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(A) The dentate nucleus on a CV-stained parasagittal section of the macaque monkey cerebellum. Scale bar 1 mm. (B) The dentate nucleus on a parasagittal CV section in the in the human cerebellum. Scale bar 1 mm. (C) Neurons in the dentate nucleus of the macaque are round or oval. Scale bar 50 μm. (D) There are many shield-shaped, distinctly multipolar, neurons in the dentate nucleus of the human. Scale bar 50 μm.
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![The inferior olive (IO) in the rat [(A), CV], cat [(B),...](publication/261957246/figure/fig4/AS:11431281252247681@1718641205059/The-inferior-olive-IO-in-the-rat-A-CV-cat-B-immunoreactivity-to-calbindin_Q320.jpg)
The cerebral cortex is greatly expanded in the human brain. There is a parallel expansion of the cerebellum, which is interconnected with the cerebral cortex. We have asked if there are accompanying changes in the organization of pre-cerebellar brainstem structures. We have examined the cytoarchitectonic and neurochemical organization of the human...
Citations
... Strominger et al., 1979Strominger et al., , 1985Onodera and Hicks, 2009) which in turn provides major input to the cerebellar cortex Brodal, 1981, 1982;Whitworth et al., 1983;Whitworth and Haines, 1986;Azizi, 2007). Interestingly, the dentate nucleus and the cerebellar hemispheres seem to have expanded during the evolution of humans and apes (Baizer, 2014;Magielse et al., 2022) concomitantly with the associated frontal as well as parietal (van Essen and Dierker, 2007;Goldring and Krubitzer, 2020;Bruner et al., 2023) cortical areas. Although a great deal of the expansion of the frontocerebellar system might be attributed to the evolution of non-motor higher cognitive functions (Magielse et al., 2022), it is equally reasonable to assume that these cortico-cerebellar changes also partly reflect specialized motor activities that evolved in human and non-human apes (Smaers et al., , 2013. ...
Introduction: The red nucleus is part of the motor system controlling limb movements. While this seems to be a function common in many vertebrates, its organization and circuitry have undergone massive changes during evolution. In primates, it is subdivided into the magnocellular and parvocellular parts that give rise to rubrospinal and rubro-olivary connection, respectively. These two subdivisions are subject to striking variation within the primates and the size of the magnocellular part is markedly reduced in bipedal primates including humans. The parvocellular part is part of the olivo-cerebellar circuitry that is prominent in humans. Despite the well-described differences between species in the literature, systematic comparative studies of the red nucleus remain rare. Methods: We therefore mapped the red nucleus in cytoarchitectonic sections of 20 primate species belonging to 5 primate groups including prosimians, new world monkeys, old world monkeys, non-human apes and humans. We used Ornstein-Uhlenbeck modelling, ancestral state estimation and phylogenetic analysis of covariance to scrutinize the phylogenetic relations of the red nucleus volume. Results: We created openly available high-resolution cytoarchitectonic delineations of the human red nucleus in the microscopic BigBrain model and human probabilistic maps that capture inter-subject variations in quantitative terms. Further, we compared the volume of the nucleus across primates and showed that the parvocellular subdivision scaled proportionally to the brain volume across the groups while the magnocellular part deviated significantly from the scaling in humans and non-human apes. These two groups showed the lowest size of the magnocellular red nucleus relative to the whole brain volume and the largest relative difference between the parvocellular and magnocellular subdivision. Discussion: That is, the red nucleus has transformed from a magnocellular-dominated to a parvocellular-dominated station. It is reasonable to assume that these changes are intertwined with evolutionary developments in other brain regions, in particular the motor system. We speculate that the interspecies variations might partly reflect the differences in hand dexterity but also the tentative involvement of the red nucleus in sensory and cognitive functions. KEYWORDS red nucleus, human brain, primate brain, cytoarchitectonic probability maps, Julich-Brain, BigBrain, evolution CITATION Stacho M, Häusler AN, Brandstetter A, Iannilli F, Mohlberg H, Schiffer C, Smaers JB and Amunts K (2024) Phylogenetic reduction of the magnocellular red nucleus in primates and inter-subject variability in humans.
... The brainstem has been thought of an evolutionarily conserved structure, limited to physiological (e.g., breathing) and basic motor functions (e.g., locomotion) (Baizer, 2014), with the exception of neuromodulatory nuclei (e.g., locus coeruleus). The red nucleus, located in the midbrain, first emerged as quadruped precursors began coordinating extremities for movement (Basile et al., 2021;De Lange, 1912;Padel, 1993;Padel et al., 1986;Ten Donkelaar, 1988). ...
