Boosting visual cortex function and plasticity with acetylcholine to enhance visual perception

Traditionally, human primary visual cortex (V1) has been thought to mature within the first few years of life, based on anatomical studies of synapse formation, and establishment of intracortical and intercortical connections. Human vision, however, develops well beyond the first few years. Previously, we found prolonged development of some GABAergic proteins in human V1 (Pinto et al., 2010). Yet as >80% of synapses in V1 are excitatory, it remains unanswered whether the majority of synapses regulating experience-dependent plasticity and receptive field properties develop late, like their inhibitory counterparts. To address this question, we used Western blotting of postmortem tissue from human V1 (12 female, 18 male) covering a range of ages. Then we quantified a set of postsynaptic glutamatergic proteins (PSD-95, GluA2, GluN1, GluN2A, GluN2B), calculated indices for functional pairs that are developmentally regulated (GluA2:GluN1; GluN2A:GluN2B), and determined interindividual variability. We found early loss of GluN1, prolonged development of PSD-95 and GluA2 into late childhood, protracted development of GluN2A until ∼40 years, and dramatic loss of GluN2A in aging. The GluA2:GluN1 index switched at ∼1 year, but the GluN2A:GluN2B index continued to shift until ∼40 year before changing back to GluN2B in aging. We also identified young childhood as a stage of heightened interindividual variability. The changes show that human V1 develops gradually through a series of five orchestrated stages, making it likely that V1 participates in visual development and plasticity across the lifespan.SIGNIFICANCE STATEMENT Anatomical structure of human V1 appears to mature early, but vision changes across the lifespan. This discrepancy has fostered two hypotheses: either other aspects of V1 continue changing, or later changes in visual perception depend on extrastriate areas. Previously, we showed that some GABAergic synaptic proteins change across the lifespan, but most synapses in V1 are excitatory leaving unanswered how they change. So we studied expression of glutamatergic proteins in human V1 to determine their development. Here we report prolonged maturation of glutamatergic proteins, with five stages that map onto life-long changes in human visual perception. Thus, the apparent discrepancy between development of structure and function may be explained by life-long synaptic changes in human V1.

Expectations about forthcoming visual motion shaped by observers' experiences are known to induce anticipatory smooth eye movements (ASEMs) and changes in visual perception. Previous studies have demonstrated discrete effects of expectations on the control of ASEM and perception. However, the tasks designed in those studies were not able to segregate the effects of expectations and execution of ASEM itself on perception. In the present study, we attempted to directly examine the effect of ASEM itself on visual speed perception with a two-alternative forced-choice (2AFC) task, in which observers were asked to track a pair of sequentially presented visual motion stimuli with their eyes and to judge whether the second stimulus (test stimulus) was faster or slower than the first (reference stimulus). Our results showed that observers' visual speed perception, quantified by a psychometric function, shifted according to ASEM velocity. This was the case even though there was no difference in the steady-state eye velocity. Further analyses revealed that the observers' perceptual decisions could be explained by a difference in the magnitude of retinal slip velocity in the initial phase of ocular tracking when the reference and test stimuli were presented, rather than in the steady-state phase. Our results provide psychophysical evidence of the importance of initial ocular tracking in visual speed perception and the strong impact of ASEM.NEW & NOTEWORTHY We provide psychophysical evidence that the execution of anticipatory smooth eye movement (ASEM) leads to underestimation of visual speed perception, that is, observers perceive the object motion velocity as slower than when ASEM is not induced, even though the performance of subsequent ocular tracking is comparable. Moreover, our results showed that such perceptual decisions regarding object motion velocity were derived from the ASEM-induced decrease in retinal slip velocity during the initial phase of ocular tracking.

Visual areas I and II of cerebral cortex of rabbit.

The cholinergic system is involved in cortical plasticity, attention, and learning. Within the visual cortex the cholinergic system seems to play a role in visual perception. The cholinergic neurons which project into the visual cortex are located in the basal forebrain. It has been shown that mice deficient for the low-affinity neurotrophin receptor p75NTR display increased numbers of cholinergic neurons in the basal forebrain and a denser cholinergic innervation of the hippocampus. This prompted us to analyze whether the cholinergic system is altered in adult p75NTR deficient mice. By analyzing the densities of cholinergic fibers within layer IV as well as within layer V of the visual cortex, we found that adult p75NTR deficient mice display increased cholinergic fiber densities. However, this increase was not accompanied by an increase in the density of local cholinergic neurons within the visual cortex. This indicates that the enhanced cholinergic innervation of the visual cortex is due to alteration of the cholinergic neurons located in the basal forebrain, projecting to the visual cortex. The increased cholinergic innervation of the visual cortex makes the p75NTR deficient mice an attractive model to study the necessity of the cholinergic system for the visual cortex.

