Introduction

Memory refers to the storage of perceived information, the cognitive process essential for learning and developing other cognitive skills. The human brain perceives the stimuli through sensory memory, stores them in short-term or working memory, and passes the information to long-term memory (Baars & Gage, 2010). Though sensory memory and short-term memory process the perceived representations, long-term memory is necessary for the long-term storage, retrieval, and association of information (Brem et al., 2013). Long-term memory significantly contributes to the unlimited storage and stabilization of information for memory retrieval. Further, memory storage, reactivation, and retrieval also play a significant role in learning. The retrieval of memory facilitates learning by accessing the relevant information and connecting them with the current stimuli (Packard & Knowlton, 2002).

Studies on cognitive neuroscience demonstrate that the storage and maintenance of memory are influenced by the transmission of information from sensory memory to long-term memory through the synaptic plasticity between neurons. Also, it is known that billions of neurons present in the human brain act as information messengers by transmitting information, thus strengthening them for a longer time (Knierim, 2014). This rapid and consistent transmission and strengthening of information are required for memory and learning (Raman et al., 2019).

Despite decades of research exploring the relationship between memory and learning, the holistic understanding of the psychological and neurobiological process of memory retrieval from long-term memory and its role in learning is still lacking. Therefore, this article provides the psychological, neurobiological, and biochemical perspectives of memory retrieval by shedding light on how long-term memory plays an important role in learning. In an attempt to know the neurobiological processes of memory and learning, the article explains the process of synaptic plasticity between neurons for the transmission of information and long-term potentiation for the strengthening and retention of memory that is necessary for learning. In addition, the article discusses the neurotransmitters, genetic transcription factors, and theta waves that are activated to transmit and strengthen the information for memory retention and retrieval.

Memory Retrieval

Memory retrieval is remembering and reinstating stored information from long-term memory. The retrieval of memory updates the old memories with new stimuli and environmental cues (Lockhart, 2001). The process of memory retrieval is equally important for learning, similar to the process of encoding and storing memory. Whenever the memory is encoded, the information forms a memory trace or engram. During retrieval, the memory traces are changed and reactivated for effective learning (Katkov et al., 2017; Woodward et al., 1973). The engram cells in the brain undergo biochemical changes that help to store and retain memory. While learning, the engram cells are activated and modified depending on the external stimuli (Han et al., 2021). These learning-induced changes by engram cells induce persistent changes in the neurons. During the perception of stimuli, the neuronal excitability state of engram cells decides the retrieval of memory (Tonegawa et al., 2018). Following that, the reactivation of those engram cells increases the excitability state during the retrieval. The reactivation or awakening of the engram cell for the process of retrieval requires contextual cues from the environmental stimuli. This process of influencing the engram out of its latent state into manifested activity is called ecphory (Steinvorth et al., 2006; Tulving et al., 1983). Figure 1 shows the activation of engram cells during encoding and the learning-induced changes during retrieval.

Fig. 1
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Activation of engram cell. Modified and reused with permission from (Tonegawa et al., 2015)

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The effective retrieval of memory requires the rehearsal and reactivation of information. After the perception of memory, the spacing between the information encoded and the duration of information stored depends on the time window of memory (Kornmeier et al., 2014). The time window is a limited period within which additional information interferes with the primary memory, thus strengthening or weakening the memory (Bell et al., 2014). During this spacing, the information would be labile, and the process of memory consolidation stabilizes the information from short-term to long-term memory (Alberini & Ledoux, 2013). Further, the stabilized memory is reactivated by memory reconsolidation that modifies and strengthens the memory for permanent storage. The process of consolidation and reconsolidation strengthens and enhances the memory to be more accessible during the retrieval (Alberini, 2011; Herszage & Censor, 2017). Figure 2 illustrates the process of consolidation and reconsolidation for the stabilization of memory.

Fig. 2
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Stabilization of memory

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Though the memories can be stabilized in the long-term memory, sometimes the stored memory may get interfered with or disrupted during retrieval, causing retrieval failure or forgetting of the memory (Anderson & Neely, 1996; Kerrén et al., 2021). The retrieval failure majorly occurs by memory decay and memory interference. Though long-term memory stores information for an extended period, some information fades or decays from long-term memory (Davis & Zhong, 2017). In an experimental study of memory decay, Ebbinghaus (1855) found the forgetting curve, which shows that memory decreases exponentially with time. The experiment proposes that any new information learned and processed in long-term memory decays if the information is not reactivated at regular intervals (Nelson, 1985). The time gap between first-time and second-time learning decides the saving measure of the primary input. This saving measure decides the retrieval of the information and also saves time when the information is learned for the second time (Miller, 2021). On relearning, the saving measure increases, and the information is relearned in a short interval of time. However, when a long time is taken to relearn the information, the measure of saving decreases leading to the decay of the memory (Murre & Dros, 2015). Retrieval failure also occurs when there is an interference of associated memories during retrieval. Proactive interference occurs when the previous knowledge interferes with the recently perceived information. Retroactive interference occurs when the newly learned information disrupts the already stored information in long-term memory (Chanales et al., 2019; Unsworth et al., 2013). Figure 3 explains the exponential nature of forgetting by plotting a forgetting curve with the time window between retention and memory decay that decides the storage period of the information.