The red nucleus is a large brainstem structure that coordinates limb movement for locomotion in quadrupedal animals (Basile et al., 2021). The humans red nucleus has a different pattern of anatomical connectivity compared to quadrupeds, suggesting a unique purpose (Hatschek, 1907). Previously the function of the human red nucleus remained unclear at least partly due to methodological limitations with brainstem functional neuroimaging (Sclocco et al., 2018). Here, we used our most advanced resting-state functional connectivity (RSFC) based precision functional mapping (PFM) in highly sampled individuals (n = 5) and large group-averaged datasets (combined N ∼ 45,000), to precisely examine red nucleus functional connectivity.
Notably, red nucleus functional connectivity to motor-effector networks (somatomotor hand, foot, and mouth) was minimal. Instead, red nucleus functional connectivity along the central sulcus was specific to regions of the recently discovered somato-cognitive action network (SCAN; (Gordon et al., 2023)). Outside of primary motor cortex, red nucleus connectivity was strongest to the cingulo-opercular (CON) and salience networks, involved in action/cognitive control (Dosenbach et al., 2007; Newbold et al., 2021) and reward/motivated behavior (Seeley, 2019), respectively. Functional connectivity to these two networks was organized into discrete dorsal-medial and ventral-lateral zones. Red nucleus functional connectivity to the thalamus recapitulated known structural connectivity of the dento-rubral thalamic tract (DRTT) and could prove clinically useful in functionally targeting the ventral intermediate (VIM) nucleus. In total, our results indicate that far from being a ‘motor’ structure, the red nucleus is better understood as a brainstem nucleus for implementing goal-directed behavior, integrating behavioral valence and action plans.
... nuclei in primates compared to rodents. Actually, the cerebellar cytoarchitecture and cellular composition does not change significantly in primates compared to rodents (Larsell and Jansen, 1967;Baizer, 2014), but the human cerebellar cortex has a much higher index of gyrification than the rat cerebellar cortex (compare Figures 3, 4). Regarding the pontine nuclei, it seems that the differences between rodents and primates are quantitative (with a significant expansion of these nuclei in the human brainstem as showed in Figure 4D) without the addition of new neuron types (Mihailoff et al., 1981;Schmahmann and Pandya, 1997). ...
The expansion of human and non-human primate central nervous system structures has been a paramount question for classic and contemporary studies in comparative vertebrate neuroanatomy. These studies can benefit from framing data analysis within the Prosomeric Model, which defines a common Bauplan for all vertebrate species, including mammals. According to this model, the vertebrate nervous system is composed of several Fundamental Morphological Units (FMUs) that are defined and delineated by characteristic gene expression profiles. Thus, the expansion of neural structures can be traced back to heterochronic neurogenesis, cell lineage specification, and axon growth in their corresponding FMUs. In the present article, we exemplify the use of the Prosomeric Model as the proper theoretical framework for analyzing the expansion of the cerebral and cerebellar cortices, the pontine nuclei, the striatum, the nigrostriatal dopaminergic system, the thalamus, and the amygdala in primates compared to rodents. We describe the quantitative (volume and neuron number) and qualitative (cytoarchitectonic and cell type differences) expansion of these structures in primates versus rodents and define different expansion modes. Then, we relate these modes to the developmental primary events of specification and secondary events of histogenesis, like neurogenesis. We conclude that the systematic analysis of the molecular regulation of primary and secondary developmental events in each FMU in rats, primates, and other mammals could provide the necessary insight to identify the causal mechanisms of the expansion modes described in the present article.
... The brain is an extremely complex organ with three main compartments: Cerebrum, brainstem, and cerebellum [1,2]. The cerebrum is necessary for controlling motor and sensory pathways, consciousness, behavior, and memory [3], and cerebral disorders are the most common cause of seizures, visual deficits, mental changes, facial paralysis, circling, and head-turning [4]. ...
... The aims of this retrospective study were: (1) To determine the association between patient characteristics and MRI lesion location, (2) to determine the association between neurological signs and MRI brain lesion location, (3) to classify intracranial diseases of cats using the DAMNIT-V method based on brain lesion location, (4) to compare blood profiles of cats with the presence or absence of inflammatory lesions based on brain MRI, and (5) to compare patient blood profiles with the presence or absence of structural brain lesions on MRI. ...
Background and Aim
Magnetic resonance imaging (MRI) has been widely used as a non-invasive modality to evaluate neurological organ structures. However, brain MRI studies in cats with neurological signs are limited. This study evaluated the association between patient characteristics, neurological signs, and brain lesion locations identified by MRI. Blood profiles of cats with presumptive inflammatory and structural brain lesions were also determined.
