Developmental changes in GABAergic neurotransmission to presympathetic and cardiac parasympathetic neurons in the brainstem

Abstract

Cardiovascular function is regulated by a dynamic balance composed of sympathetic and parasympathetic activity. Sympathoexcitatory presympathetic neurons (PSNs) in the rostral ventrolateral medulla project directly to cardiac and vasomotor sympathetic preganglionic neurons in the spinal cord. In proximity to the PSNs in the medulla, there are preganglionic cardiac vagal neurons (CVNs) within the nucleus ambiguus, which are critical for parasympathetic control of heart rate. Both CVNs and PSNs receive GABAergic synaptic inputs that change with challenges such as hypoxia and hypercapnia (H/H). Autonomic control of cardiovascular function undergoes significant changes during early postnatal development; however, little is known regarding postnatal maturation of GABAergic neurotransmission to these neurons. In this study, we compared changes in GABAergic inhibitory postsynaptic currents (IPSCs) in CVNs and PSNs under control conditions and during H/H in postnatal day 2–5 (P5), 16–20 (P20), and 27–30 (P30) rats using an in vitro brainstem slice preparation. There was a significant enhancement in GABAergic neurotransmission to both CVNs and PSNs at age P20 compared with P5 and P30, with a more pronounced increase in PSNs. H/H did not significantly alter this enhanced GABAergic neurotransmission to PSNs in P20 animals. However, the frequency of GABAergic IPSCs in PSNs was reduced by H/H in P5 and P30 animals. In CVNs, H/H elicited an inhibition of GABAergic neurotransmission in all ages studied, with the most pronounced inhibition occurring at P20. In conclusion, there are critical development periods at which significant rearrangement occurs in the central regulation of cardiovascular function.

Direct projections from hypothalamic orexin neurons to brainstem cardiac vagal neurons

“…Orexin has previously been shown to contribute substantially to central cardiovascular and respiratory regulation (Peyron et al, 1998, Ciriello and de Oliveira, 2003, Ciriello et al, 2003, Dergacheva et al, 2005, Iigaya et al, 2012, Carrive, 2013, Dergacheva et al, 2013). Intraventricular administration of orexin elicits tachycardia, hypertension and hyperventilation (Samson et al, 1999, Shirasaka et al, 1999, Chen et al, 2000, Matsumura et al, 2001, Zhang et al, 2005), while orexin knock-out animals have reduced blood pressure and diminished cardiovascular response to bicuculline injections in the hypothalamus (Kayaba et al, 2003).…”

“…Parasympathetic CVNs were labeled as described previously (Dergacheva et al, 2013, Dergacheva, 2015). At postnatal days 4–5 orexin-Cre rats were anesthetized with hypothermia, the heart was exposed and 0.05 ml of 1–5% rhodamine (XRITC; Molecular Probes, Eugene, OR) was injected into the pericardial sac.…”

“…Compelling evidence indicates orexin neurons and receptors play an important role in the regulation of cardiovascular function (Peyron et al, 1998, Ciriello and de Oliveira, 2003, Ciriello et al, 2003, Dergacheva et al, 2005, Carrive, 2013, Dergacheva et al, 2013). Orexin is well known to exert sympathoexcitatory effects such as increases in heart rate, blood pressure and sympathetic nerve activity (Samson et al, 1999, Shirasaka et al, 1999, Chen et al, 2000, Antunes et al, 2001, Matsumura et al, 2001).…”

Intrinsic properties of rostral ventrolateral medulla presympathetic and bulbospinal respiratory neurons of juvenile rats are not affected by chronic intermittent hypoxia

“…) and only recently in brainstem slices from juvenile rats (Dergacheva et al . ; Gao & Derbenev, ). In spite of these recent studies, the main original question related to these RVLM presympathetic neurons remains to be answered.…”

Brain Stem Mechanisms Responsible for the Trigeminocardiac Reflex

“…As an example, the acetylcholinesterase inhibitor neostigmine inhibits the glutamatergic neurotransmission to CVNs upon stimulation of trigeminal fibers. 4,9,10 The synaptic transmission onto neurons in the trigeminal nucleus remains unaffected by isoflurane or fentanyl, suggesting that both of these agents either act on receptors that are more densely localized to the synapses surrounding CVNs or more readily modify the subunit composition of receptors involved in neurotransmission to CVNs than they modify receptors involved in neurotransmission to spinal trigeminal neurons. However, the peak amplitude of EPSC evoked by trigeminal stimulation was inhibited by the muscarinic acetylcholine receptor (mAChR) agonist bethenecol and facilitated by the mAChR antagonist atropine, providing additional evidence for endogenous inhibition of this reflex pathway by acetylcholine, specifically via activation of mAChRs.…”