The mammalian red nucleus and its role in motor systems, including the emergence of bipedalism and language.

The human red nucleus consists of the well-developed parvicellular red nucleus (pNr) and the rudimentary magnocellular red nucleus (mNr). It is believed that the human pNr is separated from the nucleus accessorius medialis of Bechterew (NB), which, generally speaking, is located in the ventral central gray. It was initially suggested that the "rolled sheet" model of the human pNr that we proposed included the view that the human NB does not occupy the ventral central gray but is placed in the dorsomedial part of the red nucleus. It is perhaps more appropriate to state that the NB, the origin of the medial tegmental tract (MTT), over time became displaced from the ventral central gray and was in part shifted to the adjacent reticular formation. The majority of the MTT tract however remained in its established location. Evolutionarily speaking, this separation of the NB and the nucleus of Darkschewitsch (ND), and the translocation of the position of the NB just referred to, might have begun within the lineage of the apes prior to the emergence of man. Furthermore it is generally believed that the human mNr consists of a scattered few groups of giant-to-large neurons situated among the fiber bundles of the superior cerebellar peduncle at the level of the oculomotor nerve fibers. It has long been considered impossible to clearly draw an outline of the human mNr such that it could be seen as a self-contained structural entity. However, we now demonstrate just such an outline of the rudimentary human adult mNr through employment of the concepts of the so-called "Mannen's closed nucleus" and "Ogawa's human mNr": descriptions that exclude the associated area that contains neurons which possess melanin pigment. Interestingly, recent studies have shown that the human fetus and newborns have a well-developed semilunar mNr, and this observation raises the possibility that the associated transient but well-developed rubrospinal tract seen in the perinatal state might have had an important role for the development of upright bipedalism in hominids. The well-developed human prefrontal-NB-olivo-lateral cerebellar circuit might possibly have resulted in the emergence of language.

GPI-1046 increases presenilin-1 expression and restores NMDA channel activity.

BACKGROUND: Previously we showed that 6-hydroxydopamine lesions of the substantia nigra eliminate corticostriatal LTP and that the neuroimmunolophilin ligand (NIL), GPI-1046, restores LTP. METHODS: We used cDNA microarrays to determine what mRNAs may be over- or under-expressed in response to lesioning and/or GPI-1046 treatment. Patch clamp recordings were performed to investigate changes in NMDA channel function before and after treatments. RESULTS: We found that 51 gene products were differentially expressed. Among these we found that GPI-1046 treatment up-regulated presenilin-1 (PS-1) mRNA abundance. This finding was confirmed using QPCR. PS-1 protein was also shown to be over-expressed in the striatum of lesioned/GPI-1046-treated rats. As PS-1 has been implicated in controlling NMDA-receptor function and LTP is reduced by lesioning we assayed NMDA mediated synaptic activity in striatal brain slices. The lesion-induced reduction of dopaminergic innervation was accompanied by the near complete loss of NDMA receptor-mediated synaptic transmission between the cortex and striatum. GPI-1046 treatment of the lesioned rats restored NMDA-mediated synaptic transmission but not the dopaminergic innervation. Restoration of NDMA channel function was apparently specific as the sodium channel current density was also reduced due to lesioning but GPI-1046 did not reverse this effect. We also found that restoration of NMDA receptor function was also not associated with either an increase in NMDA receptor mRNA or protein expression. CONCLUSION: As it has been previously shown that PS-1 is critical for normal NMDA receptor function, our data suggest that the improvement of excitatory neurotransmission occurs through the GPI-1046-induced up-regulation of PS-1.

Carbocyanine dye usage in demarcating boundaries of the aged human red nucleus.

BACKGROUND: Though the adult human magnocellular Red nucleus (mNr) is essentially vestigial and its boundaries with neighbouring structures have never been well demarcated, human studies in utero have shown a well developed semilunar mNr wrapping around the caudal parvicellular Red nucleus (pNr), similar to what is seen in quadrupeds. In the present study, we have sought to better delineate the morphological determinants of the adult human Red nucleus (ahRn). METHODS AND FINDINGS: Serial sections of ahRn show fine myelinated fibers arising from pNr and turning toward the central tegmental tract. DiI was deposited within a well restricted region of ahRn at the fasciculus retroflexus level and the extent of label determined. Nissl-stained serial sections allowed production of a 3-D mNr model, showing rudimentary, vestigial morphology compared with its well developed infant homologue. DiI within this vestigial mNr region at the level of the oculomotor nerve showed labeled giant/large mNr neurons, coarse fiber bundles at the ventral tegmental decussation and lateral lemniscal label. CONCLUSIONS: Large amounts of DiI and a long incubation time have proven useful in aged human brain as a marker of long axons and large cell bodies of projecting neurons such as the rubrospinal projection and for clarifying nuclear boundaries of closed nuclei (e.g., the large human pNr). Our 3D model of adult human mNr appeared shrunken in shape and axially rotated compared with the infant mNr, the rotation being a common feature among mammalian mNr.

