Learning-related fine-scale specificity imaged in motor cortex circuits of behaving mice

Komiyama, Takaki; Satō, Takashi; O’Connor, Daniel H.; Zhang, Ying Xin; Huber, Daniel; Hooks, Bryan M.; Gabitto, Mariano I.; Svoboda, Karel

doi:10.1038/nature08897

Cited by 434 publications

(441 citation statements)

References 37 publications

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“…The nature of these fluctuations seems similar to fluctuations in the BOLD fMRI signal in nonhuman (25) and human (26) primates and in the IOS and Doppler signals from rodents (24). Thus, the transcrianal imaging technique we used may be of use to explore the mechanistic basis of these ubiquitous oscillations (27) in behaving mice (28,29).…”

Section: Discussionmentioning

confidence: 87%

Fluctuating and sensory-induced vasodynamics in rodent cortex extend arteriole capacity

Drew

Shih

Kleinfeld

2011

Proc. Natl. Acad. Sci. U.S.A.

266

388

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Neural activity in the brain is followed by localized changes in blood flow and volume. We address the relative change in volume for arteriole vs. venous blood within primary vibrissa cortex of awake, head-fixed mice. Two-photon laser-scanning microscopy was used to measure spontaneous and sensory evoked changes in flow and volume at the level of single vessels. We find that arterioles exhibit slow (<1 Hz) spontaneous increases in their diameter, as well as pronounced dilation in response to both punctate and prolonged stimulation of the contralateral vibrissae. In contrast, venules dilate only in response to prolonged stimulation. We conclude that stimulation that occurs on the time scale of natural stimuli leads to a net increase in the reservoir of arteriole blood. Thus, a "bagpipe" model that highlights arteriole dilation should augment the current "balloon" model of venous distension in the interpretation of fMRI images.ocalized changes in the flow and volume of oxygenated blood in the brain are commonly used as a correlate of heightened neural activity. For two important imaging modalities, blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) (1) and intrinsic optical signal imaging (IOS) (2), the signals are generated by a complex interplay of the rate of oxidative metabolism, the flux of blood in the underlying angioarchitecture, and changes in vascular volume (3). The locus for the increase in vascular volume that follows sensory stimulation (i.e., arterioles or venules) is an enduring controversy that bears directly on interpreting and quantifying fMRI signals (4-6). To resolve this question, we used in vivo two-photon laserscanning microscopy to image spontaneous and sensory evoked vascular dynamics in the vibrissa area of parietal cortex of awake, head-fixed mice. All data were collected through a reinforced thin-skull window (7) (Fig. 1A); this method obviates potential complications from inflammation or changes in cranial pressure that may occur with a craniotomy (8). ResultsImages of the pial surface and measurements of the diameter of the lumen of surface arterioles and venules were performed while the mouse sat passively (Fig. 1B). Dilations greater than 5% of the baseline diameter occurred with frequencies of 0.07 ± 0.05 Hz (mean ± SD, n = 118 arteries in six mice). The diameters of short segments of arterioles (red in Fig. 1B) exhibited relatively large spontaneous increases in the spectral range between 0.1 Hz and 1 Hz ( Fig. 1 C and D). The peak amplitude of these fluctuations was 23% ± 10% of the initial vessel diameter across all arterioles, with instances of a 50% increases in diameter. Further, these lowfrequency oscillations were strongly coherent and synchronous over a distance of several hundred micrometers across cortex (198 pairs of vessels, in six mice, that were separated by 20-315 μm; slope of coherence = 0.001 μm −1 [nonsignificant (NS)] and slope of phase shift = 0.0009 rad/μm

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Section: Discussionmentioning

confidence: 87%

Fluctuating and sensory-induced vasodynamics in rodent cortex extend arteriole capacity

Drew

Shih

Kleinfeld

2011

Proc. Natl. Acad. Sci. U.S.A.

266

388

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“…Nevertheless, future research will have to tackle network functions at the level of ensembles of individual identified synapses and neurons in vivo. Further progress will probably depend on the development of methods to image synapses and their molecular components with high sensitivity and spatiotemporal resolution in situ [109][110][111] . Exciting recent developments mainly, but not exclusively, based on calcium imaging have achieved sufficient resolution to monitor function at the level of ensembles of spines in the neocortex 112,113 .…”

