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Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG, and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH.

Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG, and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH., Idiopathic pulmonary arterial hypertension is a rare and fatal disease with a heterogeneous treatment response. Here the authors show that unsupervised machine learning of whole blood transcriptomes from 359 patients with idiopathic pulmonary arterial hypertension identifies 3 subgroups (endophenotypes) that improve risk stratification and provide new molecular insights.

Birds are almost always said to have two visual pathways from the retina to the telencephalon: thalamofugal terminating in the Wulst, and tectofugal terminating in the entopallium. Often ignored is a second tectofugal pathway that terminates in the nidopallium medial to and separate from the entopallium (e.g., Gamlin and Cohen [1986] J Comp Neurol 250:296-310). Using standard tract-tracing and electroanatomical techniques, we extend earlier evidence of a second tectofugal pathway in songbirds (Wild [1994] J Comp Neurol 349:512-535), by showing that visual projections to nucleus uvaeformis (Uva) of the posterior thalamus in zebra finches extend farther rostrally than to Uva, as generally recognized in the context of the song control system. Projections to "rUva" resulted from injections of biotinylated dextran amine into the lateral pontine nucleus (PL), and led to extensive retrograde labeling of tectal neurons, predominantly in layer 13. Injections in rUva also resulted in extensive retrograde labeling of predominantly layer 13 tectal neurons, retrograde labeling of PL neurons, and anterograde labeling of PL. It thus appears that some tectal neurons could project to rUva and PL via branched axons. Ascending projections of rUva terminated throughout a visually responsive region of the intermediate nidopallium (NI) lying between the nucleus interface medially and the entopallium laterally. Lastly, as shown by Clarke in pigeons ([1977] J Comp Neurol 174:535-552), we found that PL projects to caudal cerebellar folia.

The Wulst of birds, which is generally considered homologous with the isocortex of mammals, comprises an elevation on the dorsum of the telencephalon that is particularly prominent in predatory species, especially those with large, frontally placed eyes, such as owls. The Wulst, therefore, is largely visual, but a relatively small rostral portion is somatosensory in nature. In barn owls this rostral somatosensory part of the Wulst forms a unique physical protuberance dedicated to the representation of the contralateral claw. Here we investigate whether the input to this ‘claw area’ arises from dorsal thalamic neurons that, in turn, receive their somatosensory input from the gracile nucleus. Following injections of biotinylated dextran amine into the gracile nucleus and cholera toxin B-chain into the claw area, terminations from the former and retrogradely labeled neurons from the latter overlapped substantially in the thalamic nucleus dorsalis intermedius ventralis anterior. These results indicate the existence in this species of a ‘classical’ trisynaptic somatosensory pathway from the body periphery to the telencephalic Wulst, via the dorsal thalamus, one that is likely involved in the barn owl’s predatory behavior. The results are discussed in the context of somatosensory projections, primarily in this and other avian species.

Learned vocalizations, such as bird song, require intricate coordination of vocal and respiratory muscles. Although the neural basis for this coordination remains poorly understood, it likely includes direct synaptic interactions between respiratory premotor neurons and vocal motor neurons. In birds, as in mammals, the medullary nucleus retroambigualis (RAm) receives synaptic input from higher level respiratory and vocal control centers and projects to a variety of targets. In birds, these include vocal motor neurons in the tracheosyringeal part of the hypoglossal motor nucleus (XIIts), other respiratory premotor neurons, and expiratory motor neurons in the spinal cord. Although various cell types in RAm are distinct in their anatomical projections, their electrophysiological properties remain unknown. Furthermore, although prior studies have shown that RAm provides both excitatory and inhibitory input onto XIIts motor neurons, the identity of the cells in RAm providing either of these inputs remains to be established. To characterize the different RAm neuron types electrophysiologically, we used intracellular recordings in a zebra finch brain stem slice preparation. Based on numerous differences in intrinsic electrophysiological properties and a principal components analysis, we identified two distinct RAm neuron types (types I and II). Antidromic stimulation methods and intracellular staining revealed that type II neurons, but not type I neurons, provide bilateral synaptic input to XIIts. Paired intracellular recordings in RAm and XIIts further indicated that type II neurons with a hyperpolarization-dependent bursting phenotype are a potential source of inhibitory input to XIIts motor neurons. These results indicate that electrically distinct cell types exist in RAm, affording physiological heterogeneity that may play an important role in respiratory–vocal signaling.

