Michael P. Stryker

Ocular dominance in layer IV of the cat's visual cortex and the effects of monocular deprivation.

1. The relation between the physiological pattern of ocular dominance and the anatomical distribution of geniculocortical afferents serving each eye was studied in layer IV of the primary visual cortex of normal and monocularly deprived cats. 2. One eye was injected with radioactive label. After allowing sufficient time for transeuronal transport, micro‐electrode recordings were made, and the geniculocoritcal afferents serving the injected eye were located autoradiographically. 3. In layer IV of normal cats, cell were clustered according to eye preference, and fewer cells were binocularly driven than in other layers. Points of transition between groups of cells dominated by one eye and those dominated by the other were marked with electrolytic lesions. A good correspondence was found between the location of cells dominated by the injected eye and the patches of radioactively labelled geniculocortical afferents. 4. Following prolonged early monocular deprivation, the patches of geniculocortical afferents in layer IV serving the deprived eye were smaller, and those serving the non‐deprived eye larger, than normal. Again there was a coincidence between the patches of radioactively labelled afferents and the location of cells dominated by the injected eye. 5. The deprived eye was found to dominate a substantial fraction (22%) of cortical cells in the fourth layer. In other cortical layers, only 7% of the cells were dominated by the deprived eye. 6. These findings suggest that the thalamocortical projection is physically rearranged as a consequence of monocular deprivation, as has been demonstrated for layer IVc of the monkeys visual cortex (Hubel, Wiesel & Le Vay, 1977).

Experience-Dependent Plasticity of Binocular Responses in the Primary Visual Cortex of the Mouse

An activity-dependent form of synaptic plasticity underlies the fine tuning of connections in the developing primary visual cortex of mammals such as the cat and monkey. Studies of the effects of manipulations of visual experience during a critical period have demonstrated that a correlation-based competitive process governs this plasticity. The cellular mechanisms underlying this competition, however, are poorly understood. Transgenic and gene-targeting technologies have led to the development of a new category of reagents that have the potential to help answer questions of cellular mechanism, provided that the questions can be studied in a mouse model. The current study attempts to characterize a developmental plasticity in the mouse primary visual cortex and to demonstrate its relevance to that found in higher mammals. We found that 4 d of monocular lid suture at postnatal day 28 (P28) induced a maximal loss of responsiveness of cortical neurons to the deprived eye. These ocular dominance shifts occurred during a well-defined critical period, between P19 and P32. Furthermore, binocular deprivation during this critical period did not decrease visual cortical responses, and alternating monocular deprivation resulted in a decrease in the number of binocularly responsive neurons. Finally, a laminar analysis demonstrated plasticity of both geniculocortical and intracortical connections. These results demonstrate that an activity-dependent, competitive form of synaptic plasticity that obeys correlation-based rules operates in the developing primary visual cortex of the mouse.

Modulation of Visual Responses by Behavioral State in Mouse Visual Cortex

Studies of visual processing in rodents have conventionally been performed on anesthetized animals, precluding examination of the effects of behavior on visually evoked responses. We have now studied the response properties of neurons in primary visual cortex of awake mice that were allowed to run on a freely rotating spherical treadmill with their heads fixed. Most neurons showed more than a doubling of visually evoked firing rate as the animal transitioned from standing still to running, without changes in spontaneous firing or stimulus selectivity. Tuning properties in the awake animal were similar to those measured previously in anesthetized animals. Response magnitude in the lateral geniculate nucleus did not increase with locomotion, demonstrating that the striking change in responsiveness did not result from peripheral effects at the eye. Interestingly, some narrow-spiking cells were spontaneously active during running but suppressed by visual stimuli. These results demonstrate powerful cell-type-specific modulation of visual processing by behavioral state in awake mice.

Highly Selective Receptive Fields in Mouse Visual Cortex

Genetic methods available in mice are likely to be powerful tools in dissecting cortical circuits. However, the visual cortex, in which sensory coding has been most thoroughly studied in other species, has essentially been neglected in mice perhaps because of their poor spatial acuity and the lack of columnar organization such as orientation maps. We have now applied quantitative methods to characterize visual receptive fields in mouse primary visual cortex V1 by making extracellular recordings with silicon electrode arrays in anesthetized mice. We used current source density analysis to determine laminar location and spike waveforms to discriminate putative excitatory and inhibitory units. We find that, although the spatial scale of mouse receptive fields is up to one or two orders of magnitude larger, neurons show selectivity for stimulus parameters such as orientation and spatial frequency that is near to that found in other species. Furthermore, typical response properties such as linear versus nonlinear spatial summation (i.e., simple and complex cells) and contrastinvariant tuning are also present in mouse V1 and correlate with laminar position and cell type. Interestingly, we find that putative inhibitory neurons generally have less selective, and nonlinear, responses. This quantitative description of receptive field properties should facilitate the use of mouse visual cortex as a system to address longstanding questions of visual neuroscience and cortical processing.

