Learning-induced Changes Research Articles

Similarity of brain activity patterns during learning and subsequent resting state predicts memory consolidation

Spontaneous reactivation of brain activity from learning to a subsequent off-line period has been implicated as a neural mechanism underlying memory consolidation. However, similarities in brain activity may also emerge as a result of individual, trait-like characteristics. Here, we introduced a novel approach for analyzing continuous electroencephalography (EEG) data to investigate learning-induced changes as well as trait-like characteristics in brain activity underlying memory consolidation. Thirty-one healthy young adults performed a learning task, and their performance was retested after a short (∼1 h) delay. Consolidation of two distinct types of information (serial-order and probability) embedded in the task were tested to reveal similarities in functional networks that uniquely predict the changes in the respective memory performance. EEG was recorded during learning and pre- and post-learning rest periods. To investigate brain activity associated with consolidation, we quantified similarities in EEG functional connectivity between learning and pre-learning rest (baseline similarity) and learning and post-learning rest (post-learning similarity). While comparable patterns of these two could indicate trait-like similarities, changes from baseline to post-learning similarity could indicate learning-induced changes, possibly spontaneous reactivation. Higher learning-induced changes in alpha frequency connectivity (8.5–9.5 Hz) were associated with better consolidation of serial-order information, particularly for long-range connections across central and parietal sites. The consolidation of probability information was associated with learning-induced changes in delta frequency connectivity (2.5–3 Hz) specifically for more local, short-range connections. Furthermore, there was a substantial overlap between the baseline and post-learning similarities and their associations with consolidation performance, suggesting robust (trait-like) differences in functional connectivity networks underlying memory processes.

Abstinence and Fear Experienced during This Period Produce Distinct Cortical and Hippocampal Adaptations in Alcohol-Dependent Rats.

Previous studies demonstrate that ethanol dependence induced by repeating cycles of chronic intermittent ethanol vapor exposure (CIE) followed by protracted abstinence produces significant gray matter damage via myelin dysfunction in the rodent medial prefrontal cortex (mPFC) and alterations in neuronal excitability in the mPFC and the dentate gyrus (DG) of the hippocampus. Specifically, abstinence-induced neuroadaptations have been associated with persistent elevated relapse to drinking. The current study evaluated the effects of forced abstinence for 1 day (d), 7 d, 21 d, and 42 d following seven weeks of CIE on synaptic plasticity proteins in the mPFC and DG. Immunoblotting revealed reduced expression of CaMKII in the mPFC and enhanced expression of GABAA and CaMKII in the DG at the 21 d time point, and the expression of the ratio of GluN2A/2B subunits did not change at any of the time points studied. Furthermore, cognitive performance via Pavlovian trace fear conditioning (TFC) was evaluated in 3 d abstinent rats, as this time point is associated with negative affect. In addition, the expression of the ratio of GluN2A/2B subunits and a 3D structural analysis of neurons in the mPFC and DG were evaluated in 3 d abstinent rats. Behavioral analysis revealed faster acquisition of fear responses and reduced retrieval of fear memories in CIE rats compared to controls. TFC produced hyperplasticity of pyramidal neurons in the mPFC under control conditions and this effect was not evident or blunted in abstinent rats. Neurons in the DG were unaltered. TFC enhanced the GluN2A/2B ratio in the mPFC and reduced the ratio in the DG and was not altered by abstinence. These findings indicate that forced abstinence from CIE produces distinct and divergent alterations in plasticity proteins in the mPFC and DG. Fear learning-induced changes in structural plasticity and proteins contributing to it were more profound in the mPFC during forced abstinence.

Learning-induced bidirectional enhancement of inhibitory synaptic metaplasticity.