We have investigated the somatosensory and auditory representations in the nucleus basalis of the barn owl. In pigeons and finches, the nucleus basalis contains a representation of the beak and an auditory area. In the barn owl, the nucleus basalis also contains a complete somatotopic map of the head and body (as in the budgerigar), with a tonotopically organized auditory area in close proximity to the representation of the facial ruff and the preaural area. Recordings within and around the nucleus basalis revealed predominantly (about 80%) contralateral responses to somatic stimulation. The somatotopic map was oriented with the head down and rostral. Penetrations revealed an over-representation of the feet in dorsal basalis, followed by the rest of the body and wings more ventrally. Towards more rostral positions in nucleus basalis, responses from the head and beak predominated ventrally. The auditory response area was encountered below the region that responded to stimulation of the facial ruff and preaural flap regions and above a region responsive to beak stimulation. Auditory responses were tonotopically organized, with low best frequencies dorsal. Some penetrations yielded predominantly monaural responses with a fairly broad dynamic range, similar to those recorded from the ventral nucleus of the lateral lemniscus (LLV) and the cochlear nucleus angularis, whereas other penetrations contained predominantly binaural responses sensitive to interaural time differences (ITD). The physiological responses could be predicted on the basis of auditory projections to the nucleus basalis. An injection of biotinylated dextran amine (BDA) in the auditory region of nucleus basalis retrogradely labeled cells in both the caudal and rostral parts of the intermediate lateral lemniscal nucleus (LLIc and LLIr), and a few cells in the anterior part of the dorsal lateral lemniscal nucleus (LLDa, previously known as nucleus ventralis lemnisci lateralis, pars anterior, or VLVa) and in the posterior part of the dorsal lateral lemniscal nucleus (LLDp, previously known as nucleus ventralis lemnisci lateralis, pars posterior, or VLVp). A large injection of cholera toxin B-chain (CTB) into the nucleus basalis also produced dense retrograde labeling of a previously unidentified nucleus on the lateral aspect of the rostral pons, that we here call nucleus pontis externus (PE). An injection of CTB into PE produced dense retrograde labeling of the contralateral dorsal column nuclei and anterograde labeling of the ipsilateral lateral and dorsolateral nucleus basalis. Together these results define major somatosensory and auditory projections to the owl telencephalon that bypass the thalamus.

Transganglionic and retrograde tracing procedures were applied to peripheral and central trigeminal structures in hatchling ring doves. The organization of the trigeminal ganglion, its somatotopic projections upon the principal sensory nucleus (PrV), and the projections of PrV upon the telencephalon are similar in adult and hatchling Columbiformes. The results suggest that development of feeding patterns in these species involves experiential differentiation of trigeminal sensorimotor circuits present at hatching.

Recordings of extracellular unit activity in the ventrolateral medulla and of electyromyographic activity in either the M. scalenus, a principal inspiratory muscle, or the abdominal expiratory muscles, were used to identify inspiratory related (IR) neurons. IR neurons extended from levels caudal to the obex through the caudal level of the descending vestibular nucleus. This distribution was found to correspond to that of a subset of cells retrogradely labeled from injections of neuronal tracers into the upper thoracic spinal cord, where motoneurons innervating the M. scalenus were located by retrograde transport. Injections of biotinylated dextran amine at the recording sites resulted in projections to the spinal cord and brainstem. Bulbospinal axons traveled in the lateral funiculus, predominantly contralaterally, and terminated in relation to the dendrites and cell bodies of motoneurons innervating the M. scalenus. Brainstem nuclei receiving projections from injections at IR loci included the retroambigualis, tracheosyringeal motor nucleus, ventrolateral nucleus of the rostral medulla, infra-olivaris superior, ventrolateral parabrachial nucleus, and the dorsomedial nucleus of the intercollicular complex. In the finches, there were also bilateral projections to nucleus uvaeformis of the posterior thalamus. The spinal and brainstem projections are similar to those found in pigeon (Reinke and Wild, [1997] J. Comp. Neurol. 379:347–362), and probably mediate the intricate coordination of the vocal (syringeal) and respiratory systems for the control of vocalization. The distribution of IR neurons in birds is similar to that of the rostral ventral respiratory group (rVRG) in mammals. J. Comp. Neurol. 391:147–163, 1998. © 1998 Wiley-Liss, Inc.

