Midbrain Dopamine Plasticity Laboratory
A new form of adult brain plasticity has recently been discovered whereby mature neurons undergo a switch in the identity of the neurotransmitter they use to communicate with other neurons. We have evidence this occurs for the neurotransmitter dopamine in midbrain neurons, including in humans, and that it is regulated by stimuli in our environment or drugs that alter midbrain neuronal activity.
Too much or not enough midbrain dopamine causes debilitating symptoms associated with several prevalent and costly brain and behavioral disorders; e.g. drug addiction, obsessive compulsive disorder, schizophrenia, depression, Parkinson’s disease, dyskinesia and attention deficit and hyperactivity disorder. These may therefore be treatable by exploiting ‘midbrain dopamine neurotransmitter plasticity’ to normalize midbrain dopamine levels.
Our laboratory is working toward this goal in two streams: (1) Testing whether environment- or drug-induced increases or decreases in the number of midbrain dopamine neurons cause changes in brain function and behavior. This is necessary and may also be sufficient for therapeutic effect in patients. (2) Investigating cellular- and molecular-level mechanisms of midbrain dopamine neurotransmitter plasticity. This will identify targets for new drug development, which, in parallel with environmental stimulation, may also offer therapeutic benefit.
We can identify midbrain neurones that have lost the ability to synthesise dopamine using a genetically modified mouse in combination with immunohistochemistry to detect cells that are dopaminergic and those that were dopaminergic but are not currently. We are using these to investigate cellular/molecular mechanisms of midbrain dopamine neurotransmitter plasticity, which will in turn identify drug targets that might increase or decrease the number of midbrain dopamine neurones in patients. A The drug apamin (an SK ion-channel antagonist) causes loss of tyrosine hydroxylase (TH, the rate-limiting enzyme in dopamine synthesis) in previously dopaminergic midbrain neurones (e.g. more β-gal+/TH- or green cells in Aii compared with Ai). B Both dopaminergic (e.g. 2) and previously dopaminergic midbrain neurones (e.g. 1) express another neurotransmitter somatostatin (SST; red, small arrows). Ci-iii Previously dopaminergic midbrain neurones (e.g. 2 & 3) express more GAD65/67, an enzyme that makes another neurotransmitter called GABA.
The Division of Behavioural Neuroscience focuses on the use and development of models that reflect aspects of human disorders such as addiction, anxiety, depression, schizophrenia, autism and neurodegenerative conditions such as Huntington’s disease. The Cognitive Neuroscience group additionally studies cognitive disorders caused by diseases such as stroke (cerebrovascular disease), Alzheimer's disease and other dementias from a clinical perspective.