Training rodents in a particularly difficult olfactory-discrimination (OD) task results in the acquisition of the ability to perform the task well, termed 'rule learning'. In addition to enhanced intrinsic excitability and synaptic excitation in piriform cortex pyramidal neurons, rule learning results in increased synaptic inhibition across the whole cortical network to the point where it precisely maintains the balance between inhibition and excitation. The mechanism underlying such precise inhibitory enhancement remains to be explored. Here, we use brain slices from transgenic mice (VGAT-ChR2-EYFP), enabling optogenetic stimulation of single GABAergic neurons and recordings of unitary synaptic events in pyramidal neurons. Quantal analysis revealed that learning-induced enhanced inhibition is mediated by increased quantal size of the evoked inhibitory events. Next, we examined the plasticity of synaptic inhibition induced by long-lasting, intrinsically evoked spike firing in post-synaptic neurons. Repetitive depolarizing current pulses from depolarized (-70mV) or hyperpolarized (-90mV) membrane potentials induced long-term depression (LTD) and long-term potentiation (LTP) of synaptic inhibition, respectively. We found a profound bidirectional increase in the ability to induce both LTD, mediated by L-type calcium channels, and LTP, mediated by R-type calcium channels after rule learning. Blocking the GABAB receptor reversed the effect of intrinsic stimulation at -90mV from LTP to LTD. We suggest that learning greatly enhances the ability to modify the strength of synaptic inhibition of principal neurons in both directions. Such plasticity of synaptic plasticity allows fine-tuning of inhibition on each particular neuron, thereby stabilizing the network while maintaining the memory of the rule. KEY POINTS: Olfactory discrimination rule learning results in long-lasting enhancement of synaptic inhibition on piriform cortex pyramidal neurons. Quantal analysis of unitary inhibitory synaptic events, evoked by optogenetic minimal stimulation, revealed that enhanced synaptic inhibition is mediated by increased quantal size. Surprisingly, metaplasticity of synaptic inhibition, induced by intrinsically evoked repetitive spike firing, is increased bidirectionally. The susceptibility to both long-term depression (LTD) and long-term potentiation (LTP) of inhibition is enhanced after learning. LTD of synaptic inhibition is mediated by L-type calcium channels and LTP by R-type calcium channels. LTP is also dependent on activation of GABAB receptors. We suggest that learning-induced changes in the metaplasticity of synaptic inhibition enable the fine-tuning of inhibition on each particular neuron, thereby stabilizing the network while maintaining the memory of the rule.

From learned value to sustained bias: how reward conditioning changes attentional priority.

Attentional bias to reward-associated stimuli can occur even when it interferes with goal-driven behavior. One theory posits that dopaminergic signaling in the striatum during reward conditioning leads to changes in visual cortical and parietal representations of the stimulus used, and this, in turn, sustains attentional bias even when reward is discontinued. However, only a few studies have examined neural activity during both rewarded and unrewarded task phases. In the current study, participants first completed a reward-conditioning phase, during which responses to certain stimuli were associated with monetary reward. These stimuli were then included as non-predictive cues in a spatial cueing task. Participants underwent functional brain imaging during both task phases. The results show that striatal activity during the learning phase predicted increased visual cortical and parietal activity and decreased ventro-medial prefrontal cortex activity in response to conditioned stimuli during the test. Striatal activity was also associated with anterior cingulate cortex activation when the reward-conditioned stimulus directed attention away from the target. Our findings suggest that striatal activity during reward conditioning predicts the degree to which reward history biases attention through learning-induced changes in visual and parietal activities.

Measuring and monitoring skill learning in closed-loop myoelectric hand prostheses using speed-accuracy tradeoffs

Objective. Closed-loop myoelectric prostheses, which combine supplementary sensory feedback and electromyography (EMG) based control, hold the potential to narrow the divide between natural and bionic hands. The use of these devices, however, requires dedicated training. Therefore, it is crucial to develop methods that quantify how users acquire skilled control over their prostheses to effectively monitor skill progression and inform the development of interfaces that optimize this process. Approach. Building on theories of skill learning in human motor control, we measured speed-accuracy tradeoff functions (SAFs) to comprehensively characterize learning-induced changes in skill—as opposed to merely tracking changes in task success across training—facilitated by a closed-loop interface that combined proportional control and EMG feedback. Sixteen healthy participants and one individual with a transradial limb loss participated in a three-day experiment where they were instructed to perform the box-and-blocks task using a timed force-matching paradigm at four specified speeds to reach two target force levels, such that the SAF could be determined. Main results. We found that the participants’ accuracy increased in a similar way across all speeds we tested. Consequently, the shape of the SAF remained similar across days, at both force levels. Further, we observed that EMG feedback enabled participants to improve their motor execution in terms of reduced trial-by-trial variability, a hallmark of skilled behavior. We then fit a power law model of the SAF, and demonstrated how the model parameters could be used to identify and monitor changes in skill. Significance. We comprehensively characterized how an EMG feedback interface enabled skill acquisition, both at the level of task performance and movement execution. More generally, we believe that the proposed methods are effective for measuring and monitoring user skill progression in closed-loop prosthesis control.

