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Functional and structural adaptation in the central nervous system Anthony Holtmaat CNS function in a nutshell Sensory stimuli are converted into electrical signals Action potentials are electrical signals carried along neurons Synapses are chemical or electrical junctions that allow electrical signals to pass from neurons to other cells Changes in the amount of activity at a synapse can enhance or reduce its function Communication between neurons is strengthened or weakened by an individual’s activities, such as exercise, stress, and drug use All perceptions, thoughts, and behaviors result from combinations of signals among neurons The vast network of cortical neurons communicates through synapses 20 billion neurons; 77% of brain volume; 2.500 cm2 1000-10.000 synapses per ‘typical’ neuron. Feldmeyer et al. J. Phys. 2006 Fluorescent proteins have revolutionized the way we can image neurons and synapses Expression of fluorescent proteins allows one to see all microstructures on neurons Muller lab Muller lab Holtmaat lab Knott lab How does this complex system develop? How does this complex system allow us to learn? Can the network adapt or repair itself to an insult? Key terms: Functional and Structural Neuronal Plasticity The brain develops with enormous speed over weeks to months to its final size, and then its circuits are optimized over many years Growth cone with filopodia Filamentous actin drives filopodia protrusion and mobility Examples of axon guidance during neuronal development Collapse assay EGFP Sema3A Repulsion assay EGFP EGFP-Sema3A In vivo Axons are guide via a myriad of (chemo)attractants, neurotrophic factors and (chemo)repellants Axons compete with one another for targets The axon that loses the battle retracts Life imaging of fluorescent axons in the ‘young’ muscle illustrates this effect Neurons receive information through dendrites Why do neurons have complex dendrites? Dendritic protrusions (spines) They are very motile during development They ‘look’ for input " . . . it is almost impossible to do experiments whose conditions approach the normal physiological state, during which the changes in position and form of the neuronal arborizations could be fleeting and erased" Santiago Ramon y Cajal, 1899, on the motility of dendrites and spines. Axon-dendrite contacts depend on partnering adhesion molecules Wiring depends on activity as well: Hebbian Learning "when an axon of cell A ... 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" (Hebb, 1949) Cells that fire together, wire together Hebb’s original drawing From: the Molecular Biology of the Cell Synaptic circuits are the building blocks for plasticity dendritic arbor Axonal Bouton axonal arbor synaptic current glu action potential B postsynaptic neuron NMDA-R Other stabilizing components A AMPA-R 0.5 µm Dendritic Spine presynaptic neuron LTP: long term potentiation Critical periods • A critical period in developmental psychology and biology represents early stages in life during which a system is highly sensitive to environmental stimuli, affecting the way it develops • The effects of the lack of appropriate stimuli during a critical period might have long lasting and irreversible effects on the functioning of the system • Different components of a neuronal circuit (cell types, nuclei, layers) can have distinct critical periods • Activity-dependent or experience-dependent development of sensory systems • The most well-known examples are: binocular vision (between one and two years for humans); hearing; parental imprinting; bird song; first language acquisition vs second language acquisition Every neural system as some sort of a critical period Different types and different regulation Formation of ocular dominance columns Activity-dependent and Hebbian-like plasticity Conceptually first postulated by Hubel and Wiesel in 1960s Axons from the deprived side permanently lose space After only a week of monocular deprivation, axons terminating in layer 4 of the primary visual cortex from LGN neurons in the thalamus driven by the deprived eye have greatly reduced numbers of branches compared with those from the open eye Developmental plasticity in the owl auditory cortex Young owl with prisms work by Eric Knudsen in the 90s Auditory stim before 42 days prism Typical projections Visual stim 1 day prism prism removed Head turning angle Projections after prism Conclusion: Structural and functional plasticity during critical periods of development But what about plasticity in adults? The body surface is functionally represented in the cortex in a topographical fashion Homunculus Wilder Penfield (1891-1976) from Kandel, Schwartz and Jessell Marshall, Penfield, Woolsey Importance of the modality ~ Size of the representation The body surface is represented in the cortex in a topographical fashion in sensory and motor cortex Somatosensory map Marshall, Penfield, Woolsey Motor map Each area has its own very detailed map Cortical map plasticity is reversible and associated with optimized performance Hand Cortical map digits Stimulating digits 2-4 on rotating disk Pairing digits 2-4 Merzenich, Kaas, Jenkins et al Cortical map plasticity might be involved in phantom limb sensations A. Stimulation of the face elicits sensation referring to the phantom limb B. Referred sensation localized to distinct areas in the stump Ramachandran, Taub Extreme forms of cortical map plasticity after amputations Amputee with Phantom sensation Amputee without Phantom sensation Healthy subject Lip touch Lotze et al. Brain 2001 Merzenich, Kaas, Taub and many others How can we study and manipulate these processes in laboratory