Topics and Speakers Lorna Role, PhD
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Synopsis
In this lecture, Dr Lorna Role discusses details of synaptic transmission in the context of motivation and reward. After quickly reviewing the brain regions associated with motivation and reward, she describes the circuit of the central nervous system (CNS) she will be focusing on (i.e., the glutamatergic synapse between the hippocampus and the nucleus accumbens), and then delves into the currents and the channels of the same. Dr Role concludes by talking about nicotine as an example of a drug of abuse to explain how synaptic transmission in this circuit changes and motivates the person to smoke more.
There are many glutamatergic projections that come into the nucleus accumbens, a brain region associated with rewards such as food and sex. The ventral tegmental area (VTA), the anterior cingulate, the prefrontal cortex, the amygdala, and the hippocampus all project their medium spiny neurons into the nucleus accumbens. The hippocampus-nucleus accumbens circuit's response to food, amphetamines, and alcohol, substances associated with motivation and desire, are discussed in detail. An interesting fact is that for the nucleus accumbens, the presentation of food is a more potent stimulus than the actual possession of it. Hence, the nucleus accumbens can be seen as a brain region that highly values anticipation, and therefore, motivation.
The mechanisms of glutamatergic transmission are explored in fascinating detail. First of all, the arrival of an action potential causes a rapid depolarization of the neuron and opens its calcium channels. Calcium then enters the axonal terminal (or presynaptic site) and interacts with different proteins, which in turn make the vesicles carrying the neurotransmitter (i.e., glutamine) dock at a specific site on the bouton's membrane. After docking, the vesicle and the bouton's membrane fuse and exocytosis, the release of the neurotransmitter into the synaptic cleft, occurs.
The neurotransmitter now finds itself in the synaptic cleft, where it awaits to be absorbed by the postsynaptic neuron's receptors. Dr Role focuses on two types of glutamate receptors: the NMDA and the AMPA receptors, both of which are ionotropic or ligand-gated ion channels. In order for glutamate to be absorbed by the postsynaptic neuron, the AMPA channel must be sufficiently depolarized by the current executed by the release of the glutamine. Meanwhile, the NMDA receptor awaits, silenced by magnesium ions. Once the AMPA channel is sufficiently depolarized by neuromodulators, the current flows and the magnesium ions "pop" out, allowing the current to flow, and hence, the glutamate to exert its excitatory effect. What is important to keep in mind is that these channels are simply V=IR circuits. They function with the resistance and capacitance associated with any ordinary electrical circuit. Dr Role then shows examples of how to assay synaptic inputs.
There are two ways in which this process of neurotransmitter reception can be terminated, thereby inactivating the neurotransmitter. The first way is through the reuptake system. After a neurotransmitter is released into the synaptic cleft, some of what's left is absorbed back into the presynaptic neuron, therefore not allowing it to be taken up by the postsynaptic neuron. The second way is through enzymatic hydrolysis, by which the neurotransmitter is degraded into smaller inactive molecules. These two mechanisms ensure that the neurotransmitter action only remains transient.
Dr Role concludes the lecture by showing how nicotine, a drug of abuse, interacts with synaptic transmission. By way of an illustrative example and animation, nicotine is shown to cause a long-term potentiation in the neuron, even after the person has smoked for one minute. The excitation continues for half an hour in the neuron. The problem with this is two-fold: First, the excitation causes a decrease in synaptic transmission. Second, the nicotinic receptors are located in neurons that are associated with the "reward" system of the brain (i.e., the nucleus accumbens, hippocampus, and amygdala). Therefore, the person must smoke more in order to return the synaptic transmission to normal and get the "calming effect" associated with cigarette smoking. Nicotine-induced synaptic facilitation is also associated with the release of inhibitory neurotransmitters such as GABA and serotonin, thereby making smoking even more addictive. Current research on motivational synapses, such as this one, has led to interest in other synapses related to both addiction and even obesity. New drugs are being studied that mediate these motivational circuits, not only at the level of the nucleus accumbens but also at the level of the synaptic cleft, rendering their action even more effective.
