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Nucleus accumbens (NAc) neurons integrate excitatory inputs from cortical and limbic structures, contributing to critical cognitive functions, including decision-making. As these afferents mature from adolescence through adulthood, incoming signals to the NAc may summate differently between age groups. Decision-making evaluates both reward and risk before action selection, suggesting an interplay between reward- and risk-related circuits. Medial orbitofrontal cortex (MO)-NAc circuits permit risk assessment behaviors and likely underlie risk information incorporation. As adolescents make reward-centric choices regardless of risk, we hypothesized the impact of MO activity alters reward-related NAc circuits in an age-dependent manner. To test this hypothesis, we used single-unit electrophysiology to measure MO train stimulation’s effect on reward-related pathways, specifically the basolateral amygdala (BLA)-NAc circuit, in adult and adolescent rats. MO train stimulation altered the strength but not the timing of BLA–NAc interactions in a frequency-dependent manner. In adults, MO train stimulation produced a frequency-dependent, bidirectional effect on BLA-evoked NAc AP probability. Contrastingly, MO train stimulation uniformly attenuated BLA-NAc interactions in adolescents. While the mature MO can govern reward-related circuits in an activity-dependent manner, perhaps to adapt to positive or negative decision-making outcomes, the adolescent MO may be less able to bidirectionally impact reward-related pathways resulting in biased decision-making.

Abnormal fear and anxiety can manifest as psychiatric disorders. The bed nucleus of the stria terminalis (BNST) is implicated in sustained responding to, or anticipation of, an aversive event which can be expressed as anticipatory anxiety. The BLA is also active during anticipatory anxiety and sends projections to the BNST. However, little is known about the role for BLA neurons that project to BNST (BLA-BNST) in anticipatory anxiety in rodents. To address this, we tested whether chemogenetic inactivation of the BLA-BNST pathway attenuates sustained conditioned responses produced by anticipation of an aversive stimulus. For comparison, we also assessed BLA-BNST inactivation during social interaction, which is sensitive to unlearned anxiety. We found that BLA-BNST inactivation reduced conditioned sustained freezing and increased social behaviors, but surprisingly, only in males. To determine whether sex differences in BLA-BNST neuronal activity contribute to the differences in behavior, we usedin vivoandex vivoelectrophysiological approaches. In males, BLA-BNST projection neurons were more active and excitable, which coincided with a smaller after-hyperpolarization current (IAHP) compared with other BLA neurons; whereas in females, BLA-BNST neurons were less excitable and had largerIAHPcompared with other BLA neurons. These findings demonstrate that activity of BLA-BNST neurons mediates conditioned anticipatory anxiety-like behavior in males. The lack of a role of BLA-BNST in females in this behavior, possibly because of low excitability of these neurons, also highlights the need for caution when generalizing the role of specific neurocircuits in fear and anxiety.SIGNIFICANCE STATEMENTAnxiety disorders disproportionately affect women. This hints toward sex differences within anxiety neurocircuitry, yet most of our understanding is derived from male rodents. Furthermore, debilitating anticipation of adverse events is among the most severe anxiety symptoms, but little is known about anticipatory anxiety neurocircuitry. Here we demonstrated that BLA-BNST activity is required for anticipatory anxiety to a prolonged aversive cue, but only in males. Moreover, BLA-BNST neurons are hypoactive and less excitable in females. These results uncover BLA-BNST as a key component of anticipatory anxiety circuitry, and cellular differences may explain the sex-dependent role of this circuit. Uncovering this disparity provides evidence that the assumed basic circuitry of an anxiety behavior might not readily transpose from males to females.

Microglia are critical for regulation of neuronal circuits that mature from adolescence to adulthood. The morphological complexity and process length of microglia can indicate different activation states. These states are sensitive to a variety of environmental and stress conditions. Microglia are sensitive to many factors that also regulate social behavior, and in turn, microglial manipulations can impact social function. Brief social isolation is one factor that can lead to robust social changes. Here, we explored the role of microglia in the effects of brief social isolation on social recognition memory. Using morphological measures of Iba1 to index microglial intensity, complexity, and process length, we identified different effects of brief isolation on microglial complexity in the basal region of the amygdala between adults and adolescents alongside overall increases in intensity of Iba1 in several cortical brain regions. Short-term social recognition memory is sensitive to the amount of social engagement, and provides an opportunity to test if social engagement produced by brief isolation enhances social learning in a manner that relies on microglia. We found that brief isolation facilitated social interaction across ages but had opposing effects on short-term social recognition. Isolation increased novel partner investigation in adolescents, which is consistent with better social recognition, but increased familiar partner investigation in adults. Depletion of microglia with PLX3397 prevented these effects of brief isolation in adolescents, and reduced them in adults. These results suggest that distinct changes in microglial function driven by the social environment may differentially contribute to subsequent social recognition memory during development.

