Neurodevelopment of children exposed to prolonged anesthesia in infancy: GABA study interim analysis of resting-state brain networks at 2, 4, and 10-months old.

BACKGROUND: Previous studies have raised concerns regarding neurodevelopmental impacts of early exposures to general anesthesia and surgery. Electroencephalography (EEG) can be used to study ontogeny of brain networks during infancy. As a substudy of an ongoing study, we examined measures of functional connectivity in awake infants with prior early and prolonged anesthetic exposures and in control infants. METHODS: EEG functional connectivity was assessed using debiased weighted phase lag index at source and sensor levels and graph theoretical measures for resting state activity in awake infants in the early anesthesia (n = 26 at 10 month visit, median duration of anesthesia = 4 [2, 7 h]) and control (n = 38 at 10 month visit) groups at ages approximately 2, 4 and 10 months. Theta and low alpha frequency bands were of primary interest. Linear mixed models incorporated impact of age and cumulative hours of general anesthesia exposure. RESULTS: Models showed no significant impact of cumulative hours of general anesthesia exposure on debiased weighted phase lag index, characteristic path length, clustering coefficient or small-worldness (conditional R2 0.05-0.34). An effect of age was apparent in many of these measures. CONCLUSIONS: We could not demonstrate significant impact of general anesthesia in the first months of life on early development of resting state brain networks over the first postnatal year. Future studies will explore these networks as these infants grow older.

Evolutionary dependence of host type and chasmothecial appendage morphology in obligate plant parasites belonging to Erysipheae (powdery mildew, Erysiphaceae).

Evolutionary relationships between the morphological and ecological traits of fungi are poorly understood. The appendages of chasmothecia, which are sexual reproductive organs of Erysiphaceae, are considered to play a crucial role in the overwintering strategies of these fungi on host plants. Previous studies suggested that both the host type and appendage morphology evolved at the same nodes and transitioned from complex appendages on deciduous hosts to simple appendages on herb/evergreen hosts. However, the evolutionary dependence between host type and appendage morphology remains unproven owing to the limited species data used in analyses. To elucidate the evolutionary relationship between host type and appendage morphology, we used phylogenetic comparative methods (PCMs) to investigate the state transition, ancestral state, evolutionary dependence, and contingent evolution within Erysipheae, the largest and most diverse tribe in Erysiphaceae. Our PCMs, based on a comprehensive data set of Erysipheae, revealed that the most ancestral states were deciduous host types and complex appendages. From these ancestral states, convergent evolution toward the herb/evergreen host types and simple appendages occurred multiple times at the same nodes. For the first time in Erysiphaceae, we detected an evolutionary dependence between host type and appendage morphology. This is one of the few examples in which evolutionary dependence between host phenology and morphological traits in plant-parasitic fungi was demonstrated using PCMs. Appendage simplification on herb/evergreen hosts and complications on deciduous hosts can be reasonably explained by the functional advantages of each appendage type in different overwintering strategies. These expected appendage functions can explain approximately 90% of host type and appendage morphology combinations observed in the analyzed taxa. However, our results also highlighted the occurrence of evolutionary shifts that deviate from the expected advantages of each appendage morphology. These seemingly irrational shifts might be interpretable from the flexibility of overwintering strategies and quantification of appendage functions.

Maximal Memory Capacity Near the Edge of Chaos in Balanced Cortical E-I Networks.

We examine the efficiency of information processing in a balanced excitatory and inhibitory (E-I) network during the developmental critical period, when network plasticity is heightened. A multimodule network composed of E-I neurons was defined, and its dynamics were examined by regulating the balance between their activities. When adjusting E-I activity, both transitive chaotic synchronization with a high Lyapunov dimension and conventional chaos with a low Lyapunov dimension were found. In between, the edge of high-dimensional chaos was observed. To quantify the efficiency of information processing, we applied a short-term memory task in reservoir computing to the dynamics of our network. We found that memory capacity was maximized when optimal E-I balance was realized, underscoring both its vital role and vulnerability during critical periods of brain development.

Durable recovery from amblyopia with donepezil.