Materials and Methods
Medical records of 114 cats that underwent brain MRI were retrospectively reviewed. Cats were categorized into five groups based on the location of their lesion: Cerebrum, brainstem, cerebellum, multifocal, and non-structural. Patient characteristics, neurological signs, and hematological profiles were obtained from their medical records. Disease classification was categorized based on their etiologies. Associations were determined using Fisher’s exact test. Blood parameters were compared using the Kruskal–Wallis test.
Results
A total of 114 cats met the inclusion criteria. Lesions were identified in the cerebrum (21.1%), brainstem (8.8%), cerebellum (6.1%), multifocal (39.5%), and non-structural (24.6%) of the cats. Common neurological signs included seizure activity (56.1%), cerebellar signs (41.2%), and anisocoria (25.4%). The most common brain abnormality was inflammation (40.4%). There was no significant difference in hematological profiles between cats with presumptive inflammatory and non-inflammatory brain lesions. Neutrophils, platelets, total protein, and globulin concentrations were higher in cats with structural brain lesions.
Conclusion
The most common neurological signs and brain disease category were seizure activity and inflammation, respectively. However, the hematological profile did not predict inflammatory and structural brain lesions.
... The neurological mapping and maintenance of articulatory targets are likely facilitated via a basal ganglion-motor cortical network (Graybiel, 2005;Enard, 2011;Alm, 2021;Ekström, 2022b), where the cerebellum is responsible for continual adjustment of fine-motor behavior (Paulin, 1993), including those involved in speech (Ackermann, 2008;Alm, 2021). In modern humans, there has been significant phylogenetic development of subcortical structures including the cerebellum (Baizer, 2014;Guevara et al., 2021). This is consistent with the emerging picture in neurolinguistics, that a distributed network, rather than any one or few language center(s), is responsible for linguistic abilities (Lieberman, 2000;Murdoch, 2001;Dronkers et al., 2007;Friederici and Gierhan, 2013;Ekström, 2022b). ...
The tongue is one of the organs most central to human speech. Here, the evolution and species-unique properties of the human tongue is traced, via reference to the apparent articulatory behavior of extant non-human great apes, and fossil findings from early hominids – from a point of view of articulatory phonetics, the science of human speech production. Increased lingual flexibility provided the possibility of mapping of articulatory targets, possibly via exaptation of manual-gestural mapping capacities evident in extant great apes. The emergence of the human-specific tongue, its properties, and morphology were crucial to the evolution of human articulate speech.
... The cerebellum shows anatomical [41] and functional [4] connectivity to spinal motoneurons via the brainstem nuclei. Thus, the hypothesis that cerebellar TMS modulates the excitability of the spinal motoneuron pool even in the resting state [7], since it was able to elicit motor responses during surgery, is quite tenable. ...
Since individuals with cerebellar lesions often exhibit hypotonia, the cerebellum may contribute to the regulation of muscle tone and spinal motoneuron pool excitability. Neurophysiological methods using transcranial magnetic stimulation (TMS) of the cerebellum have been recently proposed for testing the role of the cerebellum in spinal excitability. Under specific conditions, single-pulse TMS administered to the cerebellar hemisphere or vermis elicits a long-latency motor response in the upper or lower limb muscles and facilitates the H-reflex of the soleus muscle, indicating increased excitability of the spinal motoneuron pool. This literature review examined the methods and mechanisms by which cerebellar TMS modulates spinal excitability.
... Calcium-binding protein cell phenotype analysis across a high number of representative mammalian species showed that the types of positive neurons generally coincided among species. Previous analysis indicated that these proteins have a highly phylogenetically conserved molecular structure in the brain in general and in the cerebellum in particular (30,43,44). Thus, superior colliculus and cerebellum (Supplementary Figure 1) have been analyzed as positive controls, showing immunostaining properties similar to those reported for humans and other high mammals, such as the common marmoset (29). ...
... SO interconnects several of the seasonality nuclei (PVN and ARC), directly projecting to the pituitary gland and to the region surrounding the third ventricle (44,45) Because SO is involved in glial activation, we will analyze its morphological features more extensively in the next section (51). Despite differences in animal size, SO nucleus and its neurons are much larger in ewes than in rodents, but they have the same topographical distribution (26, 41). ...
