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1.  Anatomical observations of the caudal vestibulo-sympathetic pathway 
The vestibular system senses the movement and position of the head in space and uses this information to stabilize vision, control posture, perceive head orientation and self-motion in three-dimensional space, and modulate autonomic and limbic activity in response to locomotion and changes in posture. Most vestibular signals are not consciously perceived and are usually appreciated through effector pathways classically described as the vestibulo-ocular, vestibulo-spinal, vestibulo-collic and vestibulo-autonomic reflexes. The present study reviews some of the recent data concerning the connectivity and chemical anatomy of vestibular projections to autonomic sites that are important in the sympathetic control of blood pressure.
PMCID: PMC3570023  PMID: 21422542
Vestibular nuclei; vestibulo-sympathetic pathways; vestibulo-sympathetic reflex; vestibulo-autonomic control
2.  The IRG Mouse: A Two-Color Fluorescent Reporter for Assessing Cre-Mediated Recombination and Imaging Complex Cellular Relationships In Situ 
Genesis (New York, N.y. : 2000)  2008;46(6):308-317.
The Cre-loxP system is widely used for making conditional alterations to the mouse genome. Cre-mediated recombination is frequently monitored using reporter lines in which Cre expression activates a reporter gene driven by a ubiquitous promoter. Given the distinct advantages of fluorescent reporters, we developed a transgenic reporter line, termed IRG, in which DsRed-Express, a red fluorescent protein (RFP) is expressed ubiquitously prior to Cre-mediated recombination and an enhanced green fluorescent protein (EGFP) following recombination. Besides their utility for monitoring Cre-mediated recombination, we show that in IRG mice red and green native fluorescence can be imaged simultaneously in thick tissue sections by confocal microscopy allowing for complex reconstructions to be created that are suitable for analysis of neuronal morphologies as well as neurovascular interactions in brain. IRG mice should provide a versatile tool for analyzing complex cellular relationships in both neural and nonneural tissues.†
PMCID: PMC2928670  PMID: 18543298
Cre recombinase; loxP; conditional gene activation; DsRed-express; red fluorescent protein; enhanced green fluorescent protein; transgenic mice
Neuroscience  2010;175:104-117.
While the basic pathways mediating vestibulo-ocular, -spinal, and -collic reflexes have been described in some detail, little is known about vestibular projections to central autonomic sites. Previous studies have primarily focused on projections from the caudal vestibular region to solitary, vagal and parabrachial nuclei, but have noted a sparse innervation of the ventrolateral medulla. Since a direct pathway from the vestibular nuclei to the rostral ventrolateral medulla would provide a morphological substrate for rapid modifications in blood pressure, heart rate and respiration with changes in posture and locomotion, the present study examined anatomical evidence for this pathway using anterograde and retrograde tract tracing and immunofluorescence detection in brainstem sections of the rat medulla. The results provide anatomical evidence for direct pathways from the caudal vestibular nuclear complex to the rostral and caudal ventrolateral medullary regions. The projections are conveyed by fine and highly varicose axons that ramify bilaterally, with greater terminal densities present ipsilateral to the injection site and more rostrally in the ventrolateral medulla. In the rostral ventrolateral medulla, these processes are highly branched and extremely varicose, primarily directed toward the somata and proximal dendrites of non-catecholaminergic neurons, with minor projections to the distal dendrites of catecholaminergic cells. In the caudal ventrolateral medulla, the axons of vestibular nucleus neurons are more modestly branched, with fewer varicosities, and their endings are contiguous with both the perikarya and dendrites of catecholamine-containing neurons. These data suggest that vestibular neurons preferentially target the rostral ventrolateral medulla, and can thereby provide a morphological basis for a short latency vestibulo-sympathetic pathway.
PMCID: PMC3029471  PMID: 21163335
Vestibular nuclei; vestibulo-sympathetic pathways; vestibulo-sympathetic reflex; vestibulo-autonomic control
4.  Selective Expression of Presenilin 1 in Neural Progenitor Cells Rescues the Cerebral Hemorrhages and Cortical Lamination Defects in Presenilin 1-Null Mutant Mice 
Development (Cambridge, England)  2005;132(17):3873-3883.
Mice with a null mutation of the presenilin 1 gene (Psen1-/-)die during late intrauterine life or shortly after birth and exhibit multiple CNS and non-CNS abnormalities, including cerebral hemorrhages and altered cortical development. The cellular and molecular basis for the developmental effects of Psen1 remain incompletely understood. Psen1 is expressed in neural progenitors in developing brain, as well as in postmitotic neurons. We crossed transgenic mice with either neuron-specific or neural progenitor-specific expression of Psen1 onto the Psen1-/- background. We show that neither neuron-specific nor neural progenitor-specific expression of Psen1 can rescue the embryonic lethality of the Psen1-/- embryo. Indeed neuron-specific expression rescued none of the abnormalities in Psen1-/- mice. However, Psen1 expression in neural progenitors rescued the cortical lamination defects, as well as the cerebral hemorrhages, and restored a normal vascular pattern in Psen1-/- embryos. Collectively, these studies demonstrate that Psen1 expression in neural progenitor cells is crucial for cortical development and reveal a novel role for neuroectodermal expression of Psen1 in development of the brain vasculature.
