Grants And Publications
|
|
Making new dopamine cells in the adult brain
|
|
|
|
|
|
|
|
|
Parkinsons Disease,Other,
|
|
|
|
|
|
Aim 1. Is the pool of cells available for recruitment into SNc DA neurones expandable?
We demonstrated that neurogenesis does occur in the midbrain of adult mice and that some of these “new-born” cells express markers of dopaminergic neurons. Thus the pool of cells available for recruitment into SNc DA neurones is expandable in the adult rodent brain.
Aim 2. To what extent do brain circuits (i.e. extrinsic synaptic input onto SNc neurones) regulate the number of DAergic SNc cells?
We infused GABAA receptor agonists or antagonists directly into the midbrain of adult mice continuously for 2 weeks then counted the number of DAergic SNc cells. GABAA receptors mediate the majority of extrinsic synaptic input to SNc neurones. The number of DAergic cells decreased by ~20% (~1000 cells) with the agonist and decreased by ~30% (~1500 cells) with the antagonist. Further, we determined that infusion of a D2 DA receptor agonist into the striatum dramatically increased the number of SNc DAergic cells whereas similar infusions of D1 DA receptor agonists or antagonists or D2 DA receptor antagonists had no effect. These results are consistent with the idea that extrinsic synaptic input onto SNc neurones, possibly mediated via the indirect D2 DA receptor pathway through striatum, can regulate the number of DAergic SNc cells. Further, the extent of this regulation is significant and potentially therapeutic.
Aim 3. Is recruitment of new SNc DAergic cells associated with DAergic reinnervation of the striatum, increased striatal DA release and motor symptom relief?
Parts of this aim have been achieved and the remaining parts will be achieved in the near future (~3 months time). We have tested one group of PD model rats who were administered the drug 1-EBIO (an SK channel agonist) for 8 weeks. There was no beneficial effect on their motor symptoms. The histology on these brains is underway to determine whether there was any striatal reinnervation. A second cohort of PD model rats is currently under experiment. These rats will receive D2 DA receptor agonist infusion into the striatum, which dramatically increases the number of SNc DAergic neurones in normal mice (Aim 2), to determine if their motor symptoms are reversed and whether or not increased striatal reinnervation and DA release occur.
|
|
|
Refereed papers:
1.T.D. Aumann, K. Egan, J. Lim & M.K. Horne “Changes in tyrosine hydroxylase expression in adult mouse substantia nigra pars compacta neurons following localized pharmacological manipulations of ion-channels and dopamine receptors” (Submitted to J Neurochem January 2010).
2.T.D. Aumann, & M.K. Horne “Regulation of tyrosine hydroxylase expression in substantia nigra pars compacta neurons by cell excitability and intracellular calcium” (Review, in preparation).
3.T.D. Aumann, K. Lord & M.K. Horne “Recover of nigrostriatal function in rodent models of Parkinson’s disease following administration of SK channel agonists and D2 dopamine receptor agonists” (In preparation).
4.S.S. Lu, M.K. Horne & T.D. Aumann “Dopamine neurogenesis in the midbrain of adult mice” (In preparation).
Conference papers:
1.Egan, K., Horne, M.K. & Aumann, T.D. (2008) Excitability regulates tyrosine hydroxylase expression in substantia nigra pars compacta neurons. Program No. 140.9. 2008 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2008. Online.
2.Egan, K., Lim, J., Horne, M.K. & Aumann, T.D. (2010) Excitability regulates tyrosine hydroxylase expression in substantia nigra neurons. Proceedings of the Australian Neuroscience Society, ORAL-08-02.
|
|
|
The major achievements of this project were:
(1)Obtaining evidence that the electrical activity of brain cells regulates their capacity to synthesize the chemical dopamine. Abnormal levels of brain dopamine cause symptoms of diseases such as Parkinson’s disease, schizophrenia, attention deficit hyperactivity disorder (ADHD) and drug addiction. This finding identifies a number of new drug targets (ion-channels and receptors affecting electrical activity in these cells) which might help normalize brain dopamine levels and reduce symptoms in these patients.
(2)Resolving a long-standing controversy about whether or not new dopamine cells can be generated in a part of the brain affected in these diseases. Our data clearly demonstrates that new dopamine cells are generated here. If we can understand how this occurs we might be able to control it to replace dead and dying dopamine cells which cause the motor symptoms of Parkinson’s disease for example.
|
|
<< Back To Grants And Publications List
|
|
|