Microglia Elimination Increases Neural Circuit Connectivity and Activity in Adult Mouse Cortex.

Microglia have crucial roles in sculpting synapses and maintaining neural circuits during development. To test the hypothesis that microglia continue to regulate neural circuit connectivity in adult brain, we have investigated the effects of chronic microglial depletion, via CSF1R inhibition, on synaptic connectivity in the visual cortex in adult mice of both sexes. We find that the absence of microglia dramatically increases both excitatory and inhibitory synaptic connections to excitatory cortical neurons assessed with functional circuit mapping experiments in acutely prepared adult brain slices. Microglia depletion leads to increased densities and intensities of perineuronal nets. Furthermore, in vivo calcium imaging across large populations of visual cortical neurons reveals enhanced neural activities of both excitatory neurons and parvalbumin-expressing interneurons in the visual cortex following microglia depletion. These changes recover following adult microglia repopulation. In summary, our new results demonstrate a prominent role of microglia in sculpting neuronal circuit connectivity and regulating subsequent functional activity in adult cortex.SIGNIFICANCE STATEMENT Microglia are the primary immune cell of the brain, but recent evidence supports that microglia play an important role in synaptic sculpting during development. However, it remains unknown whether and how microglia regulate synaptic connectivity in adult brain. Our present work shows chronic microglia depletion in adult visual cortex induces robust increases in perineuronal nets, and enhances local excitatory and inhibitory circuit connectivity to excitatory neurons. Microglia depletion increases in vivo neural activities of both excitatory neurons and parvalbumin inhibitory neurons. Our new results reveal new potential avenues to modulate adult neural plasticity by microglia manipulation to better treat brain disorders, such as Alzheimer's disease.

Cholinergic manipulations affect sensory responses but not attentional enhancement in macaque MT.

BACKGROUND: Attentional modulation in the visual cortex of primates is characterized by multiplicative changes of sensory responses with changes in the attentional state of the animal. The cholinergic system has been linked to such gain changes in V1. Here, we aim to determine if a similar link exists in macaque area MT. While rhesus monkeys performed a top-down spatial attention task, we locally injected a cholinergic agonist or antagonist and recorded single-cell activity. RESULTS: Although we confirmed cholinergic influences on sensory responses, there was no additional cholinergic effect on the attentional gain changes. Neither a muscarinic blockage nor a local increase in acetylcholine led to a significant change in the magnitude of spatial attention effects on firing rates. CONCLUSIONS: This suggests that the cellular mechanisms of attentional modulation in the extrastriate cortex cannot be directly inferred from those in the primary visual cortex.

Characteristics of fMRI responses to visual stimulation in anesthetized vs. awake mice.

The functional characteristics of the mouse visual system have not previously been well explored using fMRI. In this research, we examined 9.4 T BOLD fMRI responses to visual stimuli of varying pulse durations (1 - 50 ms) and temporal frequencies (1 - 10 Hz) under ketamine and xylazine anesthesia, and compared fMRI responses of anesthetized and awake mice. Under anesthesia, significant positive BOLD responses were detected bilaterally in the major structures of the visual pathways, including the dorsal lateral geniculate nuclei, superior colliculus, lateral posterior nucleus of thalamus, primary visual area, and higher-order visual area. BOLD responses increased slightly with pulse duration, were maximal at 3 - 5 Hz stimulation, and significantly decreased at 10 Hz, which were all consistent with previous neurophysiological findings. When the mice were awake, the BOLD fMRI response was faster in all active regions and stronger in the subcortical areas compared with the anesthesia condition. In the V1, the BOLD response was biphasic for 5 Hz stimulation and negative for 10 Hz stimulation under wakefulness, whereas prolonged positive BOLD responses were observed at both frequencies under anesthesia. Unexpected activation was detected in the extrastriate postrhinal area and non-visual subiculum complex under anesthesia, but not under wakefulness. Widespread positive BOLD activity under anesthesia likely results from the disinhibition and sensitization of excitatory neurons induced by ketamine. Overall, fMRI can be a viable tool for mapping brain-wide functional networks.

