Ashwell Research Lab - Comparative and Developmental Neuroscience
A/Prof. Ashwell's background and interest is as a neuroanatomist, with studies in comparative mammalian neuroanatomy (in particular marsupials and monotremes), human and rodent brainstem and hypothalamus development and neuroteratology. A/Prof. Ashwell has published 87 papers in international refereed journals, 3 books (Atlas of the Developing Rat Nervous System 2nd and 3rd edition and A Chemoarchitectural Atlas Of The Rat Forebrain) and 6 book chapters. He has directly supervised 17 research students (3 PhD, 2 MSc and 12 BSc Hons) and co-supervised a further 9 research students. He regularly reviews papers submitted to Journal of Comparative Neurology, J Histochem Cytochem, Brain, Behaviour and Evolution. He is currently Associate Dean for Research Students in the Faculty of Medicine at UNSW and Head of the Dept of Anatomy at UNSW.
Research
An Acute Exposure Mouse Model of the Fetal Alcohol Syndrome (FAS)
In this study, a mouse model of FAS was used to determine the sensitive period of development for the induction of the optic nerve damage seen in almost half the human children reported to have FAS. Exposure to alcohol on the 8th day of development in mice (equivalent to the second or third week of pregnancy in humans) leads ultimately to a 35% reduction in the number of nerve fibres in the optic nerve. Moreover, many of these fibres have deficient myelin sheaths. In another part of the study, the effects of very early prenatal exposure to alcohol (8th gestational day) on volume and nerve cell numbers of ventromedial and lateral forebrain areas was examined. Even animals without the abnormal facies of FAS had significantly damaged ventromedial forebrain nuclei (septal nuclei, nucleus accumbens, nuclei of the diagonal band of Broca), as well as significant deficits in the cerebral cortex (neocortex, primary olfactory cortex, entorhinal area). These results serve to emphasize the importance of health education programmes aimed at reducing the prevalence of binge drinking among girls and women of reproductive age. Such measures are particularly important since considerable damage to the brain and optic nerve may follow alcoholic binges during early fetal life, when the mother may be unaware of her pregnancy.
Recovery of the Fetal Brain from Cytotoxic Damage
Prenatal exposure to the cytotoxic drug, methylazoxymethanol has been used as a model of prenatal brain damage for several decades. This agent produces similar abnormalities in the brains of rodents exposed during early fetal life as are seen in human brains damaged by prenatal ionising radiation, viruses or hyperthermia. The studies undertaken as part of this project have examined the effects of this damage on the microglial populations of the forebrain, the development of vasculature in the cerebral cortex and the radial glia and neuronal heterotopiae. Several aspects of this project are still under investigation and it is intended that when complete, this series of studies will provide a comprehensive insight into the mechanisms by which the developing brain repairs itself.
The Role of the Vestibular Ganglion in Cerebellar Development
This project is aimed at determining how vestibular ganglion cell central processes, which are the earliest afferents to the mammalian cerebellum, influence the developmental processes underway in the cerebellum. In particular we are examining the contacts made between the vestibular ganglion axons and migrating neuronal groups (external granular layer, Purkinje cells).
Microglia and Developmental Cell Death
This work has involved the examination of the role of microglia in the clearance of cell death in the retina, forebrain, cerebellum and trigeminal nuclear complex. This work currently involves collaboration with Dr Yuri Bobryshev of the Institute of the Human Brain, St Petersburg, Russia on a study of the role of microglia in clearance of cell death in the human embryonic brain.
Development of Neocortical Commissural Connections
Development of Neocortical Commissural Connections in the Wallaby Marsupial brains differ markedly from those of placentals in that placentals possess a corpus callosum which connects the two cerebral hemispheres, while marsupial brains lack a corpus callosum, and use an enlarged anterior commissure for interhemispheric connections. While the mechanisms whereby neocortical connections are formed in placental mammals is well-studied, there have been no studies of the development of these connections in Australian marsupials. This project is being pursued in collaboration with A/Prof Phil Waite of the School of Anatomy, UNSW, and Prof. Richard Mark and Dr Lauren Marotte of the Research School of Biological Sciences, ANU.