An elevated threshold for neuroplasticity limits visual gains with treatment of residual amblyopia in older children and adults. Acetylcholinesterase inhibitors (AChEI) can enable visual neuroplasticity and promote recovery from amblyopia in adult mice. Motivated by these promising findings, we sought to determine whether donepezil, a commercially available AChEI, can enable recovery in older children and adults with residual amblyopia. In this open-label pilot efficacy study, 16 participants (mean age 16 years; range 9-37 years) with residual anisometropic and/or strabismic amblyopia were treated with daily oral donepezil for 12 weeks. Donepezil dosage was started at 2.5 or 5.0 mg based on age and increased by 2.5 mg if the amblyopic eye visual acuity did not improve by 1 line from the visit 4 weeks prior for a maximum dosage of 7.5 or 10 mg. Participants < 18 years of age further patched the dominant eye. The primary outcome was visual acuity in the amblyopic eye at 22 weeks, 10 weeks after treatment was discontinued. Mean amblyopic eye visual acuity improved 1.2 lines (range 0.0-3.0), and 4/16 (25%) improved by ≥ 2 lines after 12 weeks of treatment. Gains were maintained 10 weeks after cessation of donepezil and were similar for children and adults. Adverse events were mild and self-limited. Residual amblyopia improves in older children and adults treated with donepezil, supporting the concept that the critical window of visual cortical plasticity can be pharmacologically manipulated to treat amblyopia. Placebo-controlled studies are needed.

Rapid synaptic and gamma rhythm signature of mouse critical period plasticity.

Early-life experience enduringly sculpts thalamocortical (TC) axons and sensory processing. Here, we identify the very first synaptic targets that initiate critical period plasticity, heralded by altered cortical oscillations. Monocular deprivation (MD) acutely induced a transient (<3 h) peak in EEG γ-power (~40 Hz) specifically within the visual cortex, but only when the critical period was open (juvenile mice or adults after dark-rearing, Lynx1-deletion, or diazepam-rescued GAD65-deficiency). Rapid TC input loss onto parvalbumin-expressing (PV) inhibitory interneurons (but not onto nearby pyramidal cells) was observed within hours of MD in a TC slice preserving the visual pathway - again once critical periods opened. Computational TC modeling of the emergent γ-rhythm in response to MD delineated a cortical interneuronal gamma (ING) rhythm in networks of PV-cells bearing gap junctions at the start of the critical period. The ING rhythm effectively dissociated thalamic input from cortical spiking, leading to rapid loss of previously strong TC-to-PV connections through standard spike-timing-dependent plasticity rules. As a consequence, previously silent TC-to-PV connections could strengthen on a slower timescale, capturing the gradually increasing γ-frequency and eventual fade-out over time. Thus, ING enables cortical dynamics to transition from being dominated by the strongest TC input to one that senses the statistics of population TC input after MD. Taken together, our findings reveal the initial synaptic events underlying critical period plasticity and suggest that the fleeting ING accompanying a brief sensory perturbation may serve as a robust readout of TC network state with which to probe developmental trajectories.

N-acetylcysteine treatment mitigates loss of cortical parvalbumin-positive interneuron and perineuronal net integrity resulting from persistent oxidative stress in a rat TBI model.

Traumatic brain injury (TBI) increases cerebral reactive oxygen species production, which leads to continuing secondary neuronal injury after the initial insult. Cortical parvalbumin-positive interneurons (PVIs; neurons responsible for maintaining cortical inhibitory tone) are particularly vulnerable to oxidative stress and are thus disproportionately affected by TBI. Systemic N-acetylcysteine (NAC) treatment may restore cerebral glutathione equilibrium, thus preventing post-traumatic cortical PVI loss. We therefore tested whether weeks-long post-traumatic NAC treatment mitigates cortical oxidative stress, and whether such treatment preserves PVI counts and related markers of PVI integrity and prevents pathologic electroencephalographic (EEG) changes, 3 and 6 weeks after fluid percussion injury in rats. We find that moderate TBI results in persistent oxidative stress for at least 6 weeks after injury and leads to the loss of PVIs and the perineuronal net (PNN) that surrounds them as well as of per-cell parvalbumin expression. Prolonged post-TBI NAC treatment normalizes the cortical redox state, mitigates PVI and PNN loss, and - in surviving PVIs - increases per-cell parvalbumin expression. NAC treatment also preserves normal spectral EEG measures after TBI. We cautiously conclude that weeks-long NAC treatment after TBI may be a practical and well-tolerated treatment strategy to preserve cortical inhibitory tone post-TBI.

Tactile sensitivity and motor coordination in infancy: Effect of age, prior surgery, anaesthesia & critical illness.