animals? Special case: The whisker to cortex projections The representation of the snout in the rodent SI is very large The mouse and rat barrel cortex Woolsey, Van der Loos! • The dense neurpil of the projections can be seen by various staining procedures • Whiskers are individually represented in barrel-related cortical columns The whisker to barrelcortex pathway Information flows through the (1) trigeminal nucleus (cranial nerve V) in the brain stem, (2) VPM of the thalamus to the (3) cortex The layers of the barrel cortex • • Thalamocortical input in layer 4 Layer 5 and 6 are themain output to subcortical somatosensory and motor areas such as thalamus, pons and striatum Activity dependent development of the barrel cortex • • • • • Formation of the barrel pattern by the thalamocortical afferents No pattern at one day after birth (A) At 2, 3 and 4 the patterns becomes increasingly clear Deprivation, genetic lesions, or transections of the peripheral nerve during the thalamacortical ingrowth disturbs the the formation of barrel patterns Later in life this has no effect Cranial windows in mice skull coverglass dura S1 Mice in the microscope Revisiting dendrites and spines Transient and persistent spines in the adult neocortex At least two classes of spines (L5B neurons): 1. Persistent spines: large, stable spines Survival fraction 2. Transient spines: thin spines that appear and disappear 1 Transient fraction 0.8 0.6 0.4 Persistent fraction 0.2 0 0 4 8 12 16 20 24 28 Time (days) Trachtenberg et al 2002. Nature; Holtmaat et al 2005. Neuron; Grutzendler et al 2002. Nature Experience-dependent plasticity in barrel cortex Trim all whiskers except D1 Fox, Simons, Ebner, Diamond et al Representations change upon peripheral manipulations Inducing experience-dependent plasticity combined with long-term imaging Control or Trimmed Fraction Persistent Spines Gained Spine density (mm-1) 16 12 Control 500 * * 400 100µm m 300 A1 * * * * * * * 200 * * * * * * 0* * *8 16* PND 69 Time (days) * 24 * α β γ C1 * 0.15 D1 δ E1 0.05 0 28 24 α* * 0.2 β * 0.15 C1 A1 * 0.2 * B1 * 20 Trimmed 0.25 0.25 * 0.1 * * 100 0* 8 Fraction Persistent Spines Lost 4 0 Imaging day * control * * * * * * * * * * * * trimmed PND 165 B1 * * * * *γ * D1 0.1 δ * 0.05 * 0 * * Spared Deprived E1 * *control trimmed * * * 5 µm day0 8 12 16 20 28 Holtmaat et al. 2006, Nature Experient dependent spine and synapse formation in the barrel cortex could underly map plasticity Barrel C1 Barrel D1 deprived spared spared SELECT SAMPLE activity change due to whisker clipping trimming Spine dynamics after monocular deprivation New stabilized spines can be potentiated more easily by a second MD Hofer et al, Nature 2008 Motor learning induces spine formation and stabilization Stabilization of new spines is enhanced by training Xu et al, Nature 2009 Yang et al, Nature 2009 Ziff and Ahissar, Nature 2009 Structural plasticity after whisker follicle lesions Functional expansion of spared whisker representations Before follicle ablation 2 months after follicle ablation X X X X E1! E1! X X D1! B 1! X X D1! X X A 1! B 1! A 1! Schubert, Lebrecht and Holtmaat, in progress Dendritic or axonal branch dynamics after whisker follicle ablation? * L5 New persistent spines on L2/3 L5B cells lesion ctrl lesion spared depr δ Marik et al. PLoS 2010 Tailby et al. PNAS 2005 depr Structural plasticty after retinal lesions Thus, our brain can to some extent cope with permanent peripheral nerve damage Can it adapt or recover from damage of itself? Central nervous system lesions Alzheimer’s Stroke Amyotrophic lateral sclerosis Huntington’s Parkinson’s Multiple Sclerosis Creutzfeldt-Jacob disease Spinal Cord Lesion Brain Tumor Spinocerebellar ataxia Peripheral versus central regeneration Peripheral nerves can regenerate after lesion Peripheral nerves can regenerate after a lesion Henry Head’s peripheral nerve regeneration experiment (year 1905). Henry lesioned his radial nerve. Initially the region that was insensitive to painful stimuli was large. Large part of this region had recovered sensation after 6 months (but it was not complete, even after 2 years). Regrowth of damaged neurons in the CNS is very difficult and complicated Central glial cells, myelin and other scar-components most likely prevent regeneration Peripheral nerve grafts in the central nervous system might be a solution The growth promoting properties of Schwann cells facilitate growth of damaged optic nerve fibers that would normally not regenerate. They even make synapses upon regrowth into the superior colliculus. This indicates that central neurons have not lost their capacity to grow. Cortical map plasticity can be useful: recovery from stroke Overlaid images of control and stroke patients. Blue is the normal representation of finger tapping, red the adapted response after stroke! 10 days 4 months 2 years Jaillard, A. et al. Brain 2005 motor cortex activity upon finger tapping measured with fMRI patients recovered from stroke controls without stroke This is linked to structural changes Brown et al, J. Neurosci 2007, 2008 Murphy-lab Induction of ‘Hebbian’ plasticity using neural implants in the motor cortex Conditioning period Summary 1. The nervous system develops guided by chemical cues and activity 2. Critical periods define important events during CNS development in which activity-driven plasticity permanently impacts its circuit function 3. Plasticity remains present in a limited form during adulthood and serves adaptation to new experiences and learning 4. Peripheral nerves regenerate pretty well 5. Central nerves do not regenerate in a CNS environment 6. The central nervous system can use ‘plasticity’ to deal with partial loss of function