Maturation Of Circuits Research Articles

Inhibitory Neuron Transplantation into Adult Visual Cortex Creates a New Critical Period that Rescues Impaired Vision

The maturation of inhibitory circuits in juvenile visual cortex triggers a critical period in the development of the visual system. Although several manipulations of inhibition can alter the timing of the critical period, none have demonstrated the creation of a new critical period in adulthood. We developed a transplantation method to reactivate critical period plasticity in the adult visual cortex. Transplanted embryonic inhibitory neurons from the medial ganglionic eminence reinstate ocular dominance plasticity in adult recipients. Transplanted inhibitory cells develop cell-type-appropriate molecular characteristics and visually evoked responses. In adult mice impaired by deprivation during the juvenile critical period, transplantation also recovers both visual cortical responses and performance on a behavioral test of visual acuity. Plasticity and recovery are induced when the critical period would have occurred in the donor animal. These results reveal that the focal reactivation of visual cortical plasticity using inhibitory cell transplantation creates a new critical period that restores visual perception after childhood deprivation.

Serotonin Modulates Developmental Microglia via 5-HT2B Receptors: Potential Implication during Synaptic Refinement of Retinogeniculate Projections.

Maturation of functional neuronal circuits during central nervous system development relies on sophisticated mechanisms. First, axonal and dendritic growth should reach appropriate targets for correct synapse elaboration. Second, pruning and neuronal death are required to eliminate redundant or inappropriate neuronal connections. Serotonin, in addition to its role as a neurotransmitter, actively participates in postnatal establishment and refinement of brain wiring in mammals. Brain resident macrophages, that is, microglia, also play an important role in developmentally regulated neuronal death as well as in synaptic maturation and elimination. Here, we tested the hypothesis of cross-regulation between microglia and serotonin during postnatal brain development in a mouse model of synaptic refinement. We found expression of the serotonin 5-HT2B receptor on postnatal microglia, suggesting that serotonin could participate in temporal and spatial synchronization of microglial functions. Using two-photon microscopy, acute brain slices, and local delivery of serotonin, we observed that microglial processes moved rapidly toward the source of serotonin in Htr2B(+/+) mice, but not in Htr2B(-/-) mice lacking the 5-HT2B receptor. We then investigated whether some developmental steps known to be controlled by serotonin could potentially result from microglia sensitivity to serotonin. Using an in vivo model of synaptic refinement during early brain development, we investigated the maturation of the retinal projections to the thalamus and observed that Htr2B(-/-) mice present anatomical alterations of the ipsilateral projecting area of retinal axons into the thalamus. In addition, activation markers were upregulated in microglia from Htr2B(-/-) compared to control neonates, in the absence of apparent morphological modifications. These results support the hypothesis that serotonin interacts with microglial cells and these interactions participate in brain maturation.

Impact of Mineralocorticoid, Glucocorticoid and Thyroid Hormones on Respiratory Control Development in Lithobates Catesbeianus

The emergence of air breathing during Lithobates catesbeianus development requires significant changes to the brainstem circuits that generate and regulate breathing; however, the mechanisms responsible for this transformation remain largely unknown. Because this metamorphosis is regulated by hormones such as corticosterone, aldosterone, and thyroid hormone (T3), we tested the hypothesis that exposing the brainstem to these hormones augments the fictive air breathing frequency in Lithobates tadpoles. Brainstems were isolated from pre‐metamorphic tadpoles (TK V to X) and placed in a bottle containing artificial cerebrospinal fluid and one of the following hormones: aldosterone (100nM), corticosterone (100nM), T3 (100 nM) or a combination of two of the preceding components for 24 hours. The effect of hormone exposure on respiratory activity was quantified by extracellular recording of rhythmic motor output from cranial nerves V and X. By comparison with preparations subjected to sham treatment, hormone exposure generally increased fictive air breathing frequency; the highest lung burst frequency was observed in brainstems exposed to the aldosterone‐T3 combination. To assess the treatment effects on the overall system functionality, sham and hormone treated tadpoles were kept in a recording chamber for 24h after which we recorded their ventilator activity by measuring changes in buccal pressure. Interestingly, the results showed the same trend as the one observed with the brainstem preparation. We conclude that hormones play an important role in the maturation of the neural circuits that generate and regulate breathing in this species.

Repeated exposure to ketamine-xylazine during early development impairs motor learning-dependent dendritic spine plasticity in adulthood.

