Neuronal Development of Hearing and Language: Cochlear Implants and Critical Periods.

The modern cochlear implant (CI) is the most successful neural prosthesis developed to date. CIs provide hearing to the profoundly hearing impaired and allow the acquisition of spoken language in children born deaf. Results from studies enabled by the CI have provided new insights into (a) minimal representations at the periphery for speech reception, (b) brain mechanisms for decoding speech presented in quiet and in acoustically adverse conditions, (c) the developmental neuroscience of language and hearing, and (d) the mechanisms and time courses of intramodal and cross-modal plasticity. Additionally, the results have underscored the interconnectedness of brain functions and the importance of top-down processes in perception and learning. The findings are described in this review with emphasis on the developing brain and the acquisition of hearing and spoken language.

Recent Advances in Behavioral (Epi)Genetics in Eusocial Insects.

Eusocial insects live in societies in which distinct family members serve specific roles in maintaining the colony and advancing the reproductive ability of a few select individuals. Given the genetic similarity of all colony members, the diversity of morphologies and behaviors is surprising. Social communication relies on pheromones and olfaction, as shown by mutants of orco, the universal odorant receptor coreceptor, and through electrophysiological analysis of neuronal responses to pheromones. Additionally, neurohormonal factors and epigenetic regulators play a key role in caste-specific behavior, such as foraging and caste switching. These studies start to allow an understanding of the molecular mechanisms underlying social behavior and provide a technological foundation for future studies of eusocial insects. In this review, we highlight recent findings in eusocial insects that advance our understanding of genetic and epigenetic regulations of social behavior and provide perspectives on future studies using cutting-edge technologies.

Glial Control of Cortical Neuronal Circuit Maturation and Plasticity.

The brain is a highly adaptable organ that is molded by experience throughout life. Although the field of neuroscience has historically focused on intrinsic neuronal mechanisms of plasticity, there is growing evidence that multiple glial populations regulate the timing and extent of neuronal plasticity, particularly over the course of development. This review highlights recent discoveries on the role of glial cells in the establishment of cortical circuits and the regulation of experience-dependent neuronal plasticity during critical periods of neurodevelopment. These studies provide strong evidence that neuronal circuit maturation and plasticity are non-cell autonomous processes that require both glial-neuronal and glial-glial cross talk to proceed. We conclude by discussing open questions that will continue to guide research in this nascent field.

Central role of the habenulo-interpeduncular system in the neurodevelopmental basis of susceptibility and resilience to anxiety in mice.

Having experienced stress during sensitive periods of brain development strongly influences how individuals cope with later stress. Some are prone to develop anxiety or depression, while others appear resilient. The as-yet-unknown mechanisms underlying these differences may lie in how genes and environmental stress interact to shape the circuits that control emotions. Here, we investigated the role of the habenulo-interpeduncular system (HIPS), a critical node in reward circuits, in early stress-induced anxiety in mice. We found that habenular and IPN components characterized by the expression of Otx2 are synaptically connected and particularly sensitive to chronic stress (CS) during the peripubertal period. Stress-induced peripubertal activation of this HIPS subcircuit elicits both HIPS hypersensitivity to later stress and susceptibility to develop anxiety. We also show that HIPS silencing through conditional Otx2 knockout counteracts these effects of stress. Together, these results demonstrate that a genetic factor, Otx2, and stress interact during the peripubertal period to shape the stress sensitivity of the HIPS, which is shown to be a key modulator of susceptibility or resilience to develop anxiety.

The Influence of Microglia on Neuroplasticity and Long-Term Cognitive Sequelae in Long COVID: Impacts on Brain Development and Beyond.

Microglial cells, the immune cells of the central nervous system, are key elements regulating brain development and brain health. These cells are fully responsive to stressors, microenvironmental alterations and are actively involved in the construction of neural circuits in children and the ability to undergo full experience-dependent plasticity in adults. Since neuroinflammation is a known key element in the pathogenesis of COVID-19, one might expect the dysregulation of microglial function to severely impact both functional and structural plasticity, leading to the cognitive sequelae that appear in the pathogenesis of Long COVID. Therefore, understanding this complex scenario is mandatory for establishing the possible molecular mechanisms related to these symptoms. In the present review, we will discuss Long COVID and its association with reduced levels of BDNF, altered crosstalk between circulating immune cells and microglia, increased levels of inflammasomes, cytokines and chemokines, as well as the alterations in signaling pathways that impact neural synaptic remodeling and plasticity, such as fractalkines, the complement system, the expression of SIRPα and CD47 molecules and altered matrix remodeling. Together, these complex mechanisms may help us understand consequences of Long COVID for brain development and its association with altered brain plasticity, impacting learning disabilities, neurodevelopmental disorders, as well as cognitive decline in adults.