Cannabis use impacts pre-stimulus neural activity in the visual cortices of people with HIV.

People with HIV (PWH) use cannabis at a higher rate than the general population, but the influence on neural activity is not well characterized. Cannabis use among PWH may have a beneficial effect, as neuroinflammation is known to be a critical problem in PWH and cannabis use has been associated with a reduction in proinflammatory markers. Thus, it is important to understand the net impact of cannabis use on brain and cognitive function in PWH. In this study, we collected magnetoencephalographic (MEG) brain imaging data on 81 participants split across four demographically matched groups (i.e., PWH using cannabis, controls using cannabis, non-using PWH, and non-using controls). Participants completed a visuospatial processing task during MEG. Time-frequency resolved voxel time series were extracted to identify the dynamics of oscillatory and pre-stimulus baseline neural activity. Our results indicated strong theta (4-8 Hz), alpha (10-16 Hz), and gamma (62-72 Hz) visual oscillations in parietal-occipital brain regions across all participants. PWH exhibited significant behavioral deficits in visuospatial processing, as well as reduced theta oscillations and elevated pre-stimulus gamma activity in visual cortices, all of which replicate prior work. Strikingly, chronic cannabis use was associated with a significant reduction in pre-stimulus gamma activity in the visual cortices, such that PWH no longer statistically differed from controls. These results provide initial evidence that cannabis use may normalize some neural aberrations in PWH. This study fills an important gap in understanding the impact of cannabis use on brain and cognitive function in PWH.

DPP-4 inhibitor reduces striatal microglial deramification after sensorimotor cortex injury induced by external force impact.

Dipeptidyl peptidase-4 inhibitors (or gliptins), a class of antidiabetic drugs, have recently been shown to have protective actions in the central nervous system. Their cellular and molecular mechanisms responsible for these effects are largely unknown. In the present study, two structurally different gliptins, sitagliptin and vildagliptin, were examined for their therapeutic actions in a controlled cortical impact (CCI) model of moderate traumatic brain injury (TBI) in mice. Early post-CCI treatment with sitagliptin, but not vildagliptin, significantly reduced body asymmetry, locomotor hyperactivity, and brain lesion volume. Sitagliptin attenuated post-CCI microglial deramification in the ipsilateral dorsolateral (DL) striatum, while vildagliptin had no effect. Sitagliptin also reduced striatal expression of galectin-3 and monocyte chemoattractant protein 1(MCP-1), and increased the cortical and striatal levels of the anti-inflammatory cytokine IL-10 on the ipsilateral side. These data support a differential protective effect of sitagliptin against TBI, possibly mediated by an anti-inflammatory effect in striatum to preserve connective network. Both sitagliptin and vildagliptin produced similar increases of active glucagon-like peptide-1 (GLP-1) in blood and brain. Increasing active GLP-1 may not be the sole molecular mechanisms for the neurotherapeutic effect of sitagliptin in TBI.

Synaptic Connectivity and Cortical Maturation Are Promoted by the ω-3 Fatty Acid Docosahexaenoic Acid.

Brain development is likely impacted by micronutrients. This is supported by the effects of the ω-3 fatty acid docosahexaenoic acid (DHA) during early neuronal differentiation, when it increases neurite growth. Aiming to delineate DHA roles in postnatal stages, we selected the visual cortex due to its stereotypic maturation. Immunohistochemistry showed that young mice that received dietary DHA from birth exhibited more abundant presynaptic and postsynaptic specializations. DHA also increased density and size of synapses in a dose-dependent manner in cultured neurons. In addition, dendritic arbors of neurons treated with DHA were more complex. In agreement with improved connectivity, DHA enhanced physiological parameters of network maturation in vitro, including bursting strength and oscillatory behavior. Aiming to analyze functional maturation of the cortex, we performed in vivo electrophysiological recordings from awake mice to measure responses to patterned visual inputs. Dietary DHA robustly promoted the developmental increase in visual acuity, without altering light sensitivity. The visual acuity of DHA-supplemented animals continued to improve even after their cortex had matured and DHA abolished the acuity plateau. Our findings show that the ω-3 fatty acid DHA promotes synaptic connectivity and cortical processing. These results provide evidence that micronutrients can support the maturation of neuronal networks.

