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Microglia dynamically survey the brain parenchyma. Microglial processes interact with neuronal elements; however, what role neuronal network activity plays in regulating microglial dynamics is not entirely clear. Most studies of microglial dynamics use either slice preparations or in vivo imaging in anesthetized mice. Here we demonstrate that microglia in awake mice have a relatively reduced process area and surveillance territory and that reduced neuronal activity under general anesthesia increases microglial process velocity, extension and territory surveillance. Similarly, reductions in local neuronal activity through sensory deprivation or optogenetic inhibition increase microglial process surveillance. Using pharmacological and chemogenetic approaches, we demonstrate that reduced norepinephrine signaling is necessary for these increases in microglial process surveillance. These findings indicate that under basal physiological conditions, noradrenergic tone in awake mice suppresses microglial process surveillance. Our results emphasize the importance of awake imaging for studying microglia–neuron interactions and demonstrate how neuronal activity influences microglial process dynamics.

Monocular deprivation evokes a prominent shift of neuronal responses in the visual cortex toward the open eye, accompanied by functional and structural synaptic rearrangements. This shift is reversible, but it is unknown whether the recovery happens at the level of individual neurons or whether it reflects a population effect. We used ratiometric Ca²⁺ imaging to follow the activity of the same excitatory layer 2/3 neurons in the mouse visual cortex over months during repeated episodes of ocular dominance (OD) plasticity. We observed robust shifts toward the open eye in most neurons. Nevertheless, these cells faithfully returned to their predeprivation OD during binocular recovery. Moreover, the initial network correlation structure was largely recovered, suggesting that functional connectivity may be regained despite prominent experience-dependent plasticity.

Monkeys, like humans, normally have face domains in inferotemporal cortex; however, monkeys raised without exposure to faces do not develop face patches. Normally reared monkeys, like humans, preferentially look at faces, but face-deprived monkeys do not. These results highlight the importance of early experience for normal sensory and cognitive development. Here we report that monkeys raised without exposure to faces did not develop face domains, but did develop domains for other categories and did show normal retinotopic organization, indicating that early face deprivation leads to a highly selective cortical processing deficit. Therefore, experience must be necessary for the formation (or maintenance) of face domains. Gaze tracking revealed that control monkeys looked preferentially at faces, even at ages prior to the emergence of face domains, but face-deprived monkeys did not, indicating that face looking is not innate. A retinotopic organization is present throughout the visual system at birth, so selective early viewing behavior could bias category-specific visual responses toward particular retinotopic representations, thereby leading to domain formation in stereotyped locations in inferotemporal cortex, without requiring category-specific templates or biases. Thus, we propose that environmental importance influences viewing behavior, viewing behavior drives neuronal activity, and neuronal activity sculpts domain formation.

Developmental myelination is a protracted process in the mammalian brain 1 . One theory for why oligodendrocytes mature so slowly posits that myelination may stabilize neuronal circuits and temper neuronal plasticity as animals age 2 – 4 . We tested this theory in the visual cortex, which has a well-defined critical period for experience-dependent neuronal plasticity 5 . During adolescence, visual experience modulated the rate of oligodendrocyte maturation in visual cortex. To determine whether oligodendrocyte maturation in turn regulates neuronal plasticity, we genetically blocked oligodendrocyte differentiation and myelination in adolescent mice. In adult mice lacking adolescent oligodendrogenesis, a brief period of monocular deprivation led to a significant decrease in visual cortex responses to the deprived eye, reminiscent of the plasticity normally restricted to adolescence. This enhanced functional plasticity was accompanied by a greater turnover of dendritic spines and coordinated reductions in spine size following deprivation. Furthermore, inhibitory synaptic transmission, which gates experience-dependent plasticity at the circuit level, was diminished in the absence of adolescent oligodendrogenesis. These results establish a critical role for oligodendrocytes in shaping the maturation and stabilization of cortical circuits and support the concept of developmental myelination acting as a functional brake on neuronal plasticity. Through genetic blocking of oligodendrocyte differentiation and myelination in adolescent mice, we demonstrate that oligodendrocytes have a critical role in shaping the maturation and stabilization of visual cortical circuits.

Key Points Sensory deprivation is associated with striking crossmodal neuroplastic changes in the brain. Following sensory deprivation (for example, blindness or deafness), there is functional recruitment of brain areas that are normally associated with the processing of the lost sense by those sensory modalities that are spared. These changes seem to underlie adaptive and compensatory behaviours in both blind and deaf individuals. In the case of blindness, occipital cortical areas are recruited to process non-visual forms of sensory information such as touch, hearing and verbal memory. In the case of deafness, auditory and language-related areas are recruited to process tactile as well as linguistic and non-linguistic visual information. Experiments in animal models have helped to uncover potential mechanisms underlying these neuroplastic changes, such as the existence of direct cortico-cortical connections between relevant sensory processing areas. Not all neuroplastic changes are beneficial. There is the possibility of maladaptive consequences, particularly in the context of rehabilitation and the restoration of lost sensory function. The remarkable functional and structural changes that take place in the brains of blind and deaf individuals following sensory loss enable them to operate effectively in their environment. Here the authors discuss the current understanding of the mechanisms that underlie this crossmodal neuroplasticity and its implications for rehabilitation. There is growing evidence that sensory deprivation is associated with crossmodal neuroplastic changes in the brain. After visual or auditory deprivation, brain areas that are normally associated with the lost sense are recruited by spared sensory modalities. These changes underlie adaptive and compensatory behaviours in blind and deaf individuals. Although there are differences between these populations owing to the nature of the deprived sensory modality, there seem to be common principles regarding how the brain copes with sensory loss and the factors that influence neuroplastic changes. Here, we discuss crossmodal neuroplasticity with regards to behavioural adaptation after sensory deprivation and highlight the possibility of maladaptive consequences within the context of rehabilitation.

