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Mark Hübener, PhD

Phone:+49 (0)89 8578 - 3697
Email:mark@...

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Figure 2 (Movie)

Green fluorescent protein labeled neuron in mouse visual cortex.

Synapses – Circuits – Plasticity: Visual System Development

Visual system development

During development, specific connections among neurons within the visual cortex as well as its in- and outputs are established, ultimately leading to a functional network enabling fine grain analysis of the visual world. While the basic circuitry is set up early in life, the visual cortex of adult animals displays some degree of plasticity, too. We study the cellular and molecular mechanisms underlying circuit formation and plasticity in the visual cortex during development and in adult animals. To address these questions at the functional as well as the structural level, we use a number of imaging techniques, such as two-photon microscopy and intrinsic signal imaging.


<p>Figure 1: Color coded activation pattern in mouse visual cortex evoked by presenting small visual stimuli at different locations in the visual field independently to both eyes.</p>
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Figure 1: Color coded activation pattern in mouse visual cortex evoked by presenting small visual stimuli at different locations in the visual field independently to both eyes.

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In mouse visual cortex, plasticity can be readily induced by closing one eye for a couple of days. This intervention, termed monocular deprivation, shifts the balance between the representation of the two eyes in the visual cortex, such that inputs from the deprived eye are weakened, while open eye inputs gain influence. We use intrinsic signal imaging to map the representation of the two eyes in the visual cortex (see Figure 1) and to visualize changes in functional connectivity following monocular deprivation. We could recently show that the visual cortex retains a lasting memory of this experience: If an animal undergoes a second episode of monocular deprivation many weeks later, the shift in eye balance is induced much faster and lasts longer than in naïve mice. Thus, the animal has learned to learn, reminding us of our own experience that exposure to an altered sensory environment, a new sensorimotor task, or a foreign language makes for easier learning of the similar information later in life.

In order to unravel the cellular mechanisms underlying this enhanced plasticity by prior experience, we studied the fine structure of neurons in the visual cortex using two-photon microscopy. Repeated imaging of neurons expressing green fluorescent protein (see Figure 2) demonstrated that monocular deprivation increased the number of dendritic spines, tiny protrusions that correspond to synaptic inputs. We believe that these newly formed synapses mediate the strengthening of open eye inputs seen after monocular deprivation. Importantly, the added spines did not disappear after reopening of the temporary closed eye, suggesting that they might form a lasting structural trace which mediates the enhanced plasticity seen after a second monocular deprivation. Indeed, a second closure of the eye did not result in the further addition of spines, despite the fact that the shift in eye representation occurred even faster than in inexperienced mice. These experiments indicate that specific structural modifications serve to store information about past experiences, thereby endowing the cortex with an improved ability to adapt to similar experiences in the future.


<p>Figure 3: Two-photon imaging of calcium signals demonstrate how individual neurons in mouse visual cortex change their eye-preference after closure of one eye.</p>
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Figure 3: Two-photon imaging of calcium signals demonstrate how individual neurons in mouse visual cortex change their eye-preference after closure of one eye.

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Intrinsic signal imaging is well suited to measure the eye preference of a large population of neurons, but its spatial resolution does not allow assessing how individual cells in the visual cortex change their responses after monocular deprivation. We addressed this question using two-photon imaging of neurons loaded with a calcium indicator dye, enabling us to record the visually evoked activity of hundreds of neurons at the same time. As we had expected, monocular deprivation shifted the eye preference of most neurons, such that they were driven more strongly by the non-deprived eye (see Figure 3). Surprisingly, though, a small number of cells resisted this overall shift, and, instead, responded more vigorously to the deprived eye. We think that the change in response properties of these cells is driven by a homeostatic mechanism, which increases the cell’s responsiveness following a drop in afferent drive. Thus, at the cellular level, the effects of monocular deprivation are not only by caused by competition between the two eyes, but also by homeostatic changes.


<p>Figure 4: <strong>TOP</strong> Color coded maps of visual space in mouse visual cortex obtained with intrinsic signal imaging. The cortical region silenced by a small lesion regains responsiveness over time.<br> <strong>BOTTOM</strong> Repeated two-photon microscopy of a stretch of dendrite in mouse visual cortex.</p>
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Figure 4: TOP Color coded maps of visual space in mouse visual cortex obtained with intrinsic signal imaging. The cortical region silenced by a small lesion regains responsiveness over time.
BOTTOM Repeated two-photon microscopy of a stretch of dendrite in mouse visual cortex.

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A striking example of the adult visual cortex’ capacity for plasticity is revealed by lesioning a small part of the retina in one eye. The permanent removal of the inputs from this part of the retina renders the corresponding region of the visual cortex initially silent. Over the following weeks and months, however, the silenced cortical region regains responsiveness for visual stimuli. Using intrinsic signal imaging, we were able to follow this recovery process over time in individual mice (see Figure 4, top panels). This functional reorganization is paralleled by a massive restructuring of cortical circuitry, as we could demonstrate by repeatedly imaging fluorescently labeled neurons in the visual cortex of these mice with two-photon microscopy (see Figure 4, bottom panels). The rate at which dendritic spines – sites of synaptic contacts on cortical neurons – disappeared and reappeared was massively increased following lesioning of the retina, such that only a fraction of the initial spines were still present two months later. Clearly, the adult cerebral cortex has the capacity for major restructuring of neuronal connections, contributing to functional reorganization following a loss of inputs.

 
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