Genes and environments, development and time.

A now substantial body of science implicates a dynamic interplay between genetic and environmental variation in the development of individual differences in behavior and health. Such outcomes are affected by molecular, often epigenetic, processes involving gene-environment (G-E) interplay that can influence gene expression. Early environments with exposures to poverty, chronic adversities, and acutely stressful events have been linked to maladaptive development and compromised health and behavior. Genetic differences can impart either enhanced or blunted susceptibility to the effects of such pathogenic environments. However, largely missing from present discourse regarding G-E interplay is the role of time, a "third factor" guiding the emergence of complex developmental endpoints across different scales of time. Trajectories of development increasingly appear best accounted for by a complex, dynamic interchange among the highly linked elements of genes, contexts, and time at multiple scales, including neurobiological (minutes to milliseconds), genomic (hours to minutes), developmental (years and months), and evolutionary (centuries and millennia) time. This special issue of PNAS thus explores time and timing among G-E transactions: The importance of timing and timescales in plasticity and critical periods of brain development; epigenetics and the molecular underpinnings of biologically embedded experience; the encoding of experience across time and biological levels of organization; and gene-regulatory networks in behavior and development and their linkages to neuronal networks. Taken together, the collection of papers offers perspectives on how G-E interplay operates contingently within and against a backdrop of time and timescales.

Disruptions in Hypothalamic-Pituitary-Gonadal Axis Development and Their IgG Modulation after Prenatal Systemic Inflammation in Male Rats.

The development of the neuroendocrine system, including the hypothalamic-pituitary-gonadal (HPG) axis, is sensitive to environmental impacts during critical developmental periods. Maternal immune system activation by bacterial or viral infection may be one of the negative impacts. This study focused on the effect of systemic inflammation induced by lipopolysaccharides (LPS E. coli) on the HPG axis development in male rat offspring, corrected by the anti-inflammatory action of polyclonal IgG and monoclonal anti-interleukin (IL)-6 receptor antibodies (IL-6RmAbs). A single LPS exposure on the 12th embryonic day (ED) led to a decrease in the number of afferent synaptic inputs on gonadotropin-releasing, hormone-producing neurons in adult male offspring. LPS exposure on ED18 did not lead to such disruptions. Moreover, after the LPS injections on ED12, circulating follicle-stimulating hormone and sex steroid levels were reduced, and the gonadal structure was disrupted. A prenatal IL-6R blockade with IL-6RmAbs and polyclonal IgG reduced the negative effects of inflammation on fetal HPG axis development. Overall, the data obtained confirm the morphogenetic effect of inflammation on fetal HPG development and IL-6 involvement in these processes.

FEATURES OF MORPHOGENESIS OF THE BONES OF THE HUMAN ORBIT.

OBJECTIVE: The aim: To find out the sources of origin, the chronology of ossification, the peculiarities of age-related topographical and anatomical changes in the bones of the human orbit. PATIENTS AND METHODS: Materials and methods: The research was carried out on the specimens of 18 human embryos and prefetuses aged from 4th to 12th weeks of intrauterine development and 12 human fetuses aged from 4th to 9th months which were studied by microscopic examination and 3D reconstruction. RESULTS: Results: The first signs of osteogenesis around the main nervous and visceral contents of the orbit rudiment are observed in 6-week-old embryos in the form of seven cartilaginous bone models. The first signs of ossification in the region of the orbit are found in the maxilla. During the 6th month of intrauterine development, intensive processes of ossification of the frontal, sphenoidal, ethmoidal bones and maxilla are noticeable. From the beginning of the fetal pe¬riod of human ontogenesis, the ossification of bone rudiments that form the walls of the orbit continues. The processes of ossification of the structures of the sphenoidal bone continue, which leads to morphological transformations of the orbit in 5-month-old fetuses - it is separated from the sphenopalatine and infratemporal fossae by a bone layer, the optic canal is formed, and in 6-month-old fetuses, processes of ossification of the frontal, sphenoidal and ethmoidal bones and maxilla occur, Müller's muscle changes its structure to a fibrous one. CONCLUSION: Conclusions: Critical periods of the orbit development are the 6th month of prenatal ontogenesis and the 8th month.

Developmental Regulation of Homeostatic Plasticity in Mouse Primary Visual Cortex.

