Amygdala circuit transitions supporting developmentally-appropriate social behavior

Abstract

Social behaviors dynamically change throughout the lifespan alongside the maturation of neural circuits. The basolateral region of the amygdala (BLA), in particular, undergoes substantial maturational changes from birth throughout adolescence that are characterized by changes in excitation, inhibition, and dopaminergic modulation. In this review, we detail the maturational trajectory through which BLA circuits mature and are influenced by dopaminergic systems to guide transitions in social behavior in infancy and adolescence using data from rodents. In early life, social behavior is oriented towards approaching the attachment figure, with minimal BLA involvement. Around weaning age, dopaminergic innervation of the BLA introduces avoidance of novel peers into rat pups’ behavioral repertoire. In adolescence, social behavior transitions towards peer-peer interactions with a high incidence of social play-related behaviors. This transition coincides with an increasing role of the BLA in the regulation of social behavior. Adolescent BLA maturation can be characterized by an increasing integration and function of local inhibitory GABAergic circuits and their engagement by the medial prefrontal cortex (mPFC). Manipulation of these transitions using viral circuit dissection techniques and early adversity paradigms reveal the sensitivity of this system and its role in producing age-appropriate social behavior.

Introduction

The neural circuitry supporting early social behavior reflects the unique social world of the developing individual. Unlike the adult who participates in complex social hierarchies and seeks a mate, the primary social relationship for the infant is with the caregiver. For altricial species, born immature, the caregiver provides key resources such as food, protection, and warmth, and as such, the social brain of the infant must support approach behavior toward the caregiver. To promote this robust approach behavior, circuits that promote early approach, or attachment, are engaged while those which support avoidance, including fear circuits, are inactive or suppressed by the caregiver. As infants mature and prepare for independence and more intricate social behavior, neural circuits promoting a balance of approach and avoidance become engaged in social tasks.

After infancy and into adolescence, social bonds consist of primarily peer-peer relationships. Social engagement, as in infancy, is both guided by and critical for the maturing brain. For rodents, the ongoing late maturation of the brain is postulated to contribute to a rich, diverse social repertoire with behaviors ranging from play-fighting to investigation. Social play is especially important during adolescence, as it promotes cognitive flexibility and requires a high degree of reciprocal engagement. Across adolescence, social engagement becomes increasingly guided by the environment and social partner, shifting the likelihood of social avoidance and approach to adult-like patterns. The increasing ability to selectively socially engage based on environmental circumstances overlaps with neural circuit maturation and the ability to retain contextual representations, and may therefore be based on the ability to delineate prosocial environments promoting approach versus negative social environments promoting avoidance. Altogether, these shifts in social circuits help prepare infants and adolescents for developmental behavioral transitions given evolving social demands.

Here, we discuss rodent social development and control of this behavior by the maturation of a specific set of brain regions, including the medial prefrontal cortex (mPFC), lateral habenula (LHb), ventral tegmental area (VTA), with a strong focus on the contribution of the basolateral amygdala (BLA). These regions are critical for developing social behavior, undergo substantial maturational changes during early life, and form a circuit whereby cortical and habenula regions regulate VTA dopamine release to downstream targets, including the amygdala. We argue that the coordinated influence of mPFC, LHb, and VTA on the maturing BLA may play an essential role in promoting age-appropriate social behaviors.

Neural circuits promoting infant attachment to a caregiver

The social life of the altricial infant reflects the unique demands of its environment. Unlike adults, altricial infants lack the motoric skills to independently acquire resources necessary for survival, such as food and protection. Instead, they must rely on the caregiver for these resources and thus are thought to possess an evolutionary drive to form an attachment to the caregiver. Following observations of imprinting in birds^1,2, John Bowlby articulated this concept in his Attachment Theory, which described how forming an emotional bond, or attachment, to a caregiver was an innate drive that promotes seeking proximity to a caregiver^3,4.

