Bacterial infection early in life protects against stressor-induced depressive-like symptoms in adult rats

Abstract

Both early-life stress and immune system activation in adulthood have been linked independently to depression in a number of studies. However, the relationship between early-life infection, which may be considered a "stressor", and later-life depression has not been explored. We have reported that neonatal bacterial infection in rats leads to exaggerated brain cytokine production, as well as memory impairments, to a subsequent peripheral immune challenge in adulthood, and therefore predicted that stressor-induced depressive-like symptoms would be more severe in these rats as well. Rats treated on postnatal day 4 with PBS or E. coli were as adults exposed to inescapable tailshock stress (IS), and then tested for sucrose preference, social exploration with a juvenile, and overall activity, 1, 3, 5, and 7 days following the stressor. Serum corticosterone and extracellular 5-HT within the basolateral amygdala were measured in a second group of rats in response to the IS. IS resulted in profound depressive-like behaviors in adult rats, but, surprisingly, rats that suffered a bacterial infection early in life had blunted corticosterone responses to the stressor and were remarkably protected from the depressive symptoms compared to controls. These data suggest that early-life infection should be considered within a cost/benefit perspective, in which outcomes in adulthood may be differentially protected or impaired. These data also suggest that the immune system likely plays a previously unsuspected role in "homeostatic" HPA programming and brain development, which may ultimately lend insight into the often-contradictory literature on cytokines, inflammation, and depression.

Overcoming neonatal sickness: Sex-specific effects of sickness on physiology and social behavior

“…For example, LPS treatment attenuates testicular development in pre-pubertal male hamsters, though the same investigation has not been done in females [24]. In another study, male rats that received neonatal E. coli had attenuated corticosterone responses following tail shock when compared with vehicle-injected males [45]. Further, studies examining the effects of immune challenge on physiology and behavior in females are often inconsistent.…”

“…For example, adult male rats show increased anxiety-like behavior following neonatal LPS administration, as evidenced by decreased exploration of the open arm of the elevated plus maze [53]. Further, male rats postnatally injected with E. coli show reduced exploration following an adult stressor, but they are able to recover more quickly than males injected with phosphate buffered saline (PBS) [45]. While it is important to understand how animals behave in a non-social context, animals must often interact with others in a social setting in order to successfully reproduce and survive.…”

Analgesia for Early-Life Pain Prevents Deficits in Adult Anxiety and Stress in Rats

“…For example, neonatally injured rats show decreased sensitivity to an acute noxious stimulus, but exaggerated hypersensitivity to a prolonged, severe noxious insult [18,19,24] . Neonatal (P4) endotoxin exposure increases sucrose preference and social interaction, and decreases corticosterone following acute tail shock [43] . However, adult chronic stress exposure or lipopolysaccharide administration increases anxiogenic behavior in these animals, increases acoustic startle amplitude and elevates corticosterone release [43,44] .…”

“…Neonatal (P4) endotoxin exposure increases sucrose preference and social interaction, and decreases corticosterone following acute tail shock [43] . However, adult chronic stress exposure or lipopolysaccharide administration increases anxiogenic behavior in these animals, increases acoustic startle amplitude and elevates corticosterone release [43,44] . Interestingly, a model of chronic maternal separation (3 h/day, P2-P14) shows basal hyperactivation of the HPA axis in response to acute air puff startle stress, but reduced ACTH and corticosterone following chronic stress [45] , supporting dichotomous dysregulation of the HPA axis in both directions as a result of early-life perturbations.…”

Interaction of Stress, Corticotropin-Releasing Factor, Arginine Vasopressin and Behaviour

“…This is at least in part due to the difficulty of distinguishing resilient animals from controls (Schmidt et al, 2010; Stedenfeld et al, 2011). However, resilience mechanisms are now the focus of considerable investigation (Bilbo et al, 2008; Champagne et al, 2008) because they represent an innovative approach to both understanding pathophysiology as well as drug development for a range of stress-related syndromes.…”