Learning, Memory and Synaptic Plasticity PDF (November 2024)

LEARNING, MEMORY and SYNAPTIC PLASTICITY Block: Nervous System Block Director: Haley O'Brien, PhD Session Date: Tuesday, November 05, 2024 Time: 9:00 – 10:00a Instructor: Todd Vanderah Department: Pharmacology Email: [email protected]...

LEARNING, MEMORY and SYNAPTIC PLASTICITY Block: Nervous System Block Director: Haley O'Brien, PhD Session Date: Tuesday, November 05, 2024 Time: 9:00 – 10:00a Instructor: Todd Vanderah Department: Pharmacology Email: [email protected] INSTRUCTIONAL METHODS Primary Method: IM13: Lecture ☐ Flipped Session Resource Types: RE18: Written or Visual Media (or Digital Equivalent) INSTRUCTIONS Please read lecture notes and watch the VIDEO to prepare for an interactive session. READINGS N/A LEARNING OBJECTIVES 1. Compare and contrast explicit and implicit memory, and the parts of the CNS involved in these two types of memory. 2. Interpret working memory and indicate the parts of CNS critical for its normal function. 3. Determine (and name, where possible) the afferent and efferent pathways of the hippocampus along with the blood supply to the hippocampus. 4. Differentiate the terms anterograde amnesia, global amnesia, and retrograde amnesia, and indicate the parts of the CNS where damage is associated with each. 5. Summarize the four processes of explicit memory. 6. Formulate the role of acetylcholine and other neurotransmitters in learning and memory. Refer to earlier lectures to specify the cells of origin of these neurotransmitters. 7. Integrate the effects of age on learning and memory. 8. Compare and contrast the NMDA receptor to other ligand-gated ion channels. 9. Determine the role of NMDA receptors in LTP, and the mechanisms of activation of NMDA receptors. 10. Evaluate LTD and how it may result in the plasticity of the nervous system. 11. Interpret the dual roles of protein synthesis in synaptic plasticity. 12. Critique the major classes of molecules involved in mediating experience-dependent synaptic plasticity. CURRICULAR CONNECTIONS Below are the competencies, educational program objectives (EPOs), disciplines and threads that most accurately describe the connection of this session to the curriculum. [Block: Nervous System | VANDERAH] [1 of 16] LEARNING, MEMORY and SYNAPTIC PLASTICITY Related Related Competency\EPO Disciplines Threads COs LOs CO-01 LO #1 MK-01: Core of basic sciences Neuroscience N/A CO-01 LO# 2 MK-01: Core of basic sciences Neuroscience N/A CO-01 LO #3 MK-02: The normal structure and Neuroscience N/A function of the body as a whole and of each of the major organ systems CO-03 LO #4 MK-05: The altered structure and Neuroscience Select Thread function (pathology & pathophysiology) of the body/organs in disease CO-01 LO #5 MK-02: The normal structure and Neuroscience N/A function of the body as a whole and of each of the major organ systems CO-01 LO #6 MK--03: The molecular, cellular Neuroscience N/A and biochemical mechanisms of homeostasis CO-03 LO#7 MK-05: The altered structure and Neuroscience Health & function (pathology & Individual: pathophysiology) of the Geriatrics body/organs in disease CO-01 LO#8 MK--03: The molecular, cellular Neuroscience N/A and biochemical mechanisms of homeostasis CO-01 LO#9 MK--03: The molecular, cellular Neuroscience N/A and biochemical mechanisms of homeostasis CO-03 LO#10 MK-05: The altered structure and Neuroscience Select Thread function (pathology & pathophysiology) of the body/organs in disease CO-05 LO#11 MK--03: The molecular, cellular Neuroscience N/A and biochemical mechanisms of homeostasis CO-05 LO#12 MK--03: The molecular, cellular Neuroscience N/A and biochemical mechanisms of homeostasis [Block: Nervous System | VANDERAH] [2 of 16] LEARNING, MEMORY and SYNAPTIC PLASTICITY INTRODUCTION Adaptation to our environment results in a mechanism known as learning and memory. Learning is the set of processes by which we acquire knowledge about the world, while memory is the set of processes by which that knowledge is encoded, stored and later retrieved. Many behaviors, good and bad, are learned; hence we are who we are largely because of what we learn. Learned behaviors include motor skills, languages, and social behaviors as well as dysfunctional behaviors that in some cases can be categorized as psychological disorders. Therefore, the study of learning and memory is central to understanding behavioral disorders. Memory can be categorized as Implicit or Explicit Memory involves many regions of the brain however, studies have identified certain regions of the brain as much more important in the storage of information. In the 1940’s Dr. Penfield started placing electrodes in different regions of the brain in order to try and help individuals with epilepsy. On many occasions Dr. Penfield found that electrical stimulation of the temporal lobes resulted in a coherent recollection of an earlier experience. Further studies/observations of patients with bilateral lesions of the temporal lobes as treatment for epilepsy have resulted in more convincing evidence that the temporal lobes play a role in memory. A well-studied case