1
|
Fischer M, Kukley M. Hidden in the white matter: Current views on interstitial white matter neurons. Neuroscientist 2024:10738584241282969. [PMID: 39365761 DOI: 10.1177/10738584241282969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/06/2024]
Abstract
The mammalian brain comprises two structurally and functionally distinct compartments: the gray matter (GM) and the white matter (WM). In humans, the WM constitutes approximately half of the brain volume, yet it remains significantly less investigated than the GM. The major cellular elements of the WM are neuronal axons and glial cells. However, the WM also contains cell bodies of the interstitial neurons, estimated to number 10 to 28 million in the adult bat brain, 67 million in Lar gibbon brain, and 450 to 670 million in the adult human brain, representing as much as 1.3%, 2.25%, and 3.5% of all neurons in the cerebral cortex, respectively. Many studies investigated the interstitial WM neurons (IWMNs) using immunohistochemistry, and some information is available regarding their electrophysiological properties. However, the functional role of IWMNs in physiologic and pathologic conditions largely remains unknown. This review aims to provide a concise update regarding the distribution and properties of interstitial WM neurons, highlight possible functions of these cells as debated in the literature, and speculate about other possible functions of the IWMNs and their interactions with glial cells. We hope that our review will inspire new research on IWMNs, which represent an intriguing cell population in the brain.
Collapse
Affiliation(s)
- Maximilian Fischer
- Institut de Neurociències and Departamento Bioquímica i Biología Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
| | - Maria Kukley
- Achucarro Basque Centre for Neuroscience, Leioa, Spain
- IKERBASQUE Basque Foundation for Science, Bilbao, Spain
| |
Collapse
|
2
|
Barbaresi P, Fabri M, Lorenzi T, Sagrati A, Morroni M. Intrinsic organization of the corpus callosum. Front Physiol 2024; 15:1393000. [PMID: 39035452 PMCID: PMC11259024 DOI: 10.3389/fphys.2024.1393000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 05/16/2024] [Indexed: 07/23/2024] Open
Abstract
The corpus callosum-the largest commissural fiber system connecting the two cerebral hemispheres-is considered essential for bilateral sensory integration and higher cognitive functions. Most studies exploring the corpus callosum have examined either the anatomical, physiological, and neurochemical organization of callosal projections or the functional and/or behavioral aspects of the callosal connections after complete/partial callosotomy or callosal lesion. There are no works that address the intrinsic organization of the corpus callosum. We review the existing information on the activities that take place in the commissure in three sections: I) the topographical and neurochemical organization of the intracallosal fibers, II) the role of glia in the corpus callosum, and III) the role of the intracallosal neurons.
Collapse
Affiliation(s)
- Paolo Barbaresi
- Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, Marche Polytechnic University, Ancona, Italy
| | - Mara Fabri
- Department of Life and Environmental Sciences, Marche Polytechnic University, Ancona, Italy
| | - Teresa Lorenzi
- Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, Marche Polytechnic University, Ancona, Italy
| | - Andrea Sagrati
- Department of Life and Environmental Sciences, Marche Polytechnic University, Ancona, Italy
| | - Manrico Morroni
- Electron Microscopy Unit, Azienda Ospedaliero-Universitaria, Ancona, Italy
| |
Collapse
|
3
|
Zouridakis A, Ayala I, Minogue G, Kawles A, Keszycki R, Macomber A, Bigio E, Geula C, Mesulam MM, Gefen T. Shades of gray in human white matter. J Comp Neurol 2023; 531:2109-2120. [PMID: 37376715 PMCID: PMC10751392 DOI: 10.1002/cne.25512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 05/22/2023] [Accepted: 05/31/2023] [Indexed: 06/29/2023]
Abstract
Anatomists have long expressed interest in neurons of the white matter, which is by definition supposed to be free of neurons. Hypotheses regarding their biochemical signature and physiological function are mainly derived from animal models. Here, we investigated 15 whole-brain human postmortem specimens, including cognitively normal cases and those with pathologic Alzheimer's disease (AD). Quantitative and qualitative methods were used to investigate differences in neuronal size and density, and the relationship between neuronal processes and vasculature. Double staining was used to evaluate colocalization of neurochemicals. Two topographically distinct populations of neurons emerged: one appearing to arise from developmental subplate neurons and the other embedded within deep, subcortical white matter. Both populations appeared to be neurochemically heterogeneous, showing positive reactivity to acetylcholinesterase (AChE) [but not choline acetyltransferase (ChAT)], neuronal nuclei (NeuN), nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d), microtubule-associated protein 2 (MAP-2), somatostatin (SOM), nonphosphorylated neurofilament protein (SMI-32), and calcium-binding proteins calbindin-D28K (CB), calretinin (CRT), and parvalbumin (PV). PV was more richly expressed in superficial as opposed to deep white matter neurons (WMNs); subplate neurons were also significantly larger than their deeper counterparts. NADPH-d, a surrogate for nitric oxide synthase, allowed for the striking morphological visualization of subcortical WMNs. NADPH-d-positive subcortical neurons tended to embrace the outer walls of microvessels, suggesting a functional role in vasodilation. The presence of AChE positivity in these neurons, but not ChAT, suggests that they are cholinoceptive but noncholinergic. WMNs were also significantly smaller in AD compared to control cases. These observations provide a landscape for future systematic investigations.