Recent studies in rodents suggest that repeated and prolonged anesthetic exposure at early stages of development leads to cognitive and behavioral impairments later in life. However, the underlying mechanism remains unknown. In this study, we tested whether exposure to general anesthesia during early development will disrupt the maturation of synaptic circuits and compromise learning-related synaptic plasticity later in life. Mice received ketamine-xylazine (20/3 mg/kg) anesthesia for one or three times, starting at either early (postnatal day 14 [P14]) or late (P21) stages of development (n = 105). Control mice received saline injections (n = 34). At P30, mice were subjected to rotarod motor training and fear conditioning. Motor learning-induced synaptic remodeling was examined in vivo by repeatedly imaging fluorescently labeled postsynaptic dendritic spines in the primary motor cortex before and after training using two-photon microscopy. Three exposures to ketamine-xylazine anesthesia between P14 and P18 impair the animals' motor learning and learning-dependent dendritic spine plasticity (new spine formation, 8.4 ± 1.3% [mean ± SD] vs. 13.4 ± 1.8%, P = 0.002) without affecting fear memory and cell apoptosis. One exposure at P14 or three exposures between P21 and P25 has no effects on the animals' motor learning or spine plasticity. Finally, enriched motor experience ameliorates anesthesia-induced motor learning impairment and synaptic deficits. Our study demonstrates that repeated exposures to ketamine-xylazine during early development impair motor learning and learning-dependent dendritic spine plasticity later in life. The reduction in synaptic structural plasticity may underlie anesthesia-induced behavioral impairment.

The effect of early visual deprivation on the neural bases of multisensory processing.

Developmental vision is deemed to be necessary for the maturation of multisensory cortical circuits. Thus far, this has only been investigated in animal studies, which have shown that congenital visual deprivation markedly reduces the capability of neurons to integrate cross-modal inputs. The present study investigated the effect of transient congenital visual deprivation on the neural mechanisms of multisensory processing in humans. We used functional magnetic resonance imaging to compare responses of visual and auditory cortical areas to visual, auditory and audio-visual stimulation in cataract-reversal patients and normally sighted controls. The results showed that cataract-reversal patients, unlike normally sighted controls, did not exhibit multisensory integration in auditory areas. Furthermore, cataract-reversal patients, but not normally sighted controls, exhibited lower visual cortical processing within visual cortex during audio-visual stimulation than during visual stimulation. These results indicate that congenital visual deprivation affects the capability of cortical areas to integrate cross-modal inputs in humans, possibly because visual processing is suppressed during cross-modal stimulation. Arguably, the lack of vision in the first months after birth may result in a reorganization of visual cortex, including the suppression of noisy visual input from the deprived retina in order to reduce interference during auditory processing.

Maturation of short-interval inhibitory and excitatory circuits in the human primary motor cortex

s / Brain Stimulation 8 (2015) 360e377 372 spasticity in 4 post-stroke subjects that affected tonic stretch reflex threshold (TSRT) [2], i.e., the joint angle at which the stretch reflex begins to act due to the descending and segmental influences on motoneurons. The rectangular (4.5 cm 9 cm) electrodes were placed on each side of the spine (5 cm apart) over the paravertebral skin at the twelfth thoracic and first lumbar vertebral levels [3]. We found that only the high frequency (2100 Hz) sinusoidal stimulation (HFSS) and not the low frequency sinusoidal stimulation (LFSS) (20Hz) significantly affected the TSRT during tsACS application (45mins). LFSS showed significant aftereffects only after 45mins of tsACS application. Therefore, HFSS and LFSS may involve different mechanisms based on the ion channel distributions and their response properties in the neural tissue of the dorsal column [1].

Pentraxins Coordinate Excitatory Synapse Maturation and Circuit Integration of Parvalbumin Interneurons

Circuit computation requires precision in the timing, extent, and synchrony of principal cell (PC) firing that is largely enforced by parvalbumin-expressing, fast-spiking interneurons (PVFSIs). To reliably coordinate network activity, PVFSIs exhibit specialized synaptic and membrane properties that promote efficient afferent recruitment such as expression of high-conductance, rapidly gating, GluA4-containing AMPA receptors (AMPARs). We found that PVFSIs upregulate GluA4 during the second postnatal week coincident with increases in the AMPAR clustering proteins NPTX2 and NPTXR. Moreover, GluA4 is dramatically reduced in NPTX2(-/-)/NPTXR(-/-) mice with consequent reductions in PVFSI AMPAR function. Early postnatal NPTX2(-/-)/NPTXR(-/-) mice exhibit delayed circuit maturation with a prolonged critical period permissive for giant depolarizing potentials. Juvenile NPTX2(-/-)/NPTXR(-/-) mice display reduced feedforward inhibition yielding a circuit deficient in rhythmogenesis and prone to epileptiform discharges. Our findings demonstrate an essential role for NPTXs in controlling network dynamics highlighting potential therapeutic targets for disorders with inhibition/excitation imbalances such as schizophrenia.

