mGreenLantern: a bright monomeric fluorescent protein with rapid expression and cell filling properties for neuronal imaging.

Although ubiquitous in biological studies, the enhanced green and yellow fluorescent proteins (EGFP and EYFP) were not specifically optimized for neuroscience, and their underwhelming brightness and slow expression in brain tissue limits the fidelity of dendritic spine analysis and other indispensable techniques for studying neurodevelopment and plasticity. We hypothesized that EGFP's low solubility in mammalian systems must limit the total fluorescence output of whole cells, and that improving folding efficiency could therefore translate into greater brightness of expressing neurons. By introducing rationally selected combinations of folding-enhancing mutations into GFP templates and screening for brightness and expression rate in human cells, we developed mGreenLantern, a fluorescent protein having up to sixfold greater brightness in cells than EGFP. mGreenLantern illuminates neurons in the mouse brain within 72 h, dramatically reducing lag time between viral transduction and imaging, while its high brightness improves detection of neuronal morphology using widefield, confocal, and two-photon microscopy. When virally expressed to projection neurons in vivo, mGreenLantern fluorescence developed four times faster than EYFP and highlighted long-range processes that were poorly detectable in EYFP-labeled cells. Additionally, mGreenLantern retains strong fluorescence after tissue clearing and expansion microscopy, thereby facilitating superresolution and whole-brain imaging without immunohistochemistry. mGreenLantern can directly replace EGFP/EYFP in diverse systems due to its compatibility with GFP filter sets, recognition by EGFP antibodies, and excellent performance in mouse, human, and bacterial cells. Our screening and rational engineering approach is broadly applicable and suggests that greater potential of fluorescent proteins, including biosensors, could be unlocked using a similar strategy.

Activation of Somatostatin Interneurons by Nicotinic Modulator Lypd6 Enhances Plasticity and Functional Recovery in the Adult Mouse Visual Cortex.

The limitation of plasticity in the adult brain impedes functional recovery later in life from brain injury or disease. This pressing clinical issue may be resolved by enhancing plasticity in the adult brain. One strategy for triggering robust plasticity in adulthood is to reproduce one of the hallmark physiological events of experience-dependent plasticity observed during the juvenile critical period: to rapidly reduce the activity of parvalbumin (PV)-expressing interneurons and disinhibit local excitatory neurons. This may be achieved through the enhancement of local inhibitory inputs, particularly those of somatostatin (SST)-expressing interneurons. However, to date the means for manipulating SST interneurons for enhancing cortical plasticity in the adult brain are not known. We show that SST interneuron-selective overexpression of Lypd6, an endogenous nicotinic signaling modulator, enhances ocular dominance plasticity in the adult primary visual cortex (V1). Lypd6 overexpression mediates a rapid experience-dependent increase in the visually evoked activity of SST interneurons as well as a simultaneous reduction in PV interneuron activity and disinhibition of excitatory neurons. Recapitulating this transient activation of SST interneurons using chemogenetics similarly enhanced V1 plasticity. Notably, we show that SST-selective Lypd6 overexpression restores visual acuity in amblyopic mice that underwent early long-term monocular deprivation. Our data in both male and female mice reveal selective modulation of SST interneurons and a putative downstream circuit mechanism as an effective method for enhancing experience-dependent cortical plasticity as well as functional recovery in adulthood.SIGNIFICANCE STATEMENT The decline of cortical plasticity after closure of juvenile critical period consolidates neural circuits and behavior, but this limits functional recovery from brain diseases and dysfunctions in later life. Here we show that activation of cortical somatostatin (SST) interneurons by Lypd6, an endogenous modulator of nicotinic acetylcholine receptors, enhances experience-dependent plasticity and recovery from amblyopia in adulthood. This manipulation triggers rapid reduction of PV interneuron activity and disinhibition of excitatory neurons, which are known hallmarks of cortical plasticity during juvenile critical periods. Our study demonstrates modulation of SST interneurons by Lypd6 to achieve robust levels of cortical plasticity in the adult brain and may provide promising targets for restoring brain function in the event of brain trauma or disease.

Systematic Analysis of Environmental Chemicals That Dysregulate Critical Period Plasticity-Related Gene Expression Reveals Common Pathways That Mimic Immune Response to Pathogen.