Fig. 3
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Forgetting curve

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Synaptic Plasticity

The retention of information in the memory traces and stabilization of information by memory consolidation requires the transmission of information from one neuron to another. The neurons are the fundamental units of the brain that transmit information perceived by the sensory region of the brain. Synaptic plasticity is the process of strengthening or weakening the synapses to effectively communicate with neurons. The synapse is the junction between the axon of one neuron and the dendrite of another neuron (Langille & Brown, 2018; Lee et al., 2021). Further, the neuron which initially passes the information is called a presynaptic neuron, and the neuron which receives the information is called a postsynaptic neuron (Abraham & Bear, 1996). According to Hebb’s postulate, synaptic plasticity follows the principle, “the neurons that fire together, wire together” (Hebb, 1949). When neuron A is excited, it fires spikes or action potential that cause depolarization of neuron A which reaches a threshold to wire with neuron B (Choi and Kaang, 2022; Mittal et al., 2018). In addition, the synapses can be either excitatory or inhibitory; when neuron A is excited, and neuron B is also excited, there will be an increase in excitatory postsynaptic potential. When neuron A is excited, and neuron B is not excited, it inhibits the postsynaptic membrane potential (Adams et al., 2016; Druckmann et al., 2014). Also, the connection between the presynaptic and postsynaptic neurons is of two kinds, electrical synapse and chemical synapse. The electrical synapse uses the gap junction between neurons, and the chemical synapse uses the synaptic cleft, where the neurotransmitters transmit the information between the neurons (Goto, 2022).

The neurotransmitters are the chemical signals packed inside small sacs called vesicles in the presynaptic terminal. After the depolarization of the presynaptic neuron, the voltage-gated calcium ions present in the neuron move toward the neurotransmitters that activate its transmission. Further, the neurotransmitters pass through the synaptic cleft to reach the postsynaptic neuron (González-Espinosa & Guzmán-Mejía, 2013). Then the neurotransmitters are transmitted to the chemically gated channels on the recipient postsynaptic neuron (Südhof, 2012). When these chemically gated channels of the postsynaptic neuron open with sodium ions present on its surface, it causes excitation in the postsynaptic neuron, and when the channels open with potassium and chloride ions, it inhibits the postsynaptic membrane potential (Kneussel & Hausrat, 2016; Silva et al., 2021).

Therefore, the excitatory postsynaptic potential between the neurons decides the synaptic strength and effective synaptic plasticity (Fusi, 2008; Jackman & Regehr, 2017). Depending on the number of neurotransmitters released, the information gets transmitted and stored effectively in the memory. This synaptic plasticity plays a central role in storing memory traces or engram for further consolidation and reconsolidation of memory (Evans, 1990). The transmission of information from presynaptic neurons and postsynaptic neurons with synaptic plasticity increases the strength of the information for effective memory retrieval and learning. Thus, pairing the presynaptic and postsynaptic neurons by synaptic plasticity is essential for memory and learning (Abraham et al., 2019).

The neurotransmitters that are majorly involved in synaptic transmission are glutamate or glutamic acid (Glu). Glutamate is the excitatory neurotransmitter, where the excitatory neurotransmitters increase the efficacy of the presynaptic neuron with the action potential (Riedel et al., 2003). The neurotransmitter glutamate further activates the ionotropic glutamate receptor (iGluR) and metabotropic glutamate receptor (mGluR) (Gasbarri & Pompili, 2013). The iGluR are the ion channels that make the excitatory synaptic plasticity faster in the Central nervous system (CNS) in the hippocampus (Traynelis et al., 2010). The mGluR regulates neuronal excitability when the action potential is rapidly released in the hippocampal-dependent spatial learning and memory (Mukherjee & Manahan-Vaughan, 2013). But, the neurotransmitter gamma-aminobutyric acid (GABA), which is mostly present in Central Nervous System (CNS), inhibits the synaptic connectivity with the postsynaptic neuron (Barron, 2021; Zacharopoulos et al., 2021). Inhibiting the synapse from being connected with other synapses can stop the unwanted information from being processed and stored in long-term memory. This way, only the necessary information relevant to the previously held memory will be activated for synaptic plasticity (Schmitz et al., 2017). The inhibitory control of GABA also plays a significant role in associative learning, which forms semantic knowledge by connecting relevant information (Spurny et al., 2020).