Modulation of anxiety by cortical serotonin 1A receptors.

Serotonin (5-HT) plays an important role in the modulation of behavior across animal species. The serotonin 1A receptor (Htr1a) is an inhibitory G-protein coupled receptor that is expressed both on serotonin and non-serotonin neurons in mammals. Mice lacking Htr1a show increased anxiety behavior suggesting that its activation by serotonin has an anxiolytic effect. This outcome can be mediated by either Htr1a population present on serotonin (auto-receptor) or non-serotonin neurons (hetero-receptor), or both. In addition, both transgenic and pharmacological studies have shown that serotonin acts on Htr1a during development to modulate anxiety in adulthood, demonstrating a function for this receptor in the maturation of anxiety circuits in the brain. However, previous studies have been equivocal about which Htr1a population modulates anxiety behavior, with some studies showing a role of Htr1a hetero-receptor and others implicating the auto-receptor. In particular, cell-type specific rescue and suppression of Htr1a expression in either forebrain principal neurons or brainstem serotonin neurons reached opposite conclusions about the role of the two populations in the anxiety phenotype of the knockout. One interpretation of these apparently contradictory findings is that the modulating role of these two populations depends on each other. Here we use a novel Cre-dependent inducible allele of Htr1a in mice to show that expression of Htr1a in cortical principal neurons is sufficient to modulate anxiety. Together with previous findings, these results support a hetero/auto-receptor interaction model for Htr1a function in anxiety.

Adolescent maturation of inhibitory inputs onto cingulate cortex neurons is cell-type specific and TrkB dependent.

The maturation of inhibitory circuits during adolescence may be tied to the onset of mental health disorders such as schizophrenia. Neurotrophin signaling likely plays a critical role in supporting inhibitory circuit development and is also implicated in psychiatric disease. Within the neocortex, subcircuits may mature at different times and show differential sensitivity to neurotrophin signaling. We measured miniature inhibitory and excitatory postsynaptic currents (mIPSCs and mEPSCs) in Layer 5 cell-types in the mouse anterior cingulate (Cg) across the periadolescent period. We differentiated cell-types mainly by Thy1 YFP transgene expression and also retrobead injection labeling in the contralateral Cg and ipsilateral pons. We found that YFP− neurons and commissural projecting neurons had lower frequency of mIPSCs than neighboring YFP+ neurons or pons projecting neurons in juvenile mice (P21–25). YFP− neurons and to a lesser extent commissural projecting neurons also showed a significant increase in mIPSC amplitude during the periadolescent period (P21–25 vs. P40–50), which was not seen in YFP+ neurons or pons projecting neurons. Systemic disruption of tyrosine kinase receptor B (TrkB) signaling during P23–50 in TrkBF616A mice blocked developmental changes in mIPSC amplitude, without affecting miniature excitatory post synaptic currents (mEPSCs). Our data suggest that the maturation of inhibitory inputs onto Layer 5 pyramidal neurons is cell-type specific. These data may inform our understanding of adolescent brain development across species and aid in identifying candidate subcircuits that may show greater vulnerability in mental illness.

The role of nicotinic acetylcholine receptors in autosomal dominant nocturnal frontal lobe epilepsy.

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a focal epilepsy with attacks typically arising in the frontal lobe during non-rapid eye movement (NREM) sleep. It is characterized by clusters of complex and stereotyped hypermotor seizures, frequently accompanied by sudden arousals. Cognitive and psychiatric symptoms may be also observed. Approximately 12% of the ADNFLE families carry mutations on genes coding for subunits of the heteromeric neuronal nicotinic receptors (nAChRs). This is consistent with the widespread expression of these receptors, particularly the α4β2* subtype, in the neocortex and thalamus. However, understanding how mutant nAChRs lead to partial frontal epilepsy is far from being straightforward because of the complexity of the cholinergic regulation in both developing and mature brains. The relation with the sleep-waking cycle must be also explained. We discuss some possible pathogenetic mechanisms in the light of recent advances about the nAChR role in prefrontal regions as well as the studies carried out in murine models of ADNFLE. Functional evidence points to alterations in prefrontal GABA release, and the synaptic unbalance probably arises during the cortical circuit maturation. Although most of the available functional evidence concerns mutations on nAChR subunit genes, other genes have been recently implicated in the disease, such as KCNT1 (coding for a Na+-dependent K+ channel), DEPD5 (Disheveled, Egl-10 and Pleckstrin Domain-containing protein 5), and CRH (Corticotropin-Releasing Hormone). Overall, the uncertainties about both the etiology and the pathogenesis of ADNFLE point to the current gaps in our knowledge the regulation of neuronal networks in the cerebral cortex.

