 In this video, I will list the structures that form the limbic system and explain the general functions of the limbic system, distinguish between declarative and procedural memory, and define long-term potentiation, describe the pathophysiology of Alzheimer's disease. The limbic system is a functional network of brain structures that are involved in establishing emotional states and behavioral drives, regulating memory storage and retrieval. The regions of the diencephalon that are involved in the limbic system include nuclei of the thalamus, as well as nuclei of the hypothalamus. The surrounding regions of the cerebrum include portions of the temporal lobe, including the hippocambus and amygdala, as well as regions of the parietal, frontal and insular lobes, and the cingulate gyrus is this region of the parietal and frontal lobes located just superior to the corpus callosum deep within the longitudinal fissure. Memory is a major function of the limbic system, and we have learned that there are two distinct types of memory, or at least two different kinds of memory. There are declarative memories, which are what type of memories, the storage of facts like names and dates, as well as the information of the spatial environment where an event occurred, so the context in which those facts were learned is also part of this declarative memory. The other type of memory is procedural memory, the how-to memories, which include things like skilled motor commands, such as learning the ability to ride a bike or learning to tie your shoes. You develop these memories through practice, but you do not develop a memory of the specific context, instead it is just the motor commands that get stored. The procedural type memories are thought to involve processing networks in the cerebellum and basal nuclei, as well as regions of the frontal lobe. Declarative memories, on the other hand, we have learned require processing in a region of the medial temporal lobe, known as the hippocampus, that's an important part of the limbic system. We've learned the importance of the hippocampus for these declarative memories by studying a famous patient who had had the hippocampus removed on both sides of the brain. This procedure was a treatment for severe epilepsy and was successful at treating epilepsy, however, following the procedure this patient, known in the literature as patient HM, lost the ability to form declarative memories. At first people studying HM thought that all memory had been lost, but a scientist by the name of Brenda Milner was creative and thought of some cognitive tests that could be used to demonstrate that HM is still capable of forming procedural memories, even though declarative memory has been lost. One of these tasks is the mirror drawing task, where the patient would be asked to draw by tracing within two concentric shapes, such as two concentric stars, as are shown here in the illustration. Now, if you were just to look at your hand while tracing between the two concentric stars, this task would be very easy, it would be trivial, and wouldn't really be a good test. Instead, the patient has to look at a mirror rather than looking at their hand, and so they're only able to look at the reflection of the paper that they're drawing on and a reflection of their hand drawing. This mirror drawing task is pretty difficult at first, but with practice you can learn this procedural skill, you can learn the procedural memory required to improve at this mirror drawing skill. And patient HM, which had completely lost the ability to form new declarative memories, he could never learn the name of this scientist, Brenda Milner, that he worked with even though she studied him many times. They had met together repeatedly, every time she would have to introduce herself, because he could not form that declarative memory. But nonetheless, he was able to improve at the mirror drawing task, demonstrating that there is this other type of memory, the procedural memory that involves a different network than the network of the limbic system that requires the hippocampus to form declarative memories. Our understanding of the cellular basis of memory involves increasing or decreasing the strength of synaptic connections between neurons. Repetitive stimulation can result in modification of a synapse in order to increase the synaptic strength by increasingly number of neurotransmitter receptors, or the number of neurotransmitters that are released, enabling it a stronger connection between the presynaptic neuron and the postsynaptic neuron. Therefore, with an increased number of receptors, the postsynaptic neuron will produce larger graded potentials every time the presynaptic neuron releases neurotransmitter. This is a mechanism that we call long-term potentiation. To understand the mechanism of long-term potentiation, we must first examine the function of ligand gated ion channels in the brain that respond to the neurotransmitter glutamate. Glutamate binds to AMPA receptors, which are ligand gated sodium ion channels, so that when glutamate binds to the AMPA receptor, the sodium ion opens, creating a depolarizing graded potential. The mechanism of long-term potentiation will involve both the AMPA glutamate receptor and another ligand gated ion channel that is a glutamate receptor known as the NMDA receptor. The NMDA receptor is a ligand gated calcium ion channel. However, there are two factors required for calcium to enter the postsynaptic cell through the NMDA receptor. Not only must glutamate bind to the NMDA receptor, the other factor is that the postsynaptic cell must be depolarized at a negative membrane potential at the resting membrane potential. Magnesium ions block the NMDA receptor, and these magnesium ions prevent calcium from entering the postsynaptic cell even when glutamate is bound to the NMDA receptor. But when the presynaptic neuron stimulates the postsynaptic neuron at high frequency with one action potential rapidly followed by another action potential, glutamate binding to AMPA receptors creates depolarization in the postsynaptic neuron, then the depolarized postsynaptic neuron will be activated again and this time when glutamate binds to the NMDA receptors on the surface of a depolarized postsynaptic neuron, the NMDA receptor will open allowing calcium to enter the cell. Calcium will then stimulate a mechanism inside the postsynaptic cell that leads to an increased number of AMPA receptors on the surface of that postsynaptic cell. Therefore, this mechanism of long-term potentiation leads to an increased synaptic strength by increasingly number of glutamate receptors on the surface of the postsynaptic cell. A phrase that was coined to help us think about the way that this works is the idea that neurons that fire together, wire together, this repetitive stimulation will modify the strength of the synaptic connections as high frequency stimulation leads to activation of the NMDA receptor allowing calcium to enter the cell and calcium will then stimulate the expression of an increased number of AMPA glutamate receptors that allow a larger graded potential to be produced every time the presynaptic neuron releases the neurotransmitter glutamate. A stronger graded potential will be produced in the postsynaptic neuron making it more likely the postsynaptic neuron will reach threshold for an action potential. Alzheimer's disease is a neurodegenerative disease that's characterized by memory impairments confusion about time or place, difficulty planning, executing tasks, poor judgment, and personality changes. Alzheimer's disease is the most common form of dementia and is strongly associated with age. About 80% of patients with Alzheimer's disease are over 75 years of age. However, there is an early onset form of Alzheimer's disease that can affect people in middle ages in their 30s and 40s. The pathology of Alzheimer's disease involves abnormal clumps of proteins that form in the synapses and disrupt neurotransmission. These are known as amyloid plaques and they're primarily formed from a protein known as amyloid beta. A mutation in the gene for the amyloid beta protein is one of the strongest risk factors for an early onset form of Alzheimer's disease. Another characteristic in the pathology of Alzheimer's disease known as neurofibrillary tangles are disruption of the microtubules in side of axons. The microtubule binding protein known as tau becomes hyperphosphorylated in Alzheimer's disease leading to disruption of the cytoskeleton in the axon that can impair neurotransmission and eventually lead to neuronal cell death. The pathology of Alzheimer's disease usually starts in the hippocampus and the symptoms that are usually noticed first with Alzheimer's disease are impairments in memory that result from damage to the hippocampus. But as the pathology spreads throughout the cerebral cortex the cognitive impairments that result can become more profound eventually leading to personality changes and loss of executive functioning skills and confusion. We can see in the image on the right here the illustration shows that there is extreme shrinkage of the hippocampus and extreme shrinkage of the cerebral cortex in the brains of patients that have died from Alzheimer's disease. They also have severely enlarged ventricles, the spaces within the brain become larger as the cells of the brain are dying.