The role of the m6A/m demethylase FTO in memory is both task and sex-dependent in mice

Formation of long-term memories requires learning-induced changes in both transcription and translation. Epitranscriptomic modifications of RNA recently emerged as critical regulators of RNA dynamics, whereby adenosine methylation (m6A) regulates translation, mRNA stability, mRNA localization, and memory formation. Prior work demonstrated a pro-memory phenotype of m6A, as loss of m6A impairs and loss of the m6A/m demethylase FTO improves memory formation. Critically, these experiments focused exclusively on aversive memory tasks and were only performed in male mice. Here we show that the task type and sex of the animal alter effects of m6A on memory, whereby FTO-depletion impaired object location memory in male mice, in contrast to the previously reported beneficial effects of FTO depletion on aversive memory. Additionally, we show that female mice have no change in performance after FTO depletion, demonstrating that sex of the mouse is a critical variable for understanding how m6A contributes to memory formation. Our study provides the first evidence for FTO regulation of non-aversive spatial memory and sexspecific effects of m6A, suggesting that identification of differentially methylated targets in each sex and task will be critical for understanding how epitranscriptomic modifications regulate memory.

Role of the histone variant H2A.Z.1 in memory, transcription, and alternative splicing is mediated by lysine modification

Creating long-lasting memories requires learning-induced changes in gene expression, which are impacted by epigenetic modifications of DNA and associated histone proteins. Post-translational modifications (PTMs) of histones are key regulators of transcription, with different PTMs producing unique effects on gene activity and behavior. Although recent studies implicate histone variants as novel regulators of memory, effects of PTMs on the function of histone variants are rarely considered. We previously showed that the histone variant H2A.Z suppresses memory, but it is unclear if this role is impacted by H2A.Z acetylation, a PTM that is typically associated with positive effects on transcription and memory. To answer this question, we used a mutation approach to manipulate acetylation on H2A.Z without impacting acetylation of other histone types. Specifically, we used adeno-associated virus (AAV) constructs to overexpress mutated H2A.Z.1 isoforms that either mimic acetylation (acetyl-mimic) by replacing lysines 4, 7 and 11 with glutamine (KQ), or H2A.Z.1 with impaired acetylation (acetyl-defective) by replacing the same lysines with alanine (KA). Expressing the H2A.Z.1 acetyl-mimic (H2A.Z.1KQ) improved memory under weak learning conditions, whereas expressing the acetyl-defective H2A.Z.1KA generally impaired memory, indicating that the effect of H2A.Z.1 on memory depends on its acetylation status. RNA sequencing showed that H2A.Z.1KQ and H2A.Z.1KA uniquely impact the expression of different classes of genes in both females and males. Specifically, H2A.Z.1KA preferentially impacts genes involved in synaptic function, suggesting that acetyl-defective H2A.Z.1 impairs memory by altering synaptic regulation. Finally, we describe, for the first time, that H2A.Z is also involved in alternative splicing of neuronal genes, whereby H2A.Z depletion, as well as expression of H2A.Z.1 lysine mutants influence transcription and splicing of different gene targets, suggesting that H2A.Z.1 can impact behavior through effects on both splicing and gene expression. This is the first study to demonstrate that direct manipulation of H2A.Z post-translational modifications regulates memory, whereby acetylation adds another regulatory layer by which histone variants can fine tune higher brain functions through effects on gene expression and splicing.

Changes in the dopaminergic circuitry and adult neurogenesis linked to reinforcement learning in corvids.