The neural circuits promoting this attachment to a caregiver have been delineated in the mammalian brain using infant rats, called pups. For pups, the maternal odor is a robust appetitive cue which elicits approach behavior. This odor is based on maternal diet and is not innate but it learned starting in utero⁵. This also means that new maternal odors can be learned through conditioning: pairing a neutral odor with maternal cues (e.g. milk, stroking with a paintbrush to mimic grooming) to elicit approach behaviors towards that odor^6-8. This is a highly robust behavioral system that involves unique circuit function, including the locus coeruleus (LC), anterior piriform cortex, and olfactory bulb (the so-called “attachment circuit”). During the first 9 days of life, rat pups learn a new maternal odor through a process whereby large amounts of norepinephrine (NE) from the LC flood the olfactory bulb (OB) during odor pairings^9-11. This occurs during this period because the infant LC physiology fails to show autoreceptor-mediated inhibitory regulation of electrical activity^12,13. The olfactory bulb axons of mitral cells project directly to the piriform cortex^14-17; this region plays an important role in assigning the hedonic value to a learned odor in a region-specific and age-dependent manner. In particular, the anterior piriform is engaged by odors learned during this sensitive period, whereas later in development, the posterior piriform is engaged in response to learned odor aversions^18-20. It is important to note that both natural maternal odor and a learned artificial maternal odor (e.g., peppermint odor combined with tactile stimulation to resemble maternal cues) generate the same responses from the olfactory bulb ^8,18. When pups are around 10 days old, the LC begins exhibiting habituated NE release and takes on more adult-like functioning. After postnatal day (PND) 10, NE from LC takes on a modulatory role in odor learning that is more similar to what has been described in adult rats ²¹.

Due to the unique physiology of the LC in infancy, this reward conditioning/approach behavior can also be elicited when neutral odors are paired with aversive cues, such as mild shock²². A strong evolutionary bias towards forming attachments to caregivers means that early pairings of neutral and aversive cues eschew the older animal’s fear/avoidance circuitry entirely. Indeed, there is a range of species-expected care quality and it would be highly maladaptive if infants avoided a caregiver following a rare instance of rough care. This bias towards approach is supported by the delayed engagement of the amygdala, a canonical “fear” nucleus across species, which is physically present by embryonic day 17 (first trimester in humans) but functionally immature before PND10^23,24. As a result of this unique system, infants fail to learn aversions to the caregiver and social approach is upheld. However, as will be discussed below, extreme variations in early experience can shift the quality of attachment that is formed, even if learned aversions to the caregiver are essentially impossible to form.

Social buffering of stress and fear learning during infancy

As infants mature, the caregiver becomes not only the ultimate social stimulus to approach, but also gains the ability to modulate the infant’s experience of the world. This process, termed social buffering, has been observed across species, such as non-human primates, dogs and chicks^25-30, and is a feature of attachment relationships throughout the lifespan^31,32. After PND10, the sensitive period for attachment formation gives way to a so-called “transitional sensitive period”, which coincides with an ecological shift whereby pups begin to leave the nest and nibble on solid food³³. At this time, endogenous increases in activity of the hypothalamic-pituitary-adrenal [HPA] axis promote activation of the stress response (including corticosterone release), and functional engagement of the amygdala under conditions of threat. However, this system is still not adult-like. From PND10-15 in rats, the caregiver’s presence blocks activation of the HPA axis and downstream targets, including the amygdala³⁴. This has also been observed in children, whose caregivers have the ability to decrease salivary cortisol in children as well as suppress amygdala reactivity as observed using fMRI^35-37.

During the sensitive period for attachment (<PND10), there is no social decision-making—the infant’s social strategy (or lack thereof) is strongly biased towards approach. This ensures access to the caregiver, the source of critical resources promoting survival. During the transitional sensitive period (PND10-15), social behavior evolves but is still not adult-like: caregiver presence can influence whether stimuli are to be approached or avoided. The development of social behavior may be understood within the framework of the developing fear system. In both rodents and four-year-old children, it has been shown that neutral stimuli paired with unconditioned aversive cues produce learned avoidance when experienced alone -- similar to the adult. However, if the caregiver is present during these pairings, the previously neutral stimuli now elicit approach behavior^19,38. This remarkable gating of fear/approach learning has been shown to depend on caregiving buffering of stress hormone release in rat pups¹⁹.