Amygdala abnormalities characterize several psychiatric disorders with prominent social deficits and often emerge during adolescence. The basolateral amygdala (BLA) bidirectionally modulates social behavior and has increased sensitivity during adolescence. We tested how an environmentally-driven social state is regulated by the BLA in adults and adolescent male rats. We found that a high social drive state caused by brief social isolation increases age-specific social behaviors and increased BLA neuronal activity. Chemogenetic inactivation of BLA decreased the effect of high social drive on social engagement. High social drive preferentially enhanced BLA activity during social engagement; however, the effect of social opportunity on BLA activity was greater during adolescence. While this identifies a substrate underlying age differences in social drive, we then determined that high social drive increased BLA NMDA GluN2B expression and sensitivity to antagonism increased with age. Further, the effect of a high social drive state on BLA activity during social engagement was diminished by GluN2B blockade in an age-dependent manner. These results demonstrate the necessity of the BLA for environmentally driven social behavior, its sensitivity to social opportunity, and uncover a maturing role for BLA and its GluN2B receptors in social engagement.SIGNIFICANCE STATEMENTSocial engagement during adolescence is a key component of healthy development. Social drive provides the impetus for social engagement and abnormalities underlie social symptoms of depression and anxiety. While adolescence is characterized by transitions in social drive and social environment sensitivity, little is known about the neural basis for these changes. We found that amygdala activity is uniquely sensitive to social environment during adolescence compared with adulthood, and is required for expression of heightened social drive. In addition, the neural substrates shift toward NMDA dependence in adulthood. These results are the first to demonstrate a unique neural signature of higher social drive and begin to uncover the underlying factors that heighten social engagement during adolescence.

Adolescents are characterized by a propensity for risky and impulsive behaviors, likely due to immature frontostriatal circuits. The medial orbitofrontal cortex (MO) is linked to risk and reward prediction during decision-making. Identifying age-dependent differences in MO activity and its inputs to downstream regions can elucidate the neural substrates that permit the transition from high-risk adolescent behaviors to increased risk assessment in adulthood. Action selection biased by information gathered by the MO is likely carried out by efferents into the nucleus accumbens (NAc), which guides reward-directed behaviors. Despite the large age dependency of risk-based decision-making, there is nothing known about adolescent MO activity. Here, we recorded action potentials of MO neurons from anesthetized adult and adolescent rats in vivo. On average, adolescent MO neurons fire faster and within narrower ranges than adults, and adolescents have more active MO neurons than adults. Using antidromic stimulation of axon terminals to identify MO neurons that project to NAc (MO→NAc), we found that adolescent MO→NAc neurons have a narrower range of firing frequencies than non-NAc-projecting MO neurons and adult MO→NAc neurons. These age-dependent differences in MO and MO→NAc populations may result from the fine-tuning of circuits between adolescence and adulthood that promote specific age-dependent behaviors.

Stress can negatively impact brain function and behaviors across the lifespan. However, stressors during adolescence have particularly harmful effects on brain maturation, and on fear and social behaviors that extend beyond adolescence. Throughout development, social behaviors are refined and the ability to suppress fear increases, both of which are dependent on amygdala activity. We review rodent literature focusing on developmental changes in social and fear behaviors, cortico-amygdala circuits underlying these changes, and how this circuitry is altered by stress. We first describe changes in fear and social behaviors from adolescence to adulthood and parallel developmental changes in cortico-amygdala circuitry. We propose a framework in which maturation of cortical inputs to the amygdala promote changes in social drive and fear regulation, and the particularly damaging effects of stress during adolescence may occur through lasting changes in this circuit. This framework may explain why anxiety and social pathologies commonly co-occur, adolescents are especially vulnerable to stressors impacting social and fear behaviors, and predisposed towards psychiatric disorders related to abnormal cortico-amygdala circuits.

