Developmental Tuning Research Articles

Adolescent social isolation disrupts developmental tuning of neuropeptide circuits in the hypothalamus to amygdala regulating social and defensive behavior

Engaging in positive social (i.e., prosocial) interactions during adolescence acts to modulate neural circuits that determine adult adaptive behavior. While accumulating evidence indicates that a strong craving for prosocial behavior contributes to sustaining neural development, the consequences of social deprivation during adolescence on social neural circuits, including those involving oxytocin (OXT) and vasopressin (AVP), are poorly characterized. We evaluated adaptive behaviors in socially isolated mice, including anxiety-like, social, and defensive behaviors, along with OXT and AVP neural profiles in relevant brain regions. Social isolation from postnatal day (P-)22 to P-48 induced enhanced defensive and exploratory behaviors, in nonsocial and social contexts. Unlike OXT neurons, AVP+ cell density in the paraventricular nucleus of the hypothalamus increases with age in males. Social isolation also modulated gene expression in the medial amygdala (MeA), including the upregulation of OXT receptors in males and the downregulation of AVP1a receptors in both sexes. Socially isolated mice showed an enhanced defensive, anogenital approach toward a novel adult female during direct social interactions. Subsequent c-Fos mapping revealed diminished neural activity in restricted brain areas, including the MeA, lateral septum, and posterior intralaminar nucleus of the thalamus, in socially isolated mice. These data indicate that neural signals arising from daily social interactions invoke region-specific modification of neuropeptide expression that coordinates with altered defensiveness and neural responsivities, including OXT- and AVP-projecting regions. The present findings indicate an involvement of OXT and AVP circuits in adolescent neural and behavioral plasticity that is tuned by daily social interaction.

CDKL5-mediated developmental tuning of neuronal excitability and concomitant regulation of transcriptome.

Cyclin-dependent kinase-like 5 (CDKL5) is a serine-threonine kinase enriched in the forebrain to regulate neuronal development and function. Patients with CDKL5 deficiency disorder (CDD), a severe neurodevelopmental condition caused by mutations of CDKL5 gene, present early-onset epilepsy as the most prominent feature. However, spontaneous seizures have not been reported in mouse models of CDD, raising vital questions on the human-mouse differences and the roles of CDKL5 in early postnatal brains. Here, we firstly measured electroencephalographic (EEG) activities via a wireless telemetry system coupled with video-recording in neonatal mice. We found that mice lacking CDKL5 exhibited spontaneous epileptic EEG discharges, accompanied with increased burst activities and ictal behaviors, specifically at postnatal day 12 (P12). Intriguingly, those epileptic spikes disappeared after P14. We next performed an unbiased transcriptome profiling in the dorsal hippocampus and motor cortex of Cdkl5 null mice at different developmental timepoints, uncovering a set of age-dependent and brain region-specific alterations of gene expression in parallel with the transient display of epileptic activities. Finally, we validated multiple differentially expressed genes (DEGs), such as glycine receptor subunit 2 and cholecystokinin, at the transcript and/or protein levels, supporting the relevance of these genes to CDKL5-regulated excitability. Our findings reveal early-onset neuronal hyperexcitability in mouse model of CDD, providing new insights into CDD etiology and potential molecular targets to ameliorate intractable neonatal epilepsy.

Small RNAs couple embryonic developmental programs to gut microbes.

Embryogenesis has long been known for its robustness to environmental factors. Although developmental tuning of embryogenesis to the environment experienced by the parent may be beneficial, little is understood on whether and how developmental patterns proactively change. Here, we show that Caenorhabditis elegans undergoes alternative embryogenesis in response to maternal gut microbes. Harmful microbes result in altered endodermal cell divisions; morphological changes, including left-right asymmetric development; double association between intestinal and primordial germ cells; and partial rescue of fecundity. The miR-35 microRNA family, which is controlled by systemic endogenous RNA interference and targets the β-transducin repeat-containing protein/cell division cycle 25 (CDC25) pathway, transmits intergenerational information to regulate cell divisions and reproduction. Our findings challenge the widespread assumption that C. elegans has an invariant cell lineage that consists of a fixed cell number and provide insights into how organisms optimize embryogenesis to adapt to environmental changes through epigenetic control.