Two distinct profiles of fMRI and neurophysiological activity elicited by acetylcholine in visual cortex.

Cholinergic neuromodulation is involved in all aspects of sensory processing and is crucial for processes such as attention, learning and memory, etc. However, despite the known roles of acetylcholine (ACh), we still do not how to disentangle ACh contributions from sensory or task-evoked changes in functional magnetic resonance imaging (fMRI). Here, we investigated the effects of local injection of ACh on fMRI and neural signals in the primary visual cortex (V1) of anesthetized macaques by combining pharmaco-based MRI (phMRI) with electrophysiological recordings, using single electrodes and electrode arrays. We found that local injection of ACh elicited two distinct profiles of fMRI and neurophysiological activity, depending on the distance from the injector. Near the injection site, we observed an increase in the baseline blood oxygen-level-dependent (BOLD) and cerebral blood flow (CBF) responses, while their visual modulation decreased. In contrast, further from the injection site, we observed an increase in the visually induced BOLD and CBF modulation without changes in baseline. Neurophysiological recordings suggest that the spatial correspondence between fMRI responses and neural activity does not change in the gamma, high-gamma, and multiunit activity (MUA) bands. The results near the injection site suggest increased inhibitory drive and decreased metabolism, contrasting to the far region. These changes are thought to reflect the kinetics of ACh and its metabolism to choline.

Effects of unilateral cortical resection of the visual cortex on bilateral human white matter.

Children with unilateral resections of ventral occipito-temporal cortex (VOTC) typically do not evince visual perceptual impairments, even when relatively large swathes of VOTC are resected. In search of possible explanations for this behavioral competence, we evaluated white matter microstructure and connectivity in eight pediatric epilepsy patients following unilateral cortical resection and 15 age-matched controls. To uncover both local and broader resection-induced effects, we analyzed tractography data using two complementary approaches. First, the microstructural properties were measured in the inferior longitudinal and the inferior fronto-occipital fasciculi, the major VOTC association tracts. Group differences were only evident in the ipsilesional, and not in the contralesional, hemisphere, and single-subject analyses revealed that these differences were limited to the site of the resection. Second, graph theory was used to characterize the connectivity of the contralesional occipito-temporal regions. There were no changes to the network properties in patients with left VOTC resections nor in patients with resections outside the VOTC, but altered network efficiency was observed in two cases with right VOTC resections. These results suggest that, in many, although perhaps not all, cases of unilateral VOTC resections in childhood, the white matter profile in the preserved contralesional hemisphere along with residual neural activity might be sufficient for normal visual perception.

Water-soluble variant of human Lynx1 positively modulates synaptic plasticity and ameliorates cognitive impairment associated with α7-nAChR dysfunction.