Development of Respiratory Centre Connections
Fetuses of many mammals are known to make ventilatory movements in utero. However, these respiratory movements are modulated in response to changing levels of arterial O2 and CO2 in different ways from postnatal animals. A major problem with interpreting the results of such experiments is that no information is available concerning the development of connections between respiratory centres in any mammal. In particular, it is unknown whether there are developmental alterations in the structural connections which may underlie the observed functional changes. This project is aimed at analysing the development of these vital connections.
Grants
"Abnormalities of the brain in a mouse model of the fetal alcohol syndrome" Clive and Vera Ramaciotti Foundations 1990 - $25,090
Dr K.W.S. Ashwell.
"The response of glia and vasculature to prenatal brain damage" The Apex Foundation for Research into Mental Retardation 1990 - $6,200
Dr K.W.S. Ashwell.
"Dysmorphogenesis of the forebrain and optic nerve in the fetal alcohol syndrome" National Health and Medical Research Council 1990 - $25,232; 1991 - $18,634; 1992 - $18,634
Dr K.W.S. Ashwell.
"Development of the anterior commissure in wallabies" Australian Research Council 1992 - $12,000.00, 1993 - $9,950. Co-investigators: Dr Phil Waite, School of Anatomy, UNSW and Prof. Richard Mark (RSBS, ANU).
"The role of the vestibular ganglion in cerebellar development" National Health and Medical Research Council 1993 - $44,549, 1994 - $44,549, 1995 - $44,549
Dr K.W.S. Ashwell.
"Morphological study of microglia localization and cell death in the human fetal cortex" Dept of Industry, Technology and Regional Development 1993 - $14,202. Co-investigator: Dr Yuri Bobryshev, Institute of the Human Brain, St Petersburg, Russia.
"Chemoarchitecture of the echidna cerebral cortex" Australian Research Council 1996 - $10,000.
Dr K.W.S. Ashwell and Prof. G. Paxinos (Psychology, UNSW).
"Microscope and digital photolab" 1996 National Health and Medical Research Council - $61,515. Prof. G. Paxinos (Psychology),
Dr K.W.S. Ashwell.
"Microscope and digital photolab for the human brain project" 1996 Clive and Vera Ramaciotti Foundation $10,000. Prof. G. Paxinos (Psychology, UNSW),
Dr K.W.S. Ashwell.
"A comparative study of a possible marker of synaptic plasticity" 1996 Alexander von Humboldt Foundation 32,600DM.
Dr K.W.S. Ashwell.
"Development of respiratory centre connections" 1997 Australian Research Council $16,800.
Dr K.W.S. Ashwell.
Recent Publications (2003 - 05)
Papers in International Refereed Journals
Hassiotis M,
Ashwell KW. (2003) Neuronal classes in the isocortex of a monotreme, the Australian echidna (Tachyglossus aculeatus).
Brain Behav Evol. 61:6-27.
Mahns DA, Coleman GT,
Ashwell KW, Rowe MJ. (2003) Tactile sensory function in the forearm of the monotreme Tachyglossus aculeatus.
J Comp Neurol. 459:173-85.
Mai JK, Krajewski S,
Ashwell KWS, Andressen C (2003) A CD-15 immunoreactive subpopulation of radial glial cells in the developing human lateral ganglionic eminence.
Neuroembryology 2: 64-71.
Rowe MJ, Mahns DA, Bohringer RC,
Ashwell KWS, Sahai V (2003) Tactile neural mechanisms in monotremes.
Comp Biochem Physiol Series A 136: 883-893
Hassiotis M, Paxinos G,
Ashwell KWS (2003) Anatomy of the cerebral cortex of the echidna (Tachyglossus aculeatus).
Comp Biochem Physiol Series A 136: 827-850
Cheng Gang, Marotte LR,
Ashwell KWS (2003) Cyto- and chemoarchitecture of the hypothalamus of a wallaby (Macropus eugenii), with special emphasis on oxytocin and vasopressinergic neurons.
Anat Embryol 207: 233-253
Hassiotis M, Paxinos G,
Ashwell KWS (2004) Anatomy of the central nervous system of the Australian echidna.
Proc. Linn Soc NSW 125:287-300
Koutcherov Y,
Ashwell KWS, Paxinos G (2004) Organisation of the human dorsomedial hypothalamic nucleus.