BACKGROUND: Tactile sensitivity in the infant period is poorly characterized, particularly among children with prior surgery, anaesthesia or critical illness. The study aims were to investigate tactile sensitivity of the foot and the associated coordination of lower limb motor movement in typically developing infants with and without prior hospital experience, and to develop feasible bedside sensory testing protocols. MATERIALS AND METHODS: A prospective, longitudinal study in 69 infants at 2 and 4 months-old, with and without prior hospital admission. Mechanical stimuli were applied to the foot at graded innocuous and noxious intensities. Primary outcome measures were tactile and nociceptive threshold (lowest force required to evoke any leg movement, or brisk leg withdrawal, respectively), and specific motor flexion threshold (ankle-, knee-, hip-flexion). Secondary analysis investigated (i) single vs multiple trials reliability, and (ii) the effect of age and prior surgery, anaesthesia, or critical illness on mechanical threshold. RESULTS: Magnitude of evoked motor activity increased with stimulus intensity. Single trials had excellent reliability for knee and hip flexion at age 1-3m and 4-7m (ICC range: 0.8 to 0.98, p >0.05). Nociceptive threshold varied as a function of age. Tactile sensitivity was independent of age, number of surgeries, general anaesthesia and ICU stay. CONCLUSIONS: This brief sensory testing protocol may reliably measure tactile and nociceptive reactivity in human infants. Age predicts nociceptive threshold which likely reflects ongoing maturation of spinal and supraspinal circuits. Prior hospital experience has a negligible global effect on sensory processing demonstrating the resilience of the CNS in adverse environments.

Lifestyle Evolution Analysis by Binary-State Speciation and Extinction (BiSSE) Model.

Phylogenetic comparative methods (PCMs) combine statistics and evolutionary models to infer the dynamics of trait evolution and diversification that underlie the observed phylogeny. While PCMs have been used to study macro-evolutionary processes and evolutionary transitions of macroorganisms, their application to microbes is still limited. With the abundance of publicly available genomic and trait character data for diverse microbes nowadays, applications of PCMs on these data can provide insights into the fundamental principles that govern microbial evolution. Here, we introduce the Binary-State Speciation and Extinction (BiSSE) model, which is a relatively simple yet powerful approach for analyzing trait evolution. We begin by explaining the theoretical background and intuition behind the BiSSE model. Then, R commands for running the BiSSE model are presented. Finally, we introduce a case study that successfully applied the BiSSE model to investigate generalist and specialist microbial lifestyle evolution.

Phenotypic systems biology for organisms: Concepts, methods and case studies.

Design principles of phenotypes in organisms are fundamental issues in physical biology. So far, understanding "systems" of living organisms have been chiefly promoted by understanding the underlying biomolecules such as genes and proteins, and their intra- and inter-relationships and regulations. After a long period of sophistication, biophysics and molecular biology have established a general framework for understanding 'molecular systems' in organisms without regard to species, so that the findings of fly studies can be applied to mouse studies. However, little attention has been paid to exploring "phenotypic systems" in organisms, and thus its general framework remains poorly understood. Here I review concepts, methods, and case studies using butterfly and moth wing patterns to explore phenotypes as systems. First, I present a unifying framework for phenotypic traits as systems, termed multi-component systems. Second, I describe how to define components of phenotypic systems, and also show how to quantify interactions among phenotypic parts. Subsequently, I introduce the concept of the macro-evolutionary process, which illustrates how to generate complex traits. In this point, I also introduce mathematical methods, "phylogenetic comparative methods", which provide stochastic processes along molecular phylogeny as bifurcated paths to quantify trait evolution. Finally, I would like to propose two key concepts, macro-evolutionary pathways and genotype-phenotype loop (GP loop), which must be needed for the next directions. I hope these efforts on phenotypic biology will become one major target in biophysics and create the next generations of textbooks. This review article is an extended version of the Japanese article, Biological Physics in Phenotypic Systems of Living Organisms, published in SEIBUTSU-BUTSURI Vol. 61, p. 31-35 (2021).

Translating the Biology of Adversity and Resilience Into New Measures for Pediatric Practice.