PMCID: PMC1698506  PMID: 16079160
Cortical development; CNS hemorrhages; Familial Alzheimer’s disease; Neural progenitor cells; Presenilin 1 (PS1, Psen1); Transgenic mice; Vascular development
5.  Distribution and cellular localization of imidazoleacetic acid-ribotide, an endogenous ligand at imidazol(in)e and adrenergic receptors, in rat brain 
Imidazoleacetic acid-ribotide (IAA-RP) is a putative neurotransmitter/modulator recently discovered in mammalian brain. The present study examines the distribution of IAA-RP in the rat CNS using a highly specific antiserum raised in rabbit against IAA-RP with immunostaining of aldehyde-fixed rat CNS. IAA-RP-immunoreactive neurons were present throughout the neuraxis; neuroglia were not labeled. In each region, only a subset of the neuronal pool was immunostained. In the forebrain, ribotide-immunolabeled neurons were common in neocortex, in hippocampal formation, and in subcortical structures including basal ganglia, thalamus and hypothalamus. Labeling was prominent limbic areas including olfactory bulb, basal forebrain, pyriform cortex and amygdala. In the mid- and hindbrain, immunolabled neurons were concentrated in specific nuclei and, in some areas, in specific subregions of those nuclei. Structures of the motor system, including cranial nerve motor nuclei, precerebellar nuclei, the substantia nigra, and the red nucleus were clearly labeled. Staining was intense in cells and/or puncta in the rostral and caudal ventrolateral medullary reticular formation, nucleus tractus solitarius and the caudal vestibular nuclear complex. Within neurons, the ribotide was found predominantly in somata and dendrites; some myelinated axons and occasional synaptic terminals were also immunostained.
These data indicate that IAA-RP contributes to the neurochemical phenotype of many neuronal populations further support our suggestion that, in autonomic structures, the IAA-RP may serve as a chemical mediator in complex circuits involved in blood pressure regulation and, more generally, sympathetic drive.
PMCID: PMC1907380  PMID: 17210242
imidazole-4-acetic acid-riboside; imidazol(in)e receptors; adrenergic receptors; rostroventral lateral medulla
6.  Age-Related Atrophy of Motor Axons in Mice Deficient in the Mid-Sized Neurofilament Subunit 
The Journal of Cell Biology  1999;146(1):181-192.
Neurofilaments are central determinants of the diameter of myelinated axons. It is less clear whether neurofilaments serve other functional roles such as maintaining the structural integrity of axons over time. Here we show that an age-dependent axonal atrophy develops in the lumbar ventral roots of mice with a null mutation in the mid-sized neurofilament subunit (NF-M) but not in animals with a null mutation in the heavy neurofilament subunit (NF-H). Mice with null mutations in both genes develop atrophy in ventral and dorsal roots as well as a hind limb paralysis with aging. The atrophic process is not accompanied by significant axonal loss or anterior horn cell pathology. In the NF-M–null mutant atrophic ventral root, axons show an age-related depletion of neurofilaments and an increased ratio of microtubules/neurofilaments. By contrast, the preserved dorsal root axons of NF-M–null mutant animals do not show a similar depletion of neurofilaments. Thus, the lack of an NF-M subunit renders some axons selectively vulnerable to an age-dependent atrophic process. These studies argue that neurofilaments are necessary for the structural maintenance of some populations of axons during aging and that the NF-M subunit is especially critical.
PMCID: PMC2199745  PMID: 10402469
aging; axonal atrophy; neurofilament proteins; neuronal cytoskeleton; knockout mice
7.  Requirement of Heavy Neurofilament Subunit in the Development of Axons with Large Calibers  
The Journal of Cell Biology  1998;143(1):195-205.
Neurofilaments (NFs) are prominent components of large myelinated axons. Previous studies have suggested that NF number as well as the phosphorylation state of the COOH-terminal tail of the heavy neurofilament (NF-H) subunit are major determinants of axonal caliber. We created NF-H knockout mice to assess the contribution of NF-H to the development of axon size as well as its effect on the amounts of low and mid-sized NF subunits (NF-L and NF-M respectively). Surprisingly, we found that NF-L levels were reduced only slightly whereas NF-M and tubulin proteins were unchanged in NF-H–null mice. However, the calibers of both large and small diameter myelinated axons were diminished in NF-H–null mice despite the fact that these mice showed only a slight decrease in NF density and that filaments in the mutant were most frequently spaced at the same interfilament distance found in control. Significantly, large diameter axons failed to develop in both the central and peripheral nervous systems. These results demonstrate directly that unlike losing the NF-L or NF-M subunits, loss of NF-H has only a slight effect on NF number in axons. Yet NF-H plays a major role in the development of large diameter axons.
PMCID: PMC2132822  PMID: 9763431
neurofilament proteins; neuronal cytoskeleton; mice; knockout; gene targeting; large diameter axons
8.  Absence of the Mid-sized Neurofilament Subunit Decreases Axonal Calibers, Levels of Light Neurofilament (NF-L), and Neurofilament Content  
The Journal of Cell Biology  1998;141(3):727-739.
Neurofilaments (NFs) are prominent components of large myelinated axons and probably the most abundant of neuronal intermediate filament proteins. Here we show that mice with a null mutation in the mid-sized NF (NF-M) subunit have dramatically decreased levels of light NF (NF-L) and increased levels of heavy NF (NF-H). The calibers of both large and small diameter axons in the central and peripheral nervous systems are diminished. Axons of mutant animals contain fewer neurofilaments and increased numbers of microtubules. Yet the mice lack any overt behavioral phenotype or gross structural defects in the nervous system. These studies suggest that the NF-M subunit is a major regulator of the level of NF-L and that its presence is required to achieve maximal axonal diameter in all size classes of myelinated axons.
PMCID: PMC2132741  PMID: 9566972

Results 1-8 (8)