Neurokinin-1 receptor (NK1R) and mu-opioid receptor (muOR) agonists affected respiratory rhythm when injected directly into the preBötzinger Complex (preBötC), the hypothesized site for respiratory rhythmogenesis in mammals. These effects were mediated by actions on preBötC rhythmogenic neurons. The distribution of NK1R+ neurons anatomically defined the preBötC. Type 1 neurons in the preBötC, which have rhythmogenic properties, expressed both NK1Rs and muORs, whereas type 2 neurons expressed only NK1Rs. These findings suggest that the preBötC is a definable anatomic structure with unique physiological function and that a subpopulation of neurons expressing both NK1Rs and muORs generate respiratory rhythm and modulate respiratory frequency.

Current consensus holds that a single medullary network generates respiratory rhythm in mammals. Pre-Bötzinger Complex inspiratory (I) neurons, isolated in transverse slices, and preinspiratory (pre-I) neurons, found only in more intact en bloc preparations and in vivo, are each proposed as necessary for rhythm generation. Opioids slow I, but not pre-I, neuronal burst periods. In slices, opioids gradually lengthened respiratory periods, whereas in more intact preparations, periods jumped nondeterministically to integer multiples of the control period (quantal slowing). These findings suggest that opioid-induced quantal slowing results from transmission failure of rhythmic drive from pre-I neurons to preBötC I networks, depressed below threshold for spontaneous rhythmic activity. Thus, both I (in the slice), and pre-I neurons are sufficient for respiratory rhythmogenesis.

Transcription control regions of eukaryotic genes contain multiple sequence elements proposed to function independently to regulate transcription. We developed transgenic mice carrying fos-lacZ fusion genes with clustered point mutations in each of several distinct regulatory sequences: the sis-inducible element, the serum response element, the fos AP-1 site, and the calcium/cAMP response element. Analysis of Fos-lacZ expression in the CNS and in cultured cells demonstrated that all of the regulatory elements tested were required in concert for tissue- and stimulus-specific regulation of the c-fos promoter. This implies that the regulation of c-fos expression requires the concerted action of multiple control elements that direct the assembly of an interdependent transcription complex.

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Potentiation and depression of glutamate receptor function in hippocampal, cerebellar, and cortical neurons are examples of persistent changes in synaptic function that underlie important behavioral adaptations such as learning and memory. Persistent changes in synaptic function relevant for motor behaviors have not been demonstrated in mammalian motoneurons. We demonstrate that adaptive changes in (؎)-␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide (AMPA) receptor function at endogenously active synapses occur in motoneurons in neonatal rodents. We found a form of serotonin (5-HT)-dependent synaptic plasticity in hypoglossal (XII) motoneurons, which control tongue muscles affecting upper airway function, that is metamodulated by metabotropic glutamate receptors. Episodic, but not continuous, activation of postsynaptic 5-HT type 2 (5-HT2) receptors on hypoglossal (XII) motoneurons leads to long-lasting increases in their AMPA receptor-mediated respiratory drive currents and associated XII nerve motor output. Antagonism of group-I metabotropic glutamate receptors blocks induction of the 5-HT-induced increase in excitability. We propose that this activity-independent postsynaptic 5-HT-mediated plasticity represents the cellular mechanism underlying long-term facilitation, i.e., persistent increases in respiratory motor output and ventilation seen in humans and rodents in response to episodic hypoxia. Loss of activity in XII motoneurons is common during sleep causing snoring and, in serious cases, airway obstruction that interrupts breathing, a condition known as obstructive sleep apnea. These results may provide the basis for rationale development of therapeutics for obstructive sleep apnea in humans.excitability ͉ respiration ͉ breathing ͉ learning ͉ apnea M otoneurons produce behavior by integrating and transforming patterns of premotoneuronal activity into commands for skeletal muscle contraction. The principal fast excitatory neurotransmitter affecting motoneurons is glutamate (1), acting mainly through (Ϯ)-␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide (AMPA)-type receptors (2). Changes in AMPA receptor function contribute to neuronal plasticity, such as occurs in long-term potentiation and depression in the hippocampus, cerebellum, cortex, and dorsal spinal cord (3-5); this is partly mediated through intracellular second messengers affecting the functional characteristics of AMPA receptors (3, 6, 7). Whether similar long-term plasticity at AMPA synapses can be induced in mammalian motoneurons, which are often viewed as passive relays (1), is not known.Long-lasting changes in neuronal excitability are an important component of adaptive behavior. Such changes in motoneuronal excitability could play a role in the fine tuning and͞or coordination of movement and in motor learning. Persistent, compensatory increases in breathing movements, termed long-term facilitation (LTF) (8), can be induced in neonatal ‡ and adult (10-12) rats by episodic but not continuous exposure to hypo...