We have recorded extracellular, inspiratory-related (IR) unit activity in the medulla at locations corresponding to those of neurons retrogradely labeled by injections of retrograde tracers in the lower brachial and upper thoracic spinal cord, injections that covered cell bodies and dendrites of motoneurons innervating inspiratory muscles. Bulbospinal neurons were distributed throughout the dorsomedial and ventrolateral medulla, from the spinomedullary junction through about 0.8 mm rostral to the obex. Almost all of the 104 IR units recorded were located in corresponding parts of the ventrolateral medulla, rostral to nucleus retroambigualis, where expiratory related units are found. Injections of biotinylated dextran amine at the recording sites labeled projections both to the spinal cord and to the brainstem. In the lower brachial and upper thoracic spinal cord, bulbospinal axons traveled predominantly in the contralateral dorsolateral funiculus and terminated in close relation to the dendrites of inspiratory motoneurons retrogradely labeled with cholera toxin B-chain. In the brainstem, there were predominantly ipsilateral projections to the nucleus retroambigualis, tracheosyringeal motor nucleus (XIIts), ventrolateral nucleus of the rostral medulla, infraolivary superior nucleus, ventrolateral parabrachial nucleus, and dorsomedial nucleus of the intercollicular complex. In all these nuclei, except XIIts, retrogradely labeled neurons were also found, indicating reciprocity of the connections. These results suggest the possibility of monosynaptic connections between inspiratory premotor neurons and inspiratory motoneurons, which, together with connections of IR neurons with other brainstem respiratory-vocal nuclei, seem likely to mediate the close coordination that exists in birds between the vocal and respiratory systems. The distribution of IR neurons in birds is similar to that of the rostral ventral respiratory group (rVRG) in mammals. J. Comp. Neurol. 379:347–362, 1997. © 1997 Wiley-Liss, Inc.

Injections of neuronal tracers were made into the dorsomedial nucleus of the intercollicular complex (DM) of pigeons and zebra finches in order to investigate the projections of this nucleus which has long been implicated in respiratory-vocal control. Despite the fact that pigeons are nonsongbirds and zebra finches are songbirds, the projections were very similar in both species. Most descended throughout the brainstem, taking ventral and dorsal trajectories, which merged in the medulla. Those descending ventrally terminated upon the ventrolateral parabrachial nucleus (PBvl), the nucleus infraolivaris superior, a nucleus of the rostral ventrolateral medulla (RVL), and the nucleus retroambigualis (RAm). Those taking a dorsal trajectory via the occipitomesencephalic tract terminated in the tracheosyringeal part of the hypoglossal nucleus (XIIts), the suprahypoglossal region, and nucleus retroambigualis. There were also substantial projections throughout an arc extending, between XIIts and RVL rostrally, and XIIts and RAm caudally. Neurons throughout this arc, which include inspiratory premotor neurons at levels straddling the obex and expiratory premotor neurons more caudally (in RAm), were retrogradely labeled from spinal injections. The DM projections were predominantly ipsilateral, but there were distinct contralateral projections to all the homologous nuclei in both species. All but the projections to PBvl and XIIts were reciprocal. In summary, the projections of DM suggest that it is able to influence all the key motor and premotor nuclei involved in patterned respiratory-vocal activity. J. Comp. Neurol. 377:392–413, 1997. © 1997 Wiley-Liss, Inc.

