Experience-dependent plasticity in adult visual cortex

Experience-dependent plasticity is a prominent feature of the mammalian visual cortex. Although such neural changes are most evident during development, adult cortical circuits can be modified by a variety of manipulations, such as perceptual learning and visual deprivation. Elucidating the underlying mechanisms at the cellular and synaptic levels is an essential step in understanding neural plasticity in the mature animal. Although developmental and adult plasticity share many common features, notable differences may be attributed to developmental cortical changes at multiple levels. These range from shifts in the molecular profiles of cortical neurons to changes in the spatiotemporal dynamics of network activity. In this review, we will discuss recent progress and remaining challenges in understanding adult visual plasticity, focusing on the primary visual cortex.     

Simulation of plasticity in the adult visual cortex

 Retinal plasticity has been shown in the adult visual nervous system in mammals. Following a retinal lesion (scotoma) there is a reorganization of the cortical receptive field distribution: cortical neurons selective to visual stimuli in the area of the visual field corresponding to the retinal lesion, become selective to other parts of the visual field. In this work, we study this effect with a self-organizing neural network. In a first stage, the network reaches a pattern of connectivity that represents normal development of neuronal selectivity. The scotoma is simulated by perturbing accordingly the properties of a region of the input layer representing the retina. The system evolves to a new receptive field distribution mainly by means of the reorganization of the intra cortical connectivity. No major change of the geniculo cortical connectivity is detected. This may explain the surprisingly short time scale of the event. Received: 6 June 2000 / Accepted in revised form: 16 October 2000     

NMDA receptor-dependent ocular dominance plasticity in adult visual cortex

The binocular region of mouse visual cortex is strongly dominated by inputs from the contralateral eye. Here we show in adult mice that depriving the dominant contralateral eye of vision leads to a persistent, NMDA receptor-dependent enhancement of the weak ipsilateral-eye inputs. These data provide in vivo evidence for metaplasticity as a mechanism for binocular competition and demonstrate that an ocular dominance shift can occur solely by the mechanisms of response enhancement. They also show that adult mouse visual cortex has a far greater potential for experience-dependent plasticity than previously appreciated. These insights may force a revision in how data on ocular dominance plasticity in mutant mice have been interpreted.     

Adaptation-induced plasticity of orientation tuning in adult visual cortex

A key emergent property of the primary visual cortex (V1) is the orientation selectivity of its neurons. The extent to which adult visual cortical neurons can exhibit changes in orientation selectivity is unknown. Here we use single-unit recording and intrinsic signal imaging in V1 of adult cats to demonstrate systematic repulsive shifts in orientation preference following short-term exposure (adaptation) to one stimulus orientation. In contrast to the common view of adaptation as a passive process by which responses around the adapting orientation are reduced, we show that changes in orientation tuning also occur due to response increases at orientations away from the adapting stimulus. Adaptation-induced orientation plasticity is thus an active time-dependent process that involves network interactions and includes both response depression and enhancement.     

Nutrient‐dependent allometric plasticity in a male‐diphenic mite

Male secondary sexual traits often scale allometrically with body size. These allometries can be variable within species and may shift depending on environmental conditions, such as food quality. Such allometric plasticity has been hypothesized to initiate local adaptation and evolutionary diversification of scaling relationships, but is under‐recorded, and its eco‐evolutionary effects are not well understood. Here, we tested for allometric plasticity in the bulb mite (Rhizoglyphus robini), in which large males tend to develop as armed adult fighters with thickened third legs, while small males become adult scramblers without thickened legs. We first examined the ontogenetic timing for size‐ and growth‐dependent male morph determination, using experimentally amplified fluctuations in growth rate throughout juvenile development. Having established that somatic growth and body size determine male morph expression immediately before metamorphosis, we examined whether the relationship between adult male morph and size at metamorphosis shifts with food quality. We found that the threshold body size for male morph expression shifts toward lower values with deteriorating food quality, confirming food‐dependent allometric plasticity. Such allometric plasticity may allow populations to track prevailing nutritional conditions, potentially facilitating rapid evolution of allometric scaling relationships.     