The tens of thousands of industrial and synthetic chemicals released into the environment have an unknown but potentially significant capacity to interfere with neurodevelopment. Consequently, there is an urgent need for systematic approaches that can identify disruptive chemicals. Little is known about the impact of environmental chemicals on critical periods of developmental neuroplasticity, in large part, due to the challenge of screening thousands of chemicals. Using an integrative bioinformatics approach, we systematically scanned 2001 environmental chemicals and identified 50 chemicals that consistently dysregulate two transcriptional signatures of critical period plasticity. These chemicals included pesticides (e.g., pyridaben), antimicrobials (e.g., bacitracin), metals (e.g., mercury), anesthetics (e.g., halothane), and other chemicals and mixtures (e.g., vehicle emissions). Application of a chemogenomic enrichment analysis and hierarchical clustering across these diverse chemicals identified two clusters of chemicals with one that mimicked an immune response to pathogen, implicating inflammatory pathways and microglia as a common chemically induced neuropathological process. Thus, we established an integrative bioinformatics approach to systematically scan thousands of environmental chemicals for their ability to dysregulate molecular signatures relevant to critical periods of development.

Lynx1 Limits Dendritic Spine Turnover in the Adult Visual Cortex.

UNLABELLED: Dendritic spine turnover becomes limited in the adult cerebral cortex. Identification of specific aspects of spine dynamics that can be unmasked in adulthood and its regulatory molecular mechanisms could provide novel therapeutic targets for inducing plasticity at both the functional and structural levels for robust recovery from brain disorders and injuries in adults. Lynx1, an endogenous inhibitor of nicotinic acetylcholine receptors, was previously shown to increase its expression in adulthood and thus to limit functional ocular dominance plasticity in adult primary visual cortex (V1). However, the role of this "brake" on spine dynamics is not known. We examined the contribution of Lynx1 on dendritic spine turnover before and after monocular deprivation (MD) in adult V1 with chronic in vivo imaging using two-photon microscopy and determined the spine turnover rate of apical dendrites of layer 5 (L5) and L2/3 pyramidal neurons in adult V1 of Lynx1 knock-out (KO) mice. We found that the deletion of Lynx1 doubled the baseline spine turnover rate, suggesting that the spine dynamics in the adult cortex is actively limited by the presence of Lynx1. After MD, adult Lynx1-KO mice selectively exhibit higher rate of spine loss with no difference in gain rate in L5 neurons compared with control wild-type counterparts, revealing a key signature of spine dynamics associated with robust functional plasticity in adult V1. Overall, Lynx1 could be a promising therapeutic target to induce not only functional, but also structural plasticity at the level of spine dynamics in the adult brain. SIGNIFICANCE STATEMENT: Dendritic spine turnover becomes limited in the adult cortex. In mouse visual cortex, a premier model of experience-dependent plasticity, we found that the deletion of Lynx1, a nicotinic "brake" for functional plasticity, doubled the baseline spine turnover in adulthood, suggesting that the spine dynamics in the adult cortex is actively limited by Lynx1. After visual deprivation, spine loss, but not gain rate, remains higher in adult Lynx1 knock-out mice than in control wild-type mice, revealing a key signature of spine dynamics associated with robust functional plasticity. Lynx1 would be a promising target to induce not only functional, but also structural plasticity at the level of spine dynamics in adulthood.

Unmasking Proteolytic Activity for Adult Visual Cortex Plasticity by the Removal of Lynx1.

Experience-dependent cortical plasticity declines with age. At the molecular level, experience-dependent proteolytic activity of tissue plasminogen activator (tPA) becomes restricted in the adult brain if mice are raised in standard cages. Understanding the mechanism for the loss of permissive proteolytic activity is therefore a key link for improving function in adult brains. Using the mouse primary visual cortex (V1) as a model, we demonstrate that tPA activity in V1 can be unmasked following 4 d of monocular deprivation when the mice older than 2 months are raised in standard cages by the genetic removal of Lynx1, a negative regulator of adult plasticity. This was also associated with the reduction of stubby and thin spine density and enhancement of ocular dominance shift in adult V1 of Lynx1 knock-out (KO) mice. These structural and functional changes were tPA-dependent because genetic removal of tPA in Lynx1 KO mice can block the monocular deprivation-dependent reduction of dendritic spine density, whereas both genetic and adult specific inhibition of tPA activity can ablate the ocular dominance shift in Lynx1 KO mice. Our work demonstrates that the adult brain has an intrinsic potential for experience-dependent elevation of proteolytic activity to express juvenile-like structural and functional changes but is effectively limited by Lynx1 if mice are raised in standard cages. Insights into the Lynx1-tPA plasticity mechanism may provide novel therapeutic targets for adult brain disorders. SIGNIFICANCE STATEMENT: Experience-dependent proteolytic activity of tissue plasminogen activator (tPA) becomes restricted in the adult brain in correlation with the decline in cortical plasticity when mice are raised in standard cages. We demonstrated that removal of Lynx1, one of negative regulators of plasticity, unmasks experience-dependent tPA elevation in visual cortex of adult mice reared in standard cages. This proteolytic elevation facilitated dendritic spine reduction and ocular dominance plasticity in adult visual cortex. This is the first demonstration of adult brain to retain the intrinsic capacity to elevate tPA in an experience-dependent manner but is effectively limited by Lynx1. tPA-Lynx1 may potentially be a new candidate mechanism for interventions that were shown to activate plasticity in adult brain.