Collapse
Affiliation(s)
- Antonia Zouridakis
- Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Ivan Ayala
- Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Grace Minogue
- Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Allegra Kawles
- Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Rachel Keszycki
- Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Alyssa Macomber
- Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Eileen Bigio
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Changiz Geula
- Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Department of Cell and Developmental Biology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - M.-Marsel Mesulam
- Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Tamar Gefen
- Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| |
Collapse
|
4
|
Neuronal nitric oxide synthase positive neurons in the human corpus callosum: a possible link with the callosal blood-oxygen-level dependent (BOLD) effect. Brain Struct Funct 2023; 228:511-523. [PMID: 36460768 DOI: 10.1007/s00429-022-02599-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 11/18/2022] [Indexed: 12/04/2022]
Abstract
Brain functions have been investigated in the past decades via the blood-oxygen-level dependent (BOLD) effect using functional magnetic resonance imaging. One hypothesis explaining the BOLD effect involves the Nitric Oxide (NO) gaseous neurotransmitter, possibly released also by cells in the corpus callosum (CC). The eventual presence of NO releasing neurons and/or glial cells in the CC can be assessed by immunohistochemistry. Serial sections both from paraffin-embedded and frozen samples of CC obtained from adult human brains autopsy were studied with immunohistochemistry and immunofluorescence analysis, using an antibody against the neuronal isoform of Nitric Oxide Synthase (nNOS), the enzyme synthetizing the NO. The staining revealed the presence of many nNOS-immunopositive cells in the CC, shown to be neurons with immunofluorescence. Neuronal NOS-positive neurons presented different morphologies, were more numerous 4 mm apart from the midline, and displayed a peak in the body of the CC. In some cases, they were located at the upper boundary of the CC, more densely packed in the proximity of the callosal arterioles. The significant presence of nNOS-immunopositive neurons within the commissure suggests their probable role in the CC neurovascular regulation in the adult brain and could explain the BOLD effect detected in human CC.
Collapse
|
5
|
Sakharkar M, Rockland KS, Duque A. Complex Neurochemical Microstructure of the Stria Terminalis in Infant and Adult Macaque Monkey. Front Neuroanat 2022; 16:891608. [PMID: 35692258 PMCID: PMC9174467 DOI: 10.3389/fnana.2022.891608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 04/20/2022] [Indexed: 11/29/2022] Open
Abstract
The stria terminalis (ST) is a major bidirectional fiber tract anchored in the amygdala and bed nucleus (BNST). Extensive investigations in rodents report a complex arrangement of neurochemically diverse neurons within the ST, but fewer data are available for non-human primates. Given the functional importance of the ST, we investigated its microarchitecture in one newborn, four infant, and two adult macaque brains, by parallel immunocytochemical series for cells or fibers. Main results are as follows: (1) The pan-neuronal marker NeuN shows scattered neurons and small neuronal clusters in both the dorsal and ventral ST, but more numerous dorsally; (2) smaller neuronal subpopulations are labeled by calretinin (CR), neuropeptide Y (NPY), calbindin (CB), and somatostatin (SOM), of which the CR + neurons are the most numerous; (3) the infant brains on average have more neurons in the ST than the adult brains, but across our sample, there is notable individual variability; and (4) fiber architectonics have a complex organization, which can be referenced to myelin-poor or myelin-dense zones. Myelin-poor zones coincide with concentrations of fibers positive for CB, CR, or tyrosine hydroxylase (TH). Neurons have been reported in other white matter domains (e.g., anterior commissure, corpus callosum, cingulum bundle, and subcortical white matter). Like these, at least some neurons within the ST may give rise to long-distance connections, and/or participate in more local functions, such as vascular regulation or axon guidance/maintenance.
Collapse
Affiliation(s)
| | - Kathleen S. Rockland
- Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, United States
| | - Alvaro Duque
- Department of Neuroscience, Yale University School of Medicine, New Haven, CT, United States
- *Correspondence: Alvaro Duque,
| |
Collapse
|
6
|
Lorenzi T, Sagrati A, Montanari E, Senzacqua M, Morroni M, Fabri M. Hypoxia-induced expression of neuronal nitric oxide synthase in astrocytes of human corpus callosum. Brain Struct Funct 2021; 226:1353-1361. [PMID: 33709161 DOI: 10.1007/s00429-021-02244-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 02/22/2021] [Indexed: 10/22/2022]
Abstract
Nitric oxide (NO) is a gaseous neurotransmitter largely diffused in the brain; among other functions, it regulates the cerebral blood flow in response to hypoxia. NO can be synthetized by three different isoforms of the enzyme NO synthase: neuronal (nNOS), typical of neurons, endothelial and inducible. The aim of this study was to assess nNOS expression in human corpus callosum (CC) astrocytes, and its relationship with the hypoxia duration. Autoptic samples of CC from adult human subjects have been processed with immunohistochemistry and immunofluorescence using antibodies anti-nNOS and anti-glial fibrillary acidic protein (GFAP), the astrocyte marker. Results demonstrated for the first time the presence of nNOS-immunopositive astrocytes in the human CC. In particular, nNOS-positive astrocytes were absent in subjects deceased after a short hypoxia; their number and labeling intensity, however, increased with hypoxia prolongation. Neuronal NOS immunopositivity of CC astrocytes seems thus related to the hypoxia duration and the consequent brain damage.
