Evidence from clinical observations and experimental investigations indicates that few enduring functional impairments are produced by subtotal damage to monoaminergic neurons, despite considerable evidence for their involvement in a wide variety of physiological and behavioral processes. We have proposed that this apparent paradox results from the capacity for """"""""synaptic homeostasis"""""""" that exists in these systems and that leads to compensatory events occurring after partial injury. We propose to use a multidisciplinary approach to describe at the cellular level the initial deficits, recovery of function and residual deficits produced by subtotal destruction of such a monoaminergic system and then to explore the biological bases of those phenomena. Our work will focus on the dopaminergic projection of the nigrostriatal bundle. Where appropriate, other monoaminergic systems will be used for these studies, including the sympathoadrenal system and the noradrenergic locus coeruleus-hippocampus projection. First, we will examine the impact of subtotal injury on monoaminergic function as determined by biochemical, physiological, electrophysilogical, and behavioral measurements. Second, we will attempt to determine the biological bases of the sparing of function that occurs after moderate lesions and the recovery of function that occurs after larger lesions. Third, we will test the ability of certain treatments to extend recovery of striatal function. Fourth, we will examine several other states which may be related to lesion induced-hypoinnervation, including development and chronic neuroleptic treatment. Finally, we will examine the influence of the age at which brain injury is sustained on the behavioral and biological consequences. These results should provide insights into the neurobiology of monoaminergic systems under normal conditions and after damage, as well as provide information of relevance to the detection and treatment of subclinical brain damage in disorders involving abnormalities of monoamine-containing systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS019608-07
Application #
3099756
Study Section
Neurological Disorders Program Project Review B Committee (NSPB)
Project Start
1983-07-01
Project End
1991-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
7
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
Schools of Arts and Sciences
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Jaumotte, Juliann D; Wyrostek, Stephanie L; Zigmond, Michael J (2016) Protection of cultured dopamine neurons from MPP(+) requires a combination of neurotrophic factors. Eur J Neurosci 44:1691-9
Ayadi, Amina El; Zigmond, Michael J; Smith, Amanda D (2016) IGF-1 protects dopamine neurons against oxidative stress: association with changes in phosphokinases. Exp Brain Res 234:1863-1873
Napier, T Celeste; Corvol, Jean-Christophe; Grace, Anthony A et al. (2015) Linking neuroscience with modern concepts of impulse control disorders in Parkinson's disease. Mov Disord 30:141-9
Zigmond, Michael J; Smeyne, Richard J (2014) Exercise: is it a neuroprotective and if so, how does it work? Parkinsonism Relat Disord 20 Suppl 1:S123-7
Jaumotte, Juliann D; Zigmond, Michael J (2014) Comparison of GDF5 and GDNF as neuroprotective factors for postnatal dopamine neurons in ventral mesencephalic cultures. J Neurosci Res 92:1425-33
Ahrens, Allison M; Nobile, Cameron W; Page, Lindsay E et al. (2013) Individual differences in the conditioned and unconditioned rat 50-kHz ultrasonic vocalizations elicited by repeated amphetamine exposure. Psychopharmacology (Berl) 229:687-700
Zigmond, Michael J; Cameron, Judy L; Hoffer, Barry J et al. (2012) Neurorestoration by physical exercise: moving forward. Parkinsonism Relat Disord 18 Suppl 1:S147-50
Cohen, Ann D; Zigmond, Michael J; Smith, Amanda D (2011) Effects of intrastriatal GDNF on the response of dopamine neurons to 6-hydroxydopamine: time course of protection and neurorestoration. Brain Res 1370:80-8
El Ayadi, Amina; Zigmond, Michael J (2011) Low concentrations of methamphetamine can protect dopaminergic cells against a larger oxidative stress injury: mechanistic study. PLoS One 6:e24722
Allen, Erika; Carlson, Kirsten M; Zigmond, Michael J et al. (2011) L-DOPA reverses motor deficits associated with normal aging in mice. Neurosci Lett 489:1-4

Showing the most recent 10 out of 16 publications