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Title page for ETD etd-03292010-213241

Type of Document Dissertation
Author Kusnoor, Sheila Vijay
Author's Email Address sheila.v.kusnoor@vanderbilt.edu
URN etd-03292010-213241
Title Thalamostriatal Neurons and Parkinsonism
Degree PhD
Department Neuroscience
Advisory Committee
Advisor Name Title
Danny Winder Committee Chair
Ariel Deutch Committee Member
Maureen Gannon Committee Member
Roger Colbran Committee Member
  • parafascicular
  • dopamine
  • thalamus
  • Cbln1
  • striatum
  • medium spiny neuron
Date of Defense 2010-03-22
Availability unrestricted
The thalamic caudal intralaminar nuclear complex is composed of the centromedian-parafascicular (CM-PF) nuclei in primates and the PF in rodents. These thalamic neurons project to the striatum and synapse onto the dendritic shafts and spines of medium spiny neurons (MSNs). In Parkinson’s disease (PD), nigrostriatal dopamine neurons and CM-PF neurons degenerate. We evaluated if substantia nigra (SN) dopamine neurons project to the PF and determined if loss of nigrostriatal dopamine neurons causes the degeneration of PF neurons in rats.

We found that the SN projection to the PF is non-dopaminergic. A previous study reported that 6-hydroxydopamine (6-OHDA) lesions of the median forebrain bundle, which contains dopaminergic and noradrenergic axons, decreased the number of retrogradely-labeled PF thalamostriatal neurons. Given the lack of an SN dopaminergic innervation of the PF, we hypothesized that the loss of retrograde labeling was secondary to forebrain noradrenergic depletion. However, we observed no significant differences in retrograde labeling or in the total number of PF neurons in rats with nigrostriatal dopamine or forebrain noradrenergic depletion. Thus, it appears that the loss of CM-PF neurons is not caused by the transsynaptic degeneration of catecholaminergic neurons in PD.

We next sought to determine how lesions of the PF alter striatal MSNs. However, conventional lesions of the PF invariably damage surrounding nuclei. We searched for genes encoding proteins that were selectively expressed in the PF. We found that Cbln1 was enriched in the PF of rats. Virtually all PF neurons expressed Cbln1, and ultrastructural studies revealed that Cbln1-immunoreactive axon terminals formed axodendritic and axospinous synapses with MSNs.

Previous studies indicated that Cbln1 regulates the formation and maintenance of cerebellar synapses. We therefore hypothesized that a loss of Cbln1 in thalamostriatal neurons would modify the dystrophic changes in MSN dendritic spines seen in the dopamine-depleted (parkinsonian) striatum. We found that in the cbln1 null mutant mouse, MSN spine density was markedly increased, with a corresponding increase in the density of axospinous synapses. Our findings suggest that modulation of Cbln1 may be a novel means of slowing progression in PD.

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