Mitochondrial aconitase 1 regulates age‐related memory impairment via autophagy/mitophagy‐mediated neural plasticity in middle‐aged flies

Age‐related memory impairment (AMI) occurs in many species, including humans. The underlying mechanisms are not fully understood. In wild‐type Drosophila (w¹¹¹⁸ ), AMI appears in the form of a decrease in learning (3‐min memory) from middle age (30 days after eclosion [DAE]). We performed in vivo, DNA microarray, and behavioral screen studies to identify genes controlling both lifespan and AMI and selected mitochondrial Acon1 (mAcon1). mAcon1 expression in the head of w¹¹¹⁸ decreased with age. Neuronal overexpression of mAcon1 extended its lifespan and improved AMI. Neuronal or mushroom body expression of mAcon1 regulated the learning of young (10 DAE) and middle‐aged flies. Interestingly, acetyl‐CoA and citrate levels increased in the heads of middle‐aged and neuronal mAcon1 knockdown flies. Acetyl‐CoA, as a cellular energy sensor, is related to autophagy. Autophagy activity and efficacy determined by the positive and negative changes in the expression levels of Atg8a‐II and p62 were proportional to the expression level of mAcon1. Levels of the presynaptic active zone scaffold protein Bruchpilot were inversely proportional to neuronal mAcon1 levels in the whole brain. Furthermore, mAcon1 overexpression in Kenyon cells induced mitophagy labeled with mt‐Keima and improved learning ability. Both processes were blocked by pink1 knockdown. Taken together, our results imply that the regulation of learning and AMI by mAcon1 occurs via autophagy/mitophagy‐mediated neural plasticity.     

Identification of distinct and age‐dependent p16High microglia subtypes

Cells expressing high levels of the cyclin‐dependent kinase (CDK)4/6 inhibitor p16 (p16^High) accumulate in aging tissues and promote multiple age‐related pathologies, including neurodegeneration. Here, we show that the number of p16^High cells is significantly increased in the central nervous system (CNS) of 2‐year‐old mice. Bulk RNAseq indicated that genes expressed by p16^High cells were associated with inflammation and phagocytosis. Single‐cell RNAseq of brain cells indicated p16^High cells were primarily microglia, and their accumulation was confirmed in brains of aged humans. Interestingly, we identified two distinct subpopulations of p16^High microglia in the mouse brain, with one being age‐associated and one present in young animals. Both p16^High clusters significantly differed from previously described disease‐associated microglia and expressed only a partial senescence signature. Taken together, our study provides evidence for the existence of two p16‐expressing microglia populations, one accumulating with age and another already present in youth that could positively and negatively contribute to brain homeostasis, function, and disease.     

MeCP2 prevents age‐associated cognitive decline via restoring synaptic plasticity in a senescence‐accelerated mouse model

Age‐related cognitive decline in neurodegenerative diseases, such as Alzheimer''s disease (AD), is associated with the deficits of synaptic plasticity. Therefore, exploring promising targets to enhance synaptic plasticity in neurodegenerative disorders is crucial. It has been demonstrated that methyl‐CpG binding protein 2 (MeCP2) plays a vital role in neuronal development and MeCP2 malfunction causes various neurodevelopmental disorders. However, the role of MeCP2 in neurodegenerative diseases has been less reported. In the study, we found that MeCP2 expression in the hippocampus was reduced in the hippocampus of senescence‐accelerated mice P8 (SAMP8) mice. Overexpression of hippocampal MeCP2 could elevate synaptic plasticity and cognitive function in SAMP8 mice, while knockdown of MeCP2 impaired synaptic plasticity and cognitive function in senescence accelerated‐resistant 1 (SAMR1) mice. MeCP2‐mediated regulation of synaptic plasticity may be associated with CREB1 pathway. These results suggest that MeCP2 plays a vital role in age‐related cognitive decline by regulating synaptic plasticity and indicate that MeCP2 may be promising targets for the treatment of age‐related cognitive decline in neurodegenerative diseases.     

Monocular focal retinal lesions induce short-term topographic plasticity in adult cat visual cortex

Electrophysiological recording in primary visual cortex (VI) was performed both prior to and in the hours immediately following the creation of a discrete retinal lesion in one eye with an argon laser. Lesion projection zones (LPZs; 21-64 mm2) were defined in the visual cortex by mapping the extent of the lesion onto the topographic representation in cortex. There was no effect on neuronal responses to the unlesioned eye or on its topographic representation. However, within hours of producing the retinal lesion, receptive fields obtained from stimulation of the lesioned eye were displaced onto areas surrounding the scotoma and were enlarged compared with the corresponding field obtained through the normal eye. The proportion of such responsive recording sites increased during the experiment such that 8-11 hours post-lesion, 56% of recording sites displayed neurons responsive to the lesioned eye. This is an equivalent proportion to that previously reported with long-term recovery (three weeks to three months). Responsive neurons were evident as far as 2.5 mm inside the border of the LPZ. The reorganization of the lesioned eye representation produced binocular disparities as great as 15 degrees, suggesting interactions between sites in VI up to 5.5 mm apart.     

