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A link exists between immune function and psychiatric conditions, particularly depressive and anxiety disorders. Psychological stress is a powerful trigger for these disorders and stress influences immune state. However, the nature of peripheral immune changes after stress conflicts across studies, perhaps due to the focus on few measures of pro-inflammatory or anti-inflammatory processes. The basolateral amygdala (BLA) is critical for emotion, and plays an important role in the effects of stress on anxiety. As such, it may be a primary central nervous system (CNS) mediator for the effects of peripheral immune changes on anxiety after stress. Therefore, this study aimed to delineate the influence of stress on peripheral pro-inflammatory and anti-inflammatory aspects, BLA immune activation, and its impact on BLA neuronal activity. To produce a more encompassing view of peripheral immune changes, this study used a less restrictive approach to categorize and group peripheral immune changes. We found that repeated social defeat stress in adult male Sprague-Dawley rats increased the frequencies of mature T-cells positive for intracellular type 2-like cytokine and serum pro-inflammatory cytokines. Principal component analysis and hierarchical clustering was used to guide grouping of T-cells and cytokines, producing unique profiles. Stress shifted the balance towards a specific set that included mostly type 2-like T-cells and pro-inflammatory cytokines. Within the CNS component, repeated stress caused an increase of activated microglia in the BLA, increased anxiety-like behaviors across several assays, and increased BLA neuronal firing in vivo that was prevented by blockade of microglia activation. Because repeated stress can trigger anxiety states by actions in the BLA, and altered immune function can trigger anxiety, these results suggest that repeated stress may trigger anxiety-like behaviors by inducing a pro-inflammatory state in the periphery and the BLA. These results begin to uncover how stress may recruit the immune system to alter the function of brain regions critical to emotion., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Pro-inflammatory cytokines produce manifestations of sickness during inflammation, such as malaise and lethargy. They also contribute to effects of inflammation on mood. Anti-inflammatory cytokines counteract damage caused by inflammatory processes and can limit the severity of inflammation. However, very little is known about the role of anti-inflammatory cytokines in sickness and mood changes during immune activation. The purpose of this study was to determine if a prototypical anti-inflammatory cytokine, interleukin 10 (IL-10), can offset sickness behavior and anxiety caused by a pro-inflammatory cytokine, and whether IL-10 itself modifies anxiety. Rodent models of sickness display suppression of behavioral activity that may reflect lethargy or malaise, while models of anxiety display reduced exploration in several tasks. The effects of peripheral single dose of cytokines on open field exploration, social interaction and elevated plus maze (EPM) tests in adult male Sprague-Dawley rats were measured at 30-50 min post-treatment. The prototypical pro-inflammatory cytokine IL-1β (1 μg, i.p.) caused a decrease in locomotor activity indicative of sickness behavior, but disproportionately reduced central area exploration in the open field, open arm exploration in the EPM and lowered social interaction. IL-10 (1 μg, i.p.) had no effect on locomotor activity, but itself produced anxiety-like behavior in the open field and EPM. However, rats co-treated with both IL-10 and IL-1β showed locomotor activity, open field, social interaction and EPM behaviors very similar to control groups. This data demonstrate that IL-10 is capable of mitigating the sickness and anxiogenic effects caused by IL-1β, but that immune imbalance toward either a pro-inflammatory or an anti-inflammatory state can produce anxiety. This has importance for understanding the scope of immune changes that produce psychiatric symptoms, and provides preliminary indication that anti-inflammatory cytokines may be potentially useful in treatment of anxiety induced by inflammatory conditions., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Repeated stress can trigger episodes of depression, along with symptoms of anhedonia and anxiety. Although often modeled separately, anxiogenic factors potently modulate hedonic, or appetitive, behavior. While repeated stress can increase anxiety and decrease appetitive behavior, it is not clear whether repeated stress can influence the impact of anxiogenic factors on appetitive behavior. This study tests whether repeated stress shifts behavior in a task that measures anxiogenic-appetitive balance. To test this, adult male rats were trained to lever press for sucrose pellet reward, and the effect of anxiogenic bright light on this behavior was measured. The impact of the bright light anxiogenic stimulus on lever pressing was compared between groups exposed to either daily repeated social defeat stress or control handling. We found that repeated stress reduced exploration in the open field and decreased social interaction, but had minimal effect on baseline lever pressing for reward. Repeated stress substantially enhanced the effect of anxiogenic bright light on lever pressing. This effect was greater two days after the last stress exposure, and began to diminish within two weeks. These data demonstrate that the anxiogenic and anhedonic features induced by repeated stress can be separately measured, and that the impact of anxiogenic stimuli can be greatly enhanced after repeated stress, even in the face of appetitive drive. The data also demonstrate that some apparent anhedonic-like effects of repeated stress can be due to increased sensitivity to anxiogenic stimuli, and may reflect an imbalance in an appetitive approach-withdrawal continuum., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Repeated stress can trigger a range of psychiatric disorders, including anxiety. The propensity to develop abnormal behaviors after repeated stress is related to the severity, frequency and number of stressors. However, the pattern of stress exposure may contribute to the impact of stress. In addition, the anxiogenic nature of repeated stress exposure can be moderated by the degree of coping that occurs, and can be reflected in homotypic habituation to the repeated stress. However, expectations are not clear when a pattern of stress presentation is utilized that diminishes habituation. The purpose of these experiments is to test whether interrupted stress exposure decreases homotypic habituation and leads to greater effects on anxiety-like behavior in adult male rats. We found that repeated interrupted restraint stress resulted in less overall homotypic habituation compared to repeated daily restraint stress. This was demonstrated by greater production of fecal boli and greater corticosterone response to restraint. Furthermore, interrupted restraint stress resulted in a lower body weight and greater adrenal gland weight than daily restraint stress, and greater anxiety-like behavior in the elevated plus maze. Control experiments demonstrated that these effects of the interrupted pattern could not be explained by differences in the total number of stress exposures, differences in the total number of days that the stress periods encompased, nor could it be explained as a result of only the stress exposures after an interruption from stress. These experiments demonstrate that the pattern of stress exposure is a significant determinant of the effects of repeated stress, and that interrupted stress exposure that decreases habituation can have larger effects than a greater number of daily stress exposures. Differences in the pattern of stress exposure are therefore an important factor to consider when predicting the severity of the effects of repeated stress on psychiatric disorders.

