Functional Programming of the Autonomic Nervous System by Early Life Immune Exposure: Implications for Anxiety

Abstract

Neonatal exposure of rodents to an immune challenge alters a variety of behavioural and physiological parameters in adulthood. In particular, neonatal lipopolysaccharide (LPS; 0.05 mg/kg, i.p.) exposure produces robust increases in anxiety-like behaviour, accompanied by persistent changes in hypothalamic-pituitary-adrenal (HPA) axis functioning. Altered autonomic nervous system (ANS) activity is an important physiological contributor to the generation of anxiety. Here we examined the long term effects of neonatal LPS exposure on ANS function and the associated changes in neuroendocrine and behavioural indices. ANS function in Wistar rats, neonatally treated with LPS, was assessed via analysis of tyrosine hydroxylase (TH) in the adrenal glands on postnatal days (PNDs) 50 and 85, and via plethysmographic assessment of adult respiratory rate in response to mild stress (acoustic and light stimuli). Expression of genes implicated in regulation of autonomic and endocrine activity in the relevant brain areas was also examined. Neonatal LPS exposure produced an increase in TH phosphorylation and activity at both PNDs 50 and 85. In adulthood, LPS-treated rats responded with increased respiratory rates to the lower intensities of stimuli, indicative of increased autonomic arousal. These changes were associated with increases in anxiety-like behaviours and HPA axis activity, alongside altered expression of the GABA-A receptor α2 subunit, CRH receptor type 1, CRH binding protein, and glucocorticoid receptor mRNA levels in the prefrontal cortex, hippocampus and hypothalamus. The current findings suggest that in addition to the commonly reported alterations in HPA axis functioning, neonatal LPS challenge is associated with a persistent change in ANS activity, associated with, and potentially contributing to, the anxiety-like phenotype. The findings of this study reflect the importance of changes in the perinatal microbial environment on the ontogeny of physiological processes.

A Rodent Model of Anxiety: The Effect of Perinatal Immune Challenges on Gastrointestinal Inflammation and Integrity

“…Alterations in immune responses may be modulated by the ANS, which is part of the GBA and one of the primary systems for the maintenance or reinstatement of homeostasis during stress. Following exposure to a stressor, such as infection, the ANS affords the most immediate response, inducing a rapid increase in the formation of noradrenaline from tyrosine hydroxylase (TH) in the sympathetic nerve terminals and in the adrenal medulla [21-23], leading to prompt alterations in physiological states through neural innervation of end organs [24]. During inflammation the ANS is activated to restore homeostasis, in part by regulating the inflammatory and subsequent immune response [25] through the release of inflammatory mediators [16].…”

Amygdala mediates respiratory responses to sudden arousing stimuli and to restraint stress in rats

“…In rats, sudden alerting stimuli of various sensory modalities provoke vigorous respiratory responses (sniffing) (16,24). These responses are likely linked with animals' anxiety state, as they are sensitive to anxiolytic drug diazepam (23) and are significantly increased in rats with induced high-anxiety behavior (32). There are also substantial differences in respiratory pattern between rats bred for low-anxiety behavior compared with animals bred for high-anxiety behavior (5).…”

Factors in Early-Life Programming of Reproductive Fitness

“…Inflammatory responses associated with perinatal LPS exposure have been implicated in long-term programming of a variety of physiological and behavioural outcomes, such as adult immune responses [54,55,56,57], metabolic function [58,59] and neurobehavioural outcomes [60,61,62]. Only a few studies, however, have investigated the impact of perinatal immune challenge on reproduction.…”

“…Suppressed LH pulses were also observed in neonatally LPS-treated females in response to a subsequent LPS challenge in adulthood, along with an increased expression of corticotropin-releasing hormone (CRH) receptor 1 in the medial preoptic area [69]. In rodents, the hypothalamic-pituitary-adrenal (HPA) axis completes its development postnatally during the 1st week of life [70], and neonatal exposure to LPS has been repeatedly shown to program long-term changes in the HPA axis activity, with increases in basal and stress-induced corticosterone levels, increases in hypothalamic expression of CRH and reduced negative feedback sensitivity in adulthood [13,14,60,71]. The HPA and HPG axes are known to co-regulate one another, and stress has been shown to suppress reproduction via CRH-mediated inhibition of GnRH release and glucocorticoid-mediated inhibition of pituitary hormones and adrenal sex steroids [72,73].…”

“…Therefore, the impairment in mating strategies characterises a subfertile, rather than infertile, phenotype. Neonatal LPS exposure has been repeatedly shown to predispose to increased stress responsivity and anxiety-like behaviours in adulthood [60,79]. An anxiety-like phenotype is often associated with anhedonia-like symptoms.…”