Injections of cholera toxin B-chain conjugated to horseradish peroxidase into individual peripheral branches of the trigeminal nerve or into the trigeminal ganglion showed that an ascending trigeminal tract (TTA) terminated in distinct ventral and dorsal divisions of the principal sensory nucleus (PrVv and PrVd, respectively), and a descending tract (TTD) terminated within pars oralis, pars interpolaris, and pars caudalis divisions of the nucleus of TTD (nTTD) and within the dorsal horn of the first six cervical spinal segments. In PrVD, mandibular, ophthalmic, and maxillary projections were predominantly located dorsally, ventrally, and medially, respectively. In nTTD, mandibular projections lay dorsomedially, ophthalmic projections lay ventrolaterally, and maxillary projections lay in between. At caudal medullary and spinal levels, mandibular projections were situated medially, ophthalmic projections were situated laterally, and maxillary projections were situated centrally. The terminations within the dorsal horn were most dense in laminae III and IV and were least dense in lamina II, with laminae III-IV also receiving topographically organised contralateral projections. Extratrigeminal projections were mainly to the external cuneate nucleus by way of a lateral descending trigeminal tract (ITTD; Dubbeldam and Karten [1978] J. Comp. Neurol. 180:661–678) and to the region of the tract of Lissauer and lamina I of the dorsal horn. Other projections were to a region medial to the apex of pars interpolaris, to the nuclei ventrolateralis anterior (Vla) and presulcalis anterior (Pas) of the solitary complex, and sparsely to the lateral reticular formation (plexus of Horsley) ventral to TTD. No projections were seen to the trigeminal motor nuclei or to the cerebellum. © 1996 Wiley-Liss, Inc.

Projections of dorsal column, spinal, and cochlear nuclei upon the central nucleus of the torus semicircularis (otherwise known as nucleus mesencephalicus lateralis, pars dorsalis, or MLd) and upon other toral nuclei were investigated in pigeon by anterograde and retrograde tracing and electrophysiological methods. The anatomical results showed that caudal regions of the dorsal column nuclei and medial lamina V of the upper four cervical spinal segments have extensive projections upon the contralateral central auditory nucleus and upon other nuclei of the torus, in particular the core portion of the preisthmic superficial area of Puelles et al. (L. Puelles, C. Rrobles, M. Martiez-de-la-Torre, and S. Martinez, 1994, J. Comp. Neurol. 340:98–125). The projections of nucleus angularis were found to terminate throughout most of the contralateral central nucleus except the dorsomedial portion at rostral levels, where the majority of the projections of nucleus laminaris were concentrated. Nucleus angularis (and to a lesser extent nucleus laminaris) was also found to have substantial projections to certain noncentral toral nuclei, in particular to the caudomedial shell nucleus of Puelles et al. (1994). As shown positively with both Nissl and cytochrome oxidase staining and negatively with substance P labeling, this nucleus is a medial extension of more caudal regions of the central nucleus, and it is suggested that it should be included as part of the auditory midbrain. The electrophysiological results confirmed the anatomical findings by showing that evoked potentials and multiunit activity can be recorded throughout the central and noncentral toral nuclei by using electrical stimulation of the radial nerve and auditory click stimuli. The core portion of the preisthmic superficial area, however, can be regarded as a distinct somatosensory nucleus of the midbrain. It is concluded that there is substantial convergence of somatosensory and auditory inputs within both central auditory and noncentral nuclei of the torus semicircularis in pigeon. © 1995 Wiley-Liss, Inc.