As the science of adversity and resilience advances, and public awareness of the health consequences of stress grows, primary care providers are being increasingly asked to address the effects of adverse experiences on child wellbeing. Given limited tools for assessing these effects early in life, the authors explore how enhanced capacity to measure stress activation directly in young children could transform the role and scope of pediatric practice. When employed within a trusted relationship between caregivers and clinicians, selective use of biological measures of stress responses would help address the documented limitations of rating scales of adverse childhood experiences as a primary indicator of individual risk and strengthen the ability to focus on variation in intervention needs, assess their effectiveness, and guide ongoing management. The authors provide an overview of the potential benefits and risks of such expanded measurement capacity, as well as an introduction to candidate indicators that might be employed in an office setting. The ultimate value of such measures for both pediatricians and parents will require vigilant attention to the ethical responsibilities of assuring their correct interpretation and minimizing the harm of inappropriate labeling, especially for children and families experiencing the hardships and threats of racism, poverty, and other structural inequities. Whereas much work remains to be done to advance measurement development and ensure its equitable use, the potential of validated markers of stress activation and resilience to strengthen the impact of primary health care on the lives of young children facing significant adversity demands increased attention.

Sensitive period-regulating genetic pathways and exposure to adversity shape risk for depression.

Animal and human studies have documented the existence of developmental windows (or sensitive periods) when experience can have lasting effects on brain structure or function, behavior, and disease. Although sensitive periods for depression likely arise through a complex interplay of genes and experience, this possibility has not yet been explored in humans. We examined the effect of genetic pathways regulating sensitive periods, alone and in interaction with common childhood adversities, on depression risk. Guided by a translational approach, we: (1) performed association analyses of three gene sets (60 genes) shown in animal studies to regulate sensitive periods using summary data from a genome-wide association study of depression (n = 807,553); (2) evaluated the developmental expression patterns of these genes using data from BrainSpan (n = 31), a transcriptional atlas of postmortem brain samples; and (3) tested gene-by-development interplay (dGxE) by analyzing the combined effect of common variants in sensitive period genes and time-varying exposure to two types of childhood adversity within a population-based birth cohort (n = 6254). The gene set regulating sensitive period opening associated with increased depression risk. Notably, 6 of the 15 genes in this set showed developmentally regulated gene-level expression. We also identified a statistical interaction between caregiver physical or emotional abuse during ages 1-5 years and genetic risk for depression conferred by the opening genes. Genes involved in regulating sensitive periods are differentially expressed across the life course and may be implicated in depression vulnerability. Our findings about gene-by-development interplay motivate further research in large, more diverse samples to further unravel the complexity of depression etiology through a sensitive period lens.

Evolutionary patterns of host type and chasmothecial appendage morphology in obligate plant parasites belonging to Cystotheceae (powdery mildew, Erysiphaceae).

The chasmothecial appendages of Erysiphaceae are considered to function in the overwintering strategy and evolve morphologically in line with transitions of different host type. However, the evolutionary patterns and relationships of these traits have not yet been verified using statistical models based on phylogenetic information. We aimed to clarify the evolutionary process of host type and appendage morphology in Cystotheceae using phylogenetic comparative methods (PCMs) and to evaluate the evolutionary relationship of these traits. The ancestral state estimation of host types showed that the deciduous type is the most ancestral in Cystotheceae, and the herb or evergreen types evolved secondarily four times and twice, respectively. Branched- or circinate-type appendages were estimated to be the most ancestral, and the mycelioid and rudimentary types evolved secondarily thrice and once, respectively. The results of the random forest analysis showed that the host type was predictable from the phylogeny and appendage morphology. The ancestral state estimation suggested that simultaneous transitions of the host type and appendage morphology occurred at several ancestral nodes. These results suggest some functional relationships between host type and appendage morphology, but there was no statistical support for an overall trend in evolutionary dependence between these traits. Our results demonstrate the utility of PCMs in the study of trait evolution in Cystotheceae, which can be applied to a broader phylogeny of powdery mildews to elucidate the evolutionary relationship and functional causality of phenotypic traits.

Dynamical Characteristics of Wild-Type Mouse Spontaneous Pupillary Fluctuations.

Spontaneous pupil size fluctuations in humans and mouse models are noninvasively measured data that can be used for early detection of neurodevelopmental spectrum disorders. While highly valuable in such applied studies, pupillometry dynamics and dynamical characteristics have not been fully investigated, although their understanding may potentially lead to the discovery of new information, which cannot be readily uncovered by conventional methods. Properties of pupillometry dynamics, such as determinism, were previously investigated for healthy human subjects; however, the dynamical characteristics of pupillometry data in mouse models, and whether they are similar to those of human subjects, remain largely unknown. Therefore, it is necessary to establish a thorough understanding of the dynamical properties of mouse pupillometry dynamics and to clarify whether it is similar to that of humans. In this study, dynamical pupillometry characteristics from 115 wild-type mouse datasets were investigated by methods of nonlinear time series analysis. Results clearly demonstrated a strong underlying determinism in the investigated data. Additionally, the data's trajectory divergence rate and predictability were estimated.

