Sleep state dependence of ventilatory long-term facilitation following acute intermittent hypoxia in Lewis rats

Breathing is a vital behavior that is particularly amenable to experimental investigation. We review recent progress on three problems of broad interest. (i) Where and how is respiratory rhythm generated? The preBötzinger Complex is a critical site, whereas pacemaker neurons may not be essential. The possibility that coupled oscillators are involved is considered. (ii) What are the mechanisms that underlie the plasticity necessary for adaptive changes in breathing? Serotonin-dependent long-term facilitation following intermittent hypoxia is an important example of such plasticity, and a model that can account for this adaptive behavior is discussed. (iii) Where and how are the regulated variables CO2 and pH sensed? These sensors are essential if breathing is to be appropriate for metabolism. Neurons with appropriate chemosensitivity are spread throughout the brainstem; their individual properties and collective role are just beginning to be understood.

Intermittent hypoxia causes a form of serotonin-dependent synaptic plasticity in the spinal cord known as phrenic long-term facilitation (pLTF). Here we show that increased synthesis of brain-derived neurotrophic factor (BDNF) in the spinal cord is necessary and sufficient for pLTF in adult rats. We found that intermittent hypoxia elicited serotonin-dependent increases in BDNF synthesis in ventral spinal segments containing the phrenic nucleus, and the magnitude of these BDNF increases correlated with pLTF magnitude. We used RNA interference (RNAi) to interfere with BDNF expression, and tyrosine kinase receptor inhibition to block BDNF signaling. These disruptions blocked pLTF, whereas intrathecal injection of BDNF elicited an effect similar to pLTF. Our findings demonstrate new roles and regulatory mechanisms for BDNF in the spinal cord and suggest new therapeutic strategies for treating breathing disorders such as respiratory insufficiency after spinal injury. These experiments also illustrate the potential use of RNAi to investigate functional consequences of gene expression in the mammalian nervous system in vivo.

Repeated isocapnic hypoxia evokes long-term facilitation (LTF) of phrenic nerve activity in rats. We wished to determine: (1) whether hypoxia-induced LTF is serotonin dependent; and (2) whether hypoxia-induced LTF is a property of upper airway motoneurons. Phrenic and hypoglossal nerve activities were recorded in urethane anesthetized, vagotomized, paralyzed and artificially ventilated rats (n = 7). Rats were exposed to three, 5-min hypoxic episodes (FIo2 = 0.10) separated by 5 min of hyperoxia (FIo2 = 0.50). One hour after the final hypoxic episode, integrated phrenic and hypoglossal amplitudes and burst frequency were increased above control values (63 +/- 17%, 78 +/- 26% and 9.6 +/- 2.1 bursts/min, respectively: p < 0.05). In rats pretreated with methysergide (n = 7; 4 mg/kg), no changes in phrenic or hypoglossal activity from pre-stimulus control values were observed at any time post-stimulation. The results indicate that hypoxia-induced LTF requires 5-HT receptors and is characteristic of both hypoglossal and phrenic motor output.