NeuroReport 15:107-111
Ashwell KWS, Hardman C, Paxinos G (2004) The claustrum is not missing from all monotreme brains.
Brain Behav Evol 64:223-241
Hassiotis M, Paxinos G,
Ashwell KWS (2004) Cyto- and chemoarchitecture of the cerebral cortex of the Australian echidna (Tachyglossus aculeatus). I Areal organization.
J Comp Neurol 475:495-517.
Cheng G, Zhou X, Jia Qu,
Ashwell KWS, Paxinos G (2004) Central vagal sensory and motor connections: Human embryonic and fetal development.
Autonomic Neuroscience 114: 83-96.
Ashwell KWS, Halasz P (2004) An acrobat based program for gross anatomy revision.
Medical Education 38: 1185-1186.
Ashwell KWS, Mai JK, Andressen C (2004) CD15 immunoreactivity in the developing brain of a marsupial, the Tammar wallaby (Macropus eugenii).
Anat Embryol 209: 157-168.
Hassiotis M, Paxinos G,
Ashwell KWS (2005) Cyto- and chemoarchitecture of the cerebral cortex of the Australian echidna (Tachyglossus aculeatus). II Laminar organization and synaptic density.
J Comp Neurol 482: 94-122.
Ashwell KW, Zhang LL, Marotte LR (2005) Cyto- and chemoarchitecture of the cortex of the tammar wallaby (Macropus eugenii): Areal organization.
Brain Behav Evol 66: 114-136.
Ashwell KW, Hardman CD, Paxinos G (2005) Cyto- and chemoarchitecture of the amygdala of a monotreme, Tachyglossus aculeatus (the short beaked echidna). J Chem Neuroanat (in press).
Book Chapters
Ashwell, K.W.S. & Bobryshev, Y.V. (1996) The developmental role of microglia. In "Topical issues in microglia research", pp 65-82, eds EA Ling, CK Tan, CBC Tan, Singapore Neuroscience Association, Singapore.
Books
Paxinos, G., Kus, L.,
Ashwell, K.W.S. & Watson, C.R.R. (1998) A Chemoarchitectural Atlas of the Rat Forebrain. Academic, San Diego.
Research Topics Available for Studies Leading to BMedSc, BSc (Hons), MSc, PhD
The Role of a Transient CD15+ Sling in Cerebellar Development
The existence of a transient bundle of fibres immunoreactive for the cell surface molecule CD15 has recently been shown by Dr Ashwell in the prenatal mouse cerebellum.
This bundle differs in its trajectory from any previously identified axonal or glial fascicle and appears immediately after migration of the external granular layer cells over the cerebellar primordium.
This project will involve the analysis of the ultrastructural relationship between these CD15+ fibres and migrating cerebellar neuronal groups during prenatal development to try to determine the role of these fibres.
The Effect of Prenatal Brain Injury on the Course and Extent of Postnatal Neuronal Death
Prenatal exposure to cytotoxic teratogens such as MAM causes not only an immediate effect on the proliferative cell populations of the developing brain, but leads to a delayed effect whereby neurons in the postnatal brain die several weeks after exposure (Ashwell & Webster, Neurotoxic. & Teratol., 10: 65-75).
This delayed effect may profoundly influence the organisation of these damaged brains. In particular, it appears that some neuronal systems (e.g. those serving vision) are more severely affected by the delayed effect than others (e.g. ascending reticular activating system).
The aim of this project is to determine exactly which neural systems are affected by the delayed neuronal death and how this may modify the behaviour of the offspring.
Organisation of the Cerebral Cortex in the Echidna
The Echidna belongs to a group of mammals known as monotremes. This group diverged from the eutherian lineage of mammals which gave rise to humans, rodents etc.) up to 120 million years ago.
The cerebral cortex of the echidna is highly unusual for several reasons: its large relative size and high degree of folding, the large proportion occupied by so-called "silent areas" and the very large percentage which appears to correspond to prefrontal cortex (more than in humans!!!).
The aim of this project is to compare the cellular and chemical organisation of the echidna cerebral cortex with that in humans and other eutheria to try to explain these unusual features.