Adolescence is characterized by increased susceptibility to the development of fear- and anxiety-related disorders. Adolescents also show elevated fear responding and aversive learning that is resistant to behavioral interventions, which may be related to alterations in the circuitry supporting fear learning. These features are linked to ongoing adolescent development of medial prefrontal cortical (PFC) inputs to the basolateral amygdala (BLA) that regulate neural activity and contribute to the refinement of fear responses. Here, we tested the hypothesis that the extent of PFC inhibition of the BLA following fear learning is greater in adults than in adolescents, using anesthetized in vivo recordings to measure local field potentials (LFPs) evoked by stimulation of PFC or auditory thalamic (MgN) inputs to BLA. We found that BLA LFPs evoked by stimulation of MgN inputs were enhanced in adults following fear conditioning. Fear conditioning also led to reduced summation of BLA LFPs evoked in response to PFC train stimulation, and increased the capacity of PFC inhibition of MgN inputs in adults. These data suggest that fear conditioning recruits additional inhibitory capacity by PFC inputs to BLA in adults, but that this capacity is weaker in adolescents. These results provide insight into how the development of PFC inputs may relate to age differences in memory retention and persistence following aversive learning.

Urological emergencies represent 7 % of the outpatients at the emergency department (ED). We assessed the effect of setting up a post-emergency consultation (CPU) after deferred urological medical regulation.All patients admitted to the ED in a university center over the period December 2017 to July 2018 and for whom a CPU was scheduled were included. The regulation concerned the date of CPU and supplementary exams. The main outcome was the ability to provide an efficient response according to a predefined grid of specific solutions.One hundred and twenty-eight patients were included. The median age was 57 years (18-97). Efficacy of the CPU was 76 %. This rate was lower in no-show patients or consulting for rare and complex motives (47 %, n=60). The no-show were not reachable on the first call in 51.6 % of cases, with a similar age and motives distribution to the others. Only 6,9 % (n=128) of all consultants (n=1863) had been referred to the CPU by emergency physicians. The decision was a second consultation in 70 % (48), a new exam in 10 % (7), deferred emergency surgery in 12 % (8) and finally 18 % (12) of no follow-up.CPU following early regulation by a urologist provides an effective response in 76 % of situations. Assessment of "no-shows" helped to identify groups at risk.III.

The amygdala plays a key role in a range of adaptive social and emotional behaviors. As might be expected for a region that facilitates rapid changes, the amygdala is highly sensitive to the environment, in particular, challenges and stressors that are faced by the organism. Over short time periods, the amygdala can be primed to facilitate protective behavioral responses to stressors. However, prolonged stress experiences can lead to long-lasting changes that may be adaptive in only limited environmental settings. This chapter focuses on how acute and prolonged stress recruits and modifies the amygdala. We present evidence that stressors can produce a shift in the balance of activity and excitability of amygdala nuclei, leading to a shift in the stream of information processing through the amygdala and heightened sensitivity of the amygdala to the environment. We propose a specific set of changes in the balance between amygdala nuclei after acute stress that focuses amygdala activity towards specific stimuli, but different changes after prolonged stress that make amygdala circuits more responsive to many stimuli. This, in turn, promotes some of the behavioral changes observed after prolonged stress, such as increased sensitivity to surroundings, and loss of specificity for the environmental stimuli that are judged to be relevant. These shifts evoke emotional changes, and enhanced emotional responding, that often presents as increased anxiety.

Cognitive regulation of emotion develops from childhood into adulthood. This occurs in parallel with maturation of prefrontal cortical (PFC) regulation over the amygdala. The cellular substrates for this regulation may include PFC activation of inhibitory GABAergic elements in the amygdala. The purpose of this study was to determine whether PFC regulation over basolateral amygdala area (BLA) in vivo is immature in adolescence, and if this is due to immaturity of GABAergic elements or PFC excitatory inputs. Using in vivo extracellular electrophysiological recordings from anesthetized male rats we found that in vivo summation of PFC inputs to the BLA was less regulated by GABAergic inhibition in adolescents (postnatal day 39) than adults (postnatal day 72–75). In addition, stimulation of either prelimbic or infralimbic PFC evokes weaker inhibition over basal (BA) and lateral (LAT) nuclei of the BLA in adolescents. This was dictated by both weak recruitment of inhibition in LAT and weak excitatory effects of PFC in BA. The current results may contribute to differences in adolescent cognitive regulation of emotion. These findings identify specific elements that undergo adolescent maturation and may therefore be sensitive to environmental disruptions that increase risk for psychiatric disorders.