Developmental Neurobiology

Bradley E. Alger

Vanessa C.Z. Anseloni, Psy.D., Ph.D.

Robert J. Bloch, Ph.D.

Reha Erzurumlu, Ph.D.

Gary Fiskum, Ph.D.

Douglas O. Frost, Ph.D.

Asaf Keller, Ph.D.

Bruce K. Krueger, Ph.D.

W. Jonathan Lederer, M.D., Ph.D.

David Litwack, Ph.D.

Paul W. Luther, Ph.D.

Frank L. Margolis, Ph.D.

Margaret M. McCarthy, Ph.D.

Jessica Mong, Ph.D.

Patricio O'Donnell, M.D., Ph.D.

Elizabeth Powell, Ph.D.

Adam Puche, Ph.D.

Scott M. Thompson, Ph.D.

Michael W. Vogel, Ph.D.

Paul J. Yarowsky, Ph.D.

Yonathan Zohar, Ph.D.

Research

Development of the nervous system is characterized by a number of essential cellular processes. Neurons are generated and then migrate to their final resting place where they mature and differentiate. Upon differentiation, neurons send out axons to connect with targets either within the CNS or in the periphery. Once these crude connections are formed, more refined connections are sustained through activity dependent mechanisms. Each of these developmental processes is the subject of intense investigation. This research at the anatomical, physiological, cellular and molecular levels will lead to our understanding of how each of these developmental processes takes place, what mechanisms may be altered that lead to congenital abnormalities of the nervous system and how we can re-instate these processes for repair and regeneration of the diseased or damaged adult nervous system. Some specific developmental disorders of the nervous system being studied in our group are Downs syndrome, developmental mechanisms of schizophrenia, agenesis of the corpus callosum, holoprosencephaly, epilepsy, autism, and mood disorders. We are also studying how therapeutic drugs and drugs of abuse ingested by the mother may lead to defects in brain development.

Areas of particular emphasis in the Developmental Neurobiology Focus Group are:

Cell proliferation and migration
In the CNS, neurons are generated in the ventricular zone at temporally precise stages of development and in the ventricular zone of the adult brain (so called neural stem cells). Researchers at the University of Maryland are interested in how cell proliferation may be disrupted in disorders such as Downs Syndrome and epilepsy through changes in the length of the cell cycle. Once cells are generated in the ventricular zone they then migrate to other regions of the brain, sometimes over large distances before they locate their final resting place and begin to differentiate. Specific questions being investigated here are how interneurons of the cerebral cortex that are born in the ventral forebrain are able to migrate and locate their final destination in the dorsal telencephalon, and how do neurons within the rostral migratory stream locate their migratory targets in the olfactory bulb both during development and throughout life. The recent identification of human neural stem cells has advanced our understanding of the basic differences between normal and abnormal cortical development in both adult and developmental brain disorders. Multipotent neural stem cells have been isolated from either fetal or adult human brain in addition to being isolated from the rodent brain. Under appropriate conditions their properties of self-renewal and multipotential differentiation, such as generating neurons of different types, can be harnessed for studying various aspects of disorders of brain development in vitro as well as for grafting the stem cells into the CNS and studying their properties of migration and differentiation in vivo. Scientists in our group are using neural stem cells derived from both the adult and fetal nervous system to understand mechanisms of neuronal proliferation, migration and differentiation.

Neuronal and Glial differentiation
The nervous system is made up of both neurons and glia. The differentiation of both cell types is essential for a proper functioning nervous system. Scientists in our group have identified glial structures within the developing brain that secrete molecules that guide axons towards their targets. Glial are also essential for the formation of synapses between neurons. An example we study is in the developing olfactory system where glia provide scaffolds for the formation of glomeruli (functional units) within the olfactory bulb.

Axon guidance
How is the brain is wired up during development? This question is being investigated by several groups at the University of Maryland. Two systems that are being investigated are the development of midline projections across the corpus callosum and of topographically specific connections between the cerebral cortex and the pons. The correct wiring of the brain is essential for normal function. Improper wiring is the basis for a large number of human congenital syndromes and other disorders such as autism, epilepsy, dyslexia and schizophrenia.

Cortical map formation and brain circuitry
Once the crude map of connections is formed within the brain the fine circuitry is refined by both environmental factors (for example neurotrophins and monoamines) and by activity dependent mechanisms. This refinement leads to the formation of specific patterns of connections that allow information from the periphery to be represented within the brain. A good example of this is the developing visual system where connections are formed in visual cortex and then refined by activity into maps representing the visual field. Scientists in our group are studying how neuronal circuits are formed and then sculpted into the kinds of maps formed in the visual cortex by activity.

Development of sex differences in the brain
A large number of differences exist between the male and female brain. Scientists in our group are investigating how these differences arise by examining which developmental processes are regulated by hormones and how these alterations in cell number or neuronal connectivity manifest themselves as behavioral differences later in life.

Pediatric brain damage
Early in life is also a time of enhanced vulnerability to brain damage due caused by prematurity, birth trauma, drug and alcohol exposure or accidents. Members of our group have been exploring animal models of early brain damage with an emphasis on developing age appropriate and gender specific therapeutics to protect against the devastating consequences of such events.

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