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October 2008 Neuroscience Journal Club Experience-dependent plasticity of dendritic spines in the developing rat barrel cortex in vivo Balazs Lendvai*, Edward A. Stern, Brian Chen & Karel Svoboda Processing of Sensory Informations BRAIN: what for? ELABORATION OF STIMULA • COLLECTION OF (SENSORY) INPUTS • PROCESSING OF INFO (Cortex) → RECORDING • SPAWNING A (MOTOR) OUTPU Analogous to neurons processing BRAIN: what for? MEMORIZATION • ENCODING: analysis of sensorial informations • STORAGE: keep a copy or permanent recording of coded informations • RETRIEVAL: following use of the information stored, in order to behave in a certain way or to solve a problem. October 2008 Where is memory stored? • Where in the brain are memories stored? • How do we know this? • How does the brain store electrical patterns of activity with cells? • Lashley K.: lesioned various portion of the cortex to localize the one responsible for mnemonic retention • H.M.: following a surgery, he suffered from anterograde amnesia • Penfield W.: electrical stimulation of cortex surface PENFIELD • Hebb rule for Synaptic Plasticity (1946): synaptic facilitation can derive from each experience • The trace (persistence or repetition of a reverberatory activity) tends to induce lasting cellular changes that adds to its stability and that can be retrieved several years later through an electrical current, without loosing any detail October 2008 The substrate of memory is: dendritic spines – maybe… October 2008 How is long-term memory stored? •Neurons form circuits where electrical signals (spikes) propogate between synapses •Once a circuit is stimulated, under certain circumstances it is easier to stimulate again •Reverberating circuits •Long term potentiation •example of an electrical stimulation causing permanent change •Inhibitors of protein synthesis or calcium signals prevent LTP Cellular mechanisms of learning and memory: LTP and LTD → Repeated stimulus leaves a TRACE → Nervous track repeatedly crossed can be subjected to LTP → Activation of cascade biochemical mechanisms that determine STRUCTURAL MODIFICATIONS of the circuit itself Cellular mechanisms of learning and memory: LTP and LTD From Science, 2006 → Activation/deactivation of synapses → Protrusion/retraction of spines/filopodia Do changes in neuronal structure underlie cortical plasticity?1,2 1. Bailey, C. H. & Kandel, E. R. Annu. Rev. Physiol. 55, 397±426 (1993). 2. Buonomano, D. V. & Merzenich, M. M. Annu. Rev. Neurosci. 21, 149±186 (1998). Methods • Infection of neocortical neurons in vivo with SIN±EGFP with injection into brain parenchyma In vivo high-resolution imaging of barrel cortex neurons infected with SINEGFP (Sindbis virus containing the gene for Enhanced GFP). • Sensory deprivation: trimming • Intracellular recording in vivo Methods • Time lapse two photon microscopy • In vivo imaging of the structural dynamics of dendritic spines and filopodia in the intact brain • Piramidal neurons in layer 2/3 of developing (P8-18) rat barrel cortex Objectives •Modulating sensory inputs by trimming whiskers changes the response properties of neurons. •Examine the effects of the rat's sensory experience on the structure and dynamics of spiny protrusions as a substrate of experienced-dependent plasticity Barrel Cortex Spatial arrangement of the whiskers on the rat’s face : matrix of large hairs represented in these brain areas by a topographically similar matrix of cell rings. (A, B) Barrels: aggregates of cell rings in layer IV of the cerebral cortex . Barrel cortex: area in the somatosensory cortex (C) where neurons are grouped in barrel- like arrangements, with a hollow center of lesser cell density surrounded by a circle of higher cell density. IMP: one-to-one relationship between each vibrissa and its corresponding barrel. Barrel Cortex 2P Time-lapse Imaging • Characterization of dendritic protrusions: high resolution 2PLSM images. • Quantification of motility: lenght of individual protrusions vs time • Description of structural dynamics for individual protrusion: average change of lenght per sampling interval (mm per 10 min) Results • High mobility in vivo: dendritic protrusions are dynamic (changed lenght, shape, appeared/disappeared) over timescales of 10 min and over lengths of mm • Largest motility in the youngest animals (P8-12) → less filopodia Effects on the structure and dynamics of spiny protrusions • Whiskers trimming 1-3 days before imaging • Comparison of LOCATIONS: control, deprived, specificity • Comparison of AGES: during (P11-13), before (P8-10), after (P14-16) synaptogenesis (whiskers’ use in exploratory behaviour) DYNAMICS • Protrusive motility is modulated by previous experience • AGE: only during a brief critical period, P11±13, deprivation caused a large decrease in motility • LOCATION: effects of sensory deprivation are specific to the deprived region of the cortex. STRUCTURE AND DENSITY Sensory deprivation does NOT change the average structure (distributions of lengths, distr. among different morphological classes) or density of dendritic protrusions (in all ages) Effects on the development of receptive fields • • Recordings of membrane potential dynamics of regular spiking neurons in P14±16 rats Measurement of PSPs amplitudes in response to deflections of single whiskers (SW or PW) RESULTS: • • Principal whisker response was smaller than in control animals but the surround was stronger and broader Sensory deprivation has a profound effect on the TUNING of sensory maps of layer 2/3 pyramidal neurons. Effects on network synaptic activity • Measurement and computation of the distribution of MP to see if experience-dependent changes in spontaneous synaptic activity drive changes in protrusive motility RESULTS: • NO long-lasting effects on network synaptic activity • Experience-dependent changes in motility are coupled more directly to the history of sensory activity Results: summary • HIGH BASAL motility in spines and filopodia: they appeared, disappeared or changed shape over tens of minutes • Experience-dependent modulation of dendritic motility (synaptic lifetimes) is limited to a sharp critical period (P11±13) • Does sensory experience drive this motility? Yes: Sensory deprivation markedly (40%) reduced protrusive motility in deprived regions of the barrel cortex No: Whisker trimming did NOT change the density, length or shape of spines and filopodia Results: summary ELECTROPHYSIOLOGICAL MEASUREMENTS: effects on synaptic ACTIVITY • Sensory deprivation spanning the critical period is associated with defective development of layer 2/3 sensory maps • Sensory deprivation perturbs the experiencedependent rearrangements of synaptic connections required to form precise sensory maps Long Term Depression • LTP can be saturated • You only have a finite number of synapses • Your brain is in danger of getting full • Therefore you need LTD THANKS FOR YOUR ATTENTION!!!