In this study, we describe in detail the anatomy of nuclei involved in seasonal fertility regulation (SFR) in ewes. For this purpose, the intergeniculate leaflet of the visual thalamus, the caudal hypothalamic arcuate nucleus, and suprachiasmatic, paraventricular and supraoptic nuclei of the rostral hypothalamus were morphometrically and qualitatively analyzed in Nissl-stained serial sections, in the three anatomical planes. In addition, data were collected on calcium-binding proteins and cell phenotypes after immunostaining alternate serial sections for calretinin, parvalbumin and calbindin. For a complete neuroanatomical study, glial architecture was assessed by immunostaining and analyzing alternate sections for glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (IBA1). The results showed a strong microglial and astroglia reaction around the hypothalamic nuclei of interest and around the whole 3rd ventricle of the ewe brain. Moreover, we correlated cytoarchitectonic coordinates of panoramic serial sections with their macroscopic localization and extension in midline sagittal-sectioned whole brain to provide guidelines for microdissecting nuclei involved in SFR.
... Several brainstem nuclei are identified as specific to humans, with species-variable neurochemical differences in homologous nuclei and pronounced left-right asymmetry in humans (Baizer, 2014). These changes in brainstem organization were attributed to the unique human motor and cognitive abilities, as associated with the parallel expansions of cortical and cerebellar structures (Refer to Smaers and Soligo, 2013 on "brain reorganization not relative brain size."). ...
... The connections of the AN and its function is intensively discussed in literature. Together with other functional centers of the medulla oblongata the AN might be integrated in breathing control and cardiorespiratory mechanisms (Zec et al., 1997;Matturri et al., 2004;Fu and Watson, 2012;Baizer, 2014;Paradiso et al., 2018;Stonebridge et al., 2020). Finally, anterior fibers reaching the reticular formation of the medulla oblongata have been described and added to the circumolivary fiber bundle as well (Swank, 1934;Marburg, 1945;Stonebridge et al., 2020). ...
... The exact fiber connections and functions of the arcuate nuclei still remain to be discovered. Former studies postulate a functional role in breathing regulation and cardiorespiratory circuits (Zec et al., 1997;Matturri et al., 2004;Fu and Watson, 2012;Baizer, 2014;Paradiso et al., 2018;Stonebridge et al., 2020). Fiber tracking studies might underline a potential connection of the arcuate nuclei with the dorsal raphe (Zec et al., 1997). ...
The circumolivary fiber bundle (CFB) is considered to be an anatomical variation, which can be found on the surface of the human medulla oblongata. The macroscopical fiber bundle runs downwards from either the anterior median fissure, the pyramid, or both, around the inferior pole of the olive and turns upwards to reach the restiform body of the inferior cerebellar peduncle. Multiple fiber systems feed the constitution of the CFB (collateral corticospinal fibers, fibers connecting to the reticular formation, anterior external arcuate fibers). With this examination we provide a systematic analysis of the frequency of occurrence (6.14%), size, and laterality of the CFB. Including all three fiber bundle parts (descending part, genu, and ascending part), the left-sided sizes were increased. Likewise, the appearance of an unilateral left-sided CFB could be detected in more than 60% of our cases. Our morphometrical analysis currently covers the largest sample of investigated brainstem sides ( n = 489) so far. This investigation should widen the perspective on how anatomists, neuroradiologists, and neurosurgeons expect the anterolateral surface of the human medulla oblongata.
... The brainstem is an important part of the brain responsible for sensing injury and processing pain signals, and transmits and processes signals between the brain, cerebellum and spinal. The conventional wisdom about the cerebellum is that it is essential for motor function and contributes little to cognitive function (12). However, multiple studies by Middleton FA et al. showed that cerebellar output targets involved multiple cortical regions, including not only primary motor cortex (13,14), but also oculomotor nerve (15,16), prefrontal lobe and inferior temporal region (17,18), which indicates that cerebellum plays a role in both motor and cognitive function. ...
The central nervous system is the most important nervous system in vertebrates, which is responsible for transmitting information to the peripheral nervous system and controlling the body’s activities. It mainly consists of the brain and spinal cord, which contains rich of neurons, the precision of the neural structures susceptible to damage from the outside world and from the internal factors of inflammation infection, leading to a series of central nervous system diseases, such as traumatic brain injury, nerve inflammation, etc., these diseases may cause irreversible damage on the central nervous or lead to subsequent chronic lesions. After disease or injury, the immune system of the central nervous system will play a role, releasing cytokines to recruit immune cells to enter, and the immune cells will differentiate according to the location and degree of the lesion, and become specific immune cells with different functions, recognize and phagocytose inflammatory factors, and repair the damaged neural structure. However, if the response of these immune cells is not suppressed, the overexpression of some genes can cause further damage to the central nervous system. There is a need to understand the molecular mechanisms by which these immune cells work, and this information may lead to immunotherapies that target certain diseases and avoid over-activation of immune cells. In this review, we summarized several immune cells that mainly play a role in the central nervous system and their roles, and also explained the response process of the immune system in the process of some common neurological diseases, which may provide new insights into the central nervous system.