After PND15, the power of the caregiver transitions to a more modulatory effect on stress levels, similar to the effect of social partners in adulthood^31,32,39-41. A similar shift has been observed in children, whereby the caregiver’s ability to regulate amygdala-PFC connectivity in younger children wanes as children enter adolescence⁴². Another key transition occurs in the processing of the caregiver cue itself: whereas the mother’s voice modulates activity of canonical reward circuits in children (7-13.5 years old), unfamiliar female voices have this effect on the adolescent brain (13.5-17years old)⁴³. These maturational changes reflect a shift away from dependence on caregiver guidance as children begin to interact with strangers and prepare to make social decisions independently.

Gradual inclusion of amygdala in social behavior circuits as infants mature

As young individuals gain independence, social behavior circuitry becomes more complex to accommodate more complex social decision-making. These circuits now include the amygdala and its dopaminergic innervation from the ventral tegmentum. In adults, the amygdala plays an important role in social behavior^44-48. Although the human amygdala is responsive to fearsome stimuli as early as six months of age^49,50, its role in infant social behavior is poorly understood. In non-human primates, bilateral amygdala lesions impair social behavior in adulthood but not infancy^51-53, suggesting developmental transitions in amygdala involvement. In rodents, amygdala engagement is atypical in infant social behavior and premature engagement inhibits social approach toward the caregiver^54,55. As mentioned above, this early absence of the amygdala in the typical social behavior circuit supports the early social behavior bias toward approaching the mother under both threat and safety^19,56-58. As rat pups reach weaning age (~PND21), the amygdala joins the social circuit, where adversity or overstimulation can decrease social approach towards novel peers⁵⁵.

This transition may be supported by changes in the function of GABAergic systems within the basolateral amygdala (BLA) during infancy⁵⁹. Locally, GABAergic transmission within the BLA changes from depolarizing to hyperpolarizing around weaning (PND 21), suggesting a functionally distinct role for GABAergic systems prior to and following weaning⁵⁹. Parvalbumin (PV)-expressing GABAergic neurons in particular are expected to exert robust inhibitory regulation of principal neurons, controlling both action potential timing and synchrony⁶⁰. Their expression increases during infancy and is dependent on extracellular support through perineuronal nets (PNNs)^61,62. In early life, BLA PV and PNN expression is inversely correlated with BLA excitability and behavioral threat responses^63,62. Interestingly, early life adversity in the form of limited bedding and nesting for nursing rat dams has been shown to impact BLA PV expression in pups, with some studies showing accelerated PV expression patterns and others showing slowed expression^64,65. In these studies, manipulations of PNN coverage and PV activity were shown to reverse the effects of early adversity on threat behavior expression⁶⁵.The effects of an aversive social environment extend into adulthood, where juvenile/adolescent isolation (PND21-35) reduces PV excitability in the mPFC and reduces social approach⁶⁶. Altogether, the shift in GABAergic function alongside developmental-related increases in PV neuronal expression suggests that early stressors may uniquely impact mPFC-BLA PV populations to disrupt social and fear behaviors.

Dopamine (DA) released in the BLA alters the excitation:inhibition balance, increasing excitability of excitatory and inhibitory GABAergic neurons⁶⁷. As systems are maturing, and in the case of GABAergic neurons undergoing functional changes, DA may have a distinct impact on the amygdala. This has been seen with decades of microdialysis studies demonstrating that caregiver inputs such as milk decrease DA release from the VTA, the primary source of dopamine to the amygdala^68-70. Furthermore, caregiver presence prevents DA release in the basolateral amygdala (BLA) during threat exposure in the transitional sensitive period (PND10-15)⁷¹. During this period, the caregiver has been shown to regulate the broader mesolimbic dopamine circuit, including the VTA, BLA, and nucleus accumbens⁷².