In the intact adult animal, synaptic plasticity in the visual cortex (VC) is a dynamic and naturalistic phenomenon, the mechanisms of which are not yet fully understood. Given its intrinsic role in hippocampal plasticity, we investigated the eVects of pharmacological antagonism of mGluR5 on synaptic plasticity and receptor expression in the VC of freely moving adult pigmented rats, and compared this with hippocampal effects. Persistent long-term potentiation (LTP, >24 h) in layer II/III of the primary VC, and LTP in the dentate gyrus, were impaired by application of the mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine (MPEP). Long-term depression in VC was unaffected. Twenty-four hours after MPEP treatment, mGluR1a monomer expression was reduced in the VC but not in the hippocampus, whereas dimer expression was unaffected; mGluR2/3 and mGluR5 monomers were unaffected, but dimers were reduced in the VC. Our data suggest that mGluR5 is engaged in the regulation of synaptic plasticity in the adult VC and hippocampus: the mechanisms for this may be quite distinct, however. While only LTP is affected by mGluR5-antagonism in the VC, both LTP and LTD are affected in the hippocampus. Furthermore, the higher sensitivity of mGluR expression to antagonism of mGluR5 in VC compared to the hippocampus suggests that mGluR5 regulates plasticity phenomena in these structures by means of distinct mGluR-dependent processes.

Requirement of keratan sulfate proteoglycan phosphacan with a specific sulfation pattern for critical period plasticity in the visual cortex

Long-term potentiation (LTP) is a lasting enhancement of excitatory synaptic transmission that follows specific patterns of electrical stimulation. Although the mechanism of LTP has been intensively studied, particularly in the hippocampus, its significance for normal brain function remains unproven. It has been proposed that LTP-like mechanisms may contribute to naturally occurring, experience-dependent synaptic modifications in the visual cortex. The formation of normal binocular connections within the visual cortex requires simultaneous input from both eyes during a postnatal critical period that can be delayed by rearing animals in complete darkness. To explore the role of LTP in this experience-dependent maturation process, we induced LTP in visual cortical slices taken at different ages from light-reared and dark-reared rats. Susceptibility to LTP coincides with the critical period and, like the critical period, can be prolonged by rearing animals in darkness. These findings support the hypothesis that LTP reflects a normal mechanism of experience-dependent synaptic modification in the developing mammalian brain.

THE title of this lecture is at best premature and more likely absurd, but I have adopted it for two reasons. In the first place, I want to emphasize the continuing tension within psychiatry betwee...

A fundamental regulator of neuronal network development and plasticity is the extracellular matrix (ECM) of the brain. The ECM provides a scaffold stabilizing synaptic circuits, while the proteolytic cleavage of its components and cell surface proteins are thought to have permissive roles in the regulation of plasticity. The enzymatic proteolysis is thought to be crucial for homeostasis between stability and reorganizational plasticity and facilitated largely by a family of proteinases named matrix metalloproteinases (MMPs). Here, we investigated whether MMP2 and MMP9 play a role in mediating adult primary visual cortex (V1) plasticity as well as stroke-induced impairments of visual cortex plasticity in mice. In healthy adult mice, selective inhibition of MMP2/9 for 7 d suppressed ocular dominance plasticity. In contrast, brief inhibition of MMP2/9 after a cortical stroke rescued compromised plasticity. Our data indicate that the proteolytic activity of MMP2 and MMP9 is critical and required to be within a narrow range to allow adult visual plasticity.SIGNIFICANCE STATEMENT Learning and recovery from injuries depend on the plasticity of neuronal connections. The brain's extracellular matrix (ECM) provides a scaffold for stabilizing synaptic circuits, while its enzymatic proteolysis is hypothesized to regulate homeostasis between stability and reorganizational plasticity. ECM digestion is facilitated by a family of matrix metalloproteinases (MMPs). Here, we show that treatments that inhibit MMP2/9 can either inhibit or rescue cortical plasticity depending on cortical state: in the visual cortex of healthy adult mice, inhibition of MMP2/9 suppressed cortical plasticity. In contrast, brief inhibition of MMP2/9 after a stroke rescued compromised plasticity. Our data provide strong evidence that an optimal level of MMP2/9 proteolytic activity is crucial for adult visual plasticity.

