Nerve growth factor and other neurotrophins signal to neurons through the Trk family of receptor tyrosine kinases. TrkB is relatively promiscuous in vitro, acting as a receptor for brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT4) and, to a lesser extent, NT3 (refs 3-5). Mice lacking TrkB show a more severe phenotype than mice lacking BDNF, suggesting that TrkB may act as a receptor for additional ligands in vivo. To explore this possibility, we generated mice lacking NT4 or BDNF as well as mice lacking both neurotrophins. Unlike mice lacking other Trks or neurotrophins, NT4-deficient mice are long-lived and show no obvious neurological defects. Analysis of mutant phenotypes revealed distinct neuronal populations with different neurotrophin requirements. Thus vestibular and trigeminal sensory neurons require BDNF but not NT4, whereas nodose-petrosal sensory neurons require both BDNF and NT4. Motor neurons, whose numbers are drastically reduced in mice lacking TrkB, are not affected even in mice lacking both BDNF and NT4. These results suggest that another ligand, perhaps NT3, does indeed act on TrkB in vivo.

The neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT4) act via the TrkB receptor and support survival of primary somatic and visceral sensory neurons. The major visceral sensory population, the nodose-petrosal ganglion complex (NPG), requires BDNF and NT4 for survival of a full complement of neurons, providing a unique opportunity to compare gene dosage effects between the two TrkB ligands and to explore the possibility that one ligand can compensate for loss of the other. Analysis of newborn transgenic mice lacking BDNF or NT4, or BDNF and NT4, revealed that survival of many NPG afferents is proportional to the number of functional BDNF alleles, whereas only one functional NT4 allele is required to support survival of all NT4-dependent neurons. In addition, subpopulation analysis revealed that BDNF and NT4 can compensate for the loss of the other to support a subset of dopaminergic ganglion cells. Together, these data demonstrate that the pattern of neuronal dependencies on BDNF and NT4 in vivo is far more heterogeneous than predicted from previous studies in culture. Moreover, BDNF knockout animals lack a subset of afferents involved in ventilatory control and exhibit severe respiratory abnormalities characterized by depressed and irregular breathing and reduced chemosensory drive. BDNF is therefore required for expression of normal respiratory behavior in newborn animals.

A complete understanding of the neural mechanisms responsible for the chemoreceptor and baroreceptor reflexes requires precise knowledge of the locations and chemical phenotypes of higher-order neurons within these reflex pathways. In the present study, the protein product (Fos) of the c-fos protooncogene was used as a metabolic marker to trace central neural pathways following activation of carotid sinus nerve afferent fibers. In addition, immunohistochemical double-labeling techniques were used to define the chemical phenotypes of activated neurons. Both electrical stimulation of the carotid sinus nerve and physiological stimulation of the carotid bodies by hypoxia induced Fos-like immunoreactivity in catecholaminergic neurons containing tyrosine hydroxylase or phenylethanolamine-N-methyltransferase in the ventrolateral medulla oblongata and, to a lesser degree, in the dorsal vagal complex. Tyrosine hydroxylase/Fos colocalization was also observed in the locus coeruleus and the A5 noradrenergic cell group in pons. Many serotoninergic neurons in nucleus raphe pallidus, nucleus raphe magnus, and along the ventral medullary surface contained Fos-like immunoreactivity. In pons and midbrain, Fos-like immunoreactivity was observed in the lateral parabrachial and Kölliker-Fuse nuclei, the inferior colliculus, the cuneiform nucleus, and in the vicinity of the Edinger-Westphal nucleus, but no catecholaminergic or serotoninergic colocalization was observed in these regions. Although Fos-labeled cells were observed within and lateral to the dorsal raphe nucleus, few were catecholaminergic or serotoninergic. This study further defines a potential central neuroanatomical substrate for the chemoreceptor and/or baroreceptor reflexes.