Homeostatic plasticity maintains network stability by adjusting excitation, inhibition, or the intrinsic excitability of neurons, but the developmental regulation and coordination of these distinct forms of homeostatic plasticity remains poorly understood. A major contributor to this information gap is the lack of a uniform paradigm for chronically manipulating activity at different developmental stages. To overcome this limitation, we used designer receptors exclusively activated by designer drugs (DREADDs) to directly suppress neuronal activity in layer2/3 (L2/3) of mouse primary visual cortex of either sex at two important developmental timepoints: the classic visual system critical period [CP; postnatal day 24 (P24) to P29], and adulthood (P45 to P55). We show that 24 h of DREADD-mediated activity suppression simultaneously induces excitatory synaptic scaling up and intrinsic homeostatic plasticity in L2/3 pyramidal neurons during the CP, consistent with previous observations using prolonged visual deprivation. Importantly, manipulations known to block these forms of homeostatic plasticity when induced pharmacologically or via visual deprivation also prevented DREADD-induced homeostatic plasticity. We next used the same paradigm to suppress activity in adult animals. Surprisingly, while excitatory synaptic scaling persisted into adulthood, intrinsic homeostatic plasticity was completely absent. Finally, we found that homeostatic changes in quantal inhibitory input onto L2/3 pyramidal neurons were absent during the CP but were present in adults. Thus, the same population of neurons can express distinct sets of homeostatic plasticity mechanisms at different development stages. Our findings suggest that homeostatic forms of plasticity can be recruited in a modular manner according to the evolving needs of a developing neural circuit.SIGNIFICANCE STATEMENT Developing brain circuits are subject to dramatic changes in inputs that could destabilize activity if left uncompensated. This compensation is achieved through a set of homeostatic plasticity mechanisms that provide slow, negative feedback adjustments to excitability. Given that circuits are subject to very different destabilizing forces during distinct developmental stages, the forms of homeostatic plasticity present in the network must be tuned to these evolving needs. Here we developed a method to induce comparable homeostatic compensation during distinct developmental windows and found that neurons in the juvenile and mature brain engage strikingly different forms of homeostatic plasticity. Thus, homeostatic mechanisms can be recruited in a modular manner according to the developmental needs of the circuit.

The Ontogeny of Hippocampus-Dependent Memories.

The formation of memories that contain information about the specific time and place of acquisition, which are commonly referred to as "autobiographical" or "episodic" memories, critically relies on the hippocampus and on a series of interconnected structures located in the medial temporal lobe of the mammalian brain. The observation that adults retain very few of these memories from the first years of their life has fueled a long-standing debate on whether infants can make the types of memories that in adults are processed by the hippocampus-dependent memory system, and whether the hippocampus is involved in learning and memory processes early in life. Recent evidence shows that, even at a time when its circuitry is not yet mature, the infant hippocampus is able to produce long-lasting memories. However, the ability to acquire and store such memories relies on molecular pathways and network-based activity dynamics different from the adult system, which mature with age. The mechanisms underlying the formation of hippocampus-dependent memories during infancy, and the role that experience exerts in promoting the maturation of the hippocampus-dependent memory system, remain to be understood. In this review, we discuss recent advances in our understanding of the ontogeny and the biological correlates of hippocampus-dependent memories.

GluN3A NMDA receptor subunits: more enigmatic than ever?

Non-conventional N-methyl-d-aspartate receptors (NMDARs) containing GluN3A subunits have unique biophysical, signalling and localization properties within the NMDAR family, and are typically thought to counterbalance functions of classical NMDARs made up of GluN1/2 subunits. Beyond their recognized roles in synapse refinement during postnatal development, recent evidence is building a wider perspective for GluN3A functions. Here we draw particular attention to the latest developments for this multifaceted and unusual subunit: from finely timed expression patterns that correlate with plasticity windows in developing brains or functional hierarchies in the mature brain to new insight onto presynaptic GluN3A-NMDARs, excitatory glycine receptors and behavioural impacts, alongside further connections to a range of brain disorders.

Nutrition of Broodmares.

Forage availability should cover most needs for mares bred during spring and summer. Out-of-season breeding, lack of access to pasture, or good quality forage calls for nutritional supplementation. Current evaluations of broodmare needs are based on fetoplacental tissue requirements, but do not consider endocrine changes or that the maternal diet quality affects long-term foal health. This article reviews pregnant mares' current nutritional recommendations. Secondly, fetoplacental developmental stages during gestation are outlined, defining critical periods in the context of the developmental origins of health and disease. Last, examples of how maternal nutrition affects long-term foal health are presented.

The impact of foreign language caregiving on native language acquisition.