Recent circuit dissection work in rodent pups has highlighted the role of dopaminergic projections from the VTA to the BLA in generating age-specific social behavior⁵⁵. As mentioned above, pre-weaning pups demonstrate a strong bias towards social approach, whereas older pups show more inhibited social approach behavior towards novel peers. Optogenetic inhibition of BLA principal neurons or inhibition of VTA terminals in the BLA increased social approach in post-weaning (PND22, weaned at PND21) but not younger pups (PND14), suggesting these regions are not involved in inhibiting social behavior in young pups. Conversely, optogenetic stimulation of BLA principal neurons or stimulation of VTA projections to BLA inhibited typical social approach. Taken together, these results demonstrate that dopaminergic innervation of the BLA is atypical during early social behavior and recruitment of this circuit transitions a system biasing social approach toward the caregiver toward one favoring a balance of approach and avoidance as infants mature (summarized in Figure 1)

Figure 1. Changes in social behavior and socially-relevant amygdala function across early development.

In early infancy, social behavior is dominated by approach towards the caregiver and minimal BLA activity. As infants transition to independence at weaning, dopaminergic innervation of the BLA is associated with increased BLA engagement in social behavior and elaboration of social behavior to include a balance of approach and avoidance. As juveniles enter adolescence, spontaneous play behaviors increase and gradually give way to predictable sequences of behavior that become increasingly dependent on memory for contextual features and partner sex. These changes are associated with increased involvement of the mPFC and in particular, mPFC engagement of local inhibitory circuits within the BLA. Intensity of BLA shading reflects gradual increase in BLA involvement in social cue processing and social behavior.

Neural circuits critical for adolescent social behavior

From infancy to adolescence (PND28-42, conservatively) there is an emergence of social play behaviors, including chasing, rough-and-tumble, and pinning behaviors^73-76. Social play promotes cognitive flexibility and is believed to help adolescents respond to an ever-changing environment due to the reciprocal nature of the social encounter^77-79. Engagement in social play activates a network of brain regions, including the thalamus, prefrontal cortex, amygdala, and striatum^80-83. Thalamic and striatal regions transmit sensory information critical for the expression of social play, and when in socially-motivated states, social play relies on BLA activity^80,84,85.

During adolescence, there are changes in social play, where behavioral sequences (e.g. initiation of play with pouncing and transient establishment of dominance) become more predictable and involve rough-and-tumble, wrestling behaviors, with relatively spontaneous bouts occurring during PND21-30 and sequential patterns evident from PND30^74,84,86. The predictability of play behavioral sequences and the ability to flexibly respond to different play sequences is believed to rely on striatal dopaminergic and medial prefrontal cortical function^87-89. Inter-regional coordination of neural processes, and in particular, connections between cortical-amygdala and ventral striatal-amygdala regions, are postulated to support the engagement in and rewarding aspects of social play, respectively⁸². Activity in striatal and mPFC regions is positively correlated with VTA activity following social play and these regions are independently critical for play behavior⁸². Together, these results suggest that dopaminergic modulation of amygdala-centric neural circuits is related to social play and maturation of these circuits may guide changes in social play from early to late adolescence.

While the sequential nature of social behaviors remains, social play itself decreases as adolescents transition to adulthood (PND70+), alongside gradual shifts in interaction based on partner and environment⁷⁴. These changes are largely characterized by increases in sexually motivated behaviors, like mounting and lordosis, among opposite sex interactions and decreases in social play towards same sex partners that overlap with sexual maturity⁷⁴. Sexual maturity in females can be defined with vaginal opening typically between PND32-44 while balanopreputial separation defines male sexual maturity occurring around PND45-48 (please see⁹⁰ for review). Changes in expression of social behaviors encompass a transitional period from adolescence to adulthood that is not defined by maturation of behavioral expression, as these are often expressed in an adult-like manner, but rather the order of social behaviors that are increasingly guided by partner and environment⁷⁴. In line with this, the temporal retention for contextual information increases into adulthood, supporting the idea that the environment may play an increasing role in guiding social engagement^91,92. The integration of environmental information to guide social behavior may rely on amygdala activation, as amygdala activity is required for context-dependent emotional memories^82,93,94. Therefore, the increasing ability to retain contextual information, may play an important role in guiding specific social behaviors based on environmental demands (i.e. threatening and safe environments) that influences approach and avoidance behaviors.