In birds the red nucleus is the most rostral cell group in the brain having projections to all levels of the spinal cord (Cabot et al., Prog. Brain Res., 57:79–108, 1982), but its sources of afferents are incompletely known. In order to determine these, a series retrograde and anterograde tracing experiments was carried out, largely with cholera toxin B-chain conjugated to horseradish peroxidase. The results show that a sparse and diffuse projection to the red nucleus arises from deep regions of the hyperstriatum accessorium (HA) of the anterior Wulst, and that a much more dense projection arises from the caudal part of the nucleus principalis precommissuralis and the medial part of the medial spiriform nucleus (SpMm). These last two sources were themselves shown to receive a substantial projection from HA of the anterior Wulst. The red nucleus was also shown to project upon the cerebellar cortex of lobule VI, and SpM upon the cerebellar cortex of lobules VI through IX (Karten and Finger, Brain Res., 102:335–338, 1976; Clarke, J. Comp. Neurol., 174:535–552, 1977). Double retrograde labelling experiments with fluorescein and rhodamine labelled latex microspheres injected into the cerebellar cortex and spinal cord showed that the rubrocerebellar cortical neurons are a different population from, although intermixed with, the rubrospinal neurons. © 1992 Wiley-Liss, Inc.

The presence and nature of a descending projection from the ventral nucleus of the lateral lemniscus (LLV) to the cochlear nuclei (NA, NM) and the third-order nucleus laminaris (NL) was investigated in a songbird using tract tracing and GAD immunohistochemistry. Tracer injections into LLV produced anterograde label in the ipsilateral NA, NM and NL, which was found not to be GABAergic. Double retrograde labeling from LLV and NA/NM/NL ruled out the possibility that the LLV projection actually arose from collaterals of superior olivary projections to NA/NM/NL. The LLV projection may be involved in the discrimination of laterality of auditory input.

In songbirds song production requires the intricate coordination of vocal and respiratory muscles under the executive influence of the telencephalon, as for speech in humans. In songbirds the site of this coordination is suspected to be the nucleus retroambigualis (RAm), because it contains premotor neurons projecting upon both vocal motoneurons and spinal motoneurons innervating expiratory muscles, and because it receives descending inputs from the telencephalic vocal control nucleus robustus archopallialis (RA). Here we used tract-tracing techniques to provide a more comprehensive account of the projections of RAm and to identify the different populations of RAm neurons. We found that RAm comprises diverse projection neuron types, including: 1) bulbospinal neurons that project, primarily contralaterally, upon expiratory motoneurons; 2) a separate group of neurons that project, primarily ipsilaterally, upon vocal motoneurons in the tracheosyringeal part of the hypoglossal nucleus (XIIts); 3) neurons that project throughout the ipsilateral and contralateral RAm; 4) another group that sends reciprocal, ascending projections to all the brainstem sources of afferents to RAm, namely, nucleus parambigualis, the ventrolateral nucleus of the rostral medulla, nucleus infra-olivarus superior, ventrolateral parabrachial nucleus, and dorsomedial nucleus of the intercollicular complex; and 5) a group of relatively large neurons that project their axons into the vagus nerve. Three morphological classes of RAm cells were identified by intracellular labeling, the dendritic arbors of which were confined to RAm, as defined by the terminal field of RA axons. Together the ascending and descending projections of RAm confirm its pivotal role in the mediation of respiratory-vocal control.