The excitatory neurotransmitter glutamate increases synaptic plasticity, and the inhibitory neurotransmitter GABA decreases synaptic plasticity. Together, the role of glutamate and GABA in the right concentration levels will provide balance and cognitive control (Brown et al., 2021; Tian & Chen, 2021). Hence, neurotransmitters are the chemical messengers involved in memory and learning by transmitting relevant information and inhibiting irrelevant information (Yang et al., 2018).

Long-Term Potentiation

Long-term potentiation is a process that strengthens the synapses to retain memory for a longer time in the long-term memory. The synaptic connection between two neurons is activated by the presynaptic neuron, which depends on the experience of the external stimuli (Sumi & Harada, 2020). The synaptic efficacy increases when the presynaptic neuron stimulates the neurotransmitters repeatedly to be connected with the postsynaptic neuron (Stent, 1973). The repeated and persistent connection between the synapses with long-term potentiation increases the ability to store information permanently in long-term memory, which enhances memory retrieval and associative learning with new stimuli (Martinez & Derrick, 1996). The opposite process of long-term potentiation is long-term depression which reduces the strength between the neurons to be connected (Bliss & Cooke, 2011). Long-term depression is equally essential as long-term potentiation because it removes unnecessary information, allowing specific information for synaptic plasticity (Collingridge et al., 2010). The weakening of synaptic plasticity by long-term depression also enhances the process of memory retrieval and learning by inhibiting irrelevant memories. Thus, long-term depression develops the process of long-term potentiation and provides cognitive control.

The high-frequency stimulation of long-term potentiation occurs in the hippocampal region of the brain (Kemp & Manahan-Vaughan, 2004; Wang et al., 2021). The CA1 area of the hippocampus stores and retrieves long-term memory. The organization of the information in order in the CA1 neural area of the brain helps associate the information (Bartsch et al., 2011). Memory retention by the plasticity of synapses forming long-term potentiation of memory depends on the N-Methyl-D-aspartic acid or N-Methyl-D-aspartate (NMDA) receptor (Kumar, 2015). The long-term potentiation depending on the experience of the stimuli, can be divided into NMDA receptor-dependent and NMDA receptor-independent. NMDA receptor-dependent synapses connect better with the other neuron for long-term information storage than the NMDA-independent synapses (Sweatt, 2010). Together, the synaptic plasticity and the long-term potentiation with NMDA receptors and the genetic transcription of CREB and NF-kB in the region of CA1 in the hippocampus of the brain strengthen the information to be stored in long-term memory for effective retrieval and learning (Benito & Barco, 2010; Bito & Takemoto-Kimura, 2003).

Genetic Transcription

The stronger firing of the neurons for synaptic plasticity and long-term potentiation also requires genetic transcription. Specifically, the genetic activation of the cAMP response element-binding protein (CREB) in the process of synaptic plasticity is necessary for learning and memory (Kida, 2012). CREB is a transcription factor that binds to a specific DNA sequence called cAMP-response-element (CRE). The perception of stimuli, the experience, and the effect of the stimuli while learning trigger the phosphorylation of CREB-dependent gene expression (Gandolfi et al., 2017). The phosphorylation of CREB activates the synaptic plasticity between the neurons, such that the information is strengthened for the long-term potentiation of the memory (Deisseroth & Bito, 1996). Further, CREB activation in the neurons is involved in synaptic plasticity and long-term potentiation that binds the neurons for synaptic efficacy (Kaldun & Sprecher, 2019; Ortega-Martínez, 2015). Also, the CREB plays a role in initiating the process of memory consolidation, which stabilizes the information from short-term memory to long-term memory (Lonze & Ginty, 2002; Suzuki et al., 2011). The activation of the CREB gene allows switching between the memory phases that increase context-specific learning. By regulating the neuronal activity of synaptic plasticity, CREB enhances the storage of memory traces that can be reactivated during retrieval for effective learning (Wang et al., 2018). Figure 4 represents the chromosomal location of the gene CREB, and Fig. 5 shows the genetic patterns of CREB.