Amygdala maturation and regulation of adolescent social behavior

The role of the adolescent BLA (PND36-37) increases over time in its sensitivity to social behavior ^82,95. Late maturation of cortical inputs to the amygdala and inhibitory GABAergic systems within the amygdala are readily evident late into adolescence (PND 45) and coincide with developmental transitions from maternal attachment-related behaviors towards playful peer-peer relationships ^61,96-98. GABAergic systems mature throughout adolescence, with adolescent-specific decreases in the frequency of miniature IPSCs following stress exposure and notably their ability to exert inhibition over excitatory projection neurons evident until PND 39^98,99. This increase in evoked inhibition with age has been most clearly seen with medial prefrontal cortical (mPFC) inputs⁹⁸. These cortical inputs can evoke excitatory and indirect inhibitory effects on BLA activity, with the adult phenotype largely characterized by mPFC engagement of local GABAergic networks suppressing excitatory BLA neuronal activity]. In adolescence, mPFC suppression of BLA excitatory neuronal activity is reduced as a result of ongoing GABAergic integration. This provides a unique late-maturing system that relies on the pruning of extraneous cortical inputs alongside increases in cortical synaptic strength and integration of local inhibitory systems ^97,98,100.

The maturation of mPFC inputs to the BLA may contribute to transitions from adolescence (PND28-45) to adulthood (PND70) with movement away from social play, comprised of chasing, boxing, and rough-and-tumble, towards social behaviors that are guided based on environment and partner in adulthood^74,84,86,87. Adult and adolescent behavior alike can be disrupted with local mPFC or BLA interference with some of the more prominent BLA effects linked to GABAergic systems^80,101 . This is supported by adolescent environmental disruptions that persistently impair social function similarly impair BLA GABAergic systems, disrupting the excitation:inhibition balance supporting age-specific social engagement^102,103. Together, these studies provide evidence for the pivotal role of both excitation and inhibition within the BLA in maturing social behavior, wherein maturation of cortical and local inhibitory systems promote age-specific social engagement.

Dopaminergic maturation and amygdala modulation during adolescence

DA systems undergo substantial maturational changes during adolescence (approximately PND32), and their development is sensitive to social stressors that have lasting impacts into adulthood^104-107. Within the adult BLA, DA shifts the excitation:inhibition balance through direct modulation of principal excitatory and local inhibitory GABAergic neurons^108,109. Dopaminergic fibers innervate parvalbumin-expressing GABAergic interneurons, which, as discussed above, play a critical role in regulating and synchronizing amygdala neuronal activity ¹⁰⁹. These DA inputs inhibit GABAergic transmission from parvalbumin interneurons to principal neurons in the BLA via dopamine D2 receptors (D2DR¹¹⁰). However, adolescence is characterized by reduced amygdala GABAergic function, and within the basolateral amygdala, there is an increasing degree of extracellular support from perineuronal nets surrounding parvalbumin interneurons from adolescence (PND35-36) to adulthood (approximately PND70) ⁶¹. This suggests that D2DR modulation of GABAergic transmission between BLA parvalbumin and excitatory neurons may not hold the same efficacy during adolescence as in adulthood, but this modulation may increase in a manner that corresponds to perineuronal net-parvalbumin maturation.