There is increasing interest in the influence of language input during children's early years. Over the first 3 years of life, children are highly sensitive to the quantity and quality of language input they receive. The focus of this study was on whether learning a different language in the early years affects the acquisition of English over the longer term. In this study, we investigated effects of foreign language (Hokkien) caregiving on the eventual acquisition of English as well as on memory traces of Hokkien. We sampled individuals who received foreign language caregiving in Hokkien during their early years either predominantly or in addition to English. Our control group had lifetime primary exposure to English. We compared the Hokkien- and English-only reared groups on phonological, semantic, and grammatical knowledge in English. We also compared the groups on memories for Hokkien tonal phonology and vocabulary. Overall, there were no statistically significant differences in performance in English tasks between groups, yet the Hokkien-reared group demonstrated selective learning advantages in reacquiring Hokkien tonal contrasts. Findings are discussed with reference to the effects of timing and language input on later language proficiency.

Critical periods regulating the circuit integration of adult-born hippocampal neurons.

The dentate gyrus (DG) in the adult brain maintains the capability to generate new granule neurons throughout life. Neural stem cell-derived new-born neurons emerge to play key functions in the way information is processed in the DG and then conveyed to the CA3 hippocampal area, yet accumulating evidence indicates that both the maturation process and the connectivity pattern of new granule neurons are not prefigured but can be modulated by the activity of local microcircuits and, on a network level, by experience. Although most of the activity- and experience-dependent changes described so far appear to be restricted to critical periods during the development of new granule neurons, it is becoming increasingly clear that the surrounding circuits may play equally key roles in accommodating and perhaps fostering, these changes. Here, we review some of the most recent insights into this almost unique form of plasticity in the adult brain by focusing on those critical periods marked by pronounced changes in structure and function of the new granule neurons and discuss how the activity of putative synaptic partners may contribute to shape the circuit module in which new neurons become finally integrated.

Prenatal Programming of Neuroendocrine System Development by Lipopolysaccharide: Long-Term Effects.

Various stress factors during critical periods of fetal development modulate the epigenetic mechanisms controlling specific genes, which can affect the structure and function of physiological systems. Maternal immune stress by bacterial infection simulated by lipopolysaccharide (LPS) in an experiment is considered to be a powerful programming factor of fetal development. Studies of the molecular mechanisms controlling the formation and functioning of physiological systems are in the pilot stage. LPSs are the most potent natural inflammation factors. LPS-induced increases in fetal levels of pro- and anti-inflammatory cytokines can affect brain development and have long-term effects on behavior and neuroendocrine functions. The degradation of serotonergic neurons induced by LPS in the fetus is attributed to the increased levels of interleukin (IL)-6 and tumor necrosis factor (TNFα) as well as to anxiety and depression in children. Dopamine deficiency causes dysthymia, learning disability, and Parkinson's disease. According to our data, an LPS-induced increase in the levels of IL-6, leukemia inhibitory factor (LIF), and monocyte chemotactic protein (MCP-1) in maternal and fetal rats during early pregnancy disturbs the development and functioning of gonadotropin-releasing hormone production and reproductive systems. It is important to note the high responsiveness of epigenetic developmental mechanisms to many regulatory factors, which offers opportunities to correct the defects.

Cognitive Disparities: The Impact of the Great Depression and Cumulative Inequality on Later-Life Cognitive Function.

Population aging has driven a spate of recent research on later-life cognitive function. Greater longevity increases the lifetime risk of memory diseases that compromise the cognitive abilities vital to well-being. Alzheimer's disease, thought to be the most common underlying pathology for elders' cognitive dysfunction (Willis and Hakim 2013), is already the sixth leading cause of death in the United States (Alzheimer's Association 2016). Understanding social determinants of pathological cognitive decline is key to crafting interventions, but evidence is inconclusive for how social factors interact over the life course to affect cognitive function. I study whether early-life exposure to the Great Depression is directly associated with later-life cognitive function, influences risky behaviors over the life course, and/or accumulates with other life-course disadvantages. Using growth curve models to analyze the Health and Retirement Study, I find that early-life exposure to the Great Depression is associated with fluid cognition, controlling for intervening factors-evidence for a critical period model. I find little support for a social trajectory model. Disadvantage accumulates over the life course to predict worse cognitive function, providing strong evidence for a cumulative inequality model.

Bidirectional Effects of Mother-Young Contact on the Maternal and Neonatal Brains.