Cortisol reduces plasticity in the kitten visual cortex

We investigated the effect of elevated levels of cortisol on plasticity in the visual cortex of the cat. Animals were given daily injections of cortisol i.m. for 20 days starting around 35 days of age. After 10 days they were monocularly deprived, and after an additional 10 days recordings were made from the visual cortex to construct an ocular dominance histogram. The results were compared with those from normal animals of the same age, and with animals monocularly deprived for the same period but not treated with cortisol. Cortisol reduced the ocular dominance shift in a dose-dependent manner, but did not totally abolish it even at the highest doses used. Two other series of animals were recorded, one slightly later in the critical period and one slightly earlier, with care taken to give cortisol before the animals were exposed to light in the morning. In both cases, cortisol reduced the ocular dominance shift but did not abolish it. To interpret these results, we measured levels of plasma cortisol in normal cats of various ages. Average levels were fairly constant between birth and 12 months of age (0.5–1 μg/dl), and increased slightly after that, but there was a large variation between animals. Thus elevated levels of cortisol can have a substantial effect on plasticity in the visual cortex of the cat, but the decline of the critical period for plasticity between 6 weeks and 3–5 months of age does not seem to be due to a rise in cortisol levels during this time.     

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.     

miR‐124‐dependent tagging of synapses by synaptopodin enables input‐specific homeostatic plasticity

Homeostatic synaptic plasticity is a process by which neurons adjust their synaptic strength to compensate for perturbations in neuronal activity. Whether the highly diverse synapses on a neuron respond uniformly to the same perturbation remains unclear. Moreover, the molecular determinants that underlie synapse‐specific homeostatic synaptic plasticity are unknown. Here, we report a synaptic tagging mechanism in which the ability of individual synapses to increase their strength in response to activity deprivation depends on the local expression of the spine‐apparatus protein synaptopodin under the regulation of miR‐124. Using genetic manipulations to alter synaptopodin expression or regulation by miR‐124, we show that synaptopodin behaves as a “postsynaptic tag” whose translation is derepressed in a subpopulation of synapses and allows for nonuniform homeostatic strengthening and synaptic AMPA receptor stabilization. By genetically silencing individual connections in pairs of neurons, we demonstrate that this process operates in an input‐specific manner. Overall, our study shifts the current view that homeostatic synaptic plasticity affects all synapses uniformly to a more complex paradigm where the ability of individual synapses to undergo homeostatic changes depends on their own functional and biochemical state.     

NMDA receptors‐dependent plasticity in the phototaxis preference behavior induced by visual deprivation in young and adult flies

Adult mammals have experience‐dependent plasticity in visual system, but it is unclear whether adult insects also have this plasticity after the critical period of visual development. Here, we have established a modified Y‐maze apparatus for investigating experience‐dependent plasticity in Drosophila. Using this setup we demonstrate that flies after the critical period have bidirectional modifications of the phototaxis preference behavior (PPB) induced by visual deprivation and experience: Visual deprivation decreases the preference of flies for visible light, while visual experience exerts the opposite effect. We also found an age‐dependent PPB plasticity induced by visual deprivation. Molecular and cellular studies suggest that the N‐methyl‐ d ‐aspartate receptors (NMDARs) mediate ocular dominance plasticity in visual cortex in mammals, but direct behavioral evidence is lacking. Here, we used the genetic approaches to demonstrate that NMDAR1, which is NMDARs subunit in Drosophila, can mediate PPB plasticity in young and adult flies. These findings provide direct behavioral evidence that NMDAR1 mediates PPB plasticity in Drosophila. Our results suggest that mammals and insects have analogous mechanisms for experience‐dependent plasticity and its regulation by NMDAR signaling.     

Drosophila p38 MAPK interacts with BAG‐3/starvin to regulate age‐dependent protein homeostasis

As organisms age, they often accumulate protein aggregates that are thought to be toxic, potentially leading to age‐related diseases. This accumulation of protein aggregates is partially attributed to a failure to maintain protein homeostasis. A variety of genetic factors have been linked to longevity, but how these factors also contribute to protein homeostasis is not completely understood. In order to understand the relationship between aging and protein aggregation, we tested how a gene that regulates lifespan and age‐dependent locomotor behaviors, p38 MAPK (p38Kb), influences protein homeostasis as an organism ages. We find that p38Kb regulates age‐dependent protein aggregation through an interaction with starvin, a regulator of muscle protein homeostasis. Furthermore, we have identified Lamin as an age‐dependent target of p38Kb and starvin.     