Collapse
Affiliation(s)
- Teresa Lorenzi
- Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, School of Medicine, Università Politecnica delle Marche, Via Tronto 10/A, 60126, Ancona, Italy
| | - Andrea Sagrati
- Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, School of Medicine, Università Politecnica delle Marche, Via Tronto 10/A, 60126, Ancona, Italy
| | - Eva Montanari
- Department of Biomedical Sciences and Public Health, Section of Legal Medicine, Università Politecnica delle Marche, Via Tronto 10/A, 60126, Ancona, Italy
| | - Martina Senzacqua
- Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, School of Medicine, Università Politecnica delle Marche, Via Tronto 10/A, 60126, Ancona, Italy
| | - Manrico Morroni
- Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, School of Medicine, Università Politecnica delle Marche, Via Tronto 10/A, 60126, Ancona, Italy.,Electron Microscopy Unit, United Hospitals, Via Conca 71, 60020, Ancona, Italy
| | - Mara Fabri
- Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, School of Medicine, Università Politecnica delle Marche, Via Tronto 10/A, 60126, Ancona, Italy.
| |
Collapse
|
7
|
Andersson M, Kjer HM, Rafael-Patino J, Pacureanu A, Pakkenberg B, Thiran JP, Ptito M, Bech M, Bjorholm Dahl A, Andersen Dahl V, Dyrby TB. Axon morphology is modulated by the local environment and impacts the noninvasive investigation of its structure-function relationship. Proc Natl Acad Sci U S A 2020; 117:33649-33659. [PMID: 33376224 PMCID: PMC7777205 DOI: 10.1073/pnas.2012533117] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Axonal conduction velocity, which ensures efficient function of the brain network, is related to axon diameter. Noninvasive, in vivo axon diameter estimates can be made with diffusion magnetic resonance imaging, but the technique requires three-dimensional (3D) validation. Here, high-resolution, 3D synchrotron X-ray nano-holotomography images of white matter samples from the corpus callosum of a monkey brain reveal that blood vessels, cells, and vacuoles affect axonal diameter and trajectory. Within single axons, we find that the variation in diameter and conduction velocity correlates with the mean diameter, contesting the value of precise diameter determination in larger axons. These complex 3D axon morphologies drive previously reported 2D trends in axon diameter and g-ratio. Furthermore, we find that these morphologies bias the estimates of axon diameter with diffusion magnetic resonance imaging and, ultimately, impact the investigation and formulation of the axon structure-function relationship.
Collapse
Affiliation(s)
- Mariam Andersson
- Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark;
- Department of Applied Mathematics and Computer Science, Technical University of Denmark, 2800 Kongens Lyngby, Denmark
| | - Hans Martin Kjer
- Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark
- Department of Applied Mathematics and Computer Science, Technical University of Denmark, 2800 Kongens Lyngby, Denmark
| | - Jonathan Rafael-Patino
- Signal Processing Laboratory (LTS5), École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | | | - Bente Pakkenberg
- Research Laboratory for Stereology and Neuroscience, Copenhagen University Hospital, Bispebjerg, 2400 Copenhagen, Denmark
| | - Jean-Philippe Thiran
- Signal Processing Laboratory (LTS5), École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
- Radiology Department, Centre Hospitalier Universitaire Vaudois and University of Lausanne, 1011 Lausanne, Switzerland
- Center for Biomedical Imaging, 1015 Lausanne, Switzerland
| | - Maurice Ptito
- School of Optometry, University of Montreal, Montreal, QC H3T 1P1, Canada
- Department of Neuroscience, Faculty of Health Science, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Martin Bech
- Division of Medical Radiation Physics, Department of Clinical Sciences, Lund University, 221 85 Lund, Sweden
| | - Anders Bjorholm Dahl
- Department of Applied Mathematics and Computer Science, Technical University of Denmark, 2800 Kongens Lyngby, Denmark
| | - Vedrana Andersen Dahl
- Department of Applied Mathematics and Computer Science, Technical University of Denmark, 2800 Kongens Lyngby, Denmark
| | - Tim B Dyrby
- Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark;
- Department of Applied Mathematics and Computer Science, Technical University of Denmark, 2800 Kongens Lyngby, Denmark
| |
Collapse
|
8
|
Borra E, Luppino G, Gerbella M, Rozzi S, Rockland KS. Projections to the putamen from neurons located in the white matter and the claustrum in the macaque. J Comp Neurol 2019; 528:453-467. [PMID: 31483857 DOI: 10.1002/cne.24768] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 08/24/2019] [Accepted: 08/26/2019] [Indexed: 12/21/2022]
Abstract
Continuing investigations of corticostriatal connections in rodents emphasize an intricate architecture where striatal projections originate from different combinations of cortical layers, include an inhibitory component, and form terminal arborizations which are cell-type dependent, extensive, or compact. Here, we report that in macaque monkeys, deep and superficial cortical white matter neurons (WMNs), peri-claustral WMNs, and the claustrum proper project to the putamen. WMNs retrogradely labeled by injections in the putamen (four injections in three macaques) were widely distributed, up to 10 mm antero-posterior from the injection site, mainly dorsal to the putamen in the external capsule, and below the premotor cortex. Striatally projecting labeled WMNs (WMNsST) were heterogeneous in size and shape, including a small GABAergic component. We compared the number of WMNsST with labeled claustral and cortical neurons and also estimated their proportion in relation to total WMNs. Since some WMNsST were located adjoining the claustrum, we wanted to compare results for density and distribution of striatally projecting claustral neurons (ClaST). ClaST neurons were morphologically heterogeneous and mainly located in the dorsal and anterior claustrum, in regions known to project to frontal, motor, and cingulate cortical areas. The ratio of ClaST to WMNsST was about 4:1 averaged across the four injections. These results provide new specifics on the connectional networks of WMNs in nonhuman primates, and delineate additional loops in the corticostriatal architecture, consisting of interconnections across cortex, claustralstriatal and striatally projecting WMNs.