Lynx1 is a GPI-tethered protein colocalized with nicotinic acetylcholine receptors (nAChRs) in the brain areas important for learning and memory. Previously, we demonstrated that at low micromolar concentrations the water-soluble Lynx1 variant lacking GPI-anchor (ws-Lynx1) acts on α7-nAChRs as a positive allosteric modulator. We hypothesized that ws-Lynx1 could be used for improvement of cognitive processes dependent on nAChRs. Here we showed that 2 µM ws-Lynx1 increased the acetylcholine-evoked current at α7-nAChRs in the rat primary visual cortex L1 interneurons. At higher concentrations ws-Lynx1 inhibits α7-nAChRs expressed in Xenopus laevis oocytes with IC50  ~ 50 µM. In mice, ws-Lynx1 penetrated the blood-brain barrier upon intranasal administration and accumulated in the cortex, hippocampus, and cerebellum. Chronic ws-Lynx1 treatment prevented the olfactory memory and motor learning impairment induced by the α7-nAChRs inhibitor methyllycaconitine (MLA). Enhanced long-term potentiation and increased paired-pulse facilitation ratio were observed in the hippocampal slices incubated with ws-Lynx1 and in the slices from ws-Lynx1-treated mice. Long-term potentiation blockade observed in MLA-treated mice was abolished by ws-Lynx1 co-administration. To understand the mechanism of ws-Lynx1 action, we studied the interaction of ws-Lynx1 and MLA at α7-nAChRs, measured the basal concentrations of endogenous Lynx1 and the α7 nAChR subunit and their association in the mouse brain. Our findings suggest that endogenous Lynx1 limits α7-nAChRs activation in the adult brain. Ws-Lynx1 partially displaces Lynx1 causing positive modulation of α7-nAChRs and enhancement of synaptic plasticity. Ws-Lynx1 and similar compounds may constitute useful hits for treatment of cognitive deficits associated with the cholinergic system dysfunction.

Desflurane Anesthesia Alters Cortical Layer-specific Hierarchical Interactions in Rat Cerebral Cortex.

BACKGROUND: Neurocognitive investigations suggest that conscious sensory perception depends on recurrent neuronal interactions among sensory, parietal, and frontal cortical regions, which are suppressed by general anesthetics. The purpose of this work was to investigate if local interactions in sensory cortex are also altered by anesthetics. The authors hypothesized that desflurane would reduce recurrent neuronal interactions in cortical layer-specific manner consistent with the anatomical disposition of feedforward and feedback pathways. METHODS: Single-unit neuronal activity was measured in freely moving adult male rats (268 units; 10 animals) using microelectrode arrays chronically implanted in primary and secondary visual cortex. Layer-specific directional interactions were estimated by mutual information and transfer entropy of multineuron spike patterns within and between cortical layers three and five. The effect of incrementally increasing and decreasing steady-state concentrations of desflurane (0 to 8% to 0%) was tested for statistically significant quadratic trend across the successive anesthetic states. RESULTS: Desflurane produced robust, state-dependent reduction (P = 0.001) of neuronal interactions between primary and secondary visual areas and between layers three and five, as indicated by mutual information (37 and 41% decrease at 8% desflurane from wakeful baseline at [mean ± SD] 0.52 ± 0.51 and 0.53 ± 0.51 a.u., respectively) and transfer entropy (77 and 78% decrease at 8% desflurane from wakeful baseline at 1.86 ± 1.56 a.u. and 1.87 ± 1.67 a.u., respectively). In addition, a preferential suppression of feedback between secondary and primary visual cortex was suggested by the reduction of directional index of transfer entropy overall (P = 0.001; 89% decrease at 8% desflurane from 0.11 ± 0.18 a.u. at baseline) and specifically, in layer five (P = 0.001; 108% decrease at 8% desflurane from 0.12 ± 0.19 a.u. at baseline). CONCLUSIONS: Desflurane anesthesia reduces neuronal interactions in visual cortex with a preferential effect on feedback. The findings suggest that neuronal disconnection occurs locally, among hierarchical sensory regions, which may contribute to global functional disconnection underlying anesthetic-induced unconsciousness.

Effects of methylmercury on the pattern of NADPH diaphorase expression and astrocytic activation in the rat.

