{"id":49761,"date":"2023-06-30T11:46:13","date_gmt":"2023-06-30T11:46:13","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=49761"},"modified":"2023-07-11T05:45:26","modified_gmt":"2023-07-11T05:45:26","slug":"molecular-learning-and-memory-of-brain-aging","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol16no2\/molecular-learning-and-memory-of-brain-aging\/","title":{"rendered":"Molecular Learning and Memory of Brain Aging"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

As humans age, their cognitive function declines, leading to difficulties in learning and\nmemory retention. With the growing elderly population, understanding the\nmolecular mechanisms underlying cognitive aging has become increasingly\nimportant. This chapter explores the role of various molecular factors in memory formation and\nhow changes in these factors with age can affect learning and memory retention.\nMoreover, it offers a comprehensive overview of the latest research in this field and\nhighlights the potential for therapeutic interventions to improve cognitive\nfunction in aging individuals. We will discuss different aspects of molecular memory and learning in aging and explore the latest\nresearch in this area.<\/p>\n\n\n\n

Learning and Memory<\/strong><\/p>\n\n\n\n

An individual’s daily life was impacted\nby central nerves  system (CNS) dysfunction that leads to learning and memory deficits. The term \u201clearning\u201d is defined as the acquisition of an altered\nbehavioral response due to an environmental stimulus, and \u201cmemory\u201d is defined\nas the process by which the learned item is stored and retrieved 1\u20133<\/sup>. Two types of memory are defined depending on how long it persists:\nshort term (minutes to hours) and long term (days to years). It is generally\naccepted that memory results from changes in the particular synaptic structure\nand\/or function. Long-term memory has the general attribute that it undergoes a\nperiod of consolidation that involves the formation or elimination of specific\nsynapses in the brain and the synthesis of new mRNAs and proteins. Since short-term memory is too rapid to be attributed to such alterations, it was\nsuggested that changes in the release and function of neurotransmitters at\nparticular synapses are the basis of short-term memory 4\u20137<\/sup>. <\/p>\n\n\n\n

Molecular Learning and Memory <\/strong><\/p>\n\n\n\n

The current molecular basis of learning and\nmemory was based on the Hebbian theory. Hebb\nhypotheized that the simultaneous activation of pre- and postsynaptic neurons lead to modifications of\nsynaptic efficacy between the two neurons, thereby creating associative linkages between them. Memories are then stored as alterations of these synaptic\nalterations 8\u201310<\/sup>. The current hypothesis regarding the neurochemical basis of learning and\nmemory is based on three basic assumptions 2,3,11,12<\/sup>. The first assumption is that the basic\nbehavioral paradigms in learning and memory studies are conditioned responses. For example, in Pavlov\u2019s characterization\nof condition experiment, when a food stimulus is presented to a dog, a strong\nsalivatory response is elicited. This salivation is referred as an unconditioned response and the food stimulus is referred\nto as an unconditioned stimulus 2,13\u201315<\/sup>. The dog could then be trained to associate\nthe food stimulus with the ringing of a bell where, over time, the bell ring\nalone would cause a salivatory response similar to the food does. This\nbell-elicited salivation was termed conditioned response, and the bell ring was\ntermed the conditioned stimulus (CS) 2,13\u201315<\/sup>. In order for learning to occur, the\nconditioned stimulus must precede the unconditioned stimulus. The second assumption is that\nprotein synthesis occurs only in long-term memory, and not in short-term memory.\nThe formation of long-term and short-term memory can be distinguished by their\nsusceptibility to protein synthesis inhibitors 12,16\u201320<\/sup>. Since learning and short-term memory occur\nwithin milliseconds and last for minutes to hours, they are proposed to be\nmediated by post-translational modifications at the synapse. However, since\nlong-term memory require longer acquisition time and last life time. It is\npredicted to be mediated by processes that (1) require protein synthesis, (2) is neuronal genome dependent;\nand (3) require\nintraneuronal communication, such as axonal transport 12,16\u201320<\/sup>. The last assumption is that memory is\nstored in synaptic connections. The development and environment stimulation\nincrease the synaptic complexity, and such synaptic alterations are dependent on the genome regulation phenotypic\nexpression generated in the nucleus to response to the environment 12,16\u201320<\/sup>. <\/p>\n\n\n\n