The caudolateral nidopallium (NCL, an analog of the prefrontal cortex) is known to be involved in learning, memory, and discrimination in corvids (a songbird), whereas the involvement of other brain regions in these phenomena is not well explored. We used house crows (Corvus splendens) to explore the neural correlates of learning and decision-making by initially training them on a shape discrimination task followed by immunohistochemistry to study the immediate early gene expression (Arc), a dopaminoceptive neuronal marker (DARPP-32, Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa) to understand the involvement of the reward pathway and an immature neuronal marker (DCX, doublecortin) to detect learning-induced changes in adult neurogenesis. We performed neuronal counts and neuronal tracing, followed by morphometric analyses. Our present results have demonstrated that besides NCL, other parts of the caudal nidopallium (NC), avian basal ganglia, and intriguingly, vocal control regions in house crows are involved in visual discrimination. We have also found that training on the visual discrimination task can be correlated with neurite pruning in mature dopaminoceptive neurons and immature DCX-positive neurons in the NC of house crows. Furthermore, there is an increase in the incorporation of new neurons throughout NC and the medial striatum which can also be linked to learning. For the first time, our results demonstrate that a combination of structural changes in mature and immature neurons and adult neurogenesis are linked to learning in corvids.

Cerebellar interneurons control fear memory consolidation via learning-induced HCN plasticity

While synaptic plasticity is considered the basis of learning and memory, modifications of the intrinsic excitability of neurons can amplify the output of neuronal circuits and consequently change behavior. However, the mechanisms that underlie learning-induced changes in intrinsic excitability during memory formation are poorly understood. In the cerebellum, we find that silencing molecular layer interneurons completely abolishes fear memory, revealing their critical role in memory consolidation. The fear conditioning paradigm produces a lasting reduction in hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in these interneurons. This change increases intrinsic membrane excitability and enhances the response to synaptic stimuli. HCN loss is driven by a decrease in endocannabinoid levels via altered cGMP signaling. In contrast, an increase in release of cerebellar endocannabinoids during memory consolidation abolishes HCN plasticity. Thus, activity in cerebellar interneurons drives fear memory formation via a learning-specific increase in intrinsic excitability, and this process requires the loss of endocannabinoid-HCN signaling.

Examining the impact of cue similarity and fear learning on perceptual tuning

Past research on the effects of associative aversive learning on discrimination acuity has shown mixed results, including increases, decreases, and no changes in discrimination ability. An animal study found that the type of learning experience determined the direction and extent of learning-induced changes. The current preregistered web-based study aimed to translate these findings to humans. Experiment 1 (N = 245) compared changes in stimulus discrimination between simple learning (only one oriented grating cue), coarse differential conditioning (physically distinct cues), and fine differential conditioning (physically similar cues) as well as to their three respective control groups. The discrimination task consisted of a two-alternative-forced-choice task with oriented grating stimuli. During learning, a specific orientation was paired with unpleasant pictures. Our analysis using generative modeling demonstrated weak to moderate evidence that aversive learning did not alter discrimination acuity in any of the groups. In a follow-up experiment (N = 121), we replicated these findings despite successful learning trajectories in all three groups and a more detailed assessment of discrimination acuity. Contrary to prior assumptions, our findings indicate that aversive learning does not enhance perceptual discrimination, and the presence of additional safety cues does not appear to moderate this effect.

Changes in functional brain activity patterns associated with computer programming learning in novices.

Computer programming, the process of designing, writing, and testing executable computer code, is an essential skill in numerous fields. A description of the neural structures engaged and modified during programming skill acquisition could help improve training programs and provide clues to the neural substrates underlying the acquisition of related skills. Fourteen female university students without prior computer programing experience were examined by functional magnetic resonance imaging (fMRI) during the early and late stages of a 5-month 'Computer Processing' course. Brain regions involved in task performance and learning were identified by comparing responses to programming and control tasks during the early and late stages. The accuracy of performing a programming task was significantly improved during the late stage. Various regions of the frontal, temporal, parietal, and occipital cortex as well as several subcortical structures (caudate nuclei and cerebellum) were activated during programming tasks. Brain activity in the right inferior frontal gyrus was greater during the late stage and significantly correlated with improved task performance. Although the left inferior frontal gyrus was also highly active during the programming task, there were no learning-induced changes in activity or a significant correlation between activity and improved task performances. Computer programming learning among novices induces functional neuroplasticity within the right inferior frontal gyrus but not the left inferior gyrus (Broca's area).

Conditioning‑induced changes in sensory cortical maps detected in mice by intrinsic signal optical imaging.