Collapse
Affiliation(s)
- Elena Borra
- Department of Medicine and Surgery, Neuroscience Unit, University of Parma, Parma, Italy
| | - Giuseppe Luppino
- Department of Medicine and Surgery, Neuroscience Unit, University of Parma, Parma, Italy
| | - Marzio Gerbella
- Department of Medicine and Surgery, Neuroscience Unit, University of Parma, Parma, Italy
| | - Stefano Rozzi
- Department of Medicine and Surgery, Neuroscience Unit, University of Parma, Parma, Italy
| | - Kathleen S Rockland
- Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA
| |
Collapse
|
9
|
Abstract
Background The claustrum (CLA) has been discussed as central to integrated conscious percepts, although recent evidence has emphasized a role in detecting sensory novelty or in amplifying correlated cortical inputs. Objective We report that many neurons in the macaque CLA are ensheathed in perineuronal nets (PNNs), which contribute to synaptic stability and enhance neuronal excitability, among other properties. Design We visualized PNNs by wisteria floribunda agglutinin (WFA) immunohistochemistry, and quantified these in comparison these to parvalbumin+ (PV) subsets and total neurons. Results PNNs ensheath about 11% of the total neurons. These are a range of large, medium, and small neurons, likely corresponding to PV+ and/or other inhibitory interneurons. The PNNs were themselves heterogeneous, consisting of lattice-like, weakly labeled, and diffuse subtypes, and showed some regional preference for the medial CLA. Conclusion The abundant neuronal labeling by PNNs in the CLA suggests an important and nuanced role for inhibition, consistent with recent physiological studies of claustrocortical circuitry. For comparison, diversified inhibition in the reticular nucleus of the thalamus (a pan-inhibitory nucleus, with extensive cortical input) exerts a spectrum of control at different local and global spatiotemporal scales. Further investigation of PNN+ neurons in the macaque CLA offers a potentially important new approach to CLA function, relevant to the human brain both in normal and diseased conditions.
Collapse
Affiliation(s)
- Mihovil Pletikos
- Department of Anatomy and Neurobiology, Boston University School of Medicine, 72 East Concord St., Boston, MA. 02118
| | - Kathleen S Rockland
- Department of Anatomy and Neurobiology, Boston University School of Medicine, 72 East Concord St., Boston, MA. 02118
| |
Collapse
|
10
|
Mortazavi F, Romano SE, Rosene DL, Rockland KS. A Survey of White Matter Neurons at the Gyral Crowns and Sulcal Depths in the Rhesus Monkey. Front Neuroanat 2017; 11:69. [PMID: 28860975 PMCID: PMC5559435 DOI: 10.3389/fnana.2017.00069] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 07/31/2017] [Indexed: 12/14/2022] Open
Abstract
Gyrencephalic brains exhibit deformations of the six neocortical laminae at gyral crowns and sulcal depths, where the deeper layers are, respectively, expanded and compressed. The present study addresses: (1) the degree to which the underlying white matter neurons (WMNs) observe the same changes at gyral crowns and sulcal depths; and (2) whether these changes are consistent or variable across different cortical regions. WMNs were visualized by immunohistochemistry using the pan-neuronal label NeuN, and their density was quantified in eight rhesus monkey brains for four regions; namely, frontal (FR), superior frontal gyrus (SFG), parietal (Par) and temporal (TE). In all four regions, there were about 50% fewer WMNs in the sulcal depth, but there was also distinct variability from region to region. For the gyral crown, we observed an average density per 0.21 mm2 of 82 WMNs for the FR, 51 WMNs for SFG, 80 WMNs for Par and 93 WMNs for TE regions. By contrast, for the sulcal depth, the average number of WMNs per 0.21 mm2 was 41 for FR, 31 for cingulate sulcus (underlying the SFG), 54 for Par and 63 for TE cortical regions. Since at least some WMNs participate in cortical circuitry, these results raise the possibility of their differential influence on cortical circuitry in the overlying gyral and sulcal locations. The results also point to a possible role of WMNs in the differential vulnerability of gyral vs. sulcal regions in disease processes, and reinforce the increasing awareness of the WMNs as part of a complex, heterogeneous and structured microenvironment.