Cortisol reduces plasticity in the kitten visual cortex.

We investigated the effect of elevated levels of cortisol on plasticity in the visual cortex of the cat. Animals were given daily injections of cortisol i.m. for 20 days starting around 35 days of age. After 10 days they were monocularly deprived, and after an additional 10 days recordings were made from the visual cortex to construct an ocular dominance histogram. The results were compared with those from normal animals of the same age, and with animals monocularly deprived for the same period but not treated with cortisol. Cortisol reduced the ocular dominance shift in a dose-dependent manner, but did not totally abolish it even at the highest doses used. Two other series of animals were recorded, one slightly later in the critical period and one slightly earlier, with care taken to give cortisol before the animals were exposed to light in the morning. In both cases, cortisol reduced the ocular dominance shift but did not abolish it. To interpret these results, we measured levels of plasma cortisol in normal cats of various ages. Average levels were fairly constant between birth and 12 months of age (0.5-1 microgram/dl), and increased slightly after that, but there was a large variation between animals. Thus elevated levels of cortisol can have a substantial effect on plasticity in the visual cortex of the cat, but the decline of the critical period for plasticity between 6 weeks and 3-5 months of age does not seem to be due to a rise in cortisol levels during this time.     

Age‐related changes in hippocampal‐dependent synaptic plasticity and memory mediated by p75 neurotrophin receptor

The plasticity mechanisms in the nervous system that are important for learning and memory are greatly impacted during aging. Notably, hippocampal‐dependent long‐term plasticity and its associative plasticity, such as synaptic tagging and capture (STC), show considerable age‐related decline. The p75 neurotrophin receptor (p75^NTR) is a negative regulator of structural and functional plasticity in the brain and thus represents a potential candidate to mediate age‐related alterations. However, the mechanisms by which p75^NTR affects synaptic plasticity of aged neuronal networks and ultimately contribute to deficits in cognitive function have not been well characterized. Here, we report that mutant mice lacking the p75^NTR were resistant to age‐associated changes in long‐term plasticity, associative plasticity, and associative memory. Our study shows that p75^NTR is responsible for age‐dependent disruption of hippocampal homeostatic plasticity by modulating several signaling pathways, including BDNF, MAPK, Arc, and RhoA‐ROCK2‐LIMK1‐cofilin. p75^NTR may thus represent an important therapeutic target for limiting the age‐related memory and cognitive function deficits.     

Genetic control of experience-dependent plasticity in the visual cortex

Depriving one eye of visual experience during a sensitive period of development results in a shift in ocular dominance (OD) in the primary visual cortex (V1). To assess the heritability of this form of cortical plasticity and identify the responsible gene loci, we studied the influence of monocular deprivation on OD in a large number of recombinant inbred mouse strains derived from mixed C57BL/6J and DBA/2J backgrounds (BXD). The strength of imaged intrinsic signal responses in V1 to visual stimuli was strongly heritable as were various elements of OD plasticity. This has important implications for the use of mice of mixed genetic backgrounds for studying OD plasticity. C57BL/6J showed the most significant shift in OD, while some BXD strains did not show any shift at all. Interestingly, the increase in undeprived ipsilateral eye responses was not correlated to the decrease in deprived contralateral eye responses, suggesting that the size of these components of OD plasticity are not genetically controlled by only a single mechanism. We identified a quantitative trait locus regulating the change in response to the deprived eye. The locus encompasses 13 genes, two of which--Stch and Nrip1--contain missense polymorphisms. The expression levels of Stch and to a lesser extent Nrip1 in whole brain correlate with the trait identifying them as novel candidate plasticity genes.     

Development and plasticity of the primary visual cortex

Hubel and Wiesel began the modern study of development and plasticity of primary visual cortex (V1), discovering response properties of cortical neurons that distinguished them from their inputs and that were arranged in a functional architecture. Their findings revealed an early innate period of development and a later critical period of dramatic experience-dependent plasticity. Recent studies have used rodents to benefit from biochemistry and genetics. The roles of spontaneous neural activity and molecular signaling in innate, experience-independent development have been clarified, as have the later roles of visual experience. Plasticity produced by monocular visual deprivation (MD) has been dissected into stages governed by distinct signaling mechanisms, some of whose molecular players are known. Many crucial questions remain, but new tools for perturbing cortical cells and measuring plasticity at the level of changes in connections among identified neurons now exist. The future for the study of V1 to illuminate cortical development and plasticity is bright.