Perineuronal nets protect fast-spiking interneurons against oxidative stress.

A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks. The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress. Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress. These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults. We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display. Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress. In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets. Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress. The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets. Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.

Interneuron epigenomes during the critical period of cortical plasticity: Implications for schizophrenia.

Schizophrenia, a major psychiatric disorder defined by delusions and hallucinations, among other symptoms, often with onset in early adulthood, is potentially associated with molecular and cellular alterations in parvalbumin-expressing fast spiking interneurons and other constituents of the cortical inhibitory GABAergic circuitry. The underlying mechanisms, including the role of disease-associated risk factors operating in adolescence such as drug abuse and social stressors, remain incompletely understood. Here, we summarize emerging findings from animal models, highlighting the ability of parvalbuminergic interneurons (PVI) to induce, during the juvenile period, long-term plastic changes in prefrontal and visual cortex, thereby altering perception, cognition and behavior in the adult. Of note, molecular alterations in PVI from subjects with schizophrenia, including downregulated expression of a subset of GABAergic genes, have also been found in juvenile stress models of the disorder. Some of the transcriptional alterations observed in schizophrenia postmortem brain could be linked to changes in the epigenetic architecture of GABAergic gene promoters, including dysregulated DNA methylation, histone modification patterns and disruption of promoter-enhancer interactions at site of chromosomal loop formations. Therefore, we predict that, in the not-to-distant future, PVI- and other cell-type specific epigenomic mappings in the animal model and human brain will provide novel insights into the pathophysiology of schizophrenia and related psychotic diseases, including the role of cortical GABAergic circuitry in shaping long-term plasticity and cognitive function of the cerebral cortex.

Protocadherin family: diversity, structure, and function.

Protocadherins are predominantly expressed in the nervous system, and constitute the largest subgroup within the cadherin superfamily. The recent structural elucidation of the amino-terminal cadherin domain in an archetypal protocadherin revealed unique and remarkable features: the lack of an interface for homophilic adhesiveness found in classical cadherins, and the presence of loop structures specific to the protocadherin family. The unique features of protocadherins extend to their genomic organization. Recent findings have revealed unexpected allelic and combinatorial gene regulation for clustered protocadherins, a major subgroup in the protocadherin family. The unique structural repertoire and unusual gene regulation of the protocadherin family may provide the molecular basis for the extraordinary diversity of the nervous system.

How childhood social isolation causes social dysfunction: deprivation or mismatch?

There is a major gap in our understanding of how childhood social isolation causes adult social dysfunction. To stimulate future developmental mechanistic studies, we present two conceptual models which highlight that isolation can disrupt developmental events that are concurrent (social deprivation model) or subsequent (developmental mismatch model) to adverse experience.

Sustained antidepressant effects of ketamine metabolite involve GABAergic inhibition-mediated molecular dynamics in aPVT glutamatergic neurons.

Despite the rapid and sustained antidepressant effects of ketamine and its metabolites, their underlying cellular and molecular mechanisms are not fully understood. Here, we demonstrate that the sustained antidepressant-like behavioral effects of (2S,6S)-hydroxynorketamine (HNK) in repeatedly stressed animal models involve neurobiological changes in the anterior paraventricular nucleus of the thalamus (aPVT). Mechanistically, (2S,6S)-HNK induces mRNA expression of extrasynaptic GABAA receptors and subsequently enhances GABAA-receptor-mediated tonic currents, leading to the nuclear export of histone demethylase KDM6 and its replacement by histone methyltransferase EZH2. This process increases H3K27me3 levels, which in turn suppresses the transcription of genes associated with G-protein-coupled receptor signaling. Thus, our findings shed light on the comprehensive cellular and molecular mechanisms in aPVT underlying the sustained antidepressant behavioral effects of ketamine metabolites. This study may support the development of potentially effective next-generation pharmacotherapies to promote sustained remission of stress-related psychiatric disorders.