Mercury (Hg) is an environmental contaminant that poses great risk to human health. However, it is still widely used in artisanal gold-mining enterprises around the world, especially in developing countries. Methylmercury (MeHg) is produced environmentally by biomethylation of inorganic Hg present in water sediments, leading to its subsequent accumulation in the aquatic food chain. Due to its high metabolic rate, the Central Nervous System (CNS) is one of the main targets of MeHg. In the present study, we investigate the impact of chronic MeHg intoxication on NADPH diaphorase (NADPH-d) activity and astrocyte mobilization in the visual cortex of the rat. After 60 days of MeHg administration by oral gavage (0.04 mg/kg/day), tissue samples containing the visual cortex were submitted to measurements of Hg levels, NADPH-d activity, and GFAP immunohistochemistry for identification of astrocytes. MeHg intoxication was associated with increased Hg deposits and with reduced NADPH-d neuropil reactivity in the visual cortex. A morphometric analysis suggested that NADPH-d-positive neurons were mostly spared from MeHg harmful action and intoxicated animals had astrocytic activation similar to the control group. The decrease in NADPH-d neuropil reactivity may be due to the negative effect of chronic MeHg poisoning on both the synthesis and transport of this enzyme in afferent pathways to the visual cortex. The relative resistance of NADPH-d-reactive neurons to chronic MeHg intoxication may be associated with peculiarities in cell metabolism or to a protective role of nitric oxide, safeguarding those neurons from Hg deleterious effects.

Interneuron Simplification and Loss of Structural Plasticity As Markers of Aging-Related Functional Decline.

Changes in excitatory neuron and synapse structure have been recognized as a potential physical source of age-related cognitive decline. Despite the importance of inhibition to brain plasticity, little is known regarding aging-associated changes to inhibitory neurons. Here we test for age-related cellular and circuit changes to inhibitory neurons of mouse visual cortex. We find no substantial difference in inhibitory neuron number, inhibitory neuronal subtypes, or synapse numbers within the cerebral cortex of aged mice compared with younger adults. However, when comparing cortical interneuron morphological parameters, we find differences in complexity, suggesting that arbors are simplified in aged mice. In vivo two-photon microscopy has previously shown that in contrast to pyramidal neurons, inhibitory interneurons retain a capacity for dendritic remodeling in the adult. We find that this capacity diminishes with age and is accompanied by a shift in dynamics from balanced branch additions and retractions to progressive prevalence of retractions, culminating in a dendritic arbor that is both simpler and more stable. Recording of visually evoked potentials shows that aging-related interneuron dendritic arbor simplification and reduced dynamics go hand in hand with loss of induced stimulus-selective response potentiation (SRP), a paradigm for adult visual cortical plasticity. Chronic treatment with the antidepressant fluoxetine reversed deficits in interneuron structural dynamics and restored SRP in aged animals. Our results support a structural basis for age-related impairments in sensory perception, and suggest that declines in inhibitory neuron structural plasticity during aging contribute to reduced functional plasticity.SIGNIFICANCE STATEMENT Structural alterations in neuronal morphology and synaptic connections have been proposed as a potential physical basis for age-related decline in cognitive function. Little is known regarding aging-associated changes to inhibitory neurons, despite the importance of inhibitory circuitry to adult cortical plasticity and the reorganization of cortical maps. Here we show that brain aging goes hand in hand with progressive structural simplification and reduced plasticity of inhibitory neurons, and a parallel decline in sensory map plasticity. Fluoxetine treatment can attenuate the concurrent age-related declines in interneuron structural and functional plasticity, suggesting it could provide an important therapeutic approach for mitigating sensory and cognitive deficits associated with aging.

Fluoxetine-induced plasticity in the visual cortex outlasts the duration of the naturally occurring critical period.

Heightened neuronal plasticity expressed during early postnatal life has been thought to permanently decline once critical periods have ended. For example, monocular deprivation is able to shift ocular dominance in the mouse visual cortex during the first months of life, but this effect is lost later in life. However, various treatments, such as the antidepressant fluoxetine, can reactivate a critical period-like plasticity in the adult brain. When monocular deprivation is supplemented with chronic fluoxetine administration, a major shift in ocular dominance is produced after the critical period has ended. In the current study, we characterized the temporal patterns of fluoxetine-induced plasticity in the adult mouse visual cortex, using in vivo optical imaging. We found that artificially induced plasticity in ocular dominance extended beyond the duration of the naturally occurring critical period and continued as long as fluoxetine was administered. However, this fluoxetine-induced plasticity period ended as soon as the drug was not given. These features of antidepressant-induced plasticity may be useful when designing treatment strategies involving long-term antidepressant treatment in humans.

Exenatide modulates visual cortex responses.