A comparative neuroanatomical study of the red nucleus of the cat, macaque and human.

BACKGROUND: The human red nucleus (Nr) is comparatively less well-studied than that of cats or monkeys. Given the functional importance of reticular and midbrain structures in control of movement and locomotion as well as from an evolutionary perspective, we investigated the nature and extent of any differences in Nr projections to the olivary complex in quadrupedal and bipedal species. Using neuroanatomical tract-tracing techniques we developed a "neural sheet" hypothesis allowing us to propose how rubro-olivary relations differ among the three species. METHODS AND FINDINGS: Wheat germ agglutinin-horseradish peroxidase staining supports findings that the cat's nucleus accessories medialis of Bechtrew (NB) projects mainly to the lateral bend of the principal olive. We clarified boundaries among nucleus of Darkschewitsch (ND), NB and parvicellular red nucleus (pNr) of the cat's neural sheet. The macaque's ND-medial accessory olivary projection is rostro-caudally organized and the dorsomedial and ventrolateral parts of the macaque's pNr may project to the principal olive's rostral and caudal dorsal lamella; in cat it projects as well to pNr. Myelin- and Nissl-stained sections show that a well-developed dorsomedial part of the human Nr consists of densely packed cells, deriving small myelinated fibers that continue into the medial central tegmental tract. CONCLUSIONS: Based on these findings we suggest there are distinct bipedal-quadrupedal differences for Nr projections to the olivary complex. We propose the Nr of cats and monkeys comprise the ND, NB and pNr in a zonal sheet-like structure, retaining clear nuclear boundaries and an isolated, well-developed mNr. The human NB may be distinguished from its more specialised ND (ND lies alongside a well-developed pNr) in the human central gray. Phylogenetically, the NB may have been translocated into a roll-shaped Nr in the reticular formation, the dorsomedial portion of which might correspond to the cat's and monkey's NB.

A meeting of minds: interdisciplinary research in the health sciences in Canada.

Brought together by the newly formed Canadian Academy of Health Sciences (CAHS), recognized national leaders in the 6 health sciences disciplines consider the environment for conducting interdisciplinary health research (IDHR) in Canada. Based on first-hand knowledge and thoughtful reflection, the authors argue that although much progress has been made in support of IDHR in Canada, the practical experience of researchers does not always bear this out. This article examines government, industry and academia to identify the cultural and structural characteristics that demand, promote or prevent IDHR in each sector. At its heart is the question, How can universities best support and enhance IDHR, not only for the benefit of science, but also to meet the growing needs of industry and government for intellectual capital? Focusing on the predominant health sciences disciplines, the authors define IDHR as a team of researchers, solidly grounded in their respective disciplines, who come together around an important and challenging health issue, the research question for which is determined by a shared understanding in an interactive and iterative process. In addition, they suggest that IDHR is directly linked to translational research, which is the application of basic science to clinical practice and the generation of scientific questions through clinical observation. This analysis of academic, industry and government sectors is not intended to offer rigorous data on the current state of IDHR in Canada. Rather, the goal is to stimulate research-policy dialogue by suggesting a number of immediate measures that can help promote IDHR in Canada. Recommended measures to support IDHR are aimed at better resourcing and recognition (by universities and granting agencies), along with novel approaches to training, such as government-and industry-based studentships. In addition, we recommend that professional organizations reconsider their policies on publication and governance. Although intended to maintain professional scopes of practice, these policies also serve to entrench disciplinary boundaries in research. We conclude by suggesting a number of research questions for a more rigorous assessment of the climate for IDHR in Canada. We call for an inventory and comparative analysis of academic centres, institutes and consortiums in Canada that strive to facilitate IDHR; an examination of the impact of professional organizations on health research, and on IDHR in particular; and a systematic review of research training opportunities that promote IDHR, with a view to identifying and replicating proven models.