Section: Microcircuitmentioning

confidence: 99%

Structural plasticity upon learning: regulation and functions

2012

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The contributions of brain networks to information processing and learning and memory are classically interpreted within the framework of Hebbian plasticity and the notion that synaptic weights can be modified by specific patterns of activity. However, accumulating evidence over the past decade indicates that synaptic networks are also structurally plastic, and that connectivity is remodelled throughout life, through mechanisms of synapse formation, stabilization and elimination 1. This has led to the concept of structural plasticity, which can encompass a variety of morphological changes that have functional consequences. These include on the one hand structural rearrangements at pre-existing synapses, and on the other hand the formation or loss of synapses, of neuronal processes that form synapses or of neurons. In this Review we focus on plasticity that involves gains and/or losses of synapses. Its key potential implication for learning and memory is to physically alter circuit connectivity, thus providing long-lasting memory traces that can be recruited at subsequent retrieval. Detecting this form of plasticity and relating it to its possible functions poses unique challenges, which are in part due to our still limited understanding of how structure relates to function in the nervous system.We review recent studies that relate the structural plasticity of neuronal circuits to behavioural learning and memory and discuss conceptual and mechanistic advances, as well as future challenges. The studies establish a number of strong links between specific behavioural learning processes and the assembly and loss of specific synapses. Further areas of substantial progress include molecular and cellular mechanisms that regulate synapse dynamics in response to alterations in synaptic activity, the specific spatial distribution of the syn aptic changes among identified neurons and dendrites and the relative roles of excitation and inhibition in regulating structural plasticity.The new findings provide exciting early vistas of how learning and memory may be implemented at the level of structural circuit plasticity. At the same time, they highlight major gaps in our understanding of plasticity regulation at the cellular, circuit and systems levels. Accordingly, achieving a better mechanistic understanding of learning and memory processes is likely to depend on the development of more effective techniques and models to investigate ensembles of identified synapses longitudinally, both functionally and structurally. Molecular mechanisms of synapse remodellingA remarkable feature of excitatory and inhibitory synapses is their high level of structural variability 2 and the fact that their morphologies and stabilities change over time 3 . This phenomenon is regulated by activity, and the size of spine heads correlates with synaptic strength 4 , presynaptic properties 5 and the long-term stability of the synapse 6 . The morphological characteristics of synapses thus reveal important features of their function and stabilit...

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“…In a typical experiment, an area of the skull is surgically removed and replaced with a cover glass to provide optical access to the underlying structure of interest (4). For imaging during behavior, the cover glass is often attached to an optically transparent plug embedded in the skull to improve mechanical stability and to prevent the skull from growing back and blocking the optical access (5,6) (Fig. 1A).…”

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confidence: 99%

Characterization and adaptive optical correction of aberrations during in vivo imaging in the mouse cortex

Satō

Betzig

2011

Proc. Natl. Acad. Sci. U.S.A.

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184

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The signal and resolution during in vivo imaging of the mouse brain is limited by sample-induced optical aberrations. We find that, although the optical aberrations can vary across the sample and increase in magnitude with depth, they remain stable for hours. As a result, two-photon adaptive optics can recover diffraction-limited performance to depths of 450 μm and improve imaging quality over fields of view of hundreds of microns. Adaptive optical correction yielded fivefold signal enhancement for small neuronal structures and a threefold increase in axial resolution. The corrections allowed us to detect smaller neuronal structures at greater contrast and also improve the signal-to-noise ratio during functional Ca 2 imaging in single neurons.T he ability to visualize biological systems in vivo has been a major attraction of optical microscopy, because studying biological systems as they evolve in their natural, physiological state provides relevant information that in vitro preparations often do not allow (1). However, for conventional optical microscopes to achieve their optimal, diffraction-limited resolution, the specimen needs to have identical optical properties to those of the immersion media for which the microscope objective is designed. For example, one of the most widely applied microscopy techniques for in vivo imaging, two-photon fluorescence microscopy, often uses water-dipping objectives. Because biological samples are comprised of structures (i.e., proteins, nuclear acids, and lipids) with refractive indices different from that of water, they induce optical aberrations to the incoming excitation wave and result in an enlarged focal spot within the sample and a concomitant deterioration of signal and resolution (2, 3). As a result, the resolution and contrast of optical microscopes is compromised in vivo, especially deep in tissue.Many questions related to how the brain processes information on both the neuronal circuit level and the cell biological level can be addressed by observing the morphology and activity of neurons inside a living and, preferably, awake and behaving mouse (1). In a typical experiment, an area of the skull is surgically removed and replaced with a cover glass to provide optical access to the underlying structure of interest (4). For imaging during behavior, the cover glass is often attached to an optically transparent plug embedded in the skull to improve mechanical stability and to prevent the skull from growing back and blocking the optical access (5, 6) (Fig. 1A). Before the excitation light of a two-photon microscope reaches the desired focal plane inside the brain, it has to traverse first the cranial window and then the brain tissue, both with optical properties different from water. Thus, they both impart optical aberrations on the excitation light, which leads to a distorted focus, even at the surface of the brain.These sample-induced aberrations can be corrected with adaptive optics (AO) to recover diffraction-limited resolution. In AO, a wavefront-shaping device m...

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Learning-related fine-scale specificity imaged in motor cortex circuits of behaving mice

Cited by 434 publications

References 37 publications

Fluctuating and sensory-induced vasodynamics in rodent cortex extend arteriole capacity

Fluctuating and sensory-induced vasodynamics in rodent cortex extend arteriole capacity

Structural plasticity upon learning: regulation and functions

Characterization and adaptive optical correction of aberrations during in vivo imaging in the mouse cortex

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