Early Attachment Disruption, Inflammation, and Vulnerability for Depression in Rodent and Primate Models

Early experiments in nonhuman primates established the relation between disruption of filial attachment and depressive-like outcomes. Subsequent studies in rats and mice have been instrumental in linking depressive-like outcomes to disturbances in maternal behavior. Another aspect of attachment disruption, absence of the attachment object per se, may be studied more effectively in a different laboratory rodent—the guinea pig. Here, we discuss the rationale for using guinea pigs for this work. We then review guinea pig studies providing evidence for inflammatory mechanisms mediating both depressive-like behavior during separation as well as sensitization of stress responsiveness such as is thought to lead to increased vulnerability to depression at later ages. Finally, we discuss recent complementary work in adult monkeys that suggests cross-species generalizability of broad principles derived from the guinea pig experiments. Overall, the findings provide experimental support for human research implicating inflammatory mechanisms in the development of increased stress responsiveness and vulnerability to depression following attachment disruption and other forms of early-life stress. Specifically, the findings suggest inflammatory mechanisms may set in motion a cascade of underlying processes that mediate later increased stress responsiveness and, therefore, depression susceptibility

Adolescent intermittent ethanol (AIE) produces lasting, sex-specific changes in rat body fat independent of changes in white blood cell composition

Early initiation of alcohol use during adolescence, and adolescent binge drinking are risk factors for the development of alcohol use disorder later in life. Adolescence is a time of rapid sex-dependent neural, physiological, and behavioral changes as well as a period of heightened vulnerability to many effects of alcohol. The goal of the present studies was to determine age-related changes in blood (leukocyte populations) and body composition across adolescence and early adulthood, and to investigate whether adolescent intermittent ethanol (AIE) exposure would alter the trajectory of adolescent development on these broad physiological parameters. We observed significant ontogenetic changes in leukocyte populations that were mirrored by an age-related increase in cytokine expression among mixed populations of circulating leukocytes. Despite these developmental changes, AIE did not significantly alter overall leukocyte numbers or cytokine gene expression. However, AIE led to sex-specific changes in body fat mass and fat percentage, with AIE-exposed male rats showing significantly decreased fat levels and female rats showing significantly increased fat levels relative to controls. These changes suggest that while AIE may not alter overall leukocyte levels, more complex phenotypic changes in leukocyte populations could underlie previously reported differences in cytokine expression. Coupled with long-term shifts in adipocyte levels, this could have long-lasting effects on innate immunity and the capacity of individuals to respond to later immunological and physiological threats

DNaseI hypersensitivity at gene-poor, FSH dystrophy-linked 4q35.2

A subtelomeric region, 4q35.2, is implicated in facioscapulohumeral muscular dystrophy (FSHD), a dominant disease thought to involve local pathogenic changes in chromatin. FSHD patients have too few copies of a tandem 3.3-kb repeat (D4Z4) at 4q35.2. No phenotype is associated with having few copies of an almost identical repeat at 10q26.3. Standard expression analyses have not given definitive answers as to the genes involved. To investigate the pathogenic effects of short D4Z4 arrays on gene expression in the very gene-poor 4q35.2 and to find chromatin landmarks there for transcription control, unannotated genes and chromatin structure, we mapped DNaseI-hypersensitive (DH) sites in FSHD and control myoblasts. Using custom tiling arrays (DNase-chip), we found unexpectedly many DH sites in the two large gene deserts in this 4-Mb region. One site was seen preferentially in FSHD myoblasts. Several others were mapped >0.7 Mb from genes known to be active in the muscle lineage and were also observed in cultured fibroblasts, but not in lymphoid, myeloid or hepatic cells. Their selective occurrence in cells derived from mesoderm suggests functionality. Our findings indicate that the gene desert regions of 4q35.2 may have functional significance, possibly also to FSHD, despite their paucity of known genes

From Classic Aspects of the Stress Response to Neuroinflammation and Sickness: Implications for Individuals and Offspring