Long-Term Potentiation (LTP) <\/strong><\/p>\n\n\n\n

LTP is the most frequently studied as the\ncellular basis of learning and memory in vertebrates. LTP is defined as a\nlong-lasting (hours to weeks) increase of excitatory postsynaptic potentials\namplitude in synaptic efficacy as a result of high-frequency stimulation of afferent pathways 19\u201321<\/sup>. It is measured both as the amplitude of\nexcitatory postsynaptic potentials and as the magnitude of the postsynaptic\ncell population spike 19<\/sup> . LTP was first discovered by application\nof high frequency electrical stimulation to enhance synaptic transmission in\nthe rabbit 22,23<\/sup>. The brief period of stimulation can increase the\nstrength of synaptic connections of neurons and the likelihood of the cells firing action potentials in\nresponse to a constant synaptic input for hours 22,23<\/sup>. These phenomena were termed LTP 22,23<\/sup> . LTP is considered as an analog of memory since LTP is a\nlong-lasting alteration in neuronal function which is resulted from a brief\nperiod of stimulus 2,13,24,25<\/sup>. Several other properties of LTP make it a\ngood analog of mechanisms from learning and memory. There properties are state-dependent, input\nspecificity, and associativity 26\u201328<\/sup>. LTP is state-dependent since LTP only\noccurs when the postsynaptic cell reaches a\ncertain degree of\ndepolarization with a specific period of time 2,13,24,25<\/sup>. For example, the increased firing action\npotential is only possible if the postsynaptic depolarization occurs within\nabout 100 ms of presynaptic transmitter release. Since a requirement for\ncoincident activation of presynaptic and postsynaptic elements is necessary for the formation of memory according to Hebbian theory 8\u201310<\/sup>, LTP forms a theoretical framework of the\nsynaptic changes underlying learning and memory. LTP is also exhibits input specific. When LTP is\ninduced by the stimulation of one particular synapse, other synapses of the\nsame neurons remain inactive. Therefore, LTP is restricted to activated\nsynapses rather than to all of the synapses on a given neuron This properties of LTP is\nconsistent with the memory formation in which only the activated synapses are\npotentiated, leading to selectively enhancement particular sets of inputs, as is required\nfor learning and memory 26\u201328<\/sup>. Another important property of LTP is\nassociativity, which is analog of the linkage of one set of information with\nanother in neuronal network. Since weak stimulation of a synapse cannot trigger\nLTP by itself, a simultaneous input from a weak stimulation and a strong\nstimulation of a neighboring synapse of the same neuron can trigger both\nsynaptic pathways to undergo LTP 26\u201328<\/sup> . This conjoint enhancement of synaptic\ninputs is often considered as a neuronal analog of associative conditioning\nobserved in Pavlov\u2019s conditioning experiment 2,13<\/sup>. It should be noted that LTP does not equal to memory. Rather, it is\nan important component of memory formation. Moreover, LTP is a mechanism of\nactivity-dependent synaptic plasticity that is capable of detecting multiple conincidence events. Such\nproperties suggest that LTP contributes to memory consolidation, formation of complicated association,\nsequentially serving as a short-term memory buffer for assicative conditioning 2,13<\/sup> <\/p>\n\n\n\n

