0.3 0.2 0.1 0.0 0.0 0.1 0.2 0.3 0.4 Expected 1+2 (nA) Correlated activation of sub- and suprathreshold inputs (10 msec intervals between input 1 and 2) I: supra I II I: sub II: supra II: sub 2.0 Normalized EPSC Amplitude II I 2.0 Input I Input I 1.5 1.5 1.0 1.0 0.5 -10 0 10 20 30 0.5 -10 0 10 20 30 2.0 2.0 Input II Input II 1.5 1.5 1.0 1.0 0.5 0.5 -10 0 10 20 Time (min) 30 -10 0 10 20 Time (min) 30 Correlated activation of sub - and supra-threshold inputs (with 10 msec intervals) Normalized EPSC Amplitude I : sub II : supra I II 2.0 I : supra II:: sub I 2.0 Input I Input I 1.5 1.5 1.0 1.0 0.5 0.5 -10 0 2.0 10 20 Input II 3 0 -10 10 20 Input II 2.0 1.5 0 II 30 AP5 1.5 1.0 1.0 0.5 -10 0 10 20 Time (min) 30 0.5 -10 0 10 20 Time (min) 30 Change in EPSC Amplitude (%) A critical window for synaptic modification 100 I II III ∆Τ ∆Τ ∆Τ I II III 80 synaptic inputs 60 current injection LTP 40 20 0 -20 -40 LTD -60 -100 -80 -60 -40 -20 0 20 40 60 80 100 Timing of synaptic input (ms) Zhang, et. al . Nature (1998); Bi and Poo, J. Neurosci. (1998) Temporally Specific Hebb’s Learning Rule Correlated pre- and postsynaptic activities can induce either strengthening or weakening of the synapse, depending on the temporal order of spiking. * Pre before post -- strengthening * Post before pre -- weakening “Spike timing-dependent Plasticity (STDP)” reference Levy & Steward (83) Bell et. al. (97) Zhang et al. (98) Boettiger & Doupe (01) Bi & Poo (98); Li et al. (04) Debanne et al. (98) Nishiyama et al. (00) Lin et al. (03) Markram et al. (98) Egger et al. (99) Feldman (01) Sjostrom et al. (03) Froemke et al. (05) Tzounopoulos et al. (04) reference Zhang et al (98) Meliza & Dan (06) Allen et al (03), Celikel et al (04) Mehta et al (00) Schuett et al (01) Fu et al (02), Yao & Dan (01,04) Fu et al (04) Stefan et al (02), Wolters et al (03) Dan & Poo. Physiol. Rev. 86: 1033-48 (2006) Name That Tune! Tune 1 Tune 2 Memory is temporally specific: • Temporal Sequence of Events • Time Intervals of Events Sound track made by Li Zhang STDP - based strengthening / weakening of connections following uni-directional sequential excitation 19 Recall of sequential spiking by partial stimulus following uni-directional modification of connnectivity 20 Neural circuit mechanism for storing sequence information using STDP - A study using mouse visual cortex 21 Monitoring neuronal ensemble activity with multi-electrode arrays in rat primary visual cortex (V1) Sheng-jin Xu Wen-chen Jiang Receptive fields of 16 neurons recorded by multi-electrode array Sequential spiking triggered by uni-directional moving spot Conditioning with moving spot Recall of sequence spiking with test spot at “starting” and “end” points Sequence learning/memory by V1 neuronal ensemble 1. Flashes at “starting point” elicit no sequential spiking before training 2. Sequential spiking induced by uni-directional moving light spot 3. Flashes at “starting point” elicit sequence spiking after training Sorted cross correlogram showing increased post-conditioning recall of sequential spiking Anesthetized Awake 27 Specificity of cue triggered recall of spike sequence – Spearman (rank order) CCs 28 Post-conditioning “recall” of sequence spiking Anesthetized Awake 29 Spontaneous switch of brain state in awake rats Ratio 1 = P0-10 Hz / P0 -25 Hz Ratio 2 = P15-30 Hz / P15-60 Hz Red (Low state): low frequency dominant , synchronized state Blue (High state): high frequency dominant, desynchronized state 30 Sequence recall in the synchronized but not de-synchronized state Xu, et. al. Nature Neurosci. (2012) 31 Is sequential spiking of V1 neurons sufficient and necessary for learning of sequence of motion stimuli? Yan Xing-Jian Zhang Deng 32 Optogenetic Induction of Sequential Firing Viral injectionCh S PSTH 249 1 E 0 154 2 0 226 3 0 Adeno-associated virus (AAV) 251 4 8 6 7 5 34 12 hsyn NpHR-EYFP 0 ChR2-mCherry 2A 277 5 0 232 6 0 244 7 0 192 8 0 0 0.1 0.2 0.3 0.4 0.5 0.6 Time (s) 33 Sequential activation of V1 neurons with optogenetic stimulation Test Test starting point / end point at random Conditioning Sweeping light (conditioning) Test starting point / end point at random Cond Before Starting point test Ch 1 8 0 500 ms 0 500 ms 0 500 ms Ch 1 8 After Ch 1 8 34 Sequence firing in V1 is sufficient for sequence learning Example Averaged (n=9) Starting point Starting point End point End point 35 Many issues remain to be addressed 1. Is sequential spiking of V1 neuron ensembles required for sequence memory due to conditioning with the moving spot? 2. Are there indeed spike timing-dependent LTP & LTD of intracortical connections due to repetitive sequential spiking as predicted by STDP? 3. Do brain states affect the learning/memory of sequential spiking? How could persistent memory be imprinted? 4. Can non-linear (arbitrarily chosen) neuronal ensembles store memory of sequence spiking? 5. Where are the “real” long-term storage sites for sequence memory? 36 Three levels of cognition 1. Cognition about the outside world - Perception, concept and categorization - Many animals have it 2. Cognition about oneself – self-awareness - Limited to human and a few primates 3. Cognition of language - Unique to humans 37 Self-Awareness and Mirror Self-Recognition 1. Only humans and a few species of great apes are known to be capable of recognizing themselves in the mirror 2. Human babies acquire the ability of mirror self-recognition by two years of age 3. Some psychiatric and autistic patients are impaired in selfawareness Monkeys cannot recognize themselves in the mirror Training of visual-somatosensory association in the monkey chair Neng Gong Liangtang Chang Test of visual-somatosensory association 41 Test of visual-somatosensory association with a mirroring video image 42 Mark test with a low-power laser light on the training chair 43 Standard mark test with dye mark on the training hair 44 Mark tests with low-powered laser light in the home cage 45 Standard dye mark tests in the home cage 46 Does the monkey really recognize himself? --Mirror/glass wall experiments 47 Mirror-induced Spontaneous Behavior Trained (green) naïve (yellow) Mirror-induced Spontaneous behaviors Trained (green) Trained (red) Mirror-induced Spontaneous behaviors Trained (green) naïve (yellow) Mirror-mediated self-directed behaviors M1: Red M2: Green 51 Implications 1. Rhesus monkey can learn mirror self-recognition 2. Human babies may acquire the ability of mirror selfrecognition via learning during the first two years 3. Impairment in self-awareness (mirror self-recognition) in humans may be treated by training of visualsomatosensory association in front of a mirror Acknowledgement UCSD & Berkeley : Li Zhang Qiang Zhou Huizhong Tao German Sumbre Guo-qiang Bi Institute of Neuroscience, Shanghai: Shanjin Xu Deng Zhang Wen-cheng Jiang Neng Gong Xinjian Yan Liangtang Chang Collaborators : Bill Harris Christine Holt Yang Dan
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