α2-containing γ-aminobutyric acid type A receptors promote stress resiliency in male mice.

Brain α2-containing GABAA receptors play a critical role in the modulation of anxiety- and fear-like behavior. However, it is unknown whether these receptors also play a role in modulating resilience to chronic stress, and in which brain areas and cell types such an effect would be mediated. We evaluated the role of α2-containing GABAA receptors following chronic social defeat stress using male mice deficient in the α2 subunit globally or conditionally in dopamine D1- or D2-receptor-expressing neurons, e.g., within the nucleus accumbens (NAc). In addition, we examined the effect of the lack of the α2 subunit on intermediates of the glutathione synthesis pathway. We found that α2-containing GABAA receptors on D2-receptor-positive but not on D1-receptor-positive neurons promote resiliency to chronic social defeat stress, as reflected in social interaction tests. The pro-resiliency effects of α2-containing GABAA receptors on D2-receptor-positive neurons do not appear to be directly related to alterations in anxiety-like behavior, as reflected in the elevated plus-maze, light-dark box, and novel open field tests. Increases in indices of oxidative stress-reflected by increases in cystathionine levels and reductions in GSH/GSSG ratios-were found in the NAc and prefrontal cortex but not in the hippocampus of mice lacking α2-containing GABAA receptors. We conclude that α2-containing GABAA receptors within specific brain areas and cell populations promote stress resiliency independently of direct effects on anxiety-like behaviors. A potential mechanism contributing to this increased resiliency is the protection that α2-containing GABAA receptors provide against oxidative stress in NAc and the prefrontal cortex.

Kv3.1 channels regulate the rate of critical period plasticity.

Experience-dependent plasticity within visual cortex is controlled by postnatal maturation of inhibitory circuits, which are both morphologically diverse and precisely connected. Gene-targeted disruption of the voltage-dependent potassium channel Kv3.1 broadens action potentials and reduces net inhibitory function of parvalbumin (PV)-positive GABA subtypes within the neocortex. In mice lacking Kv3.1, the rate of input loss from an eye deprived of vision was slowed two-fold, despite otherwise normal critical period timecourse and receptive field properties. Rapid ocular dominance plasticity was restored by local or systemic enhancement of GABAergic transmission with acute benzodiazepine infusion. Diazepam instead exacerbated a global suppression of slow-wave oscillations during sleep described previously in these mutant mice, which therefore did not account for the rescued plasticity. Rapid ocular dominance shifts closely reflected Kv3.1 gene dosage that prevented prolonged spike discharge of their target pyramidal cells in vivo or the spike amplitude decrement of fast-spiking cells during bouts of high-frequency firing in vitro. Late postnatal expression of this unique channel in fast-spiking interneurons thus subtly regulates the speed of critical period plasticity with implications for mental illnesses.

Distributional learning of speech sound categories is gated by sensitive periods.

Perceptual attunement to the native phonetic repertoire occurs over the first year of life: an infant's discrimination of non-native phonetic contrasts declines while their discrimination of native phonetic contrasts improves, with the timing of change consistent with sensitive periods. The statistics of speech sound distributions is one source of input used to collapse non-native phonetic category boundaries, while sharpening native ones. Distributional learning can be a domain-general mechanism, yet given the timing of perceptual attunement, we hypothesized that this learning mechanism may be maturationally delimited in the content domain of phonetic categories. Here, we assessed whether sensitivity to the distribution of speech sounds in the environment declines as the period of perceptual attunement closes. We used electroencephalography (EEG) to investigate whether neuronal responses to native 'ra' and 'la' phones are modulated differently in older vs young infants by exposure to either a bimodal or unimodal sound distribution spanning the [r] ~ [l] phoneme space. The native contrast, ra-la, is discriminable at all three ages, ensuring that we were testing the distributional learning mechanism, rather than confounding it with a decline in discrimination to a non-native distinction. English monolingual infants (n = 131) at 5-, 9- and 12-months-old were familiarized to either a unimodal or bimodal distribution of /ra/-/la/ speech sounds. Immediately following familiarization, an ERP oddball task was used to assess discrimination. Results showed that brief exposure to a bi- vs uni-modal distribution is sufficient to alter neuronal responses to subsequent /ra/ vs /la/ speech sounds at 5-months and 9-months, but not at 12-months. These results are the first to capture a progressive decline in sensitivity to distributional statistics in the environment. A potential mechanistic explanation based on critical period biology is discussed.