Adaptive plasticity occurs intensely during the early postnatal period through processes like proliferation, migration, differentiation, synaptogenesis, myelination and apoptosis. Exposure to particular stimuli during this critical period has long-lasting effects on cognition, stress reactivity and behavior. Maternal care is the main source of social, sensory and chemical stimulation to the young and is, therefore, critical to "fine-tune" the offspring's neural development. Mothers providing a low quantity or quality of stimulation produce offspring that will exhibit reduced cognitive performance, impaired social affiliation and increased agonistic behaviors. Transgenerational transmission of such traits occurs epigenetically, i.e., through mechanisms like DNA methylation and post-translational modification of nucleosomal histones, processes that silence or increase gene expression without affecting the DNA sequence. Reciprocally, providing maternal care profoundly affects the behavior, learning, memory and fine neuroanatomy of the adult female. Such effects are in many cases permanent and sometimes they involve the hormones of pregnancy and lactation. The above evidence supports the idea that the mother-young dyad exerts profound and permanent effects on the brains of both adult and developing organisms, respectively. Effects on the latter can be explained by the neural developmental processes taking place during the early postnatal period. In contrast, little is known about the mechanisms mediating the plasticity of the adult maternal brain. The bidirectional effects that mother and young exert on each other's brains exemplify a remarkable plasticity of this organ for organizing itself and provide an immense source of variability for adaptation and evolution in mammals.

Increased functional connectivity between language and visually deprived areas in late and partial blindness.

In the congenitally blind, language processing involves visual areas. In the case of normal visual development however, it remains unclear whether later visual loss induces interactions between the language and visual areas. This study compared the resting-state functional connectivity (FC) of retinotopic and language areas in two unique groups of late visually deprived subjects: (1) blind individuals suffering from retinitis pigmentosa (RP), (2) RP subjects without a visual periphery but with preserved central "tunnel vision", both of whom were contrasted with sighted controls. The results showed increased FC between Broca's area and the visually deprived areas in the peripheral V1 for individuals with tunnel vision, and both the peripheral and central V1 for blind individuals. These findings suggest that FC can develop in the adult brain between the visual and language systems in the completely and partially blind. These changes start in the deprived areas and increase in size (involving both foveal and peripheral V1) and strength (from negative to positive FC) as the disease and sensory deprivation progress. These observations support the claim that functional connectivity between remote systems that perform completely different tasks can change in the adult brain in cases of total and even partial visual deprivation.

Increased salt intake during early ontogenesis lead to development of arterial hypertension in salt-resistant Wistar rats.

A direct relationship exists between salt consumption and hypertension. Increased sodium intake does not automatically lead to a rise in blood pressure (BP) because of marked intra-individual variability in salt sensitivity. Wistar rats are a salt-resistant strain and increased salt intake in adults does not induce hypertension. Mechanisms regulating BP develop during early ontogenesis and increased sodium consumption by pregnant females leads to an increase in BP of their offspring, but early postnatal stages have not been sufficiently analyzed in salt-resistant strains of rats. The aim of this work was to study the effects of increased salt during early ontogeny on cardiovascular characteristics of Wistar rats. We used 16 control (C; 8 males + 8 females) rats fed with a standard diet (0.2% sodium) and 16 experimental (S; 8 males + 8 females) rats fed with a diet containing 0.8% sodium. BP was measured weekly and plasma renin activity, aldosterone and testosterone concentrations were assayed by radioimmunoassay after the experiment in 16-week-old animals. In the kidney, AT1 receptors were determined by the western blot. BP was higher in the S as compared with the C rats and did not differ between males and females. The relative left ventricle mass was increased in S as compared with C males and no differences were recorded in females. No significant differences between groups were found in hormonal parameters and AT1 receptors. Results indicate that moderately increased salt intake during postnatal ontogeny results in a BP rise even in salt-resistant rats.

Mechanisms underlying the neuronal-based symptoms of allergy.

Persons with allergies present with symptoms that often are the result of alterations in the nervous system. Neuronally based symptoms depend on the organ in which the allergic reaction occurs but can include red itchy eyes, sneezing, nasal congestion, rhinorrhea, coughing, bronchoconstriction, airway mucus secretion, dysphagia, altered gastrointestinal motility, and itchy swollen skin. These symptoms occur because mediators released during an allergic reaction can interact with sensory nerves, change processing in the central nervous system, and alter transmission in sympathetic, parasympathetic, and enteric autonomic nerves. In addition, evidence supports the idea that in some subjects this neuromodulation is, for reasons poorly understood, upregulated such that the same degree of nerve stimulus causes a larger effect than seen in healthy subjects. There are distinctions in the mechanisms and nerve types involved in allergen-induced neuromodulation among different organ systems, but general principles have emerged. The products of activated mast cells, other inflammatory cells, and resident cells can overtly stimulate nerve endings, cause long-lasting changes in neuronal excitability, increase synaptic efficacy, and also change gene expression in nerves, resulting in phenotypically altered neurons. A better understanding of these processes might lead to novel therapeutic strategies aimed at limiting the suffering of those with allergies.