Respiratory dysfunction following neonatal sustained hypoxia exposure during a critical window of brainstem extracellular matrix formation

The extracellular matrix (ECM) modulates brain maturation and plays a major role in regulating neuronal plasticity during critical periods of development. We examined: 1) whether there is a critical postnatal period of ECM expression in brainstem cardio-respiratory control regions; and 2) if the attenuated hypoxic ventilatory response (HVR) following neonatal sustained (5 days) hypoxia exposure (SH, 11% O₂, 24hrs/day) is associated with altered ECM formation. The nucleus tractus solitarius (nTS), dorsal motor nucleus of the vagus (DMNV), the hypoglossal motor nucleus (XII), the cuneate nucleus (CN) and area postrema (AP) were immunofluorescently processed for aggrecan and Wisteria floribunda (WFA) agglutinin, a key proteoglycan of the ECM and the perineuronal net. From postnatal age 5 days (P5), aggrecan and WFA expression increased postnatally in all regions. Aggrecan expression in the nTS, a region that integrates and receives afferent inputs from the carotid body, increased abruptly between P10-15 followed by a distinct and transient plateau between P15-20. WFA expression in the nTS exhibited an analogous transient plateau, but it occurred earlier (plateauing between P10-P15). SH exposure between this period (P11-15) attenuated the HVR (assessed at P16) and increased aggrecan (but not WFA) expression in the nTS, DMNV and AP. An intracisternal micro-injection of chondroitinase ABC (ChABC), an enzyme that digests chondroitin sulfate proteoglycans, rescued the HVR and the increased aggrecan expression. These data indicate there are important stages of ECM formation that take place in key brainstem respiratory neural control regions that appear to be associated with a heightened vulnerability to hypoxia.

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