Fig. 4
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Chromosomal location of the CREB gene (2q33.3)

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Fig. 5
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CREB gene patterns from Allen Human Brain Atlas, human.brain-map.org

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Another transcription factor that regulates the functioning of neurotransmitters is the nuclear factor kappaB (NF-kB). NF-kB regulates neuronal transmission and synaptic plasticity by holding the memory trace or engram (Kaltschmidt & Kaltschmidt, 2015). With the activation of NF-kB, long-term potentiation is induced, forming memory traces. Following that, the new information forms the synaptic plasticity between the neurons. In this process, the older memory trace is reactivated, forming a connection between the prior knowledge and the external stimuli (Kaltschmidt et al., 2006). Also, the major activator for the synaptic activity of NF-kB is glutamate and Ca2 + , which regulate the transmission of information (Kaltschmidt et al., 2005). This transmission of information through neurons by the activation of CREB and NF-kB positively increases memory retention and retrieval, which influences the learning experience. Figure 6 represents the chromosomal location of the gene NF-kB, and Fig. 7 shows the genetic patterns of NF-kB.

Fig. 6
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Chromosomal location of the NF-kB gene (4q24)

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Fig. 7
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NF-kB gene patterns from Allen Human Brain Atlas, human.brain-map.org

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Theta Oscillations

Along with the neurotransmitters and the genetic transcription CREB, the hippocampal theta rhythm is activated to strengthen long-term potentiation. The theta oscillation in the brain is essential for encoding and retrieval of memory (ter Wal et al., 2021). The theta waves measure between 4 to 8 HZ and the normal functioning of the theta rhythm within this frequency mediates memory and learning (Bastiaansen et al., 2005; Kikuchi et al., 2011). During memory retrieval, the theta waves get activated and update the memory for its retainment for a longer period. Depending on the higher or lower frequency of the theta waves, the stronger or weaker firing of synapses for long-term potentiation is determined (Jacobs et al., 2006). Besides that, the transmission of information for memory storage requires synaptic plasticity, and the strong firing of presynaptic and postsynaptic neurons results from the oscillations of the theta wave in the brain (Bland, 1986; Klimesch et al., 2001). The topographical map in Fig. 8 shows an increase in the theta wave during the retention and retrieval of memory.

Fig. 8
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Topographical map to show the activation of theta wave. The plot shows amplitude where the red color shows the positive amplitude of theta and blue shows the negative amplitude of theta. The darker red or blue indicates, the higher value of theta oscillation on an average time during the retrieval of information

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Electroencephalography (EEG) and magnetoencephalography (MEG) studies have shown that theta oscillations in the brain are stimulated for hippocampal activation during working memory (Düzel et al., 2010; Gyorgy, 2002). Though the mechanism that facilitates theta brain oscillation in neural circuits is not clear, it is found that the theta burst stimulation (TBS), which is similar to the original theta activity in the brain, activates the memory consolidation and reconsolidation process, thus increasing the long-term potentiation of memory (Arai & Lynch, 1992; Larson & Munkácsy, 2015). Further, the theta burst by the human theta burst stimulation stimulates NMDA receptors that induce long-term potentiation for the storage, retainment, and retrieval of memory (Capocchi et al., 1992; McCalley et al., 2021).

EEG memory studies have involved theta burst stimulation in finding theta activity for memory storage and retrieval. The theta burst stimulation uses high-frequency stimulation bursts that resemble the original activation of theta in the hippocampal region using extracellular field potential recordings (Abrahamsson et al., 2016; Tse et al., 2018). Theta bursts are repeated to evoke synaptic plasticity, which induces long-term potentiation for memory and learning (Albouy et al., 2022; Wong et al., 1986). The theta rhythm coordinates the neural activity for synaptic plasticity and long-term potentiation that retains and retrieves memory for learning and creating a link with new knowledge. Table 1 gives an overview of the processes involved in the storage and retrieval of memory.

Table 1 Summary of processes involved in memory and learning
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Conclusions

The consolidation of information from short-term memory to long-term memory stabilizes and retains the memory for retrieval and learning. The neurobiological mechanism underlying the consolidation and reconsolidation of memories occurs when neurons communicate and transmit information. As a matter of fact, memory and learning are interconnected neurobiological phenomena that depend on the firing of neurons during acquisition and the reactivation of neurons during retrieval.

The above discussion shows that the neural signals from synaptic plasticity are mediated by neurotransmitters, including glutamate and GABA. Further, the transmitted information is strengthened by long-term potentiation mediated by NMDA receptors. This transmission and strengthening of neurons for memory and learning are activated by CREB and NF-kB genetic transcription and oscillation of theta waves. Taken together, it is reasonable to conclude that the retainment and retrieval of memory through synaptic plasticity play an important role in learning. However, more neurobiological studies could be developed on the function of neurons in acquiring, transmitting, and retrieving memory.