Functional and Brainstem Neurochemical Changes During a Critical Period of Postnatal Development

Abstract

There are distinct developmentally regulated changes in the constitutive expression of various neurochemical factors that occur in brainstem cardio‐respiratory control regions. Many of these neurodevelopmental events occur towards the end of the second postnatal (P) week of life in the rat and consist of abrupt and in some cases transient changes in the expression of various neurotransmitters (e.g. 5‐HT), glia (Iba‐1), cytokines (TNFα, IL1β), as well as components of the extracellular matrix (ECM). Such key events appear necessary for appropriate architectural organization of the maturing cardio‐respiratory nervous system, although their timing also coincides with a critical window during which the neonate exhibits a uniquely heightened and lethal vulnerability to “inflammatory” stressors. Specifically, exposure to five days of sustained hypoxia (SH, 11% O2) starting on day P11, or a single bolus injection of LPS (P12) cause profound disturbances in the acute hypoxic ventilatory response (HVR). The effects of SH and LPS appear unique to hypoxia as the hypercapnic ventilatory response is relatively less affected. LPS and SH are similar in that they each also cause an unexpected incidence of mortality which is unique to this age group as younger (P1–5) or older age groups (P21–25) appear relatively unaffected by exposure to the same stimuli, thus revealing a critical window of heightened cardio‐respiratory vulnerability. The heightened vulnerability to SH or LPS is associated with increased brainstem expression of microglia, the ECM, markers of neurogenesis and cytokines (mRNA), and a disruption to the serotonergic system. We propose, therefore, that the heightened vulnerability to either SH or LPS likely manifests as an aberrant “inflammatory” response during a critical period of brainstem neurochemical development and ECM formation, resulting in a lethal disturbance in crucial neurochemical/neurodevelopmental events. However, inhibition of microglia or enzymatic degradation of the ECM protects against the adverse effects of SH, whereas high serum TNFα represents an early biomarker that predicts vulnerability to LPS. These data have begun to shed light on the interactions between early life experiences and the cardio‐respiratory control system and the profound unintended consequences that they have during critical periods of development.