Audition-independent vocal crystallization associated with intrinsic developmental gene expression dynamics.

Complex learned behavior is influenced throughout development by both genetic and environmental factors. Birdsong, like human speech, is a complex vocal behavior acquired through sensorimotor learning and is based on coordinated auditory input and vocal output to mimic tutor song. Song is primarily learned during a specific developmental stage called the critical period. Although auditory input is crucial for acquiring complex vocal patterns, its exact role in neural circuit maturation for vocal learning and production is not well understood. Using audition-deprived songbirds, we examined whether auditory experience affects developmental gene expression in the major elements of neural circuits that mediate vocal learning and production. Compared with intact zebra finches, early-deafened zebra finches showed excessively delayed vocal development, but their songs eventually crystallized. In contrast to the different rates of song development between the intact and deafened birds, developmental gene expression in the motor circuit is conserved in an age-dependent manner from the juvenile stage until the older adult stage, even in the deafened birds, which indicates the audition-independent robustness of gene expression dynamics during development. Furthermore, even after adult deafening, which degrades crystallized song, the deteriorated songs ultimately restabilized at the same point when the early-deafened birds stabilized their songs. These results indicate a genetic program-associated inevitable termination of vocal plasticity that results in audition-independent vocal crystallization.

Fractalkine Signaling and Microglia Functions in the Developing Brain.

Microglial cells are the resident macrophages of the central nervous system (CNS). Besides their classical roles in pathological conditions, these immune cells also dynamically interact with neurons and influence their structure and function in physiological conditions. The neuronal chemokine fractalkine and its microglial receptor CX3CR1 are one important signaling pathway involved in these reciprocal interactions. In the present review, we will discuss recent evidence indicating that fractalkine signaling also determines several functions of microglial cells during normal CNS development. It has been known for a decade that microglial cells influence the neuronal death that normally occurs during CNS development. Surprisingly, recent evidence indicates that they can also support survival of developing neurons, control axon outgrowth, and laminar positioning of subsets of interneurons in the forebrain. Moreover, microglial cells influence the maturation of synaptic circuits at early postnatal stages: their phagocytic activity allows them to eliminate inappropriate synapses and they can also influence the functional expression of synaptic proteins by releasing mediators. Fractalkine signaling controls these functions of microglial cells in part by regulating their timely recruitment at sites of developing synapses. Finally, on-going research suggests that this signaling pathway is also a key player in neurodevelopmental disorders.

Significance of GABA(A) receptor heterogeneity: clues from developing neurons.

Briefly after the landmark discovery by Hanns Möhler that GABA(A) receptors (GABA(A)R) are the site of action of benzodiazepine site ligands, their distribution in the rodent CNS during development was mapped by autoradiography, demonstrating early and widespread expression of GABA(A)R in the brain and spinal cord. Ten years later, the first studies using subunit-specific antibodies revealed unsuspected heterogeneity in the subunit composition of GABA(A)R in developing brain, with striking regional specificity and rapid changes in expression and subcellular localization correlating with the maturation of neuronal circuits. These data contributed to the wealth of evidence that GABAergic neurotransmission, acting both synaptically and extrasynaptically, modulates major steps of neuronal development (proliferation, migration, differentiation, and circuit formation). In immature neurons, GABA(A)R activation leads to neuronal depolarization and activation of Ca(2+) signals, which mediate many of the developmental effects of GABA. Therefore, GABA(A)R heterogeneity might be essential to fine-tune GABA actions in the dynamics of CNS maturation. Furthermore, since a disturbance of GABAergic function during ontogeny can potentially affect many aspects of CNS maturation and contribute to the etiology of major brain disorders, GABA(A)R heterogeneity provides a substrate for the development of a tailored pharmacology targeting specific receptor subtypes. This chapter provides a brief overview of these issues with a special focus on the seminal contributions of Hanns Möhler to the emergence of these concepts of fundamental relevance in today's neuroscience research and pharmacological developments.