Synaptic Remodeling<\/strong><\/p>\n\n\n\n

As mentioned in the previous section,\nenvironmental stimulation leads to the shaping and tuning of neuronal connectivity during\ndevelopment, and this process, termed synaptic remodeling, continues throughout\nthe life-span of the organisms. Since neuronal connectivity is a dynamic\nprocess, the remodeling of synaptic connectivity occurs in response to\ngeneral environmental manipulations, sensory stimulation or learning a specific\nnew task and may even be associated with cyclic changes in the physiological\nstatus of the organism 12,16\u201318<\/sup>. The mechanisms that are known to be\ninvolved in the initiation and maintenance of synaptic plasticity are base on Hebbian theory 24,29\u201331<\/sup>. It is generally believed that the calcium\ninflux into postsynaptic neurons through excitatory amino-acid receptors,\nspecifically NMDA (N-methyl-D-aspartate) receptors, and possibly L-type\nvoltage-gated calcium channels (VGCCs), is the initial event of synaptic\nplasticity 13,23,25,31,32<\/sup>. Receptor mediated calcium influx is usually\nblocked by magnesium at resting membrane potentials. However, when glutamate is\nreleased presynaptically, it binds and activates NMDA receptors, thereby\nrelieving the magnesium and allowing calcium enters the neuron at the synapse.\nSince activation of NMDA receptors by glutamate will only occur when the\npostsynaptic cell membrane is depolarized, the NMDA receptor act as a\ncoincidence detector that only allows calcium influx when presynaptic activity and\npostsynaptic activity coincide 24,31,33,34<\/sup>. Calcium also influx into postsynaptic\nmembrane during depolarization through VGCCs 13,23,25,31,32<\/sup>. VGCCs are opened by back-propagating action\npotential, an action potential that initiate at the cell body and  back -propagating into the dendrites\nplasticity. The opening of VGCCs amplifies the excitatory postsynaptic potentials at\nthe synapse that were recently activated by glutamate receptors 24,31,33,34<\/sup>, thereby shaping the integration of synaptic\nactivity and influencing the induction of synaptic. The net result of calcium\ninflux is the activation of signaling pathways. For example, calcium influx\ncauses phosphorylation of calcium\/calmodulin-dependent protein kinases (CaMKs)\nand protein kinase C 7,32,35\u201337<\/sup>, which results in an increase in synaptic\nefficacy, and subsequently\nactivation of gene transcription and protein synthesis that can also lead to\nstructural changes in synapses 38\u201340<\/sup>. Moreover, elevation of calcium leads to rearrangement of the\ncytoskeleton at the synapse by actin polymerization and cytoskeletal\nrearrangements. These processes result in new synaptic structures 7,41\u201343<\/sup>. Since these structural alterations occur\ntoo quickly to be accounted for by nuclear or even dendritic protein synthesis,\nthey are not considered to be the result of protein synthesis. Therefore, such changes might participate\nin both short-term and long-term memory 24,29\u201331<\/sup>. The rapid changes in the concentrations of\ncalcium and other signaling molecules take place in dendritic spines. Spines\nare specialized compartments on dendrites that contain receptors, channels and\nsignaling molecules that couple synaptic activity with postsynaptic\nbiochemistry 7,44\u201346<\/sup>. Since the induction of synaptic plasticity\n(LTP induction or memory formation) leads to changes in the number or shape of\nspines 47\u201349<\/sup>, modulation of the number of dendritic\nspines and their morphology were\nproposed to associated with the excitatory synaptic transmission alterations during learning 50\u201353<\/sup>. Alteration of spine number and morphology\ndepends on the\nspecialized structure of\ncytoskeletal actin filament 41\u201343,54<\/sup>. Actin is present ubiquitously in the spine to interact with the receptors, channels and\nsignaling molecules, and the reorganization and\/or polymerization of actin\nalter spine stability and contribute to structural plasticity of spines after\nLTP induction and learning 24,29\u201331<\/sup>. The orientation, kinetics of assembly and\nstability of actin filaments are regulated by extracellular stimulation, such\nas NMDA receptor activation 41\u201343,54<\/sup> 41\u201343,54<\/sup>, indicating that NMDA-dependent actin\npolymerization is important for the consolidation of memory. Another glutamate\nreceptor, AMPA (\u03b1amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor,\nis found to stabilize spine morphology 34<\/sup>. Therefore, NMDA receptors is important in the initial phase\nof spine motility, followed\nby a stabilization phase that is mediated by AMPA receptors. Since AMPA\nreceptor is activated spontaneously with NMDA receptor during glutamate release\nin synapses, the alteration and stabilization of dendritic spine also occurs\nsimultaneously 24,29\u201331<\/sup>.\nMoreover, AMPA receptor levels increase after LTP induction or learning\nexperiences, indicating that an\nincrease in AMPA receptors in spines could contribute to spine stability and\nthereby memory formation 25,31,52<\/sup>. Cytoskeleton-mediated alteration of spine\nand dendritic morphology is regulated by Rho GTPases and their downstream\neffectors (Luo et al, 2002). Another role of Rho GTPases played in synaptic plasticity is to\nmediate the activity of adhesion molecules and to regulate cellular\ninteractions 24,29\u201331<\/sup>. Adhesion molecules, such as integrins,\ncadherins, neurexin and the immunoglobulin superfamily, are membrane-bound\nmolecules that interacts with proteins in the extracellular matrix and synaptic\nmembranes to adhere the membranes between the pre- and postsynaptic components 24,29\u201331<\/sup>. This adhesion is a dynamic process that\ninvolves morphological alterations and modulation of connection between the pre\nand postsynaptic neurons, and result in new contacts 31<\/sup>. Adhesion molecules can also mediate\nsignaling pathways to regulate the extracellular connectivity with\nintracellular events that control spine morphology 24,29\u201331<\/sup>. Therefore, adhesion molecules play a\ncritical role in neuronal connectivity and spin morphology, as well as stabilization of synaptic connectivity that leads to\nconsolidation of memory 24,29\u201331<\/sup>. The formation of memory involves learning\nand consolidation. During learning, stimulation on specific synapses initiate\nmolecular changes, and cellular alterations are progressively stabilized during\nconsolidation. The initiate molecular alterations caused by learning are\ncomplex and require coordination within and between signaling pathways that involved Rho\nATPases 55\u201357<\/sup>, and the modulation and stabilization of\nneurons after LTP induction or learning is controlled in part by actin\ndynamics, a process that is initiated by NMDA receptor activation and\nstabilized by AMPA receptor activation. The process of actin dynamic in neuron\ncauses morphological changes in dendritic spins and leads to the formation and stabilization of new synaptic\ncontact of the pre and postsynaptic elements 24,29\u201331<\/sup>. The formation of new neuronal connections\nis regulated by adhesion molecules that are also affected by both the\ncytoskeleton and glutamate receptors. The remodeling of the synapses results in\nmodified neuronal circuit which represent the memory stored in the brain, and\nsynaptic plasticity are mediated by molecular activity at the synapse during\nspecific time windows after learning 24,29\u201331<\/sup>. <\/p>\n\n\n\n