Intrinsic signal optical imaging (ISOI) has been used previously for the detection of changes in sensory processing in the somatosensory cortex in response to environment alteration or after deprivation of sensory information. To date, there have been no reports of ISOI being used in learning‑induced changes in the somatosensory cortex. In the present study, ISOI was performed twice in the same mouse: before and after conditional fear learning. The conditioning paradigm consisted of pairing sensory stimulation of vibrissae with electric tail shock. In order to map the cortical representation of the vibrissa B1 with ISOI, we deflected the vibrissa with an intensive stimulation (frequency of 10 Hz for 6 s). After conditioning, we found that the cortical representation of vibrissa B1 had expanded by an average of 44%, compared with pre‑learning, by using images obtained with ISOI. Previously, we demonstrated an enlargement of the cortical representation of the vibrissae stimulated by the same behavioral training paradigm but using [14C]2‑deoxyglucose. This current investigation provides the first ISOI‑based evidence of learning‑induced changes in plasticity in the barrel cortex. The results indicate that irrespective of physiological mechanisms used for visualization of the vibrissae representation or subject's testing state (aware or anesthetized animal), the conditioning induced changes in each case in the cortical processing of intensive stimuli. This suggests specific functional reorganization of the neuronal circuits. Moreover, ISOI as a noninvasive method of mapping cortical activation in the same animal before and after behavioral training could serve as a very useful tool for precise manipulation within the cortex and for assessing the resulting effects on experience‑dependent cortical plasticity.

Dissecting the neurocomputational bases of patch-switching.

The survival and well-being of humans require solving the patch-switching problem: we must decide when to stop collecting rewards in a current patch and travel somewhere else where gains may be higher. Previous studies suggested that frontal regions are underpinned by several processes in the context of foraging decisions such as tracking task difficulty, and/or the value of exploring the environment. To dissociate between these processes, participants completed an fMRI patch-switching learning task inspired by behavioral ecology. By analyzing >11,000 trials collected across 21 participants, we found that the activation in the cingulate cortex was closely related to several patch-switching-related variables including the decision to leave the current patch, the encounter of a new patch, the harvest value, and the relative forage value. Learning-induced changes in the patch-switching threshold were tracked by activity within frontoparietal regions including the superior frontal gyrus and angular gyrus. Our findings suggest that frontoparietal regions shape patch-switching learning apart from encoding classical non-learning foraging processes. These findings provide a novel neurobiological understanding of how learning emerges neurocomputationally shaping patch-switching behavior with implications in real-life choices such as job selection and pave the way for future studies to probe the causal role of these neurobiological mechanisms.

Non-game like training benefits spoken foreign-language processing in children with dyslexia.

Children with dyslexia often face difficulties in learning foreign languages, which is reflected as weaker neural activation. However, digital language-learning applications could support learning-induced plastic changes in the brain. Here we aimed to investigate whether plastic changes occur in children with dyslexia more readily after targeted training with a digital language-learning game or similar training without game-like elements. We used auditory event-related potentials (ERPs), specifically, the mismatch negativity (MMN), to study learning-induced changes in the brain responses. Participants were 24 school-aged Finnish-speaking children with dyslexia and 24 age-matched typically reading control children. They trained English speech sounds and words with "Say it again, kid!" (SIAK) language-learning game for 5 weeks between ERP measurements. During the game, the players explored game boards and produced English words aloud to score stars as feedback from an automatic speech recognizer. To compare the effectiveness of the training type (game vs. non-game), we embedded in the game some non-game levels stripped of all game-like elements. In the dyslexia group, the non-game training increased the MMN amplitude more than the game training, whereas in the control group the game training increased the MMN response more than the non-game training. In the dyslexia group, the MMN increase with the non-game training correlated with phonological awareness: the children with poorer phonological awareness showed a larger increase in the MMN response. Improved neural processing of foreign speech sounds as indicated by the MMN increase suggests that targeted training with a simple application could alleviate some spoken foreign-language learning difficulties that are related to phonological processing in children with dyslexia.

Expression of a Form of Cerebellar Motor Memory Requires Learned Alterations to the Activity of Inhibitory Molecular Layer Interneurons.