Collapse
Affiliation(s)
- Farzad Mortazavi
- Department of Anatomy and Neurobiology, Boston University School of MedicineBoston, MA, United States
| | - Samantha E. Romano
- Department of Anatomy and Neurobiology, Boston University School of MedicineBoston, MA, United States
| | - Douglas L. Rosene
- Department of Anatomy and Neurobiology, Boston University School of MedicineBoston, MA, United States
| | - Kathleen S. Rockland
- Department of Anatomy and Neurobiology, Boston University School of MedicineBoston, MA, United States
| |
Collapse
|
11
|
Rockland KS. What do we know about laminar connectivity? Neuroimage 2017; 197:772-784. [PMID: 28729159 DOI: 10.1016/j.neuroimage.2017.07.032] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Revised: 07/13/2017] [Accepted: 07/15/2017] [Indexed: 12/17/2022] Open
Abstract
In this brief review, I attempt an overview of the main components of anatomical laminar-level connectivity. These are: extrinsic outputs, excitatory and inhibitory intrinsic connectivity, and intrinsic inputs. Supporting data are biased from the visual system of nonhuman primates (NHPs), but I have drawn as much as possible from a broader span in order to treat the important issue of area-specific variability. In a second part, I briefly discuss laminar connectivity in the context of network organization (feedforward/feedback cortical connections, and the major types of corticothalamic connections). I also point out anatomical issues in need of clarification, including more systematic, whole brain coverage of tracer injections; more data on anterogradely labeled terminations; more complete, area-specific quantitative data about projection neurons, and quantitative data on terminal density and convergence. Postsynaptic targets are largely unknown, but their identification is essential for understanding the finer analysis and principles of laminar patterns. Laminar resolution MRI offers a promising new tool for exploring laminar connectivity: it is potentially fast and macro-scale, and allows for repeated investigation under different stimulus conditions. Conversely, anatomical resolution, although detailed beyond the current level of MRI visualization, offers a rich trove for experimental design and interpretation of fMRI activation patterns.
Collapse
Affiliation(s)
- Kathleen S Rockland
- Department of Anatomy&Neurobiology, Boston University School of Medicine, 72 East Concord St., Boston, MA 02118, USA.
| |
Collapse
|
12
|
Barbaresi P, Mensà E, Bastioli G, Amoroso S. Substance P NK1 receptor in the rat corpus callosum during postnatal development. Brain Behav 2017; 7:e00713. [PMID: 28638718 PMCID: PMC5474716 DOI: 10.1002/brb3.713] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
INTRODUCTION The expression of substance P (SP) receptor (neurokinin 1, NK1) was studied in the rat corpus callosum (cc) from postnatal day 0 (the first 24 hr from birth, P0) to P30. METHODS We used immunocytochemistry to study the presence of intracallosal NK1-immunopositive neurons (NK1IP-n) during cc development. RESULTS NK1IP-n first appeared on P5. Their number increased significantly between P5 and P10, it remained almost constant between P10 and P15, then declined slightly until P30. The size of intracallosal NK1IP-n increased constantly from P5 (102.3 μm2) to P30 (262.07 μm2). From P5 onward, their distribution pattern was adult-like, that is, they were more numerous in the lateral and intermediate parts of the cc, and declined to few or none approaching the midline. At P5, intracallosal NK1IP-n had a predominantly round cell bodies with primary dendrites of different thickness from which originated thinner secondary branches. Between P10 and P15, dendrites were longer and more thickly branched, and displayed several varicosities as well as short, thin appendages. Between P20 and P30, NK1IP-n were qualitatively indistinguishable from those of adult animals and could be classified as bipolar (fusiform and rectangular), round-polygonal, and pyramidal (triangular-pyriform). CONCLUSIONS Number of NK1IP-n increase between P5 and P10, then declines, but unlike other intracallosal neurons, NK1IP-n make up a significant population in the adult cc. These findings suggest that NK1IP-n may be involved in the myelination of callosal axons, could play an important role in their pathfinding. Since they are also found in adult rat cc, it is likely that their role changes during lifetime.