of a patient with bilateral removal of portions of the temporal lobe was H.M. At the age of 27, H.M., who had suffered from untreatable seizures, underwent bilateral removal of the hippocampal formation, the amygdala, and parts of the multimodal association area of the temporal cortex. His seizures were under control but the surgery left H.M. with a devastating memory deficit. The memory deficit (amnesia) was specific in the fact that he still had normal short-term memory (seconds to a minute) and he also had good long-term memory for events that had occurred before the operation. He retained a good command of language, and his IQ remained unchanged. What H.M. lacked after the surgery was the ability to transfer new short-term memory into long-term memory. He was unable to retain information for more than a minute. For example, H.M. could immediately repeat a number such as 8414317 multiple times, but when briefly distracted and then asked to repeat the number he could no longer remember. Another example is that for several years he saw his doctor on a regular basis, yet every time his doctor entered the room H.M would react as though he had never seen the physician before. In addition, H.M. had profound problems with spatial orientation. Spared memory capabilities of patients with bilateral lesions of the temporal lobe typically involve learned tasks. These include reflexive tasks and often involve habits and motor or perceptual skills, as well as do not require conscious awareness or complex cognitive processes. Typically, patients need to respond to a cue or stimulus. For example, a patient with bilateral temporal lobe damage can solve a complex mechanical puzzle as quickly as a Figure 1, Different types of learning and their probable person without damage day after day anatomical correlates. (Nolte’s the Human Brain, 7th ed. 2015, but if asked whether they had ever Elsevier) worked on the puzzle yesterday they would state “What are you talking about? I’ve never done [Block: Nervous System | VANDERAH] [3 of 16] LEARNING, MEMORY and SYNAPTIC PLASTICITY this task before.” These two types of memory - skills versus knowledge – have been demonstrated in patients with lesions in different areas of the cortex. Memory involving information about how to perform something (skill) is referred to as implicit memory (also called non-declarative memory = a memory that is recalled unconsciously). Damage to the areas that deal with motor cortex regions impairs implicit memory (Fig. 1). Factual knowledge of people, places and things, and what these facts mean, is referred to as explicit memory (or declarative memory), a memory that is recalled by deliberate conscious effort. Damage to the amygdala only, does not result in a loss of explicit memory. However, damage to the hippocampus or association areas in the temporal cortex with which the hippocampus connects (parahippocampal and entorhinal cortex) result in the impairment of explicit memory (Fig. 1). These studies suggest that knowledge stored as explicit memory is first acquired through processing in one or more of the three association cortices including the prefrontal, limbic, and parieto-occipital–temporal cortices. These areas synthesize visual, auditory and somatic information and convey the information to the parahippocampal cortex, then to the entorhinal cortex, the dentate gyrus, and to the hippocampus. HIPPOCAMPUS AND FORNIX The two hippocampi are located within the temporal lobes yet considered part of the limbic lobe, probably due to their role in connecting to parts of the cortex involved in emotional behavior. The hippocampus extends from the amygdala to the splenium of the corpus callosum (Fig. 2). A single hippocampus is composed of pyramidal cells (termed hippocampus proper) and granule cells that fold upon itself resulting in the appearance of two interlocking C’s (Fig 3). Another set of cells that play a role in projecting information from the hippocampus to other areas of the cortex is called the subiculum. Information arrives in the hippocampus by multiple pathways. The first Figure 2, A parasagittal section through the brain demonstrating the length of the hippocampus in the main route of entry into the hippocampus is temporal lobe. (Nolte, J., & Angevine J. The Human Brain in from projection neurons all over the cortices. Photos & Diagrams, 3rd ed.) Neurons from many cortical regions send information, via axons, to the entorhinal cortex of the temporal lobe (Fig 4). Cells of the entorhinal cortex send this information, via axons, into the dentate cells of the hippocampus. The dentate cells communicate with the different layers of pyramidal cells of the hippocampus (CA cells) in a fashion that results in plasticity (covered later in the notes). Information into the hippocampus also arrives by routes directly or indirectly from the amygdala, the olfactory cortices, as well as from the hypothalamus, septal nuclei (S) and basal ganglia through a bundle of fibers called the fornix (Fig 4). [Block: Nervous System | VANDERAH] [4 of 16] LEARNING, MEMORY and SYNAPTIC PLASTICITY The output of the hippocampus is via both