Project Details


This application for a First Award seeks research support for five
years to study the afferent control of substantia nigra
dopaminergic neuron activity. Many lines of evidence point towards
a dopaminergic component in schizophrenia, but there is actually
no evidence that the dopaminergic neurons themselves are
dysfunctional, and the possibility exists that the problem is one
of altered afferent modulation of dopaminergic neuron activity.
Previous attempts to study the anatomy and physiology of afferents
nigral dopaminergic neurons have been hindered by the complex
cytoarchitectonic organization of the substantia nigra, the lack
of identification of the neuron being studied as dopaminergic, and
uncertainty as to the site of origin of evoked electrophysiological
responses or synapses contacting nigral neurons. This application
proposes to study dopaminergic afferents by electrophysiological-
neuroanatomical techniques in which dopaminergic neurons will be
electrophysiologically identified in vivo and recorded
intracellularly with horseradish peroxidase (HRP)-containing
electrodes. Intrinsic properties and responses to stimulation of
suspected afferents will be observed and measured, and then the
neuron will be intracellularly injected with HRP and processed for
sequential light and electron microscopic analyses. HRP-stained
neurons will be examined, drawn and photographed with a light
microscope, and representative regions of the entire dendritic
extent of identified and individually labelled dopaminergic neuron
will be trimmed out, re-sectioned on an ultramicrotome, and
examined in the electron microscope, where a qualitative and
quantitative analyses of afferent synapses will be conducted.
Immunocytochemical labelling of synaptic terminals made onto these
neurons will be used to correlate morphologies of synaptic endings
with specific neurotransmitters and neurotransmitter-related
substances known to exist in substantia nigra, for example,
glutamic acid decarboxylase,'substance P, choline
acetyltransferase, enkephalin, dopamine beta-hydroxylase and
serotonin. The sites of origin of afferents to elec-
trophysiologically identified, HRP-filled nigral dopaminergic
neurons will be studied by electron microscopic anterograde tracing
experiments using Phaseolus vulgaris leucoagglutinin. Lesion
degeneration studies will be performed as well in order to identify
the sources of both physiologically observed responses to afferent
stimulation as well as to correlate physiological responses with
the ultrastructural morphology of synapses onto identified
dopaminergic neurons in substantia nigra.
Effective start/end date1/1/908/31/94


  • Psychiatry and Mental health


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