Developmental tuning of mineralization drives morphological diversity of gill cover bones in sculpins and their relatives

The role of osteoblast placement in skeletal morphological variation is relatively well understood, but alternative developmental mechanisms affecting bone shape remain largely unknown. Specifically, very little attention has been paid to variation in later mineralization stages of intramembranous ossification as a driver of morphological diversity. We discover the occurrence of specific, sometimes large, regions of nonmineralized osteoid within bones that also contain mineralized tissue. We show through a variety of histological, molecular, and tomographic tests that this “extended” osteoid material is most likely nonmineralized bone matrix. This tissue type is a significant determinant of gill cover bone shape in the teleostean suborder Cottoidei. We demonstrate repeated evolution of extended osteoid in Cottoidei through ancestral state reconstruction and test for an association between extended osteoid variation and habitat differences among species. Through measurement of extended osteoid at various stages of gill cover development in species across the phylogeny, we gain insight into possible evolutionary developmental origins of the trait. We conclude that this fine‐tuned developmental regulation of bone matrix mineralization reflects heterochrony at multiple biological levels and is a novel mechanism for the evolution of diversity in skeletal morphology. This research lays the groundwork for a new model in which to study bone mineralization and evolutionary developmental processes, particularly as they may relate to adaptation during a prominent evolutionary radiation of fishes.

Developmental Tuning of Epigenetic Clock.

Research in the field of gerontology has traditionally focused on later life stages. There is increasing evidence, however, that both the rate of age-related functional decline and the later-life health status can be programmed during early development. The central role of epigenetic mechanisms (methylation of DNA, histone modifications and regulation by non-coding RNAs) in mediating these long-term effects has been elucidated. Both rate and direction of age-associated change of epigenetic patterns (“epigenetic drift”) were shown to be largely dependent on early-life environmental conditions. Inter-individual divergences in epigenetic profiles may arise following the stochastic errors in maintaining epigenetic marks, but they may also be adaptively mediated by specific environmental cues. Recent cohort studies indicate that ticking rate of epigenetic clock, estimated by a DNA methylation-based methods, may be developmentally adjusted, and that individual’s discrepancies among epigenetic and chronological age would be likely programmed early in development. In this Perspective article, recent findings suggesting the importance of early-life determinants for life-course dynamics of epigenetic drift are summarized and discussed.

Alterations in audiovisual simultaneity perception in amblyopia.

Amblyopia is a developmental visual impairment that is increasingly recognized to affect higher-level perceptual and multisensory processes. To further investigate the audiovisual (AV) perceptual impairments associated with this condition, we characterized the temporal interval in which asynchronous auditory and visual stimuli are perceived as simultaneous 50% of the time (i.e., the AV simultaneity window). Adults with unilateral amblyopia (n = 17) and visually normal controls (n = 17) judged the simultaneity of a flash and a click presented with both eyes viewing. The signal onset asynchrony (SOA) varied from 0 ms to 450 ms for auditory-lead and visual-lead conditions. A subset of participants with amblyopia (n = 6) was tested monocularly. Compared to the control group, the auditory-lead side of the AV simultaneity window was widened by 48 ms (36%; p = 0.002), whereas that of the visual-lead side was widened by 86 ms (37%; p = 0.02). The overall mean window width was 500 ms, compared to 366 ms among controls (37% wider; p = 0.002). Among participants with amblyopia, the simultaneity window parameters were unchanged by viewing condition, but subgroup analysis revealed differential effects on the parameters by amblyopia severity, etiology, and foveal suppression status. Possible mechanisms to explain these findings include visual temporal uncertainty, interocular perceptual latency asymmetry, and disruption of normal developmental tuning of sensitivity to audiovisual asynchrony.