The ascending and descending projections of the parabrachial nuclear complex in the pigeon have been charted with autoradiographic and histochemical (WGA-HRP) techniques. The ascending projections originate from a group of subnuclei surrounding various components of the brachium conjunctivum, namely, the superficial lateral, dorsolateral, dorsomedial, and ventromedial subnuclei. The projections are predominantly ipsilateral and travel in the quintofrontal tract. They are primarily to the medial and lateral hypothalamus (including the periventricular nucleus and the strata cellulare internum and externum), certain dorsal thalamic nuclei, the nucleus of the pallial commissure, the bed nucleus of the stria terminalis, the ventral paleostriatum, the olfactory tubercle, the nucleus accumbens, and a dorsolateral nucleus of the posterior archistriatum. There are weaker or more diffuse projections to the rostral locus coeruleus (cell group A8), the compact portion of the pedunculopontine tegmental nucleus, the central grey and intercollicular region, the ventral area of Tsai, the medial spiriform nucleus, the nucleus subrotundus, the anterior preoptic area, and the diagonal band of Broca. The parabrachial subnuclei have partially differential projections to these targets, some of which also receive projections from the nucleus of the solitary tract (Arends, Wild, and Zeigler: J. Comp. Neurol. 278:405-429, '88). Most of the targets, particularly those in the basal forebrain (viz., the periventricular nucleus and the strata cellulare internum and externum of the hypothalamus, the bed nucleus of the stria terminalis, and its lateral extension into the ventral paleostriatum, which may be comparable with the substantia innominata), have reciprocal connections with the parabrachial and solitary tract subnuclei and therefore may be said to compose parts of a “visceral forebrain system” analogous to that described in the rat (Van der Kooy et al: J. Comp. Neurol. 224:1-24, '84). The descending projections to the lower brainstem arise in large part from a ventrolateral subnucleus that may be comparable with the Kolliker Fuse nucleus of mammals. They are mainly to the ventrolateral medulla, nucleus ambiguus, and massively to the hypoglossal nucleus, particularly its tracheosyringeal portion. These projections are therefore likely to be importantly involved in the control of vocalization and respiration (Wild and Arends: Brain Res. 407:191-194, '87). Some of these results have been presented in abstract form (Wild, Arends, and Zeigler: Soc. Neurosci. Abst. 13:308, '87).

SUMMARY The ability of pigeons to find their way home from unfamiliar sites located up to hundreds of kilometers away is well known, but the mechanisms underlying this ability remain controversial. One proposed mechanism is based on the suggestion that pigeons are equipped with magnetoreceptors that can enable the detection of either the earth's magnetic field and/or magnetic field anomalies in the local terrain over which the pigeons fly. Recent reports have suggested that these magnetoreceptors are located in the upper beak where they are innervated by the ophthalmic branch of the trigeminal nerve. Moreover, this nerve has been shown to mediate pigeons' ability to discriminate the presence versus the absence of a magnetic field anomaly in a conditioning situation. In the present study, however, we show that an intact ophthalmic branch of the trigeminal nerve is neither necessary nor sufficient for good homing performance from unfamiliar locations, but that an intact olfactory nerve is necessary.

Increasing knowledge of the avian hippocampal formation (hippocampus and parahippocampal area) suggests that it plays a role in a variety of behaviors, such as homing, cache retrieving, visual discrimination, imprinting, and sexual behavior. Knowledge of the neural circuits in the hippocampal formation and its related areas or nuclei is important for the understanding of these functions. This review therefore describes the functional neuroanatomy of the avian hippocampal formations, i.e., its subdivisions, cytoarchitecture, and afferent and efferent connections. Evidence obtained by a combination of Nissl staining and tract-tracing shows that the pigeon hippocampal formation can be divided into seven subdivisions: dorsolateral (DL), dorsomedial (DM), triangular (Tr), V-shaped (V), magnocellular (Ma), parvocellular, and cell-poor regions. DL and DM can be further divided into dorsal and ventral, and lateral and medial portions, respectively. In the hippocampal formation, reciprocal connections are found between DL-DM, DL-Tr, DL-Ma, DM-Ma, DM-V, and Tr-V. Neurons in the V-shaped layer appear to be intrinsic neurons. Sensory inputs from higher order visual and olfactory stations enter DL and DM, are modified or integrated by intrinsic hippocampal circuitry, and the outputs are sent, via DL and DM, to various telencephalic nuclei, septum, and hypothalamus. The neural pathways indicate that the hippocampal formation plays a central role in the limbic system, which also includes the dorsolateral corticoid area, nucleus taeniae of the amygdala, posterior pallial amygdala, septum, medial part of the anterior dorsolateral nucleus of the thalamus, and the lateral mammillary nucleus. Connectional and comparative studies, including the use of kainic acid excitotoxicity, suggest that the V-shaped layer is comparable to the dentate gyrus of the mammalian hippocampal formation and DM to Ammon's horn and subiculum.