Role of perinatal long-chain omega-3 fatty acids in cortical circuit maturation: Mechanisms and implications for psychopathology.

Accumulating translational evidence suggests that the long-chain omega-3 fatty acid docosahexaenoic acid (DHA) plays a role in the maturation and stability of cortical circuits that are impaired in different recurrent psychiatric disorders. Specifically, rodent and cell culture studies find that DHA preferentially accumulates in synaptic and growth cone membranes and promotes neurite outgrowth, dendritic spine stability, and synaptogenesis. Additional evidence suggests that DHA may play a role in microglia-mediated synaptic pruning, as well as myelin development and resilience. In non-human primates n-3 fatty acid insufficiency during perinatal development leads to widespread deficits in functional connectivity in adult frontal cortical networks compared to primates raised on DHA-fortified diet. Preterm delivery in non-human primates and humans is associated with early deficits in cortical DHA accrual. Human preterm birth is associated with long-standing deficits in myelin integrity and cortical circuit connectivity and increased risk for attention deficit/hyperactivity disorder (ADHD), mood, and psychotic disorders. In general, ADHD and mood and psychotic disorders initially emerge during rapid periods of cortical circuit maturation and are characterized by DHA deficits, myelin pathology, and impaired cortical circuit connectivity. Together these associations suggest that early and uncorrected deficits in fetal brain DHA accrual may represent a modifiable risk factor for cortical circuit maturation deficits in psychiatric disorders, and could therefore have significant implications for informing early intervention and prevention strategies.

Cholinergic systems are essential for late-stage maturation and refinement of motor cortical circuits.

Previous studies reported that early postnatal cholinergic lesions severely perturb early cortical development, impairing neuronal cortical migration and the formation of cortical dendrites and synapses. These severe effects of early postnatal cholinergic lesions preclude our ability to understand the contribution of cholinergic systems to the later-stage maturation of topographic cortical representations. To study cholinergic mechanisms contributing to the later maturation of motor cortical circuits, we first characterized the temporal course of cortical motor map development and maturation in rats. In this study, we focused our attention on the maturation of cortical motor representations after postnatal day 25 (PND 25), a time after neuronal migration has been accomplished and cortical volume has reached adult size. We found significant maturation of cortical motor representations after this time, including both an expansion of forelimb representations in motor cortex and a shift from proximal to distal forelimb representations to an extent unexplainable by simple volume enlargement of the neocortex. Specific cholinergic lesions placed at PND 24 impaired enlargement of distal forelimb representations in particular and markedly reduced the ability to learn skilled motor tasks as adults. These results identify a novel and essential role for cholinergic systems in the late refinement and maturation of cortical circuits. Dysfunctions in this system may constitute a mechanism of late-onset neurodevelopmental disorders such as Rett syndrome and schizophrenia.

Novel roles of microglia

AbstractPío del Río Hortega, the father of the study of microglia, referred to microglia with highly branched fine processes in the healthy brain as “resting microglia,” because he thought these cells were quiescent. After brain injury, these resting microglia change their morphology into an activated type, which have phagocytic activity at the sites of neuronal damage and inflammation. At present, approximately 90 years after the discovery of microglia, microglia in the healthy brains of live animals are found to be very active using a two‐photon scanning laser microscope, and are much more active than any other cells in the brain. Beyond their role as brain‐resident macrophages, many lines of evidence have shown that microglia have essential roles in the maturation and maintenance of neuronal circuits in the developing and adult brain through both the elimination and formation of dendritic spines through their processes. Furthermore, the length and structural complexity of highly branched fine processes are regulated by the microglial intrinsic circadian clock. Dysfunction of the dendritic spines and disturbances of the circadian clock system are widely accepted characteristic abnormalities in neuropsychiatric disorders, including autism. Therefore, the growing understanding of the movement and functions of microglial processes might aid in the development of novel pharmacological interventions against neuropsychiatric disorders, which are associated with synapse loss and aberrant neuronal connectivity.