Procedural memories formed in the cerebellum in response to motor errors depend on changes to Purkinje cell (PC) spiking patterns that correct movement when the erroneous context is repeated. Because molecular layer interneurons (MLIs) inhibit PCs, learning-induced changes to MLI output may participate in reshaping PC spiking patterns. However, it remains unclear whether error-driven learning alters MLI activity and whether such changes are necessary for the memory engram. We addressed this knowledge gap by measuring and manipulating MLI activity in the flocculus of both sexes of mice before and after vestibulo-ocular reflex (VOR) adaptation. We found that MLIs are activated during vestibular stimuli and that their population response exhibits a phase shift after the instantiation of gain-increase VOR adaptation, a type of error-driven learning thought to require climbing-fiber-mediated instructive signaling. Although acute optogenetic suppression of MLI activity did not affect baseline VOR performance, it negated the expression of gain-increase learning, demonstrating a specific role of MLI activity changes in motor memory expression. This effect was transitory; after a multiday consolidation period, the expression of VOR gain-increase learning was no longer sensitive to MLI activity suppression. Together, our results indicate that error-driven alteration of MLI activity is necessary for labile, climbing-fiber-induced motor memory expression.SIGNIFICANCE STATEMENT In the cerebellum, motor learning induces an associative memory of the sensorimotor context of an erroneous movement that, when recalled, results in a new pattern of output that improves subsequent trials of performance. Our study shows that error-driven motor learning induces changes to the activity pattern of cerebellar molecular layer interneurons (MLIs) and that this new pattern of activity is required to express the corrective motor memory.

Associative learning drives longitudinally graded presynaptic plasticity of neurotransmitter release along axonal compartments.

Anatomical and physiological compartmentalization of neurons is a mechanism to increase the computational capacity of a circuit, and a major question is what role axonal compartmentalization plays. Axonal compartmentalization may enable localized, presynaptic plasticity to alter neuronal output in a flexible, experience-dependent manner. Here, we show that olfactory learning generates compartmentalized, bidirectional plasticity of acetylcholine release that varies across the longitudinal compartments of Drosophila mushroom body (MB) axons. The directionality of the learning-induced plasticity depends on the valence of the learning event (aversive vs. appetitive), varies linearly across proximal to distal compartments following appetitive conditioning, and correlates with learning-induced changes in downstream mushroom body output neurons (MBONs) that modulate behavioral action selection. Potentiation of acetylcholine release was dependent on the CaV2.1 calcium channel subunit cacophony. In addition, contrast between the positive conditioned stimulus and other odors required the inositol triphosphate receptor, which maintained responsivity to odors upon repeated presentations, preventing adaptation. Downstream from the MB, a set of MBONs that receive their input from the γ3 MB compartment were required for normal appetitive learning, suggesting that they represent a key node through which reward learning influences decision-making. These data demonstrate that learning drives valence-correlated, compartmentalized, bidirectional potentiation, and depression of synaptic neurotransmitter release, which rely on distinct mechanisms and are distributed across axonal compartments in a learning circuit.

Fear learning-induced changes in AMPAR and NMDAR expression in the fear circuit.

NMDA receptors (NMDARs) and AMPA receptors (AMPARs) in amygdala nuclei and the dorsal hippocampus (dHipp) are critical for fear conditioning. Enhancements in synaptic AMPAR expression in amygdala nuclei and the dHipp are critical for fear conditioning, with some studies observing changes in AMPAR expression across many neurons in these brain regions. Whether similar changes occur in other nodes of the fear circuit (e.g., ventral hippocampus [vHipp]) or changes in NMDAR expression in the fear circuit occur with fear conditioning have not been sufficiently examined. To address this we used near-infrared immunohistochemistry (IHC) to measure AMPAR and NMDAR subunit expression in several nodes of the fear circuit. Long-term changes in GluR1 and GluR2 expression in the ventral hippocampus (vHipp) and anterior cingulate cortex (ACC), enhanced NR2A expression in amygdala nuclei, and changes in the ratio of GluR1/NR2A and GluR2/NR2A in the dHipp was observed with fear conditioning. Most of these changes were dependent on protein synthesis during fear conditioning and were not observed immediately after fear conditioning. The results of the study suggest that global changes in AMPARs and NMDARs occur in multiple nodes within the fear circuit and raise the possibility that these changes contribute to fear memory. Further research examining how global changes in AMPAR, NMDAR, and AMPAR/NMDAR ratios within nodes of the fear circuit contribute to fear memory is needed.