We experience the world through multiple senses simultaneously. To better understand mechanisms of multisensory processing we ask whether inputs from two senses (auditory and visual) can interact and drive plasticity in neural-circuits of the primary visual cortex (V1). Using genetically-encoded voltage and calcium indicators, we find coincident audio-visual experience modifies both the supra and subthreshold response properties of neurons in L2/3 of mouse V1. Specifically, we find that after audio-visual pairing, a subset of multimodal neurons develops enhanced auditory responses to the paired auditory stimulus. This cross-modal plasticity persists over days and is reflected in the strengthening of small functional networks of L2/3 neurons. We find V1 processes coincident auditory and visual events by strengthening functional associations between feature specific assemblies of multimodal neurons during bouts of sensory driven co-activity, leaving a trace of multisensory experience in the cortical network. Sensory stimuli usually arrive simultaneously but the neural-circuit mechanisms that combine multiple streams of sensory information are incompletely understood. The authors here show that visual-auditory pairing drives plasticity in multi-modal neuron networks within the mouse visual cortex.

Sense of agency—a feeling of control over one's actions and their outcomes—might include at least two components: free choice over which outcome to pursue and motorie control over the action causing the outcome. We orthogonally manipulated locus of outcome choice (free or instructed choice) and motorie control (active or passive movement), while measuring the perceived temporal attraction between actions and outcomes (temporal binding) as an implicit marker of agency. Participants also rated stimulus intensity so that we could measure sensory attenuation, another possible implicit marker of agency. Actions caused higher or lower levels of either painful heat or mild electrotactile stimulation. We found that both motorie control and outcome choice contributed to outcome binding. Moreover, free choice, relative to instructed choice, attenuated the perceived magnitude of high-intensity outcomes, but only when participants made an active movement. Thus, choosing, not just doing, influences temporal binding and sensory attenuation, though in different ways. Our results show that these implicit measures of agency are sensitive to both voluntary motor commands and instrumental control over action outcomes.

Sensory deprivation during the post-natal ‘critical period’ leads to structural reorganization of the developing visual cortex. In adulthood, the visual cortex retains some flexibility and adapts to sensory deprivation. Here we show that short-term (2 hr) monocular deprivation in adult humans boosts the BOLD response to the deprived eye, changing ocular dominance of V1 vertices, consistent with homeostatic plasticity. The boost is strongest in V1, present in V2, V3 and V4 but absent in V3a and hMT+. Assessment of spatial frequency tuning in V1 by a population Receptive-Field technique shows that deprivation primarily boosts high spatial frequencies, consistent with a primary involvement of the parvocellular pathway. Crucially, the V1 deprivation effect correlates across participants with the perceptual increase of the deprived eye dominance assessed with binocular rivalry, suggesting a common origin. Our results demonstrate that visual cortex, particularly the ventral pathway, retains a high potential for homeostatic plasticity in the human adult. The world around us changes all the time, and the brain must adapt to these changes. This process, known as neuroplasticity, peaks during development. Abnormal sensory input early in life can therefore cause lasting changes to the structure of the brain. One example of this is amblyopia or ‘lazy eye’. Infants who receive insufficient input to one eye – for example, because of cataracts – can lose their sight in that eye, even if the cataracts are later removed. This is because the brain reorganizes itself to ignore messages from the affected eye. Does the adult visual system also show neuroplasticity? To explore this question, Binda, Kurzawski et al. asked healthy adult volunteers to lie inside a high-resolution brain scanner with a patch covering one eye. At the start of the experiment, roughly half of the brain’s primary visual cortex responded to sensory input from each eye. But when the volunteers removed the patch two hours later, this was no longer the case. Some areas of the visual cortex that had previously responded to stimuli presented to the non-patched eye now responded to stimuli presented to the patched eye instead. The patched eye had also become more sensitive to visual stimuli. Indeed, these changes in visual sensitivity correlated with changes in brain activity in a pathway called the ventral visual stream. This pathway processes the fine details of images. Groups of neurons within this pathway that responded to stimuli presented to the patched eye were more sensitive to fine details after patching than before. Visual regions of the adult brain thus retain a high degree of neuroplasticity. They adapt rapidly to changes in the environment, in this case by increasing their activity to compensate for a lack of input. Notably, these changes are in the opposite direction to those that occur as a result of visual deprivation during development. This has important implications because lazy eye syndrome is currently considered untreatable in adulthood.

The developing brain can respond quickly to altered sensory experience by circuit reorganization. During a critical period in early life, neurons in the primary visual cortex rapidly lose responsiveness to an occluded eye and come to respond better to the open eye. While physiological and some of the molecular mechanisms of this process have been characterized, its structural basis, except for the well-known changes in the thalamocortical projection, remains obscure. To elucidate the relationship between synaptic remodeling and functional changes during this experience-dependent process, we used 2-photon microscopy to image synaptic structures of sparsely labeled layer 2/3 neurons in the binocular zone of mouse primary visual cortex. Anatomical changes at presynaptic and postsynaptic sites in mice undergoing monocular visual deprivation (MD) were compared to those in control mice with normal visual experience. We found that postsynaptic spines remodeled quickly in response to MD, with neurons more strongly dominated by the deprived eye losing more spines. These postsynaptic changes parallel changes in visual responses during MD and their recovery after restoration of binocular vision. In control animals with normal visual experience, the formation of presynaptic boutons increased during the critical period and then declined. MD affected bouton formation, but with a delay, blocking it after 3 d. These findings reveal intracortical anatomical changes in cellular layers of the cortex that can account for rapid activity-dependent plasticity.