In birds, as in humans, vocal control involves the intricate coordination of three major groups of muscles, namely, those of the vocal organ, the respiratory apparatus, and the vocal tract, including the jaw and tongue. The neural pathways involved in the control of each of these groups of muscles are described for songbirds and compared with those in non-oscine birds and mammals. The pathway in songbirds that controls the syrinx, the bird's vocal organ, originates in the telencephalon and projects via the occipito-mesencephalic tract directly upon vocal motoneurons in the medulla. Activity in this pathway configures the syrinx into phonatory positions for the production of species typical vocalizations. Another component of this pathway mediates control of respiration during vocalization, since it projects upon both expiratory and inspiratory groups of premotor neurons in the ventrolateral medulla, as well as upon several other nuclei en route. This pathway appears to be primarily involved with the control of the temporal pattern of song, but is also importantly involved in the control of vocal intensity, mediated via air sac pressure. There are extensive interconnections between the vocal and respiratory pathways, especially at brainstem levels, and it may be these that ensure the necessary temporal coordination of syringeal and respiratory activity. The pathway mediating control of the jaw appears to be different from those mediating control of the syrinx and respiratory muscles. It originates in a different part of the telencephalon and projects upon premotor neurons in the medulla that, on preliminary analysis, appear to be separate from those projecting upon the syringeal motor nucleus. The separateness of this pathway may reflect the imperfect correlation of jaw movements with the dynamic and acoustic features of song. The brainstem pathways mediating control of vocalization and respiration in songbirds have distinct similarities to those in non-oscine birds and in mammals such as cats and monkeys. However, songbirds and parrots, like humans, but unlike other non-songbirds, have developed a special telencephalic vocal control system for the production of learned vocalizations.

Nucleus basalis (Bas) of the budgerigar contains an ordered, but distorted, somatotopic representation of the whole body, as does the primary somatosensory cortex (SI) of mammals. Unlike SI, however, the beak and body regions of Bas receive their sensory input via disynaptic pathways relaying in the pons. That to the body parts originates in a previously undescribed nucleus that receives its inputs from primary afferents via a novel, ipsilateral somato sensory pathway.

Birds have well-developed basal ganglia within the telencephalon, including a striatum consisting of the medially located lobus parolfactorius (LPO) and the laterally located paleostriatum augmentatum (PA), Relatively little is known, however, about the extent and organization of the telencephalic “cortical” input to the avian basal ganglia (i. e., the avian “corticostriatal” projection system). Using retrograde and anterograde neuroanatomical pathway tracers to address this issue, we found that a large continuous expanse of the outer pallium projects to the striatum of the basal ganglia in pigeons. This expanse includes the Wulst and archistriatum as well as the entire outer rind of the pallium intervening between Wulst and archistriatum, termed by us the pallium externum (PE). In addition, the caudolateral neostriatum (NCL), pyriform cortex, and hippocampal complex also give rise to striatal projections in pigeon. A restricted number of these pallial regions (such as the “limbic” NCL, pyriform cortex, and ventral/caudal parts of the archistriatum) project to such ventral striatal structures as the olfactory tubercle (TO), nucleus accumbens (Ac), and bed nucleus of the stria terminalis (BNST). Such “limbic” pallial areas also project to medialmost LPO and lateralmost PA, while the hyperstriatum accessorium portion of the Wulst, the PE, and the dorsal parts of the archistriatum were found to project primarily to the remainder of LPO (the lateral two-thirds) and PA (the medial four-fifths). The available evidence indicates that the diverse pallial regions projecting to the striatum in birds, as in mammals, are parts of higher order sensory or motor systems. The extensive corticostriatal system in both birds and mammals appears to include two types of pallial neurons: (1) those that project to both striatum and brainstem (i. e., those in the Wulst and the archistriatum) and (2) those that project to striatum but not to brainstem (i. e., those in the PE). The lack of extensive corticostriatal projections from either type of neuron in anamniotes suggests that the anamniote-amniote evolutionary transition was marked by the emergence of the corticostriatal projection system as a prominent source of sensory and motor information for the striatum, possibly facilitating the role of the basal ganglia in movement control. © 1995 Wiley-Liss, Inc.