DA can also exert effects through dopamine D1 receptors (D1DR) receptors. These receptors are expressed throughout the amygdala and mPFC and are involved in the maintenance of social hierarchies, where D1DRs aid in the establishment of dominance and D2DRs in subordination^111-115. Within the mPFC, principal projection neurons regulate social dominance during reward competition, and the activity of PV-expressing neurons is required during adolescence for adult mPFC function^111,116. D1DRs in the mPFC increase excitability of principal excitatory neurons and GABAergic interneurons containing vasoactive intestinal peptide, whose function is to suppress other GABAergic interneurons, playing a potentially important role in social dynamics and cognitive flexibility^114,117. Similar to the mPFC, D1DRs increase the excitability of both GABAergic and principal neurons in the mature BLA⁶⁷. MPFC-BLA synapses contain D1DRs, and D1DR activity alters mPFC-evoked GABAergic inhibition in a mature mPFC-BLA circuit^112,118. D1DR modulation may thus facilitate mPFC drive of the BLA, targeting BLA GABAergic populations, due to mPFC disinhibition via vasoactive intestinal peptide GABAergic neurons. While D1Rs increase neuronal excitability in a mature circuit, these receptors are not uniformly responsive from adolescence (approximately PND20-32) to adulthood, indicating a shift in their impact over time^104,107. Developmental differences in mPFC-BLA and D1DR function may therefore be partially driven by developmental differences in GABA processes. It is possible that D1DR-modulation of the mPFC-BLA pathway could have minimal effects due to ongoing dopaminergic and circuit maturation, or may augment mPFC-BLA function to resemble an adult-like neuronal phenotype. Overall, the maturation of several systems in parallel indicates a potential age-dependent role for D1R in the modulation of maturing mPFC-amygdala circuitry supporting age-specific social behaviors.

Lateral habenula as a key locus for developmental transitions in social behavior

Recent work in rodents suggests that the behavioral changes that accompany these circuit transitions may also involve an upstream modulator of VTA dopamine release, the lateral habenula (LHb). This region serves as an interface between the forebrain and the dopamine/serotonin systems and is widely considered the brain’s “anti-reward region”, as it robustly responds to aversive cues or the absence of expected rewards by suppressing DA release from the VTA^119,120. Although this region is known to be important for adult social behavior flexibility¹²¹, its role in development is poorly understood. Recent work in pups suggests that the LHb promotes a developmental transition in social behavior when threats are present. Specifically, when a threat cue is present, the LHb increases approach towards a social cue in pre-weaning pups, whereas the LHb inhibits approach in post-weaning pups^122,123. In this way, the LHb may be supporting developmentally-specific social behavior: when the infant is threatened, approaching the social partner for safety (e.g. caregiver) is adaptive, whereas later in development, social partners are more ambiguous and may themselves be threats.

In adults, the mPFC-LHb projection inhibits social approach¹²¹. The transition in LHb contribution to social behavior may be related to ongoing maturation of mPFC inputs to the LHb and/or dopaminergic modulation developing affective neural circuitry. For example, ongoing mPFC maturation during adolescence may progressively increase in the ability to engage the LHb in social circumstances, altering social approach and avoidance from infancy to adulthood. These changes in cortically-mediated LHb engagement alter LHb-dependent coordination of valence-related information to several brain regions governing affective responding to social circumstances, including maternal-related stressors that increase the excitability of the LHb¹²⁴. This may be a primary factor in the role of the maturing neural systems during age-specific social behavior, particularly after aversive experiences.

Impact of early care quality on developing social behavior circuits

The plasticity that permits caregiver regulation of the infant brain also renders the infant uniquely vulnerable to environmental impacts. These impacts can disrupt typical development of social circuits and produce lasting outcomes, including increased vulnerability to psychiatric disorders^123,125-128. Given the importance of the caregiver-infant dyad as an early template for social behavior, early disruptions in care quality have the ability to compromise social behavior throughout the lifespan.