Actin Cytoskeleton Role in the Maintenance of Neuronal Morphology and Long-Term Memory.

Evidence indicates that long-term memory formation creates long-lasting changes in neuronal morphology within a specific neuronal network that forms the memory trace. Dendritic spines, which include most of the excitatory synapses in excitatory neurons, are formed or eliminated by learning. These changes may be long-lasting and correlate with memory strength. Moreover, learning-induced changes in the morphology of existing spines can also contribute to the formation of the neuronal network that underlies memory. Altering spines morphology after memory consolidation can erase memory. These observations strongly suggest that learning-induced spines modifications can constitute the changes in synaptic connectivity within the neuronal network that form memory and that stabilization of this network maintains long-term memory. The formation and elimination of spines and other finer morphological changes in spines are mediated by the actin cytoskeleton. The actin cytoskeleton forms networks within the spine that support its structure. Therefore, it is believed that the actin cytoskeleton mediates spine morphogenesis induced by learning. Any long-lasting changes in the spine morphology induced by learning require the preservation of the spine actin cytoskeleton network to support and stabilize the spine new structure. However, the actin cytoskeleton is highly dynamic, and the turnover of actin and its regulatory proteins that determine and support the actin cytoskeleton network structure is relatively fast. Molecular models, suggested here, describe ways to overcome the dynamic nature of the actin cytoskeleton and the fast protein turnover and to support an enduring actin cytoskeleton network within the spines, spines stability and long-term memory. These models are based on long-lasting changes in actin regulatory proteins concentrations within the spine or the formation of a long-lasting scaffold and the ability for its recurring rebuilding within the spine. The persistence of the actin cytoskeleton network within the spine is suggested to support long-lasting spine structure and the maintenance of long-term memory.

The central importance of nuclear mechanisms in the storage of memory

The neurobiological nature of the memory trace (engram) remains controversial. The most widely accepted hypothesis at present is that long-term memory is stored as stable, learning-induced changes in synaptic connections. This hypothesis, the synaptic plasticity hypothesis of memory, is supported by extensive experimental data gathered from over 50 years of research. Nonetheless, there are important mnemonic phenomena that the synaptic plasticity hypothesis cannot, or cannot readily, account for. Furthermore, recent work indicates that epigenetic and genomic mechanisms play heretofore underappreciated roles in memory. Here, we critically assess the evidence that supports the synaptic plasticity hypothesis and discuss alternative non-synaptic, nuclear mechanisms of memory storage, including DNA methylation and retrotransposition. We argue that long-term encoding of memory is mediated by nuclear processes; synaptic plasticity, by contrast, represents a means of relatively temporary memory storage. In addition, we propose that memories are evaluated for their mnemonic significance during an initial period of synaptic storage; if assessed as sufficiently important, the memories then undergo nuclear encoding.

The role of p21-activated kinase in maintaining the fear learning-induced modulation of excitation/inhibition ratio in lateral amygdala

We study the relations between different learning paradigms and enduring changes in excitatory synaptic transmission. Here we show that auditory fear conditioning (AFC), but not olfactory fear conditioning (OFC) training, led to enduring enhancement in AMPA-mediated miniature EPSCs (mEPSCs). Moreover, olfactory unpaired training led to a stable significant reduction in excitatory synaptic transmission. However, olfactory discrimination learning (OD) did not modulate postsynaptic AMPA-mediated mEPSCs in LA. The p21-activated kinase (PAK) activity, previously shown to have a key role in maintaining persistent long-lasting enhancement in synaptic inhibition after OFC, has an opposing effect on excitatory synaptic transmission. PAK maintained the level of excitatory synaptic transmission in the amygdala in all experimental groups, except in neurons in the OFC trained rats. PAK also maintained excitatory synaptic transmission in all neurons of auditory fear conditioning and naïve training groups except in neurons of the auditory safety learning. Safety learning was previously shown in our study to enhance synaptic inhibition. We thus suggest that PAK maintains inhibitory synaptic transmission in a learning-dependent manner and on the other hand affects excitatory synaptic transmission only in groups where learning has not affected inhibitory transmission. Thus, PAK controls learning-induced changes in the excitation/inhibition balance.