Accumulating evidence suggests that exposure to psychological stressors leads to increased expression of pro-inflammatory cytokines and activation of inflammatory-related pathways in the central nervous system. Several logical predictions arise from these findings: (1) stressor exposure should produce changes in behavior that are reminiscent of acute illness; (2) administration of antiinflammatory agents should ameliorate some behavioral consequences of stressor exposure; and (3) there should be convergence between anatomical and neurochemical pathways activated by stressor exposure and those involved in mitigating sickness behaviors. Importantly, these predictions have been tested in our laboratory across multiple stressor paradigms (footshock, maternal separation, and during acute alcohol withdrawal) using two species (rats and guinea pigs), suggesting that sickness may represent a more general motivational state that can be elicited by a diverse range of psychological challenges. Implications of these findings for understanding stress-related changes in behavior, mood and neuroinflammatory processes will be discussed with special reference to implications for the individual and reproductive fitness

From Classic Aspects of the Stress Response to Neuroinflammation and Sickness: Implications for Individuals and Offspring

Accumulating evidence suggests that exposure to psychological stressors leads to increased expression of pro-inflammatory cytokines and activation of inflammatory-related pathways in the central nervous system. Several logical predictions arise from these findings: (1) stressor exposure should produce changes in behavior that are reminiscent of acute illness; (2) administration of antiinflammatory agents should ameliorate some behavioral consequences of stressor exposure; and (3) there should be convergence between anatomical and neurochemical pathways activated by stressor exposure and those involved in mitigating sickness behaviors. Importantly, these predictions have been tested in our laboratory across multiple stressor paradigms (footshock, maternal separation, and during acute alcohol withdrawal) using two species (rats and guinea pigs), suggesting that sickness may represent a more general motivational state that can be elicited by a diverse range of psychological challenges. Implications of these findings for understanding stress-related changes in behavior, mood and neuroinflammatory processes will be discussed with special reference to implications for the individual and reproductive fitness

Neuroendocrine and neuroimmune adaptation to Chronic Escalating Distress (CED): A novel model of chronic stress

Acute and chronic stress challenges have a profound influence on the development and expression of subsequent affective disorders, alcohol use disorders, and natural aging processes. These experiments examined adaptation in neuroimmune and neuroendocrine responses that occurred as a result of exposure to a novel model of chronic stress, termed chronic escalating distress (CED). This model involves exposure to highly predictable daily stress challenges involving a systematic escalation in both the intensity and length of daily stress challenges, and has recently been shown to profoundly alter alcohol sensitivity. Male Sprague-Dawley rats were exposed to an 11 day procedure where days 1–5 consisted of 60  min of restraint, days 6–10 consisted of 60  min of restraint immediately followed by 30  min of forced swim, and on day 11 subjects were exposed to a 2 h session of intermittent footshock. Experiment 1 examined adaptation in the corticosterone (CORT) response at key points in the 11 day procedure, and found that the escalation in stressors disrupted habituation to restraint, whereas the CORT response to daily forced swim exposure increased across days. Experiment 2 investigated the impact of this stress paradigm on the expression of several cytokine (IL-1β, IL-6, TNF-α) and cellular activation marker (c-Fos, CD14, CD200R) genes in key brain regions (PVN, HPC, & PFC) known to be influenced by stress. Interestingly, a history of CED had no effect on footshock-induced neuroimmune changes (increased IL-1 in the PVN; increased IL-6 in the HPC and PFC). In addition, acute footshock and CED produced similar c-fos induction within the PVN whereas CED led to enhanced c-fos induction in both the HPC and PFC. These findings support recent work indicating that neuroimmune responses to acute stress challenges persisted in rats with a recent history of repeated stress exposure, and that these effects occurred contemporaneously with ongoing changes in HPA axis reactivity. Overall, this CED model may serve as a highly tractable model for studying adaptation to chronic stress, and may have implications for understanding stress-induced alterations in alcohol sensitivity and natural aging processes. Keywords: Corticosterone, Habituation, Interleukin-1, Escalating stress, Sequential stress, Neuroimmune, Cytokin