the subiculum cell layer (a layer of cells that receive input from the pyramidal cells) and some of the pyramidal cells directly. While Figure 3, Coronal section of the hippocampus. Diagram demonstrating the some of the interlocking C's of the dentate and hippocampal cells (CA). pyramidal cells You can also see the subiculum cells that carry information form the hippocampus send their to other areas of the CNS. (Nolte’s the Human Brain, 7th ed. 2015, Elsevier) projections out the fornix, the subiculum cell layer sends their axons back to areas of the entorhinal cortex, the amygdala, as well as through the fornix (Fig 3 & 5). The entorhinal cortex sends information back out over many cortical areas while the fornix goes off to areas of the hypothalamus, basal ganglia (VS=ventral striatum) and the mammillary bodies (two mammillary bodies each receiving information from the ipsilateral hippocampus) (Fig 5). Cells within the mammillary bodies send their projections to the thalamus earning the name the mammillothalamic tract. From the thalamus, information gets passed to many areas of the cortex. Therefore, movement in and out of the hippocampus includes fibers that project through the subiculum/entorhinal cortex and the fornix. The Blood Supply of the hippocampus is from the posterior cerebral artery (PCA). Figure 4, Diagram of a hemisected brain demonstrating pathways into the hippocampus. The major pathway in is from the cortex to through the entorhinal cortex. Inputs may also come in via the olfactory system and the fornix (Nolte’s the Human Brain, 7th ed. 2015 El i ) Figure 5, Diagram of a hemisected brain demonstrating pathways out of the hippocampus. The major output of the hippocampus is via the fornix to the mamillary bodies and then to the thalamus and back to the cortex. Alternative outputs include the entorhinal cortex, the amygdala and hypothalamus. (Nolte’s the Human Brain, 7th ed. 2015, Elsevier) [Block: Nervous System | VANDERAH] [5 of 16] LEARNING, MEMORY and SYNAPTIC PLASTICITY Flowchart of inputs and outputs of the hippocampal formation Dentate Gyrus Association Parahippocampal Entorhinal Cortices Cortex Cortex Hippocampus Mammillary body, Anterior Thalamus, Fornix Subiculum Septal nuclei, preoptic nuclei, ventral striatum, orbital and anterior cingulate cortex The fornix is a bundle of axons that transports information out of, and into, the hippocampus. The fornix, like many structures, takes on a “C-shaped” pattern that can be found close to the midline (Fig. 6) and can be divided into four segments. The axons that first come off the cell bodies of the subiculum and pyramidal cells are called the fimbria. The fimbria once it begins to leave the hippocampal proper forms the crus. Each of the crus come close together to form two large white matter tracts termed the body of the fornix. The fornix can be found in the midline just below the septum pellucidum. At the point just caudal to the interventricular foramen the fornix turns inferior (down) sending the axons through the hypothalamus called the columns ending in the mammillary bodies. In addition to the hippocampal output pathway via the entorhinal cortex, a major hippocampal output pathway includes the fornix. Some fibers from the fornix will split off and terminate in areas such as the septal nuclei, and preoptic nuclei, ventral striatum, with some fibers continuing out to the orbital and anterior cingulate cortex. The majority of fibers of the fornix will either turn posteriorly ending in the anterior thalamic nucleus or will travel through the hypothalamus Figure 6, Whole and hemisected brain in the columns of the fornix and end in the demonstrating where the fornix, and its parts, are mammillary bodies (Fig 7). located in the CNS Lesions of the right hippocampus are consistent with the findings that give rise to problems with spatial orientation, whereas lesions of the left hippocampus give rise to defects in verbal memory (Fig. 8). [Block: Nervous System | VANDERAH] [6 of 16] LEARNING, MEMORY and SYNAPTIC PLASTICITY In the case of H.M. and his ability to retain a reasonably good memory of earlier events with some retrograde amnesia (loss of some events just prior to his surgery) suggest that the hippocampus is only a temporary way station for long-term memory. Studies have demonstrated that association cortices are the ultimate repositories for explicit memory. Damage to association cortex results in patients unable to recall facts, recognize faces, objects and places in their familiar world. Explicit knowledge is not necessarily stored in one region of the neocortex. Often explicit knowledge about things, places, people, etc. requires distinct bits of information, each of which may be stored in specialized (dedicated) memory stores of the association cortices. As a Figure 7, Diagram of the hippocampus and the result, damage to a specific cortical area can different parts of the fornix. The anterior commissure is not apart for the fornix but is a white tract (axons) lead to loss of specific information and therefore pathway that allows for communication between the a fragmentation of knowledge but