BACKGROUND: Increasing evidence suggests that metabolism affects brain physiology. Here, we examine the effect of GLP-1 on simple visual-evoked functional Magnetic Resonance Imaging (fMRI) responses in cortical areas. METHODS: Lean (n = 10) and nondiabetic obese (n = 10) subjects received exenatide (a GLP-1 agonist) or saline infusion, and fMRI responses to visual stimuli (food and nonfood images) were recorded. We analysed the effect of exenatide on fMRI signals across the cortical surface with special reference to the visual areas. We evaluated the effects of exenatide on the raw fMRI signal and on the fMRI signal change during visual stimulation (vs rest). RESULTS: In line with previous studies, we find that exenatide eliminates the preference for food (over nonfood) images present under saline infusion in high-level visual cortex (temporal pole). In addition, we find that exenatide (vs saline) also modulates the response of early visual areas, enhancing responses to both food and nonfood images in several extrastriate occipital areas, similarly in obese and lean participants. Unexpectedly, exenatide increased fMRI raw signals (signal intensity during rest periods without stimulation) in a large occipital region, which were negatively correlated to BMI. CONCLUSIONS: In both lean and obese individuals, exenatide affects neural processing in visual cortex, both in early visual areas and in higher order areas. This effect may contribute to the known effect of GLP1 analogues on food-related behaviour.

A disinhibitory microcircuit initiates critical-period plasticity in the visual cortex.

Early sensory experience instructs the maturation of neural circuitry in the cortex. This has been studied extensively in the primary visual cortex, in which loss of vision to one eye permanently degrades cortical responsiveness to that eye, a phenomenon known as ocular dominance plasticity (ODP). Cortical inhibition mediates this process, but the precise role of specific classes of inhibitory neurons in ODP is controversial. Here we report that evoked firing rates of binocular excitatory neurons in the primary visual cortex immediately drop by half when vision is restricted to one eye, but gradually return to normal over the following twenty-four hours, despite the fact that vision remains restricted to one eye. This restoration of binocular-like excitatory firing rates after monocular deprivation results from a rapid, although transient, reduction in the firing rates of fast-spiking, parvalbumin-positive (PV) interneurons, which in turn can be attributed to a decrease in local excitatory circuit input onto PV interneurons. This reduction in PV-cell-evoked responses after monocular lid suture is restricted to the critical period for ODP and appears to be necessary for subsequent shifts in excitatory ODP. Pharmacologically enhancing inhibition at the time of sight deprivation blocks ODP and, conversely, pharmacogenetic reduction of PV cell firing rates can extend the critical period for ODP. These findings define the microcircuit changes initiating competitive plasticity during critical periods of cortical development. Moreover, they show that the restoration of evoked firing rates of layer 2/3 pyramidal neurons by PV-specific disinhibition is a key step in the progression of ODP.

ß-Catenin in the Adult Visual Cortex Regulates NMDA-Receptor Function and Visual Responses.

The formation, plasticity and maintenance of synaptic connections is regulated by molecular and electrical signals. ß-Catenin is an important protein in these events and regulates cadherin-mediated cell adhesion and the recruitment of pre- and postsynaptic proteins in an activity-dependent fashion. Mutations in the ß-catenin gene can cause cognitive disability and autism, with life-long consequences. Understanding its synaptic function may thus be relevant for the treatment of these disorders. So far, ß-catenin's function has been studied predominantly in cell culture and during development but knowledge on its function in adulthood is limited. Here, we show that ablating ß-catenin in excitatory neurons of the adult visual cortex does not cause the same synaptic deficits previously observed during development. Instead, it reduces NMDA-receptor currents and impairs visual processing. We conclude that ß-catenin remains important for adult cortical function but through different mechanisms than during development.

Retained Plasticity and Substantial Recovery of Rod-Mediated Visual Acuity at the Visual Cortex in Blind Adult Mice with Retinal Dystrophy.