Collapse
Affiliation(s)
- Paolo Barbaresi
- Section of Neuroscience and Cell Biology Department of Experimental and Clinical Medicine Marche Polytechnic University Ancona Italy
| | - Emanuela Mensà
- Section of Neuroscience and Cell Biology Department of Experimental and Clinical Medicine Marche Polytechnic University Ancona Italy
| | - Guendalina Bastioli
- Department of Biomedical Sciences and Public Health Marche Polytechnic University Ancona Italy
| | - Salvatore Amoroso
- Department of Biomedical Sciences and Public Health Marche Polytechnic University Ancona Italy
| |
Collapse
|
13
|
Mortazavi F, Wang X, Rosene DL, Rockland KS. White Matter Neurons in Young Adult and Aged Rhesus Monkey. Front Neuroanat 2016; 10:15. [PMID: 26941613 PMCID: PMC4761867 DOI: 10.3389/fnana.2016.00015] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 02/05/2016] [Indexed: 01/21/2023] Open
Abstract
In humans and non-human primates (NHP), white matter neurons (WMNs) persist beyond early development. Their functional importance is largely unknown, but they have both corticothalamic and corticocortical connectivity and at least one subpopulation has been implicated in vascular regulation and sleep. Several other studies have reported that the density of WMNs in humans is altered in neuropathological or psychiatric conditions. The present investigation evaluates and compares the density of superficial and deep WMNs in frontal (FR), temporal (TE), and parietal (Par) association regions of four young adult and four aged male rhesus monkeys. A major aim was to determine whether there was age-related neuronal loss, as might be expected given the substantial age-related changes known to occur in the surrounding white matter environment. Neurons were visualized by immunocytochemistry for Neu-N in coronal tissue sections (30 μm thickness), and neuronal density was assessed by systematic random sampling. Per 0.16 mm2 sampling box, this yielded about 40 neurons in the superficial WM and 10 in the deep WM. Consistent with multiple studies of cell density in the cortical gray matter of normal brains, neither the superficial nor deep WM populations showed statistically significant age-related neuronal loss, although we observed a moderate decrease with age for the deep WMNs in the frontal region. Morphometric analyses, in contrast, showed significant age effects in soma size and circularity. In specific, superficial WMNs were larger in FR and Par WM regions of the young monkeys; but in the TE, these were larger in the older monkeys. An age effect was also observed for soma circularity: superficial WMNs were more circular in FR and Par of the older monkeys. This second, morphometric result raises the question of whether other age-related morphological, connectivity, or molecular changes occur in the WMNs. These could have multiple impacts, given the wide range of putative WMN functions and their involvement in both corticothalamic and corticocortical circuitry.
Collapse
Affiliation(s)
- Farzad Mortazavi
- Department of Anatomy and Neurobiology, Boston University School of Medicine Boston, MA, USA
| | - Xiyue Wang
- Department of Anatomy and Neurobiology, Boston University School of Medicine Boston, MA, USA
| | - Douglas L Rosene
- Department of Anatomy and Neurobiology, Boston University School of Medicine Boston, MA, USA
| | - Kathleen S Rockland
- Department of Anatomy and Neurobiology, Boston University School of Medicine Boston, MA, USA
| |
Collapse
|
14
|
Fabri M, Pierpaoli C, Barbaresi P, Polonara G. Functional topography of the corpus callosum investigated by DTI and fMRI. World J Radiol 2014; 6:895-906. [PMID: 25550994 PMCID: PMC4278150 DOI: 10.4329/wjr.v6.i12.895] [Citation(s) in RCA: 110] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 09/02/2014] [Accepted: 10/29/2014] [Indexed: 02/06/2023] Open
Abstract
This short review examines the most recent functional studies of the topographic organization of the human corpus callosum, the main interhemispheric commissure. After a brief description of its anatomy, development, microstructure, and function, it examines and discusses the latest findings obtained using diffusion tensor imaging (DTI) and tractography (DTT) and functional magnetic resonance imaging (fMRI), three recently developed imaging techniques that have significantly expanded and refined our knowledge of the commissure. While DTI and DTT have been providing insights into its microstructure, integrity and level of myelination, fMRI has been the key technique in documenting the activation of white matter fibers, particularly in the corpus callosum. By combining DTT and fMRI it has been possible to describe the trajectory of the callosal fibers interconnecting the primary olfactory, gustatory, motor, somatic sensory, auditory and visual cortices at sites where the activation elicited by peripheral stimulation was detected by fMRI. These studies have demonstrated the presence of callosal fiber tracts that cross the commissure at the level of the genu, body, and splenium, at sites showing fMRI activation. Altogether such findings lend further support to the notion that the corpus callosum displays a functional topographic organization that can be explored with fMRI.
Collapse
|
15
|
Barbaresi P, Mensà E, Lariccia V, Desiato G, Fabri M, Gratteri S. Intracallosal neuronal nitric oxide synthase neurons colocalize with neurokinin 1 substance P receptor in the rat. J Comp Neurol 2014; 523:589-607. [PMID: 25312245 DOI: 10.1002/cne.23695] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Revised: 10/09/2014] [Accepted: 10/09/2014] [Indexed: 12/21/2022]
Abstract
The corpus callosum (cc) contains nitric oxide (NO)-producing neurons. Because NO is a potent vasodilator, these neurons could translate neuronal signals into vascular responses that can be detected by functional brain imaging. Substance P (SP), one of the most widely expressed peptides in the CNS, also produces vasomotor responses by inducing calcium release from intracellular stores through its preferred neurokinin 1 (NK1) receptor, thus inducing NO production via activation of neuronal NO synthase (nNOS). Single- and double-labeling experiments were performed to establish whether NK1-immunopositive neurons (NK1IP -n) are found in the rat cc and the extent of NK1 colocalization with nNOS. NK1IP -n were seen to constitute a large neuronal population in the cc and had a distribution similar to that of nNOSIP neurons (nNOSIP -n). NK1IP -n were numerous in the lateral cc and gradually decreased in the more medial portions, where they were few or absent. Intracallosal NK1IP -n and their dendritic trees were intensely labeled, allowing classification into four morphological types: bipolar, round, polygonal, and pyramidal. Confocal microscopic examination demonstrated that nearly all NK1IP -n contained nNOS (96.43%) and that 84.59% of nNOSIP -n co-expressed NK1. These data suggest that the majority of intracallosal neurons can release NO as a result of the action of SP. A small proportion of nNOSIP -n does not contain NK1 and is not activated by SP; these neurons may release NO via alternative mechanisms. The possible mechanisms by which intracallosal neurons release NO are also reviewed.