Nucleus uvaeformis (Uva), previously identified as a component of song control circuitry in songbirds, and nucleus dorsolateralis posterior thalami, pars caudalis (DLPc) in pigeon, were compared with respect to their relative positions in the dorsolateral part of the posterior thalamus, their cell types, and their afferent and efferent projections. Both nuclei are closely related to the habenulointerpeduncular tract, have similar cell types, and receive a dense projection from deep layers of the optic tectum, predominantly ipsilaterally, and a distinct projection from the dorsal column and external cuneate nuclei, predominantly contralaterally. Recordings of multiple unit activity evoked by visual and somatosensory stimuli were used to guide injections of tracer into either DLPc or Uva, and the projections to the telencephalon were charted. Both nuclei were found to have a major terminal field in the medial part of the ipsilateral neostriatum intermedium (NI), known as nucleus interfacialis (NIf) in songbirds, and a minor terminal field in the roof of the neostriatum caudale (NC). In pigeon, the DLPc terminations in NC were within a region known as neostriatum dorsale (Nd), and, in male songbirds, the Uva terminations were in the high vocal center (HVC). Recordings of visual and somatosensory evoked activity were then used to guide injections of tracer into NI, and the afferent and efferent projections were again compared in pigeon and songbirds. The projections from either DLPc or Uva were confirmed, and terminal fields were observed either in Nd in pigeon, the dorsolateral part of NC in female songbirds, or HVC in male songbirds. Injections of tracer into either Nd or HVC confirmed their sources of afferents in DLPc or Uva, respectively, and in NI, but there was incomplete overlap of the distribution of retrogradely labelled cells in NI and the terminal fields of DLPc or Uva. It is concluded that DLPc and Uva are comparable nuclei having similar afferent and efferent projections relaying visual and somatosensory information to the telencephalon. The possible role of this information in vocal control is discussed.

A series of studies is described which in general aim to identify two sets of neural linkages in the brain and spinal cord of songbirds and non-songbirds, these avian types differing along a dimension of 'complexity of vocal communication'. One set of linkages is postulated to link the vocal system with the respiratory system, since birds, like humans, require controlled expiration in order to vocalize normally. The other set is thought to link the auditory system with the vocal system, at least in songbirds, because they are dependent upon auditory feedback for vocal learning. The systems and their linkages can be regarded as forming an 'auditory-vocal-respiratory axis', around which the animal's communication system evolves and revolves. The experimental strategy used was one which began at the periphery (the abdominal expiratory muscles), then progressively identified more central neural structures using retrograde transport methods in partial combination with recordings of single cell activity. The projections delineated by these methods were then defined in detail by anterograde tracing methods. The results of the studies confirmed the expectation that the vocal and respiratory systems have many neural elements in common. They also suggested that songbirds and non-songbirds possess similar neural pathways in the brainstem and spinal cord for the control of both vocalization and respiration but indicated that there may be significant differences between the two types of birds in the degree to which the telencephalon is able to modulate respiratory-vocal activity downstream. Thus, whereas there is a cascade of descending projections terminating upon syringeal and laryngeal motoneurons and expiratory premotor neurons in both songbirds and non-songbirds, the most rostral origin of this cascade is the telencephalic nucleus robustus archistriatalis in (male) songbirds but, apparently, the dorsomedial nucleus of the intercollicular complex of the midbrain (DM) in pigeons. Connectional studies of the auditory system in pigeons delineated a series of projections which originate in Field L2, the primary telencephalic auditory area, and leave the telencephalon via the nucleus archistriatum intermedium, pars medialis (Aivm), after traversing a minimum of three synapses within the telencephalon. The extratelencephalic projections of Aivm resemble those of deep layers of mammalian auditory neocortex, having terminations in close proximity to thalamic and midbrain auditory nuclei, but a projection upon DM is conspicuous by its absence. The way in which auditory input gains access to vocal control nuclei in non-songbirds, such as pigeons, thus remains to be determined.