typically not temporal lobes of the cortex. (Nolte’s the Human Brain, complete loss of an entire topic (i.e., one with 7th ed. 2015, Elsevier) damage to the occipital cortex may not remember exactly what a dog looks like but knows that a dog barks and has hair). Damage to the hippocampus (like H.M.) produces amnesia with the inability to input new information. Amnesia, as the term is used clinically, has a very specific meaning, and refers to a relatively pure deficit in long-term memory with certain properties. The memory loss almost always includes both retrograde (prior to the injury) and anterograde (after the injury) amnesia, although the period covered by the retrograde amnesia can be relatively short. An amnesic patient is not demented. A demented patient has a general decline in intellectual functions, including memory that can be thought of as global amnesia (i.e., often seen in dementia patients). Anterograde amnesia is usually caused Figure 8, The right hippocampus is activated during by bilateral damage to the medial temporal learning about the environment. Areas with significant lobes, including structures such as the changes in activity, indexed by local perfusion change, parahippocampus and hippocampus. Since are indicated in yellow and orange. The scan on the left the area of the fornix and mammillothalmic is a coronal section and on the right is a transaxial tract from both hippocampus are close section. (Principles of Neural Science, Kandel E.R. et al, 4 th ed.) together, there are conditions in which bilateral damage can occur and result in amnesia. Under conditions in which a person does not take in enough thiamine (Vitamin B1) [Block: Nervous System | VANDERAH] [7 of 16] LEARNING, MEMORY and SYNAPTIC PLASTICITY conditions of amnesia can occur. Thiamine is a major cofactor in the metabolism of glucose. It is thought that after time and the interference with glucose metabolism that a number of events occur including a type of amnesia called Wernicke-Korsakoff syndrome. Wernicke encephalopathy includes signs of confusion, nystagmus, ophthalmoplegia (impaired eye movement), aniscoria (unequal pupil size), ataxia, coma and can even result in death if untreated. Korsakoff psychosis is characterized as having anterograde and some retrograde amnesia, along with confabulation and hallucinations. In Wernicke-Korsakoff syndrome often there is a reduction in the size/function of the mammillary bodies. The syndrome is often seen in chronic alcoholics who do not take in an appropriate amount of vitamin B1 as well as in patients that have undergone gastric bypass, bands or staples. In conclusion, memory has stages and long-term memory is represented in multiple regions throughout the nervous system. Explicit and implicit memories involve different neuronal circuits. Finally, explicit memory is the result of a least four related but distinct types of processing: encoding, consolidation, storage and retrieval. The Processes of Explicit Memory Encoding refers to the processes by which newly learned information is attended to and processed when first encountered. For a memory to persist and be well remembered, the incoming information must be encoded thoroughly and deeply. This is accomplished attending to the information and associating it meaningfully and systematically with knowledge that is already well established in memory so as to allow one to integrate the new information with what one already knows. Memory storage is stronger when one is well motivated. Consolidation refers to those processes that alter the newly stored and still labile information so as to make it more stable for long-term storage. This stage involves the expression of genes and the synthesis of new proteins giving rise to structural changes that store memory stably over time. Storage refers to the mechanism and sites by which memory is retained over time. Retrieval refers to those processes that permit the recall and use of the stored information. This involves bringing different kinds of information together that are stored separately. Retrieval of explicit memories is dependent on short-term working memory that includes mainly the prefrontal cortex with some input from parietal and occipital cortices (Fig 9). Figure 9 Encoding and retrieving episodic memories. Areas where brain activity is significantly increased during the performance of specific memory tasks are shown in orange and red of surface projections of the human brain. A. Activity of the left prefrontal cortex is particularly associated with the encoding process. Subjects are scanned while attempting to memorize words paired with category labels: country – Denmark, metal – platinum, etc. B. Activity in the right frontal cortex is associated with retrieval. Four subjects were presented with a list of category labels and examples that were not paired with the category. The subjects were then scanned when attempting to recall the examples. In addition to right frontal activation a second posterior region in the medial parietal lobe is also activated. (Principles of Neural Science, Kandel E.R. et al., 4th ed.). [Block: Nervous System | VANDERAH] [8 of 16] LEARNING, MEMORY and SYNAPTIC PLASTICITY Acetylcholine Synapses and Memory Ultimately, the outcome of changes in protein synthesis due to LTP must either produce a change in the resting activity of neurons, a change in the responsiveness at certain synapses or a change in neuronal connections. Recent evidence indicates that some of the changes occur at acetylcholine synapses. Acetylcholine bathes the entire brain and comes from neurons in the basal nucleus and the reticular formation (Fig. 10). In normal aging, some memory impairment is common; the degree of memory loss correlates with a decline in brain acetylcholine levels. People suffering from Alzheimer’s disease suffer more severe memory dysfunctions and a striking decline in brain acetylcholine content. Figure 10, Neurons of the basal nucleus and of the reticular formation secrete acetylcholine that spreads all over the brain. (Nolte’s the Human Brain, 7th ed. 2015, Elsevier) In several experiments, young adult volunteers received injections of scopolamine, a medication that blocks acetylcholine synapses. While under the influence of the medication, they showed clear deficiencies on a variety of memory tasks. Their general pattern of performance resembled that of senile people—that is, they were impaired on the same memory tasks on which senile people have the greatest troubles. Given these results, the question arises, could we improve human memory by using physostigmine or other medications that prolong the effects of acetylcholine at the synapses. Several studies have found that physostigmine does improve memory, especially in older people and others with poor memories. Unfortunately, the required doses produce prominent, unwelcome side effects such as restlessness, sweating, diarrhea, and excessive salivation. Hence, such medication treatments are not clinically useful. Researchers have also tried to increase acetylcholine production in the brain by providing dietary precursors, such as choline and lecithin. In numerous studies, these substances have been given to senile or brain-damaged people with serious memory failures. Unfortunately, they apparently produce no significant benefits. Perhaps senility and other memory failures are associated with such a massive depletion of acetylcholine synapses that a slight rise in the availability of the neurotransmitter is ineffective. [Block: Nervous System | VANDERAH] [9 of 16] LEARNING, MEMORY and SYNAPTIC PLASTICITY It is thought that acetylcholine plays an important Waking Slow Wave Sleep REM Sleep role in learning and memory during the Acquisition Hippocampal signaling Ongoing consolidation in wake/sleep cycles (Fig. 11). During our awake Early and ongoing May transfer contextual Information to cortex Cortex can incoporate Information relayed from consolidation cycle we attain information though sensory input. Hippocampus during SWS There is continual information flowing (electrical Sensory Input X X activity) through the hippocampus. During this High ACh Low ACh High ACh wake cycle acetylcholine levels are high. During Cortex Cortex Cortex the slow wave sleep (SWS) cycle acetylcholine levels are low and there is a heavy amount of Hippocampus Hippocampus Hippocampus information (electrical activity) that is flowing out SWS and REM sleep are important in the consolidation of memories. of the areas of the hippocampus back towards the (A.E. Powers, PNAS, 101 (2004). cortex. Finally, as one enters into REM sleep Figure 11. Sleep cycles play an important role in there is the consolidation of information that was memory consolidation and are correlated with levels of acetylcholine (ACh). relayed to the cortex during SWS by information flowing back through the hippocampus and eventually back into the cortex. Again, this correlates with high levels of acetylcholine during REM sleep and is thought to play a role in learning and memory yet exactly how acetylcholine is performing this function is unknown. In the end it is thought that both SWS and REM sleep are very important in the consolidation of memories in which these activities correlate with levels of acetylcholine (Fig. 11). So make sure and get good sleep while studying. OTHER SYNAPSES AND MEMORY Earlier we considered the role of glutamate synapses in LTP. Besides glutamate and acetylcholine, several other neurotransmitters may be necessary for the expression of learned behaviors. In old age the brain commonly suffers a decline in its supply of norepinephrine, serotonin, and dopamine, as well as acetylcholine. Studies in young monkeys with depletion of norepinephrine and dopamine input to their prefrontal cortex demonstrated signs of memory loss. Hence, norepinephrine and dopamine synapses in the prefrontal cortex are contributors to memory (specially working memory). Medications that enhance the activity of norepinephrine- releasing neurons improve memory performance in aged mice. Memory in the Young and Old Brain Ideally, investigation of the physiology of learning and memory should lead to insights about why people remember some things better than others or why some people have better