Collapse
Affiliation(s)
- Paolo Barbaresi
- Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, Marche Polytechnic University, I-60020, Ancona, Italy
| | | | | | | | | | | |
Collapse
|
16
|
Garthwaite G, Hampden-Smith K, Wilson GW, Goodwin DA, Garthwaite J. Nitric oxide targets oligodendrocytes and promotes their morphological differentiation. Glia 2014; 63:383-99. [PMID: 25327839 PMCID: PMC4309495 DOI: 10.1002/glia.22759] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Accepted: 09/26/2014] [Indexed: 11/29/2022]
Abstract
In the central nervous system, nitric oxide (NO) transmits signals from one neurone to another, or from neurones to astrocytes or blood vessels, but the possibility of oligodendrocytes being physiological NO targets has been largely ignored. By exploiting immunocytochemistry for cGMP, the second messenger generated on activation of NO receptors, oligodendrocytes were found to respond to both exogenous and endogenous NO in cerebellar slices from rats aged 8 days to adulthood. Atrial natriuretic peptide, which acts on membrane-associated guanylyl cyclase-coupled receptors, also raised oligodendrocyte cGMP in cerebellar slices. The main endogenous source of NO accessing oligodendrocytes appeared to be the neuronal NO synthase isoform, which was active even under basal conditions and in a manner that was independent of glutamate receptors. Oligodendrocytes in brainstem slices were also shown to be potential NO targets. In contrast, in the optic nerve, oligodendrocyte cGMP was raised by natriuretic peptides but not NO. When cultures of cerebral cortex were continuously exposed to low NO concentrations (estimated as 40–90 pM), oligodendrocytes responded with a striking increase in arborization. This stimulation of oligodendrocyte growth could be replicated by low concentrations of 8-bromo-cGMP (maximum effect at 1 µM). It is concluded that oligodendrocytes are probably widespread targets for physiological NO (or natriuretic peptide) signals, with the resulting rise in cGMP serving to enhance their growth and maturation. NO might help coordinate the myelination of axons to the ongoing level of neuronal activity during development and could potentially contribute to adaptive changes in myelination in the adult.
Collapse
Affiliation(s)
- Giti Garthwaite
- Wolfson Institute for Biomedical Research, University College London, London, WC1E 6BT, United Kingdom
| | | | | | | | | |
Collapse
|
17
|
Barbaresi P, Fabri M, Mensà E. Characterization of NO-producing neurons in the rat corpus callosum. Brain Behav 2014; 4:317-36. [PMID: 24944862 PMCID: PMC4055183 DOI: 10.1002/brb3.218] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2013] [Revised: 12/13/2013] [Accepted: 12/23/2013] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION The aim of this study was to determine the presence and distribution of nitric oxide (NO)-producing neurons in the rat corpus callosum (cc). MATERIAL AND METHODS To investigate this aspect of cc organization we used nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry and neuronal NO synthase (nNOS) immunocytochemistry. RESULTS Intense NADPH-d-positive (NADPH-d+) neurons were found along the rostrocaudal extension of the cc (sagittal sections). They were more numerous in the lateral cc and gradually decreased in the more medial regions, where they were very few or absent. The Golgi-like appearance of NADPH-d+ intracallosal neurons allowed dividing them into five morphological types: (1) bipolar; (2) fusiform; (3) round; (4) polygonal; and (5) pyramidal. The number of NADPH-d+ neurons (both hemispheres) was counted in two brains using 50-μm thick sections. In the first brain, counts involved 145 sections and neurons were 2959; in the second, 2227 neurons were counted in 130 sections. The distribution and morphology of nNOS-immunopositive (nNOSIP) neurons was identical to that of NADPH-d+neurons. Some of these neurons were observed in the cc ependymal region, where they might be in contact with cerebrospinal fluid (CSF), monitoring its composition, pH, and osmolality changes, or playing a role in regulating the synthesis and release of several peptides. The somatic, dendritic, and axonal processes of many NADPH-d+/nNOSIP neurons were closely associated with intracallosal blood vessels. CONCLUSIONS Such close relationship raises the possibility that these neurons are a major source of NO during neural activity. As NO is a potent vasodilator, these findings strongly suggest that NO-positive neurons transduce neuronal signals into vascular responses in selected cc regions, thus giving rise to hemodynamic changes detectable by neuroimaging.