Critical Period Plasticity as a Framework for Psychedelic-Assisted Psychotherapy.

As psychedelic compounds gain traction in psychiatry, there is a need to consider the active mechanism to explain the effect observed in randomized clinical trials. Traditionally, biological psychiatry has asked how compounds affect the causal pathways of illness to reduce symptoms and therefore focus on analysis of the pharmacologic properties. In psychedelic-assisted psychotherapy (PAP), there is debate about whether ingestion of the psychedelic alone is thought to be responsible for the clinical outcome. A question arises how the medication and psychotherapeutic intervention together might lead to neurobiological changes that underlie recovery from illness such as post-traumatic stress disorder (PTSD). This paper offers a framework for investigating the neurobiological basis of PAP by extrapolating from models used to explain how a pharmacologic intervention might create an optimal brain state during which environmental input has enduring effects. Specifically, there are developmental "critical" periods (CP) with exquisite sensitivity to environmental input; the biological characteristics are largely unknown. We discuss a hypothesis that psychedelics may remove the brakes on adult neuroplasticity, inducing a state similar to that of neurodevelopment. In the visual system, progress has been made both in identifying the biological conditions which distinguishes the CP and in manipulating the active ingredients with the idea that we might pharmacologically reopen a critical period in adulthood. We highlight ocular dominance plasticity (ODP) in the visual system as a model for characterizing CP in limbic systems relevant to psychiatry. A CP framework may help to integrate the neuroscientific inquiry with the influence of the environment both in development and in PAP. Appeared originally in Front Neurosci 2021; 15:710004.

Psychosis spectrum illnesses as disorders of prefrontal critical period plasticity.

Emerging research on neuroplasticity processes in psychosis spectrum illnesses-from the synaptic to the macrocircuit levels-fill key gaps in our models of pathophysiology and open up important treatment considerations. In this selective narrative review, we focus on three themes, emphasizing alterations in spike-timing dependent and Hebbian plasticity that occur during adolescence, the critical period for prefrontal system development: (1) Experience-dependent dysplasticity in psychosis emerges from activity decorrelation within neuronal ensembles. (2) Plasticity processes operate bidirectionally: deleterious environmental and experiential inputs shape microcircuits. (3) Dysregulated plasticity processes interact across levels of scale and time and include compensatory mechanisms that have pathogenic importance. We present evidence that-given the centrality of progressive dysplastic changes, especially in prefrontal cortex-pharmacologic or neuromodulatory interventions will need to be supplemented by corrective learning experiences for the brain if we are to help people living with these illnesses to fully thrive.

Critical Period Plasticity as a Framework for Psychedelic-Assisted Psychotherapy.

As psychedelic compounds gain traction in psychiatry, there is a need to consider the active mechanism to explain the effect observed in randomized clinical trials. Traditionally, biological psychiatry has asked how compounds affect the causal pathways of illness to reduce symptoms and therefore focus on analysis of the pharmacologic properties. In psychedelic-assisted psychotherapy (PAP), there is debate about whether ingestion of the psychedelic alone is thought to be responsible for the clinical outcome. A question arises how the medication and psychotherapeutic intervention together might lead to neurobiological changes that underlie recovery from illness such as post-traumatic stress disorder (PTSD). This paper offers a framework for investigating the neurobiological basis of PAP by extrapolating from models used to explain how a pharmacologic intervention might create an optimal brain state during which environmental input has enduring effects. Specifically, there are developmental "critical" periods (CP) with exquisite sensitivity to environmental input; the biological characteristics are largely unknown. We discuss a hypothesis that psychedelics may remove the brakes on adult neuroplasticity, inducing a state similar to that of neurodevelopment. In the visual system, progress has been made both in identifying the biological conditions which distinguishes the CP and in manipulating the active ingredients with the idea that we might pharmacologically reopen a critical period in adulthood. We highlight ocular dominance plasticity (ODP) in the visual system as a model for characterizing CP in limbic systems relevant to psychiatry. A CP framework may help to integrate the neuroscientific inquiry with the influence of the environment both in development and in PAP.