memories than other people do. For example, why do infants and old people sometimes have memory difficulties? Both infants and old people perform well on some memory tasks and poorly on others. For example, psychologists have long puzzled over infant amnesia, the phenomenon that most of us remember very few events from the first four or five years of our lives. Nevertheless, children less than four years old learn to walk, to put on clothing, to eat with fork and spoon (or chopsticks), and to perform other skills that will last a lifetime. That is, in our first four or five years we establish many procedural memories (implicit), even if we do not form factual memories (explicit) that will last long. In that regard, infant memory resembles that of people with hippocampal damage. Perhaps infants have memory problems because the hippocampus is slow to mature, and old people have troubles because the hippocampus and related structures are deteriorating. [Block: Nervous System | VANDERAH] [10 of 16] LEARNING, MEMORY and SYNAPTIC PLASTICITY Many old people and aged animals have memory problems, although one individual may differ sharply from another. Many old people who have great troubles with recent factual memories manage to learn new skills (such as walking with a cane) or adjust old skills. That is, they also share certain similarities with individuals who have a damaged hippocampus. In the case of dementia where there is a more rapid loss of memory unfortunately there is a permanent loss of neuronal mass and reflects a more Global Amnesia. Again, animal studies support this parallel. On a variety of memory tasks, old rats show deficits similar to those of rats with damage to the hippocampus or prefrontal cortex. The hippocampus of old rats includes many dead or dying neurons and axons; many of the surviving neurons are less active than they are in younger rats. Hippocampal deterioration is probably responsible for the mild memory deficits typical of normal (non-Alzheimer’s) aging. Memory may also vary from individual to individual and from age to age because of the rise and fall of levels of neurotransmitters that play a role in memory such as glutamate, acetylcholine, norepinephrine and dopamine. OVERVIEW of SYNAPTIC PLASTICITY CNS function requires bi-directional communication between pre- and postsynaptic neuronal partners. Sensory inputs are essential for the proper development of neural circuitry during early postnatal life, and for the formation of long-lasting memories and other adaptations throughout the lifespan. At any age, memories and neural adaptations are mediated by experience- dependent changes in synaptic transmission, and sometimes by structural changes in synaptic connectivity. Such synaptic plasticity is disrupted in diverse psychiatric and neurological disorders, due to toxicological, developmental, or degenerative etiologies. Synaptic activity is the ‘currency’ of experience. Synaptic activity, driven by sensory stimulation in the periphery, causes membrane depolarization and calcium influx into select target neurons, which in turn trigger molecular changes that alter synaptic connectivity within the neural circuit. “Synaptic plasticity” refers to changes in the efficacy of neurotransmission, specifically, to variation in the strength of a signal transmitted across a synapse in response to a standard stimulus. The modification of transmission at the synapse may be mediated by changes in neurotransmitter levels or release, neurotransmitter receptor phosphorylation, changes in receptor numbers, and altered ion channel conductance, among others. Some changes at the synapse are local and rapid changes in synaptic strength, whereas others operate across longer distances, e.g., to the nucleus, and over longer time periods. The latter are more likely to involve structural as well as functional changes in the synapse. The activation of calcium-sensitive signaling cascades, which lead to posttranslational modifications of proteins, or the regulation of mRNA translation, resulting in the synthesis of new proteins, occur locally at the sites of calcium entry. These mechanisms play critical roles in altering synaptic function in a synapse-specific manner. In addition to these local effects, calcium influx into the postsynaptic neuron can lead to the remodeling of synapses through the alteration of gene-transcription patterns. Calcium influx activates several signaling pathways that converge on transcription factors within the nucleus, which in turn control the expression of a large number of neuronal activity-regulated genes. The proteins encoded by these genes are important for many aspects of neuronal development, including dendritic branching, synapse maturation, and synapse elimination. Genetic mutations in several key regulators of activity-dependent transcription cause neurological disorders. Thus, studies of this activity-regulated gene- expression program will help explain the relationship between abnormal synapse development or plasticity and the occurrence of particular neurological disorders. [Block: Nervous System | VANDERAH] [11 of 16] LEARNING, MEMORY