Harnessing neuroplasticity for clinical applications

Neuroplasticity can be defined as the ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function and connections. Major advances in the understanding of neuroplasticity have to date yielded few established interventions. To advance the translation of neuroplasticity research towards clinical applications, the National Institutes of Health Blueprint for Neuroscience Research sponsored a workshop in 2009. Basic and clinical researchers in disciplines from central nervous system injury/stroke, mental/addictive disorders, paediatric/developmental disorders and neurodegeneration/ageing identified cardinal examples of neuroplasticity, underlying mechanisms, therapeutic implications and common denominators. Promising therapies that may enhance training-induced cognitive and motor learning, such as brain stimulation and neuropharmacological interventions, were identified, along with questions of how best to use this body of information to reduce human disability. Improved understanding of adaptive mechanisms at every level, from molecules to synapses, to networks, to behaviour, can be gained from iterative collaborations between basic and clinical researchers. Lessons can be gleaned from studying fields related to plasticity, such as development, critical periods, learning and response to disease. Improved means of assessing neuroplasticity in humans, including biomarkers for predicting and monitoring treatment response, are needed. Neuroplasticity occurs with many variations, in many forms, and in many contexts. However, common themes in plasticity that emerge across diverse central nervous system conditions include experience dependence, time sensitivity and the importance of motivation and attention. Integration of information across disciplines should enhance opportunities for the translation of neuroplasticity and circuit retraining research into effective clinical therapies.

Mutant mice and neuroscience: Recommendations concerning genetic background

The following scientists made significant contributions to the recommendations in this article:

New paradigm for optical imaging: temporally encoded maps of intrinsic signal.

We present a new technique for acquiring and analyzing intrinsic signal optical images of brain activity, using continuous stimulus presentation and data acquisition. The main idea is to present a temporally periodic stimulus and to analyze the component of the response at the stimulus frequency. Advantages of the new technique include the removal of heart, respiration, and vasomotor artifacts, a dramatic increase in spatial resolution, and a 30-fold or greater reduction in acquisition time. We also present a novel approach to localizing instantaneous neuronal responses using time-reversed stimuli that is widely applicable to brain imaging. To demonstrate the power of the technique, we present high-resolution retinotopic maps of five visual areas in mouse cortex and orientation maps in cat visual cortex.

Sleep enhances plasticity in the developing visual cortex.

During a critical period of brain development, occluding the vision of one eye causes a rapid remodeling of the visual cortex and its inputs. Sleep has been linked to other processes thought to depend on synaptic remodeling, but a role for sleep in this form of cortical plasticity has not been demonstrated. We found that sleep enhanced the effects of a preceding period of monocular deprivation on visual cortical responses, but wakefulness in complete darkness did not do so. The enhancement of plasticity by sleep was at least as great as that produced by an equal amount of additional deprivation. These findings demonstrate that sleep and sleep loss modify experience-dependent cortical plasticity in vivo. They suggest that sleep in early life may play a crucial role in brain development.

A Cortical Circuit for Gain Control by Behavioral State

The brains response to sensory input is strikingly modulated by behavioral state. Notably, the visual response of mouse primary visual cortex (V1) is enhanced by locomotion, a tractable and accessible example of a time-locked change in cortical state. The neural circuits that transmit behavioral state to sensory cortex to produce this modulation are unknown. In vivo calcium imaging of behaving animals revealed that locomotion activates vasoactive intestinal peptide (VIP)-positive neurons in mouse V1 independent of visual stimulation and largely through nicotinic inputs from basal forebrain. Optogenetic activation of VIP neurons increased V1 visual responses in stationary awake mice, artificially mimicking the effect of locomotion, and photolytic damage of VIP neurons abolished the enhancement of V1 responses by locomotion. These findings establish a cortical circuit for the enhancement of visual response by locomotion and provide a potential common circuit for the modulation of sensory processing by behavioral state.

Tumor Necrosis Factor-α Mediates One Component of Competitive, Experience-Dependent Plasticity in Developing Visual Cortex

Rapid, experience-dependent plasticity in developing visual cortex is thought to be competitive. After monocular visual deprivation, the reduction in response of binocular neurons to one eye is matched by a corresponding increase to the other. Chronic optical imaging in mice deficient in TNFalpha reveals the normal initial loss of deprived-eye responses, but the subsequent increase in response to the open eye is absent. This mutation also blocks homeostatic synaptic scaling of mEPSCs in visual cortex in vitro, without affecting LTP. In monocular cortex, thought not to be subject to competition, responses in TNFalpha mutants are as reduced as in the binocular zone. Pharmacological inhibition of endogenous TNFalpha in wild-type mice phenocopies the knockout. These findings suggest that experience-dependent competition in developing visual cortex is the outcome of two distinct, noncompetitive processes, a loss of deprived-eye responses followed by an apparently homeostatic increase in responses dependent on TNFalpha signaling.