As mentioned above, children attach to their caregiver regardless of the quality of care received, ensuring access to life-sustaining resources. However, poor quality care is associated with compromised attachment, resulting in disrupted social approach towards the caregiver and decreased ability of the caregiver to regulate the child’s stress system^36,129-131. To study this in rodents, researchers employ paradigms such as the Scarcity-Adversity Model of Low Bedding (SAM-LB, for review, see^130,132). In this model, the mother rodent is given insufficient bedding for nest building, resulting in rough handling of pups alongside typical levels of nurturing. This type of rearing degrades the value of maternal signals: maternal odor elicits attenuated approach and attenuated neural responses throughout the brain⁶. Furthermore, following SAM-LB, maternal presence fails to block pup fear learning¹³³. Circuit analysis showed that the VTA is not buffered by maternal cues and these cues fail to block amygdala plasticity^72,134. Furthermore, previous SAM-LB rearing resulted in precocious engagement of the BLA and VTA-BLA circuitry in social behavior, resulting in decreased social approach toward the mom and peers.

Additional recent work using SAM-LB capitalizes on the ability of animal researchers to study what is occurring during the adversity itself, an impossible manipulation in humans. In this study, transmitters were implanted in the frontal cortex of pups for wireless telemetry recording of local field potentials (LFPs)¹³⁵. Previous research had shown that nurturing inputs such as receiving milk and being groomed produced transient bursts in oscillatory power¹³⁶. During SAM-LB, these same inputs failed to produce these expected changes, despite the fact that milk/grooming inputs occurred at the same frequency in both SAM-LB and control environments. This pattern of decreased ability of the caregiver to modulate the infant brain parallels results using electroencephalography in children with impaired attachment to caregivers^137,138. Across species, impaired cortical regulation in the nest was accompanied by later deficits in social behavior with the caregiver.

The impact of maternal care on social behavior extends into adolescence. This has been clearly seen with impacts of dam-to-pup grooming levels on the amount of peri-adolescent and adolescent social play^139,140. However, the positive or negative direction of this relationship seems to depend on sex and time of testing, where licking and grooming behaviors are positively correlated with social play in adolescent males but negatively correlated in juvenile males ^139,140. The BLA is especially sensitive to social play and environmentally-driven changes in social behavior. This is supported by literature demonstrating that early life adversity and social stressors impede mPFC and BLA function, the dopaminergic modulation within these regions, and accelerate BLA parvalbumin maturation controlling social behavior ^65,141-144. Altogether, this highlights a dynamic relationship between dopaminergic modulation of maturing amygdala circuits and social sensitivity.

Conclusion

In adults, the social world involves decision-making: Do I remember this individual? Is this individual safe or threatening? Is the risk of approach worth the potential reward of interacting? This elaborate process involves numerous circuits and processes, including social recognition, memory, risk assessment and hard-wired behaviors. Social behavior is much simpler for the infant—no decisions need to be made, as the caregiver should always be approached, thereby engaging a straightforward attachment circuit. In older infants and children, circuits promoting avoidance are functional, but the caregiver can turn these off and thereby guide or even replace decision-making. As infants mature and prepare for independence at weaning age, the social brain becomes more complex and additional neural circuits, such as DA-ergic innervation of the BLA, become engaged to diversify social strategies and support a balance of approach and avoidance. During adolescence, social interactions are largely characterized by social play with peers. While these behaviors are largely spontaneous initially, social play gradually becomes increasingly contingent on prior preceding behaviors and partner sex. Within adolescent social play development, this is believed to be mediated by maturation of prefrontal cortical and amygdala function, that may be facilitated by DA-ergic inputs. Finally, this circuit ontogeny can be perturbed or accelerated when the early caregiver-infant dyad social relationship is compromised, as can occur with early caregiving adversity.

Although there is no consensus mapping rodent age onto human age, parallel circuit changes supporting ecological milestones in behavior suggest similar mechanisms supporting social re-orientation across the lifespan^145-147. Taken together, this body of work suggests that special attention to the unique function of social circuits across development will be critical for identifying points of entry for age-specific interventions that account for alterations in dopaminergic function, inhibitory GABAergic systems, and necessity of social contact for behavioral development during early life.

Highlights.

• Early social behavior supports approach toward the caregiver

• Later social behavior with peers is more complex, involving play and avoidance

• Neural circuit changes involving the amygdala promote this behavioral shift

• Immature local inhibition in amygdala characterizes adolescent behavior