A new model of strabismic amblyopia: Loss of spatial acuity due to increased temporal dispersion of geniculate X-cell afferents on to cortical neurons

Although the neural locus of strabismic amblyopia has been shown to lie at the first site of binocular integration, first in cat and then in primate, an adequate mechanism is still lacking. Here we hypothesise that increased temporal dispersion of LGN X-cell afferents driven by the deviating eye onto single cortical neurons may provide a neural mechanism for strabismic amblyopia. This idea was investigated via single cell extracellular recordings of 93 X and 50 Y type LGN neurons from strabismic and normal cats. Both X and Y neurons driven by the non-deviating eye showed shorter latencies than those driven by either the strabismic or normal eyes. Also the mean latency difference between X and Y neurons was much greater for the strabismic cells compared with the other two groups. The incidence of lagged X-cells driven by the deviating eye of the strabismic cats was higher than that of LGN X-cells from normal animals. Remarkably, none of the cells recorded from the laminae driven by the non-deviating eye were of the lagged class. A simple computational model was constructed in which a mixture of lagged and non-lagged afferents converge on to single cortical neurons. Model cut-off spatial frequencies to a moving grating stimulus were sensitive to the temporal dispersion of the geniculate afferents. Thus strabismic amblyopia could be viewed as a lack of developmental tuning of geniculate lags for neurons driven by the amblyopic eye. Monocular control of fixation by the non-deviating eye is associated with reduced incidence of lagged neurons, suggesting that in normal vision, lagged neurons might play a role in maintaining binocular connections for cortical neurons.

Infants' emerging sensitivity to emotional body expressions: insights from asymmetrical frontal brain activity.

Sensitive responding to others' emotional body expressions is an essential social skill in humans. Using event-related brain potentials, it has recently been shown that the ability to discriminate between emotional body expressions develops between 4 and 8 months of age. However, it is not clear whether the perception of emotional body expressions in others evokes sensitive brain responses linked to motivational processes in infants. We therefore examined frontal EEG alpha asymmetry in response to dynamic happy and fearful body expressions presented to 4- and 8-month-old infants in 2 orientations (upright and inverted). Our results revealed that only 8-month-olds but not 4-month-olds showed significant differences in their frontal asymmetry responses between emotional expressions when presented in an upright orientation. Specifically, 8-month-old infants showed a greater lateralization to the left hemisphere in response to happy expression, indexing a greater tendency to approach, whereas they showed a greater lateralization to the right hemisphere in response to fearful expressions, indexing a greater tendency to withdraw. These findings provide further support for the notion that infants' perception of emotion undergoes a developmental tuning during this period in development. Critically, the results suggest that the infant brain becomes sensitive to the motivational significance conveyed by the emotional body expressions.

Developmental tuning of reflexive attentional effect to biological motion cues.

The human visual system is extremely sensitive to the direction information retrieved from biological motion. In the current study, we investigate the functional impact of this sensitivity on attentional orienting in young children. We found that children as early as 4 years old, like adults, showed a robust reflexive attentional orienting effect to the walking direction of an upright point-light walker, indicating that biological motion signals can automatically direct spatial attention at an early age. More importantly, the inversion effect associated with attentional orienting emerges by 4 years old and gradually develops into a similar pattern found in adults. These results provide strong evidence that biological motion cues can guide the distribution of spatial attention in young children, and highlight a critical development from a broadly- to finely-tuned process of utilizing biological motion cues in the human social brain.

Developmental precursors of social brain networks: the emergence of attentional and cortical sensitivity to facial expressions in 5 to 7 months old infants.

