Project Details

Description

These proposed experiments are designed to investigate postnatal changes in
the neurophysiology, neuroanatomy and neuropharmacology of neostriatal and
substantia nigra dopaminergic neurons in the developing rat. There are
many reasons for needing to understand the postnatal ontogeny of neuronal
function in the basal ganglia. One is the recent finding that surviving
neurons in grafts of fetal neurons to adult hosts, currently used as both
an experimental tool as well as a novel clinical approach to treatment of
neurodegenerative disorders such as Parkinson's, Alzheimer's and
Huntington's disease, exhibit characteristics much more similar to early
neonatal neurons in situ than their corresponding adult counterparts. In
order to understand the scope and limitations of neuronal grafting as a
clinical tool, it is necessary to first understand the neurophysiological
properties of immature basal ganglia neurons that occur during the
postnatal period. A second important implication of this work is in trying
to understand the physiological bases for certain developmental disorders
of learning and behavior, for example, attention deficit disorder with
hyperactivity (ADDH), and their pharmacological management with stimulants. The experiments utilize extracellular and intracellular single unit
recording in vivo to chart the postnatal development of spontaneous and
evoked activity of neostriatal and substantia nigra dopamine neurons.
Intracellular recordings will be performed with microelectrodes containing
biocytin which will be injected into each neuron at the end of the
physiological experiments to reveal the entire structure of the neuron,
thus allowing a correlation of the postnatal development of neuronal
physiology with morphology. Other experiments will use PHA-L to label afferents to substantia nigra and
neostriatal neurons, some of which will be subsequently intracellularly
labeled with biocytin. Inspection of the tissue at the light and electron
microscopic levels will allow us to determine how the pattern of
innervation of these important afferents develops in normal postnatal
brain, as well as to determine the effect of the nigrostriatal dopamine
input on the development of cortical and thalamic synaptic inputs to
neostriatum by using 6-OHDA to destroy the dopaminergic inputs. The last major focus of these studies is to use in vitro intracellular
recordings to determine the sites and mechanisms of action whereby
amphetamine and related stimulants produce a paradoxical excitatory effect
on the firing of nigral dopaminergic neurons in early postnatal rats
instead of the inhibition that is seen in adults. This phenomenon may have
special significance to the mechanism of the paradoxical behavioral effects
of amphetamine-like compounds in the treatment of ADDH, as well as to the
phenomenon of marked differences in the effects of stimulant drugs on
mature versus immature nervous systems.Description
StatusFinished
Effective start/end date6/1/925/31/96

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)
  • Neuroscience(all)

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