The cerebral cortex changes throughout the lifespan, and the cortical gray matter in many brain regions becomes thinner with advancing age. Effects of aging on cortical thickness (CT) have been observed in many brain regions, including areas involved in basic perceptual functions such as processing visual inputs. An important property of early visual cortices is their topographic organization—the cortical structure of early visual areas forms a topographic map of retinal inputs. Primary visual cortex (V1) is considered to be the most basic cortical area in the visual processing hierarchy, and is topographically organized from posterior (central visual representation) to anterior (peripheral visual representation) along the calcarine sulcus. Some studies have reported strong age-dependent cortical thinning in portions of V1 that likely correspond to peripheral visual representations, while there is less evidence of substantial cortical thinning in central V1. However, the effect of aging on CT in V1 as a function of its topography has not been directly investigated. To address this gap in the literature, we estimated the CT of different eccentricity sectors in V1 using T1-weighted MRI scans acquired from groups of healthy younger and older adults, and then assessed whether between-group differences in V1 CT depended on cortical eccentricity. These analyses revealed age-dependent cortical thinning specific to peripheral visual field representations in anterior portions of V1, but did not provide evidence for age-dependent cortical thinning in other portions of V1. Additional analyses found similar effects when analyses were restricted to the gyral crown, sulcul depth and sulcul wall, indicating that these effects are not likely due to differences in gyral/sulcul contributions to our regions of interest (ROI). Importantly, this finding indicates that age-dependent changes in cortical structure may differ among functionally distinct zones within larger canonical cortical areas. Likely relationships to known age-related declines in visual performance are discussed to provide direction for future research in this area.

Listening to Npas4: a transcription factor is the prescription for restoring youthful plasticity in the mature brain

Catecholamines released from cerebral cortex in the cat; decrease during sensory stimulation

While it is known that an epigenetic remodeling of chromatin structure controls developmental plasticity in the visual cortex, three main questions have remained open. Which is the physiological time course of histone modifications? Is it possible, by manipulating the chromatin epigenetic state, to modulate plasticity levels during the critical period? How can we regulate histone acetylation in the adult brain in a noninvasive manner? We show that the early exposure of rat pups to enriching environmental conditions accelerates the critical period for plasticity in the primary visual cortex, linking this effect to increased histone acetylation, specifically at the BDNF gene level. Moreover, we report that the exposure of adult animals to environmental enrichment enhances histone acetylation and reopens juvenile-like plasticity.

In the present report, we focused our attention on the role played by the muscarinic acetylcholine receptors (mAChRs) in different forms of long-term synaptic plasticity. Specifically, we investigated long-term potentiation (LTP) and long-term depression (LTD) expression elicited by theta-burst stimulation (TBS) and low-frequency stimulation (LFS), respectively, in visual cortical slices obtained from different mAChR knockout (KO) mice. A normal LTP was evoked in M(1)/M(3) double KO mice, while LTP was impaired in the M(2)/M(4) double KO animals. On the other hand, LFS induced LTD in M(2)/M(4) double KO mice, but failed to do so in M(1)/M(3) KO mice. Interestingly, LFS produced LTP instead of LTD in M(1)/M(3) KO mice. Analysis of mAChR single KO mice revealed that LTP was affected only by the simultaneous absence of both M(2) and M(4) receptors. A LFS-dependent shift from LTD to LTP was also observed in slices from M(1) KO mice, while LTD was simply abolished in slices from M(3) KO mice. Using pharmacological tools, we showed that LTP in control mice was blocked by pertussis toxin, an inhibitor of G(i/o) proteins, but not by raising intracellular cAMP levels. In addition, the inhibition of phospholipase C by U73122 induced the same shift from LTD to LTP after LFS observed in M(1) single KO and M(1)/M(3) double KO mice. Our results indicate that different mAChR subtypes regulate different forms of long-term synaptic plasticity in the mouse visual cortex, activating specific G proteins and downstream intracellular mechanisms.

OP Brain and environment: towards an endogenous pharmacology