Biases in attention towards facial cues during infancy may have an important role in the development of social brain networks. The current study used a longitudinal design to examine the stability of infants' attentional biases towards facial expressions and to elucidate how these biases relate to emerging cortical sensitivity to facial expressions. Event-related potential (ERP) and attention disengagement data were acquired in response to the presentation of fearful, happy, neutral, and phase-scrambled face stimuli from the same infants at 5 and 7 months of age. The tendency to disengage from faces was highly consistent across both ages. However, the modulation of this behavior by fearful facial expressions was uncorrelated between 5 and 7 months. In the ERP data, fear-sensitive activity was observed over posterior scalp regions, starting at the latency of the N290 wave. The scalp distribution of this sensitivity to fear in ERPs was dissociable from the topography of face-sensitive modulation within the same latency range. While attentional bias scores were independent of co-registered ERPs, attention bias towards fearful faces at 5 months of age predicted the fear-sensitivity in ERPs at 7 months of age. The current results suggest that the attention bias towards fear could be involved in the developmental tuning of cortical networks for social signals of emotion.

Optical plasticity in fish lenses

In a typical fish eye, the crystalline lens is the only refractive element. It is spherical in shape and has high refractive power. Most fish species have elaborate color vision and spectral sensitivity may range from the near-infrared to the near-ultraviolet. Longitudinal chromatic aberration exceeds depth of focus and chromatic blur is compensated for by species-specific multifocality of the lens. The complex optical properties of fish lenses are subject to accurate regulation, including circadian reversible adjustments and irreversible developmental tuning. The mechanisms optimize the transfer of visual information to the retina in diverse and variable environments, and allow for rapid evolutionary changes in color vision. Active optical tuning of the lens is achieved by changes in the refractive index gradient and involves layers of mature, denucleated lens fiber cells. First steps have been taken toward unraveling the signaling systems controlling lens optical plasticity. Multifocal lenses compensating for chromatic blur are common in all major groups of vertebrates, including birds and mammals. Furthermore, the optical quality of a monofocal lens, such as in the human eye, is equally sensitive to the exact shape of the refractive index profile. Optical plasticity in the crystalline lens may thus be present in vertebrates in general.

Subcellular distribution of Lck during CD4 T-cell maturation in the thymic medulla regulates the T-cell activation threshold

Mature peripheral T cells respond to foreign but not to self-antigens. During development in the thymus, deletion of high-affinity self-reactive immature thymocytes contributes to tolerance of mature T cells. However, double-positive thymocytes are positively selected to survive if they respond to self-peptide-MHC complexes; thus, there must be mechanisms to prevent overt reactivity to those same complexes in the periphery. "Developmental tuning" is the active process through which T-cell receptor (TCR)-associated signaling pathways of single-positive (SP) thymocytes are attenuated to respond appropriately to self-peptide-MHC complexes in the periphery. We previously showed that MHC class II expression in the thymic medulla was necessary to tune CD4(+) SP (CD4 SP) thymocytes. CD4 SP thymocytes from mice lacking medullary MHC class II expression had inappropriately enhanced proximal TCR signaling to low-affinity self-ligands that was associated with altered cellular distribution of the tyrosine kinase Lck. Now, we report that activation of both tuned and untuned CD4 SP thymocytes is Lck-dependent. Untuned CD4 SP cells contain a pool of Lck with increased basal phosphorylation that is not associated with the CD4 coreceptor. Phosphorylation of this pool of Lck decreases with tuning. Immunogold transmission electron microscopy of membrane sheets permitted direct visualization of Lck. In the absence of tuning, a significant proportion of Lck and the TCR subunit CD3ζ are expressed on the same protein island; this close association of Lck and the TCR probably explains the enhanced activation of untuned CD4 SP cells. Thus, changes in membrane topography during thymic maturation determine the set point for TCR responsiveness.