Aldosterone, corticosterone, and thyroid hormone and their influence on respiratory control development in Lithobates catesbeianus: An in vitro study

The emergence of air breathing during Lithobates catesbeianus development requires significant changes to the brainstem circuits that generate and regulate breathing; however, the mechanisms responsible for initiating this transformation remain largely unknown. Because amphibian metamorphosis is regulated by hormones such as aldosterone, corticosterone, and thyroid hormone (T3), we tested the hypothesis that exposing the brainstem to these hormones augments the fictive air breathing frequency in pre-metamorphic tadpoles. Brainstems were isolated and were placed either in the recording chamber (acute; 1h+1h recovery) or in a bottle (chronic exposure; 24h) for treatment. Brainstems were exposed to artificial cerebrospinal fluid (aCSF; sham treatment) or one of the following hormones: aldosterone (100nM), corticosterone (100nM), or T3 (100nM). While acute exposure had limited effects on respiratory motor output, chronic incubation with any hormone significantly increased fictive air breathing; the burst frequencies observed following treatment were similar to those observed in adult bullfrogs. We conclude that through their long term effects, hormones regulating metamorphosis can initiate the maturation of the neural circuits that generate and regulate breathing in this species.

Frontostriatal circuits and the development of bulimia nervosa.

Bulimia nervosa (BN) is characterized by both recurrent episodes of binge eating that are, in part, defined by a sense of loss of control and compensatory behaviors to avoid weight gain. Impulsive behaviors are also common in individuals with BN, indicating more pervasive difficulties in behavioral self-regulation. Findings from functional and anatomical neuroimaging studies of individuals with BN suggest dysfunction in the dorsal frontostriatal circuits that support self-regulatory capacities and habit learning and in overlapping ventral circuits that support reward processing and reward-based learning. In this review, we describe the normal development of frontostriatal circuits and then present behavioral and neuroimaging data from adolescents and adults with BN. These data suggest that the abnormal maturation of frontostriatal circuits may contribute to the habitual binge-eating and purging behaviors of BN. Future longitudinal imaging studies will improve understanding of how these circuits contribute to the developmental trajectory of BN and will inform novel interventions that could target or prevent the impulsive and habit-like features of this disorder.

Spontaneous activity in the developing auditory system.

Spontaneous electrical activity is a common feature of sensory systems during early development. This sensory-independent neuronal activity has been implicated in promoting their survival and maturation, as well as growth and refinement of their projections to yield circuits that can rapidly extract information about the external world. Periodic bursts of action potentials occur in auditory neurons of mammals before hearing onset. This activity is induced by inner hair cells (IHCs) within the developing cochlea, which establish functional connections with spiral ganglion neurons (SGNs) several weeks before they are capable of detecting external sounds. During this pre-hearing period, IHCs fire periodic bursts of Ca(2+) action potentials that excite SGNs, triggering brief but intense periods of activity that pass through auditory centers of the brain. Although spontaneous activity requires input from IHCs, there is ongoing debate about whether IHCs are intrinsically active and their firing periodically interrupted by external inhibitory input (IHC-inhibition model), or are intrinsically silent and their firing periodically promoted by an external excitatory stimulus (IHC-excitation model). There is accumulating evidence that inner supporting cells in Kölliker's organ spontaneously release ATP during this time, which can induce bursts of Ca(2+) spikes in IHCs that recapitulate many features of auditory neuron activity observed in vivo. Nevertheless, the role of supporting cells in this process remains to be established in vivo. A greater understanding of the molecular mechanisms responsible for generating IHC activity in the developing cochlea will help reveal how these events contribute to the maturation of nascent auditory circuits.

The international society for developmental psychobiology Sackler symposium: early adversity and the maturation of emotion circuits--a cross-species analysis.

Early-life caregiving shapes the architecture and function of the developing brain. The fact that the infant-caregiver relationship is critically important for infant functioning across all altricial species, and that the anatomical circuits supporting emotional functioning are highly preserved across different species, suggests that the results of studies examining the role of early adversity and emotional functioning should be translatable across species. Here we present findings from four different research laboratories, using three different species, which have converged on a similar finding: adversity accelerates the developmental trajectory of amygdala-prefrontal cortex (PFC) development and modifies emotional behaviors. First, a rodent model of attachment learning associated with adversity is presented showing precocial disruption of attachment learning and emergence of heightened fear learning and emotionality. Second, a model of infant-mother separation is presented in which early adversity is shown to accelerate the developmental emergence of adult-like fear retention and extinction. Third, a model of early life adversity in Rhesus monkeys is presented in which a naturally occurring variation in maternal-care (abuse) is shown to alter the functioning of emotion circuits. Finally, a human model of maternal deprivation is presented in which children born into orphanages and then adopted abroad exhibit aberrant development of emotion circuits. The convergence of these cross-species studies on early life adversity suggests that adversity targets the amygdala and PFC and has immediate impact on infant behavior with the caregiver, and emotional reactions to the world. These results provide insight into mechanisms responsible for caregiver induced mental health trajectory alterations.