Transcriptomic analysis of the bagworm moth silk gland reveals a number of silk genes conserved within Lepidoptera.

Lepidopteran insects produce cocoons with unique properties. The cocoons are made of silk produced in the larval tissue silk gland and our understanding of the silk genes is still very limited. Here, we investigated silk genes in the bagworm moth Eumeta variegata, a species that has recently been found to produce extraordinarily strong and tough silk. Using short-read transcriptomic analysis, we identified a partial sequence of the fibroin heavy chain gene and its product was found to have a C-terminal structure that is conserved within nonsaturniid species. This is in accordance with the presence of fibroin light chain/fibrohexamerin genes and it is suggested that the bagworm moth is producing silk composed of fibroin ternary complex. This indicates that the fibroin structure has been evolutionarily conserved longer than previously thought. Other than fibroins we identified candidates for sericin genes, expressed strongly in the middle region of the silk gland and encoding serine-rich proteins, and other silk genes, that are structurally conserved with other lepidopteran homologues. The bagworm moth is thus considered to be producing conventional lepidopteran type of silk. We further found a number of genes expressed in a specific region of the silk gland and some genes showed conserved expression with Bombyx mori counterparts. This is the first study allowing comprehensive silk gene identification and expression analysis in the lepidopteran Psychidae family and should contribute to the understanding of silk gene evolution as well as to the development of novel types of silk.

Increase in Seizure Susceptibility After Repetitive Concussion Results from Oxidative Stress, Parvalbumin-Positive Interneuron Dysfunction and Biphasic Increases in Glutamate/GABA Ratio.

Chronic symptoms indicating excess cortical excitability follow mild traumatic brain injury, particularly repetitive mild traumatic brain injury (rmTBI). Yet mechanisms underlying post-traumatic excitation/inhibition (E/I) ratio abnormalities may differ between the early and late post-traumatic phases. We therefore measured seizure threshold and cortical gamma-aminobutyric acid (GABA) and glutamate (Glu) concentrations, 1 and 6 weeks after rmTBI in mice. We also analyzed the structure of parvalbumin-positive interneurons (PVIs), their perineuronal nets (PNNs), and their electroencephalography (EEG) signature (gamma frequency band power). For mechanistic insight, we measured cortical oxidative stress, reflected in the reduced/oxidized glutathione (GSH/GSSG) ratio. We found that seizure susceptibility increased both early and late after rmTBI. However, whereas increased Glu dominated the E/I 1 week after rmTBI, Glu concentration normalized and the E/I was instead characterized by depressed GABA, reduced per-PVI parvalbumin expression, and reduced gamma EEG power at the 6-week post-rmTBI time point. Oxidative stress was increased early after rmTBI, where transient PNN degradation was noted, and progressed throughout the monitoring period. We conclude that GSH depletion, perhaps triggered by early Glu-mediated excitotoxicity, leads to late post-rmTBI loss of PVI-dependent cortical inhibitory tone. We thus propose dampening of Glu signaling, maintenance of redox state, and preservation of PVI inhibitory capacity as therapeutic targets for post-rmTBI treatment.

Critical period regulation across multiple timescales.

Brain plasticity is dynamically regulated across the life span, peaking during windows of early life. Typically assessed in the physiological range of milliseconds (real time), these trajectories are also influenced on the longer timescales of developmental time (nurture) and evolutionary time (nature), which shape neural architectures that support plasticity. Properly sequenced critical periods of circuit refinement build up complex cognitive functions, such as language, from more primary modalities. Here, we consider recent progress in the biological basis of critical periods as a unifying rubric for understanding plasticity across multiple timescales. Notably, the maturation of parvalbumin-positive (PV) inhibitory neurons is pivotal. These fast-spiking cells generate gamma oscillations associated with critical period plasticity, are sensitive to circadian gene manipulation, emerge at different rates across brain regions, acquire perineuronal nets with age, and may be influenced by epigenetic factors over generations. These features provide further novel insight into the impact of early adversity and neurodevelopmental risk factors for mental disorders.