Collapse
Affiliation(s)
- Paolo Barbaresi
- Section of Neuroscience and Cell Biology, Department of Experimental and Clinical Medicine, Marche Polytechnic University Ancona, I-60020, Italy
| | - Mara Fabri
- Section of Neuroscience and Cell Biology, Department of Experimental and Clinical Medicine, Marche Polytechnic University Ancona, I-60020, Italy
| | - Emanuela Mensà
- Section of Neuroscience and Cell Biology, Department of Experimental and Clinical Medicine, Marche Polytechnic University Ancona, I-60020, Italy
| |
Collapse
|
18
|
Battaglia D, Karagiannis A, Gallopin T, Gutch HW, Cauli B. Beyond the frontiers of neuronal types. Front Neural Circuits 2013; 7:13. [PMID: 23403725 PMCID: PMC3566547 DOI: 10.3389/fncir.2013.00013] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2012] [Accepted: 01/21/2013] [Indexed: 11/13/2022] Open
Abstract
Cortical neurons and, particularly, inhibitory interneurons display a large diversity of morphological, synaptic, electrophysiological, and molecular properties, as well as diverse embryonic origins. Various authors have proposed alternative classification schemes that rely on the concomitant observation of several multimodal features. However, a broad variability is generally observed even among cells that are grouped into a same class. Furthermore, the attribution of specific neurons to a single defined class is often difficult, because individual properties vary in a highly graded fashion, suggestive of continua of features between types. Going beyond the description of representative traits of distinct classes, we focus here on the analysis of atypical cells. We introduce a novel paradigm for neuronal type classification, assuming explicitly the existence of a structured continuum of diversity. Our approach, grounded on the theory of fuzzy sets, identifies a small optimal number of model archetypes. At the same time, it quantifies the degree of similarity between these archetypes and each considered neuron. This allows highlighting archetypal cells, which bear a clear similarity to a single model archetype, and edge cells, which manifest a convergence of traits from multiple archetypes.
Collapse
Affiliation(s)
- Demian Battaglia
- Department of Nonlinear Dynamics, Max Planck Institute for Dynamics and Self-Organization (MPIDS) Göttingen, Germany ; Bernstein Center for Computational Neuroscience Göttingen, Germany
| | | | | | | | | |
Collapse
|
19
|
Magno L, Oliveira MG, Mucha M, Rubin AN, Kessaris N. Multiple embryonic origins of nitric oxide synthase-expressing GABAergic neurons of the neocortex. Front Neural Circuits 2012; 6:65. [PMID: 23015780 PMCID: PMC3449337 DOI: 10.3389/fncir.2012.00065] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2012] [Accepted: 08/30/2012] [Indexed: 11/13/2022] Open
Abstract
CORTICAL GABAERGIC INTERNEURONS IN RODENTS ORIGINATE IN THREE SUBCORTICAL REGIONS: the medial ganglionic eminence (MGE), the lateral/caudal ganglionic eminence (LGE/CGE), and the preoptic area (POA). Each of these neuroepithelial precursor domains contributes different interneuron subtypes to the cortex. Neuronal NOS (nNOS)-expressing neurons represent a heterogenous population of cortical interneurons. We examined the development of these cells in the mouse embryonic cortex and their abundance and distribution in adult animals. Using genetic lineage tracing in transgenic mice we find that nNOS type I cells originate only in the MGE whereas type II cells have a triple origin in the MGE, LGE/CGE, and POA. The two populations are born at different times during development, occupy different layers in the adult cortex and have distinct neurochemical profiles. nNOS neurons are more numerous in the adult cortex than previously reported and constitute a significant proportion of the cortical interneuron population. Our data suggest that the heterogeneity of nNOS neurons in the cortex can be attributed to their multiple embryonic origins which likely impose distinct genetic specification programs.
Collapse
Affiliation(s)
- Lorenza Magno
- Wolfson Institute for Biomedical Research and Department of Cell and Developmental Biology, University College London London, UK
| | | | | | | | | |
Collapse
|
20
|
Duchemin S, Boily M, Sadekova N, Girouard H. The complex contribution of NOS interneurons in the physiology of cerebrovascular regulation. Front Neural Circuits 2012; 6:51. [PMID: 22907993 PMCID: PMC3414732 DOI: 10.3389/fncir.2012.00051] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2012] [Accepted: 07/19/2012] [Indexed: 12/23/2022] Open
Abstract
Following the discovery of the vasorelaxant properties of nitric oxide (NO) by Furchgott and Ignarro, the finding by Bredt and coll. of a constitutively expressed NO synthase in neurons (nNOS) led to the presumption that neuronal NO may control cerebrovascular functions. Consequently, numerous studies have sought to determine whether neuraly-derived NO is involved in the regulation of cerebral blood flow (CBF). Anatomically, axons, dendrites, or somata of NO neurons have been found to contact the basement membrane of blood vessels or perivascular astrocytes in all segments of the cortical microcirculation. Functionally, various experimental approaches support a role of neuronal NO in the maintenance of resting CBF as well as in the vascular response to neuronal activity. Since decades, it has been assumed that neuronal NO simply diffuses to the local blood vessels and produce vasodilation through a cGMP-PKG dependent mechanism. However, NO is not the sole mediator of vasodilation in the cerebral microcirculation and is known to interact with a myriad of signaling pathways also involved in vascular control. In addition, cerebrovascular regulation is the result of a complex orchestration between all components of the neurovascular unit (i.e., neuronal, glial, and vascular cells) also known to produce NO. In this review article, the role of NO interneuron in the regulation of cortical microcirculation will be discussed in the context of the neurovascular unit.
Collapse
Affiliation(s)
- Sonia Duchemin
- Department of Pharmacology, Université de Montréal Montreal, QC, Canada
| | | | | | | |
Collapse
|