The mysterious trace amines: protean neuromodulators of synaptic transmission in mammalian brain.

The trace amines are a structurally related group of amines and their isomers synthesized in mammalian brain and peripheral nervous tissues. They are closely associated metabolically with the dopamine, noradrenaline and serotonin neurotransmitter systems in mammalian brain. Like dopamine, noradrenaline and serotonin the trace amines have been implicated in a vast array of human disorders of affect and cognition. The trace amines are unique as they are present in trace concentrations, exhibit high rates of metabolism and are distributed heterogeneously in mammalian brain. While some are synthesized in their parent amine neurotransmitter systems, there is also evidence to suggest other trace amines may comprise their own independent neurotransmitter systems. A substantial body of evidence suggests that the trace amines may play very significant roles in the coordination of biogenic amine-based synaptic physiology. At high concentrations, they have well-characterized presynaptic "amphetamine-like" effects on catecholamine and indolamine release, reuptake and biosynthesis; at lower concentrations, they possess postsynaptic modulatory effects that potentiate the activity of other neurotransmitters, particularly dopamine and serotonin. The trace amines also possess electrophysiological effects that are in opposition to these neurotransmitters, indicating to some researchers the existence of receptors specific for the trace amines. While binding sites or receptors for a few of the trace amines have been advanced, the absence of cloned receptor protein has impeded significant development of their detailed mechanistic roles in the coordination of catecholamine and indolamine synaptic physiology. The recent discovery and characterization of a family of mammalian G protein-coupled receptors responsive to trace amines such as beta-phenylethylamine, tyramine, and octopamine, including socially ingested psychotropic drugs such as amphetamine, 3,4-methylenedioxymethamphetamine, N,N-dimethyltryptamine, and lysergic acid diethylamide, have revitalized the field of scientific studies investigating trace amine synaptic physiology, and its association with major human disorders of affect and cognition.

Olivary projection from the rostral part of the nucleus of Darkschewitsch in the postnatal rat as revealed through the use of a carbocyanine dye.

Using a carbocyanine dye in postnatal rats, we have shown that the rostral part of the nucleus of Darkschewitsch (ND), consisting of a subnucleus of the so-called "area parafascicularlis prerubralis " and excluded from the rat's ND proper, projects ipsilaterally to the rostral part of the medial accessory olive. The present study suggests the existence of a precise topographic organization from subnuclei of the area parafascicularlis prerublaris to subnuclei of the inferior olive.

Temporal shaping of phasic neuronal responses by GABA- and non-GABA-mediated mechanisms in the somatosensory thalamus of the rat.

Trapezoidal mechanical movement of whiskers was used to study the responses of 44 single thalamic ventral posteromedial (VPM) neurons to dynamic and static stimulus components in urethane-anesthetized rats. The effects of local administration of the GABAA receptor antagonist, bicuculline, and the GABAB receptor antagonist, 2-hydroxysaclofen, were tested to determine whether and to what extent the responses altered when GABA-mediated inhibitory synaptic transmission was blocked. Two classes of phasically responding neurons were identified, ON/OFF and movement-sensitive types. Bicuculline enhanced the magnitudes of the responses from both types by 2.5-fold and ON/OFF responses were converted to movement-sensitive ones in 17 (43%) of the 40 ON/OFF neurons. 2-hydroxysaclofen either had no effect or appeared to act like a GABA agonist. In 21 (48%) neurons, a significantly reduced responsiveness was observed during a 100-ms period following the ON and OFF responses. This discharge suppression was especially prominent during the plateau phase of the stimulus, and in some cases extended for several 100 ms following its onset. This suppression was overcome neither by the GABA receptor antagonists, nor by ejection of AMPA or glutamate at currents that otherwise produced vigorous excitation. These results suggest that one functional role for GABAA-receptor-mediated synaptic inhibition in the somatosensory thalamus is the intramodal regulation of the form of expression of phasically responding neurons. Other thalamic inhibitory processes not mediated by GABAA or GABAB receptors that help to shape the expression of the responses of certain phasic neurons to maintained stimulation may exist. Overall, these mechanisms appear to mediate the precision of timing of thalamic neuronal firing in response to the rat's tactile environment.