Rationale: Conditions with sustained low-grade inflammation have high comorbidity with depression and anxiety and are associated with social withdrawal. The basolateral amygdala (BLA) is critical for affective and social behaviors and is sensitive to inflammatory challenges. Large systemic doses of lipopolysaccharide (LPS) initiate peripheral inflammation, increase BLA neuronal activity, and disrupt social and affective measures in rodents. However, LPS doses commonly used in behavioral studies are high enough to evoke sickness syndrome, which can confound interpretation of amygdala-associated behaviors. Objectives and methods: The objectives of this study were to find a LPS dose that triggers mild peripheral inflammation but not observable sickness syndrome in adult male rats, to test the effects of sustained mild inflammation on BLA and social behaviors. To accomplish this, we administered single doses of LPS (0–100 μg/kg, intraperitoneally) and measured open field behavior, or repeated LPS (5 μg/kg, 3 consecutive days), and measured BLA neuronal firing, social interaction, and elevated plus maze behavior. Results: Repeated low-dose LPS decreased BLA neuron firing rate but increased the total number of active BLA neurons. Repeated low-dose LPS also caused early disengagement during social bouts and less anogenital investigation and an overall pattern of heightened social caution associated with reduced gain of social familiarity over the course of a social session. Conclusions: These results provide evidence for parallel shifts in social interaction and amygdala activity caused by prolonged mild inflammation. This effect of inflammation may contribute to social symptoms associated with comorbid depression and chronic inflammatory conditions. [ABSTRACT FROM AUTHOR]

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 used in vivo and ex vivo electrophysiological 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 larger IAHP compared 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. [ABSTRACT FROM AUTHOR]

Severe and repeated stress has damaging effects on health, including initiation of depression and anxiety. Stress that occurs during development has long-lasting and particularly damaging effects on emotion. The basolateral amygdala (BLA) plays a key role in many affective behaviors, and repeated stress causes different forms of BLA hyperactivity in adolescent and adult rats. However, the mechanism is not known. Furthermore, not every individual is susceptible to the negative consequences of stress. Differences in the effects of stress on the BLA might contribute to determine whether an individual will be vulnerable or resilient to the effects of stress on emotion. The purpose of this study is to test the cellular underpinnings for age dependency of BLA hyperactivity after stress, and whether protective changes occur in resilient individuals. To test this, the effects of repeated stress on membrane excitability and other membrane properties of BLA principal neurons were compared between adult and adolescent rats, and between vulnerable and resilient rats, using in vitro whole-cell recordings. Vulnerability was defined by adrenal gland weight, and verified by body weight gain after repeated restraint stress, and fecal pellet production during repeated restraint sessions. We found that repeated stress increased the excitability of BLA neurons, but in a manner that depended on age and BLA subnucleus. Furthermore, stress resilience was associated with an opposite pattern of change, with increased slow afterhyperpolarization (AHP) potential, whereas vulnerability was associated with decreased medium AHP. The opposite outcomes in these two populations were further distinguished by differences of anxiety-like behavior in the elevated plus maze that were correlated with BLA neuronal excitability and AHP. These results demonstrate a substrate for BLA hyperactivity after repeated stress, with distinct membrane properties to target, as well as age-dependent factors that contribute to resilience to the effects of stress. [ABSTRACT FROM AUTHOR]