An Adolescent Sensitive Period for Social Dominance Hierarchy Plasticity Is Regulated by Cortical Plasticity Modulators in Mice.

Social dominance hierarchies are a common adaptation to group living and exist across a broad range of the animal kingdom. Social dominance is known to rely on the prefrontal cortex (PFC), a brain region that shows a protracted developmental trajectory in mice. However, it is unknown to what extent the social dominance hierarchy is plastic across postnatal development and how it is regulated. Here we identified a sensitive period for experience-dependent social dominance plasticity in adolescent male mice, which is regulated by mechanisms that affect cortical plasticity. We show that social dominance hierarchies in male mice are already formed at weaning and are highly stable into adulthood. However, one experience of forced losing significantly reduces social dominance during the adolescent period but not in adulthood, suggesting adolescence as a sensitive period for experience-dependent social dominance plasticity. Notably, robust adolescent plasticity can be prolonged into adulthood by genetic deletion of Lynx1, a molecular brake that normally limits cortical plasticity through modulation of cortical nicotinic signaling. This plasticity is associated with increased activation of established nodes of the social dominance network including dorsal medial PFC and medial dorsal thalamus evidenced by increased c-Fos. Pharmacologically mediated elevation of cortical plasticity by valproic acid rapidly destabilizes the hierarchy of adult wildtype animals. These findings provide insight into mechanisms through which increased behavioral plasticity may be achieved to improve therapeutic recovery from psychiatric disorders that are associated with social deficits.

Frontal-Sensory Cortical Projections Become Dispensable for Attentional Performance Upon a Reduction of Task Demand in Mice.

Top-down attention is a dynamic cognitive process that facilitates the detection of the task-relevant stimuli from our complex sensory environment. A neural mechanism capable of deployment under specific task-demand conditions would be crucial to efficiently control attentional processes and improve promote goal-directed attention performance during fluctuating attentional demand. Previous studies have shown that frontal top-down neurons projecting from the anterior cingulate area (ACA) to the visual cortex (VIS; ACAVIS) are required for visual attentional behavior during the 5-choice serial reaction time task (5CSRTT) in mice. However, it is unknown whether the contribution of these projecting neurons is dependent on the extent of task demand. Here, we first examined how behavior outcomes depend on the number of locations for mice to pay attention and touch for successful performance, and found that the 2-choice serial reaction time task (2CSRTT) is less task demanding than the 5CSRTT. We then employed optogenetics to demonstrate that suppression ACAVIS projections immediately before stimulus presentation has no effect during the 2CSRTT in contrast to the impaired performance during the 5CSRTT. These results suggest that ACAVIS projections are necessary when task demand is high, but once a task demand is lowered, ACAVIS neuron activity becomes dispensable to adjust attentional performance. These findings support a model that the frontal-sensory ACAVIS projection regulates visual attention behavior during specific high task demand conditions, pointing to a flexible circuit-based mechanism for promoting attentional behavior.

Chemogenetic suppression of anterior cingulate cortical neurons projecting to the visual cortex disrupts attentional behavior in mice.

AIM: Attention is a goal-directed cognitive process that facilitates the detection of task-relevant sensory stimuli from dynamic environments. Anterior cingulate cortical area (ACA) is known to play a key role in attentional behavior, but the specific circuits mediating attention remain largely unknown. As ACA modulates sensory processing in the visual cortex (VIS), we aim to test a hypothesis that frontal top-down neurons projecting from ACA to VIS (ACAVIS ) contributes to visual attention behavior through chemogenetic approach. METHODS: Adult, male mice were trained to perform the 5-choice serial reaction time task (5CSRTT) using a touchscreen system. An intersectional viral approach was used to selectively express inhibitory designer receptors exclusively activated by designer drugs (iDREADD) or a static fluorophore (mCherry) in ACAVIS neurons. Mice received counterbalanced injections (i.p.) of the iDREADD ligand (clozapine-N-oxide; CNO) or vehicle (saline) prior to 5CSRTT testing. Finally, mice underwent progressive ratio testing and open field testing following CNO or saline administration. RESULTS: Chemogenetic suppression of ACAVIS neuron activity decreased correct task performance during the 5CSRTT mainly driven by an increase in omission and a trending decrease in accuracy with no change in behavioral outcomes associated with motivation, impulsivity, or compulsivity. Breakpoint during the progressive ratio task and distance moved in the open field test were unaffected by ACAVIS neuron suppression. CNO administration itself had no effect on task performance in mCherry-expressing mice. CONCLUSION: These results identify long-range frontal-sensory ACAVIS projection neurons as a key enactor of top-down attentional behavior and may serve as a beneficial therapeutic target.

