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Environmentally appropriate social behavior is critical for survival across the lifespan. To support this flexible behavior, the brain must rapidly perform numerous computations taking into account sensation, memory, motor-control, and many other systems. Further complicating this process, individuals must perform distinct social behaviors adapted to the unique demands of each developmental stage; indeed, the social behaviors of the newborn would not be appropriate in adulthood and vice versa. However, our understanding of the neural circuit transitions supporting these behavioral transitions has been limited. Recent advances in neural circuit dissection tools, as well as adaptation of these tools for use at early time points, has helped uncover several novel mechanisms supporting developmentally appropriate social behavior. This review, and associated Minisymposium, bring together social neuroscience research across numerous model organisms and ages. Together, this work highlights developmentally regulated neural mechanisms and functional transitions in the roles of the sensory cortex, prefrontal cortex, amygdala, habenula, and the thalamus to support social interaction from infancy to adulthood. These studies underscore the need for synthesis across varied model organisms and across ages to advance our understanding of flexible social behavior.

The medial amygdala (MeA) is activated by social stimuli and manipulations of the MeA disrupt a wide range of social behaviors. Social stress can shift social behaviors and may accomplish this partly via effects on the MeA. However, very little is known about the effects of social stress on the electrophysiological activity of MeA neurons. The posterior division of the MeA (MeAp) has been implicated in driving social engagement. We hypothesized that repeated social stress would cause parallel changes in in vivo activity of MeAp neurons and social behavior. The resident-intruder paradigm was used to produce repeated social stress in adult male rats. After repeated social stress, MeAp neurons were recorded with in vivo single-unit electrophysiology in anesthetized rats. MeAp neurons, specifically those in the posterodorsal subnucleus (MeApd), fired faster in stressed rats than in controls, and this effect was directly associated with stressor intensity. The MeAp sends dense projections to the posterior bed nucleus of stria terminalis (pBNST) and ventromedial hypothalamus (VMH), and both regions are essential for social engagement and are sensitive to social stressors. MeAp projections to pBNST had higher activity after stress, whereas projections to the VMH were not affected. These effects were significant only in rats that displayed susceptibility to this social stressor, as demonstrated by lower weight gain. Furthermore, the effect of stress on MeApd and MeAp-pBNST neuronal firing was correlated with lower social interaction. These results indicate that heightened MeApd and MeA-pBNST activity may contribute to alterations in social behaviors following social stress. NEW & NOTEWORTHY: Social stress contributes to psychiatric disorders and impacts multiple brain regions. However, effects on a crucial area for social function, the medial amygdala (MeA), are unclear. We found that social stress increased firing of posterior MeA neurons, and particularly neurons that project to bed nucleus of the stria terminalis, a region implicated in anxiety. Effects of stress on this circuit were associated with diminished social interaction and help clarify how stress can impact social functions. [ABSTRACT FROM AUTHOR]

Relative to males, female rats can show enhanced contextual fear generalization (demonstrating a fear response in a safe or neutral context) dependent on estrogen receptor activation. The current experiment aimed to extend this finding to cued fear conditioning. Females in low-estrogen phases of the estrous cycle showed good discrimination, similar to males, between a conditional stimulus that predicted shock (CS+) and an equally familiar one that did not (CS-), while females in the proestrus (high estrogen) phase demonstrated similar levels of fear between the CS+ and CS-. These results demonstrate that cued fear generalization is similarly influenced by endogenous estrogens.

Numerous studies have indicated that the consolidation of contextual fear memories supported by an aversive outcome like footshock requires de novo protein synthesis as well as protein degradation mediated by the ubiquitin-proteasome system (UPS). Context memory formed in the absence of an aversive stimulus by simple exposure to a novel environment requires de novo protein synthesis in both the dorsal (dHPC) and ventral (vHPC) hippocampus. However, the role of UPS-mediated protein degradation in the consolidation of context memory in the absence of a strong aversive stimulus has not been investigated. In the present study, we used the context preexposure facilitation effect (CPFE) procedure, which allows for the dissociation of context learning from context-shock learning, to investigate the role of activity-dependent protein degradation in the dHPC and vHPC during the formation of a context memory. We report that blocking protein degradation with the proteasome inhibitor clasto-lactacystin beta-lactone (betaLac) or blocking protein synthesis with anisomycin (ANI) immediately after context preexposure significantly impaired context memory formation. Additionally, we examined 20S proteasome activity at different time points following context exposure and saw that the activity of proteasomes in the dHPC increases immediately after stimulus exposure while the vHPC exhibits a biphasic pattern of proteolytic activity. Taken together, these data suggest that the requirement of increased proteolysis during memory consolidation is not driven by processes triggered by the strong aversive outcome (i.e., shock) normally used to support fear conditioning.

Generalization of fear can involve abnormal responding to cues that signal safety and is common in people diagnosed with post-traumatic stress disorder. Differential auditory fear conditioning can be used as a tool to measure changes in fear discrimination and generalization. Most prior work in this area has focused on elevated amygdala activity as a critical component underlying generalization. The amygdala receives input from auditory cortex as well as the medial geniculate nucleus (MgN) of the thalamus, and these synapses undergo plastic changes in response to fear conditioning and are major contributors to the formation of memory related to both safe and threatening cues. The requirement for MgN protein synthesis during auditory discrimination and generalization, as well as the role of MgN plasticity in amygdala encoding of discrimination or generalization, have not been directly tested. GluR1 and GluR2 containing AMPA receptors are found at synapses throughout the amygdala and their expression is persistently up-regulated after learning. Some of these receptors are postsynaptic to terminals from MgN neurons. We found that protein synthesis-dependent plasticity in MgN is necessary for elevated freezing to both aversive and safe auditory cues, and that this is accompanied by changes in the expressions of AMPA receptor and synaptic scaffolding proteins (e.g., SHANK) at amygdala synapses. This work contributes to understanding the neural mechanisms underlying increased fear to safety signals after stress.