Building biases in infancy: the influence of race on face and voice emotion matching

Early in the first year of life infants exhibit equivalent performance distinguishing among people within their own race and within other races. However, with development and experience, their face recognition skills become tuned to groups of people they interact with the most. This developmental tuning is hypothesized to be the origin of adult face processing biases including the other-race bias. In adults the other-race bias has also been associated with impairments in facial emotion processing for other-race faces. The present investigation aimed to show perceptual narrowing for other-race faces during infancy and to determine whether the race of a face influences infants' ability to match emotional sounds with emotional facial expressions. Behavioral (visual-paired comparison; VPC) and electrophysiological (event-related potentials; ERPs) measures were recorded in 5-month-old and 9-month-old infants. Behaviorally, 5-month-olds distinguished faces within their own race and within another race, whereas 9-month-olds only distinguish faces within their own race. ERPs were recorded while an emotion sound (laughing or crying) was presented prior to viewing an image of a static African American or Caucasian face expressing either a happy or a sad emotion. Consistent with behavioral findings, ERPs revealed race-specific perceptual processing of faces and emotion/sound face congruency at 9 months but not 5 months of age. In addition, from 5 to 9 months, the neural networks activated for sound/face congruency were found to shift from an anterior ERP component (Nc) related to attention to posterior ERP components (N290, P400) related to perception.

Reorganizing the signaling molecules in CD4+ T cells by TCR-MHC class II interactions in the thymic medulla prevents T cell hyperactivation (50.1)

Abstract Immature thymocytes that are positively selected based upon their response to self-peptide-MHC complexes develop into mature T cells that are not overtly reactive to those same complexes. Developmental tuning is the active process through which TCR-dependent activation of single-positive thymocytes is attenuated in response to the self peptide-MHC molecules that will be encountered in the periphery. Mature “tuned” thymocytes lose responsiveness to low affinity ligands. We previously reported that tuning of CD4 T cells requires interactions with MHC II expressing thymic medullary epithelium and thymic DCs. Tuning is mediated by MHC II interaction with the TCR but not with the CD4-coreceptor, even though mature CD4 T cells depend on CD4 co-receptor associated Lck for TCR signaling. The increased threshold for TCR stimulation in tuned CD4SP thymocytes is associated with increased expression of the SHP-1 phosphatase and inhibition of ERK activation by weak ligands. Immature CD4 T cells contain a “free pool” of Lck that is not co-receptor associated. This pool of Lck localizes with TCR and may lower the activation threshold for weak ligands. Tuning limits this TCR associated pool of Lck. Thus, TCR signaling in mature T cells depends on CD4 associated Lck for activation. Taken together, our results suggest that reorganization of the TCR signalasome during thymic medullary residency defines the activation threshold of CD4 T cells and prevents hyperactivity to weak self antigens.

The Activation Threshold of CD4+ T Cells Is Defined by TCR/Peptide-MHC Class II Interactions in the Thymic Medulla

Immature thymocytes that are positively selected based upon their response to self-peptide-MHC complexes develop into mature T cells that are not overtly reactive to those same complexes. Developmental tuning is the active process through which TCR-associated signaling pathways of single-positive thymocytes are attenuated to respond appropriately to the peptide-MHC molecules that will be encountered in the periphery. In this study, we explore the mechanisms that regulate the tuning of CD4(+) single-positive T cells to MHC class II encountered in the thymic medulla. Experiments with murine BM chimeras demonstrate that tuning can be mediated by MHC class II expressed by either thymic medullary epithelial cells or thymic dendritic cells. Tuning does not require the engagement of CD4 by MHC class II on stromal cells. Rather, it is mediated by interactions between MHC class II and the TCR. To understand the molecular changes that distinguish immature hyperactive T cells from tuned mature CD4(+) T cells, we compared their responses to TCR stimulation. The altered response of mature CD4 single-positive thymocytes is characterized by the inhibition of ERK activation by low-affinity self-ligands and increased expression of the inhibitory tyrosine phosphatase SHP-1. Thus, persistent TCR engagement by peptide-MHC class II on thymic medullary stroma inhibits reactivity to self-Ags and prevents autoreactivity in the mature repertoire.