Nicotinic regulation of local and long-range input balance drives top-down attentional circuit maturation.

Cognitive function depends on frontal cortex development; however, the mechanisms driving this process are poorly understood. Here, we identify that dynamic regulation of the nicotinic cholinergic system is a key driver of attentional circuit maturation associated with top-down frontal neurons projecting to visual cortex. The top-down neurons receive robust cholinergic inputs, but their nicotinic tone decreases following adolescence by increasing expression of a nicotinic brake, Lynx1 Lynx1 shifts a balance between local and long-range inputs onto top-down frontal neurons following adolescence and promotes the establishment of attentional behavior in adulthood. This key maturational process is disrupted in a mouse model of fragile X syndrome but was rescued by a suppression of nicotinic tone through the introduction of Lynx1 in top-down projections. Nicotinic signaling may serve as a target to rebalance local/long-range balance and treat cognitive deficits in neurodevelopmental disorders.

Post-error recruitment of frontal sensory cortical projections promotes attention in mice.

The frontal cortex, especially the anterior cingulate cortex area (ACA), is essential for exerting cognitive control after errors, but the mechanisms that enable modulation of attention to improve performance after errors are poorly understood. Here we demonstrate that during a mouse visual attention task, ACA neurons projecting to the visual cortex (VIS; ACAVIS neurons) are recruited selectively by recent errors. Optogenetic manipulations of this pathway collectively support the model that rhythmic modulation of ACAVIS neurons in anticipation of visual stimuli is crucial for adjusting performance following errors. 30-Hz optogenetic stimulation of ACAVIS neurons in anesthetized mice recapitulates the increased gamma and reduced theta VIS oscillatory changes that are associated with endogenous post-error performance during behavior and subsequently increased visually evoked spiking, a hallmark feature of visual attention. This frontal sensory neural circuit links error monitoring with implementing adjustments of attention to guide behavioral adaptation, pointing to a circuit-based mechanism for promoting cognitive control.

Critical period revisited: impact on vision.

Neural circuits are shaped by experience in early postnatal life. The permanent loss of visual acuity (amblyopia) and anatomical remodeling within primary visual cortex following monocular deprivation is a classic example of critical period development from mouse to man. Recent work in rodents reveals a residual subthreshold potentiation of open eye response throughout life. Resetting excitatory-inhibitory balance or removing molecular 'brakes' on structural plasticity may unmask the potential for recovery of function in adulthood. Novel pharmacological or environmental interventions now hold great therapeutic promise based on a deeper understanding of critical period mechanisms.

FOLFIRINOX for Advanced Pancreatic Cancer Patients After Nab-Paclitaxel Plus Gemcitabine Failure.

OBJECTIVES: There is no standard chemotherapy for advanced pancreatic cancer (APC) after gemcitabine plus nab-paclitaxel (GP) failure. The aim of this study was to evaluate the efficacy and safety of FOLFIRINOX (5-Fluorouracil, leucovorin, irinotecan, and oxaliplatin) (5-Fluorouracil, leucovorin, irinotecan, and oxaliplatin) (FFX) and modified FFX (mFFX) for APC patients after GP failure. METHODS: We retrospectively evaluated the efficacy and safety of FFX in APC patients who were refractory or intolerant of GP. RESULTS: Between July 2014 and October 2018, 23 patients received FFX after failure of GP. The overall response rate (RR) was 23%, and the disease control rate (DCR) was 68%. The median progression-free survival (PFS) was 5.3 months (95% confidence interval, 2.5-8.9), and the median overall survival (OS) was 12.1 months (95% confidence interval, 4.0-14.2). Twelve patients received FFX, and 11 patients received mFFX. In the FFX group, the RR was 9%, the DCR was 73%, the PFS was 5.3 months, and the OS was 6.9 months. In the mFFX group, the RR was 23%, the DCR was 64%, the PFS was 4.3 months, and the OS was 12.8 months. There was no significant difference between the groups. CONCLUSIONS: FOLFIRINOX has potential activity for patients with APC in whom GP failed.