and SYNAPTIC PLASTICITY Below are a few samples of synaptic plasticity beginning with our understanding of learning and memory. MODIFICATION OF SYNAPTIC STRENGTH: LONG-TERM POTENTIATION Figure 12. A model synapse for explaining the early phase of long-term potentiation. NMDA and non- NMDA receptor-channels are located near each other in dendritic spines. The non-NMDA receptors here are the AMPA type. During normal, low-frequency synaptic transmission, glutamate (Glu) is released from the presynaptic terminal and acts on both the NMDA and non-NMDA receptors. Na+ and K+ flow through the non-NMDA channels but not through the NMDA channels, owing to Mg2+ blockage of this channel at the resting membrane potential. (Principles of Neural Science, Kandel E.R. et al., 4th ed.). Within the mammalian nervous system, the best candidate for the cellular and molecular basis of learning and memory is a phenomenon known as long-term potentiation (LTP). In experimentally induced LTP, a neuron is bombarded with a brief but rapid series of stimuli— typically, 100 synaptic excitations per second for 1 to 4 seconds. This burst of intense stimulation leaves the neuron “potentiated” (highly responsive to new input of the same type) for minutes, days, or weeks. LTP can result from repeated stimulation of a single synapse (like sensitization) or from nearly simultaneous stimulation of two or more synapses (more like conditioning). LTP was first discovered in studies of hippocampal neurons, where it is especially large and easy to demonstrate, but it can also occur in other parts of the nervous system. At many hippocampal synapses, LTP depends on the activation of NMDA-type glutamate receptors (Fig 12). NMDA receptors are ligand-gated ion channels that are activated by glutamate, but also require depolarization of the plasma membrane. The opening of NMDA channels results in the influx of Ca+2 and Na+; hence an excitatory event. Magnesium ions block NMDA receptors under most circumstances by sitting in the channel. Although glutamate may bind the NMDA channel, no ions can flow through the channel due to the magnesium block. However, often in the vicinity of NMDA receptors are other glutamate receptors termed AMPA and Kainate channels. (All of these receptor channels are named after the laboratory chemicals that bind to them.) These channels do not have magnesium blocking the ion-channel pore. Therefore, when glutamate binds to AMPA receptor-channels, they open and allow Na+ and some Ca+2 ions to flow into the neuron. The influx of positive charge causes local depolarization of the membrane, and that results in the magnesium ion being released from the NMDA channel pore. Now, glutamate binding can stimulate the movement of Na+ and Ca+2 ions through the NMDA channels. [Block: Nervous System | VANDERAH] [12 of 16] LEARNING, MEMORY and SYNAPTIC PLASTICITY Figure 13, A model for the induction of the early phase of long-term potentiation. According to this model NMDA and non-NMDA receptor-channels are located near each other in dendritic spines. When the postsynaptic membrane is depolarized by the actions of the non-NMDA receptor-channels, as occurs during a high-frequency tetanus that induces LTP, the depolarization relieves the Mg2+ blockage of the NMDA channel. This allows Ca2+ to flow through the NMDA channel. The resulting rise in Ca2+ in the dendritic spine triggers calcium-dependent kinases (Ca2+/calmodulin kinase and protein kinase C) and the tyrosine kinase Fyn that together induce LTP. The Ca2+/calmodulin kinase phosphorylates non-NMDA receptor-channels and increases their sensitivity to glutamate thereby also activating some otherwise silent receptor channels. These changes give rise to a post-synaptic contribution for the maintenance of LTP. In addition, once LTP is induced, the postsynaptic cell is thought to release (in ways that are still not understood) a set of retrograde messengers, one of which is thought to be nitric oxide, that act on protein kinases in the presynaptic terminal to initiate an enhancement of transmitter release that contributes to LTP. (Principles of Neural Science, Kandel E.R. et al., 4th ed.). The entry of calcium sets in motion a series of events that produce LTP, facilitating responses to those synapses that were active during the induction of LTP (Fig 13). The influx of calcium ions is critical; it results in the activation of several calcium-dependent intracellular proteins and the increase in synthesis of proteins in the postsynaptic neuron. One example is the increase in newly synthesized AMPA receptors inserted into the postsynaptic membrane. Drugs that block calcium or protein synthesis in the postsynaptic cell prevent the establishment of LTP. These findings indicate that the postsynaptic neuron initiates changes that are responsible for LTP. [Block: Nervous System | VANDERAH] [13 of 16] LEARNING, MEMORY and SYNAPTIC PLASTICITY In addition to changes that occur in the postsynaptic neuron (e.g., in the dendritic spine) due to the influx of calcium and new protein synthesis, there are retrograde signals that the postsynaptic neuron sends to the presynaptic