Anatomy and in vivo physiology of non-dopamine neurons in ventral tegmental area and substantia nigra pars compacta
Lead Research Organisation:
Imperial College London
Department Name: Institute of Clinical Sciences
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
Midbrain dopamine neurons play a fundamental role in the processing of rewards. In particular, dopamine neurons encode a reward error-prediction rule: they are excited by unexpected rewards, do not change firing to expected rewards, and are inhibited by reward omission. Dopamine neuron dysfunction is involved in Parkinson?s disease, schizophrenia and drug addiction.
My colleagues and I have recently shown that a subpopulation of presumed dopamine neurons, in the ventral tegmental area (VTA), are, in fact, not dopaminergic (Ungless, Magill & Bolam, 2004). Because these neurons were previously assumed to be dopaminergic, little is known about their anatomy and physiology and how that differs from dopamine neurons. One important difference concerns their responses to aversive stimuli. We found that dopamine neurons are uniformly inhibited by an aversive stimulus, which is consistent with reward theories of their function. In contrast, the non-dopamine neurons were typically excited by the aversive stimulus, which suggests that they may encode information about motivationally-important stimuli in a manner distinct from dopamine neurons. Our study raises a number of specific questions that will be addressed in this application. In particular, I will test the hypotheses that these neurons are phasically excited by rewards, that they use glutamate as their neurotransmitter and that they project to the prefrontal cortex. In addition I will test the hypothesis that a similar group of non-dopamine neurons are present in the neighbouring substantia nigra pars compacta (SNpc).
I will address these issues using a powerful combination of in vivo electrophysiology, single-cell juxtacellular labelling and immunohistochemical techniques. Briefly, I will record electrophysiological activity of individual neurons, in vivo in anaesthetized rats, and characterise their baseline properties and responses to a variety of stimuli. Following this, neurons will be labelled using the juxtacellular technique which allows for the selective labelling of the individual neuron recorded from. The neurochemical identity of the neuron will then be analysed using immunohistochemical fluorescence and following this the detailed 3-dimensional anatomy of the individual neuron can be reconstructed, including the full axonal projection. This approach allows for the direct correlation of anatomy, neurochemistry and in vivo physiology in individual neurons.
My colleagues and I have recently shown that a subpopulation of presumed dopamine neurons, in the ventral tegmental area (VTA), are, in fact, not dopaminergic (Ungless, Magill & Bolam, 2004). Because these neurons were previously assumed to be dopaminergic, little is known about their anatomy and physiology and how that differs from dopamine neurons. One important difference concerns their responses to aversive stimuli. We found that dopamine neurons are uniformly inhibited by an aversive stimulus, which is consistent with reward theories of their function. In contrast, the non-dopamine neurons were typically excited by the aversive stimulus, which suggests that they may encode information about motivationally-important stimuli in a manner distinct from dopamine neurons. Our study raises a number of specific questions that will be addressed in this application. In particular, I will test the hypotheses that these neurons are phasically excited by rewards, that they use glutamate as their neurotransmitter and that they project to the prefrontal cortex. In addition I will test the hypothesis that a similar group of non-dopamine neurons are present in the neighbouring substantia nigra pars compacta (SNpc).
I will address these issues using a powerful combination of in vivo electrophysiology, single-cell juxtacellular labelling and immunohistochemical techniques. Briefly, I will record electrophysiological activity of individual neurons, in vivo in anaesthetized rats, and characterise their baseline properties and responses to a variety of stimuli. Following this, neurons will be labelled using the juxtacellular technique which allows for the selective labelling of the individual neuron recorded from. The neurochemical identity of the neuron will then be analysed using immunohistochemical fluorescence and following this the detailed 3-dimensional anatomy of the individual neuron can be reconstructed, including the full axonal projection. This approach allows for the direct correlation of anatomy, neurochemistry and in vivo physiology in individual neurons.