In patients born blind with retinal dystrophies, understanding the critical periods of cortical plasticity is important for successful visual restoration. In this study, we sought to model childhood blindness and investigate the plasticity of visual pathways. To this end, we generated double-mutant (Pde6ccpfl1/cpfl1Gnat1IRD2/IRD2) mice with absent rod and cone photoreceptor function, and we evaluated their response for restoring rod (GNAT1) function through gene therapy. Despite the limited effectiveness of gene therapy in restoring visual acuity in patients with retinal dystrophy, visual acuity was, unexpectedly, successfully restored in the mice at the level of the primary visual cortex in this study. This success in visual restoration, defined by changes in the quantified optokinetic response and pattern visually evoked potential, was achieved regardless of the age at treatment (up to 16 months). In the contralateral visual cortex, cortical plasticity, tagged with light-triggered transcription of Arc, was also restored after the treatment in blind mice carrying an Arc promoter-driven reporter gene, dVenus. Our results demonstrate the remarkable plasticity of visual circuits for one of the two photoreceptor mechanisms in older as well as younger mice with congenital blindness due to retinal dystrophies.

The Effect of Combined Patching and Citalopram on Visual Acuity in Adults with Amblyopia: A Randomized, Crossover, Placebo-Controlled Trial.

Nonhuman animal models have demonstrated that selective serotonin reuptake inhibitors (SSRIs) can enhance plasticity within the mature visual cortex and enable recovery from amblyopia. The aim of this study was to test the hypothesis that the SSRI citalopram combined with part-time patching of the fellow fixing eye would improve amblyopic eye visual acuity in adult humans. Following a crossover, randomized, double-blind, placebo-controlled design, participants completed two 2-week blocks of fellow fixing eye patching. One block combined patching with citalopram (20 mg/day) and the other with a placebo tablet. The blocks were separated by a 2-week washout period. The primary outcome was change in amblyopic eye visual acuity. Secondary outcomes included stereoacuity and electrophysiological measures of retinal and cortical function. Seven participants were randomized, fewer than our prespecified sample size of 20. There were no statistically significant differences in amblyopic eye visual acuity change between the active (mean ± SD change = 0.08 ± 0.16 logMAR) and the placebo (mean change = -0.01 ± 0.03 logMAR) blocks. No treatment effects were observed for any secondary outcomes. However, 3 of 7 participants experienced a 0.1 logMAR or greater improvement in amblyopic eye visual acuity in the active but not the placebo blocks. These results from a small sample suggest that larger-scale trials of SSRI treatment for adult amblyopia may be warranted. Considerations for future trials include drug dose, treatment duration, and recruitment challenges. This study was preregistered as a clinical trial (ACTRN12611000669998).

[The postnatal development of perineuronal net, Nogo receptor and the effect of fluoxetine on remodeling it in the visual cortex of rats].