Developmental tuning and decay in senescence of oscillations linking the corticomotoneuronal system

Developmental tuning and decay in senescence of oscillations linking the corticomotoneuronal system

A Role for CD8 in the Developmental Tuning of Antigen Recognition and CD3 Conformational Change

TCR engagement by peptide-MHC class I (pMHC) ligands induces a conformational change (Deltac) in CD3 (CD3Deltac) that contributes to T cell signaling. We found that when this interaction took place between primary T lineage cells and APCs, the CD8 coreceptor was required to generate CD3Deltac. Interestingly, neither enhancement of Ag binding strength nor Src kinase signaling explained this coreceptor activity. Furthermore, Ag-induced CD3Deltac was developmentally attenuated by the increase in sialylation that accompanies T cell maturation and limits CD8 activity. Thus, both weak and strong ligands induced CD3Deltac in preselection thymocytes, but only strong ligands were effective in mature T cells. We propose that CD8 participation in the TCR/pMHC interaction can physically regulate CD3Deltac induction by "translating" productive Ag encounter from the TCR to the CD3 complex. This suggests one mechanism by which the developmentally regulated variation in CD8 sialylation may contribute to the developmental tuning of T cell sensitivity.

Developmental Alterations in Thymocyte Sensitivity Are Actively Regulated by MHC Class II Expression in the Thymic Medulla

Developing thymocytes are positively selected if they respond to self-MHC-peptide complexes, yet mature T cells are not activated by those same self-complexes. To avoid autoimmunity, positive selection must be followed by a period of maturation when the cellular response to TCR signals is altered. The mechanisms that mediate this postselection developmental tuning remain largely unknown. Specifically, it is unknown whether developmental tuning is a preprogrammed outcome of positive selection or if it is sensitive to ongoing interactions between the thymocyte and the thymic stroma. We probed the requirement for MHC class II-TCR interactions in postselection maturation by studying single positive (SP) CD4 thymocytes from K14/A(beta)(b) mice, in which CD4 T cells cannot interact with MHC class II in the thymic medulla. We report here that SP CD4 thymocytes must receive MHC class II signals to avoid hyperactive responses to TCR signals. This hyperactivity correlates with decreased expression of CD5; however, developmental tuning can occur independently of CD5, correlating instead with differences in the distribution of Lck. Thus, the maturation of postselection SP CD4 thymocytes is an active process mediated by ongoing interactions between the T cell and MHC class II molecules. This represents a novel mechanism by which the thymic medulla prevents autoreactivity.

Developmental Tuning in a Spinal Nociceptive System: Effects of Neonatal Spinalization

Recent studies indicate a modular organization of the nociceptive withdrawal reflex system. Each module has a characteristic receptive field, closely matching the withdrawal movement caused by its effector muscle. In the rat, the strength of the sensory input to each module is tuned during the first postnatal weeks, i.e., erroneous spinal connections are depressed, and adequate connections are strengthened. To clarify if this tuning is dependent on supraspinal structures, the effect of a complete neonatal spinal cord transection on the postnatal tuning of withdrawal reflexes was studied. The nociceptive receptive fields of single hindlimb muscles and compound withdrawal reflexes were examined in decerebrate unanesthetized and awake rats, respectively. Noxious thermal CO(2) laser stimulation was used to evoke reflex responses. Neonatal spinal cord transection resulted in a disrupted reflex organization in the adult rat, resembling that previously found in neonatal rats. The receptive fields of single hindlimb muscles exhibited abnormal distribution of sensitivity not matching the withdrawal action of the effector muscles. Likewise, the composite nocifensive movements, as documented in the awake rat, often resulted in erroneous movements toward the stimulus. It is concluded that withdrawal reflexes do not become functionally adapted in rats spinalized at birth. These findings suggest a critical role for supraspinal systems in the postnatal tuning of spinal nociceptive systems.

Development of rhythmic pattern generators

In contrast to the wealth of knowledge about the organizational rules of adult central pattern generators, far less is known about how these networks are assembled during development. The basic architecture for adult central pattern generators appears early in development but different generators may follow completely different developmental pathways to reach maturity. Recent evidence suggests that neuromodulatory inputs, in addition to their short-term adaptive control of central pattern generator activity, play a crucial role in both the final developmental tuning and the long-term maintenance of adult network function.