Learning and Memory in Aging <\/strong><\/p>\n\n\n\n

Learning and memory decline is a part of the\naging process 58\u201360<\/sup>. The most noticeable cognitive decline in\nage human is the hippocampus-dependent forms of memory deficits, which is\nmanifested by the difficulty of learning and remembering of new names, recent\nevents and even spatial information 2,13<\/sup>. These types of cognitive impairment can be\nrecapitulated in aging rodent by assessing their cognitive function by learning\nand retention paradigms. Therefore, the age-related cognitive impairment in\nbehavioral and cellular manifestations of learning and memory is well 52\nestablished in humans and other mammals 2,13<\/sup>. Moreover, LTP is diminished in aged animals\n58\u201360<\/sup>. However, the mechanisms underlie the\ncognitive impairment in aged animals and human are still not clear. Although\nthe bases of such decline remain unknown, oxidative stress is proposed to play\na significant role in age-related memory and synaptic plasticity dysfunction 13,19,25<\/sup>. Moreover, the decline of cognitive function\nin aging subjects can be more server due to numerous reasons, such as stroke,\nvascular problems, psychiatric disorders, Parkinson\u2019s Disease and Alzheimer\u2019s\nDisease. These conditions can cause \ncognitive impairment to be more pronounced in normal aging 2,13<\/sup>.<\/p>\n\n\n\n

Conclusion<\/strong><\/p>\n\n\n\n

Understanding the molecular mechanisms underlying cognitive aging has\nbecome increasingly important. This chapter explores the role of various\nmolecular factors in memory formation and how changes in these factors with age\ncan affect learning and memory retention. It offers a comprehensive overview of\nthe latest research in this field and highlights the potential for therapeutic\ninterventions to improve cognitive function in aging individuals.<\/p>\n\n\n\n

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