Objective: To investigate the postnatal development of perineuronal net (PNN), Nogo receptor (Nogo R) in visual development and the effect of fluoxetine(Flx) on remodeling it in the visual cortex of adult rats. Methods: Experimental study. (1) Wistar rats were divided into postnatal weeks (PW)1,PW3,PW5,PW7,PW9 group (8 rats in each group) according to the age of PW. The changes of PNN and Nogo R were observed in the visual cortex of each group. (2) The adult rats (10 weeks after birth) were randomized into Flx 0W, Flx 2W, Flx 4W, Flx 6W and Flx 8W group (8 rats in each group) according to Flx administrational weeks. The influence of Flx on the expression of PNN and Nogo receptor in the visual cortex was detected by immunofluorescence and western blots. (3) The adult rats were randomized into Cont (negative control), Flx, binocular form deprivation(BFD,positive control) and BFD+Flx group (8 rats in each group). Flx group accepted oral administration at the dosage of 0.2 mg/ml once per day for 4 weeks. The eyelids were binocularly sutured for 2 weeks to form the BFD group, and the combination of Flx administration and BFD was performed in the BFD+Flx group.No intervention was conducted in the control group (Cont group). Immunofluorescence was used to observe the expression pattern of PNN staining by biotinylated wisteria floribunda lectin (WFA). The expression of Nogo R in the visual cortex was detected by immunofluorescence and Western blots. The expression of PNN and Nogo R were examined in each group. And t test, analysis of variance and rank sum test were employed for inter-group comparison based on the homogeneity of variance. Bonferroni method was used for multiple comparison and simple linear regression analysis was used for the trend. Results: (1) The expression of PNN (standardized b=0.97, P=0.005) and Nogo R (standardized b=0.96, P=0.010) increased during the postnatal development and the Nogo R reached the matured level at PW7 (PW7 vs. PW9, 131.83±3.78 vs. 135.11±3.92, Z=1.93, P=0.062). (2) Flx significantly decreased PNN in the visual cortex of adult rats. The density of PNN-positive cells in the visual cortex of healthy adult rats fed with Flx for 4 weeks was (86.22±7.68)/mm(2), which was similar to that of 3 weeks old rats [(84.21±6.68)/mm(2), t=2.08, P=0.073]. The expression of PNN (standardized b=-0.88, P=0.040) and it's receptor Nogo R (standardized b=-0.90, P=0.007) decreased with prolongation of Flx use. (3) The expression of Nogo R (t=13.42,11.47, 18.13; P=0.012, 0.013, 0.001; Flx, BFD and BFD+Flx group vs. Cont group) and the density of PNN (t=10.09, 7.64, 13.01; P=0.007, 0.011, 0.001; Flx, BFD and BFD+Flx group vs. Cont group) could be modulated by Flx and BFD after the critical period. There are no differences in BFD and Flx group on Nogo R changes (t=2.41, P=0.153). The expression of Nogo R protein was also different among the 4 groups (H=5.69, P=0.041). The effect of Flx combined with BFD was better than the Flx or BFD alone (Flx vs. BFD+Flx, Z=4.22, P=0.005; BFD vs. BFD+Flx, Z=3.09, P=0.010). Conclusions: The expression of PNN and Nogo R increase during the postnatal development. Chronic Flx treatment decrease the expression of PNN and Nogo R after the critical period in the visual cortex of adult rats, that is the same as BFD. (Chin J Ophthalmol, 2019, 55:37-45).

Serotonin Decreases the Gain of Visual Responses in Awake Macaque V1.

Serotonin, an important neuromodulator in the brain, is implicated in affective and cognitive functions. However, its role even for basic cortical processes is controversial. For example, in the mammalian primary visual cortex (V1), heterogenous serotonergic modulation has been observed in anesthetized animals. Here, we combined extracellular single-unit recordings with iontophoresis in awake animals. We examined the role of serotonin on well-defined tuning properties (orientation, spatial frequency, contrast, and size) in V1 of two male macaque monkeys. We find that in the awake macaque the modulatory effect of serotonin is surprisingly uniform: it causes a mainly multiplicative decrease of the visual responses and a slight increase in the stimulus-selective response latency. Moreover, serotonin neither systematically changes the selectivity or variability of the response, nor the interneuronal correlation unexplained by the stimulus ("noise-correlation"). The modulation by serotonin has qualitative similarities with that for a decrease in stimulus contrast, but differs quantitatively from decreasing contrast. It can be captured by a simple additive change to a threshold-linear spiking nonlinearity. Together, our results show that serotonin is well suited to control the response gain of neurons in V1 depending on the animal's behavioral or motivational context, complementing other known state-dependent gain-control mechanisms.SIGNIFICANCE STATEMENT Serotonin is an important neuromodulator in the brain and a major target for drugs used to treat psychiatric disorders. Nonetheless, surprisingly little is known about how it shapes information processing in sensory areas. Here we examined the serotonergic modulation of visual processing in the primary visual cortex of awake behaving macaque monkeys. We found that serotonin mainly decreased the gain of the visual responses, without systematically changing their selectivity, variability, or covariability. This identifies a simple computational function of serotonin for state-dependent sensory processing, depending on the animal's affective or motivational state.