neuron in order to induce changes in its synaptic partner. Recent studies have demonstrated that small molecules such as nitric oxide (NO; see Fig 13) and lipids such as anandamide are produced in the postsynaptic neuron upon LTP induction. Release of these molecules sends signals back to the presynaptic neuron resulting in cellular changes that further strengthen the synaptic connection. We still do not know how LTP relates to learned behavior. Facilitation of a single synapse hardly explains a complex learned behavior. Yet, the LTP hypothesis is compelling because drugs that block NMDA receptors also block LTP in the rat hippocampus, as well as blocking the kind of learning (e.g., spatial) that depends on the hippocampus. Furthermore, studies of LTP suggest that protein synthesis is critical in the formation of long-term memories. Drugs that inhibit protein synthesis impair the long-term storage of memory. One hypothesis is that protein synthesis modifies the synaptic structure to facilitate information storage. Because Figure 14, Long Term Potentiation (LTP) can lead to some of our memories last a lifetime, synaptic plasticity. From (a) to (e) is speculation on how “memory building” must involve structural LTP can result in not only synaptic strengthening but can changes in the nervous system, including result in the formation of new synapse. formation of new synapses along with strengthening of existing synapses (Fig. 14). Synaptic plasticity can also occur in an opposite manner, with lasting changes due to a loss of neurotransmission as in long-term depression (LTD). MODIFICATION OF SYNAPTIC STRENGTH: LONG-TERM DEPRESSION In contrast to LTP, LTD results when there is a loss of synaptic excitability and a resulting significant decrease in synthesis of particular proteins, resulting in synaptic weakening. Cellular plasticity occurs by evidence of a decrease in receptors such as the AMPA receptor in areas of the hippocampus. If LTD persists there can be complete systems plasticity as seen in the climbing fibers of the cerebellum (Fig. 15). Figure 15. The parallel and purkinje cells of the cerebellum go through extensive reorganization with LTD being a prominent feature in synaptic plasticity. (The Human Brain, J. Nolte, 8th ed. 2019) [Block: Nervous System | VANDERAH] [14 of 16] LEARNING, MEMORY and SYNAPTIC PLASTICITY Sensory Activated Gene Transcription and Cellular Plasticity The importance of stimulus-induced transcription in neurons, and the resulting synaptic plasticity, was suggested by the observation that c-Fos transcription and c-Fos protein could be induced in neurons by synaptic activity resulting from sensory experience. In the intact brain, upregulation of c-Fos occurred in response to seizures, pain and other physiological stimuli, but only in neurons of the relevant regions (i.e., in occipital cortex following visual stimuli). Regulated c-Fos protein expression is significant because Fos and Jun proteins together comprise the AP-1 transcription factor complex, which is critical for the adaptive responses to experience (Fig. 16). For example, mice with brain-specific deletion of the c-Fos gene display deficits in learning and memory, nurturing behaviors, as well as altered sensitivity to drugs of abuse, such as cocaine. Other genes that are involved in synaptic plasticity have been discovered and characterized including the growth factors and their receptors. For example, brain-derived neurotrophic factor (BDNF) and the tyrosine kinase receptor B (trkB). Upon stimulation, BDNF is released and binds to its receptor, trkB. Typically Figure 16, Diagrammatic representation of stimuli activating the Fos- the BDNF/trkB complex Jun pathway, resulting in neuronal plasticity by promoting specific travels in a retrograde changes in gene transcription and translation. direction towards the nucleus and alters DNA transcription and translation. The activation of BDNF/trkB can result in dendritic outgrowth and synapse maturation by modulating gene transcription. The loss of BDNF or a single-amino acid polymorphism in humans (Val66Met) is associated with neurological and psychiatric disorders. Putting it all together: Experience-dependent modification of brain circuits result from the activation of multiple intracellular pathways that play critical roles not only in synaptic (and therefore, presumably, behavioral) plasticity, but also in long-term atrophic processes (Fig. 17). Targeting these cascades for the treatment of neuropsychiatric disorders may stabilize the underlying disease process [Block: Nervous System | VANDERAH] [15 of 16] LEARNING, MEMORY and SYNAPTIC PLASTICITY Figure 17, Biological mechanisms underlying neuroplasticity. The remarkable plasticity of neuronal circuits is achieved through different biological means including alterations in gene transcription and intracellular signaling cascades. These changes modify diverse neuronal properties such as neurotransmitter release, synaptic function and even morphological characteristics of neurons. (Schloesser RJ et al., Neuropsychopharmacology Reviews 33, 2008). [Block: Nervous System | VANDERAH] [16 of 16]