Mechanisms Of Memory Formation Research Articles

Histone Deacetylase Inhibition via RGFP966 Releases the Brakes on Sensory Cortical Plasticity and the Specificity of Memory Formation.

Research over the past decade indicates a novel role for epigenetic mechanisms in memory formation. Of particular interest is chromatin modification by histone deacetylases (HDACs), which, in general, negatively regulate transcription. HDAC deletion or inhibition facilitates transcription during memory consolidation and enhances long-lasting forms of synaptic plasticity and long-term memory. A key open question remains: How does blocking HDAC activity lead to memory enhancements? To address this question, we tested whether a normal function of HDACs is to gate information processing during memory formation. We used a class I HDAC inhibitor, RGFP966 (C21H19FN4O), to test the role of HDAC inhibition for information processing in an auditory memory model of learning-induced cortical plasticity. HDAC inhibition may act beyond memory enhancement per se to instead regulate information in ways that lead to encoding more vivid sensory details into memory. Indeed, we found that RGFP966 controls memory induction for acoustic details of sound-to-reward learning. Rats treated with RGFP966 while learning to associate sound with reward had stronger memory and additional information encoded into memory for highly specific features of sounds associated with reward. Moreover, behavioral effects occurred with unusually specific plasticity in primary auditory cortex (A1). Class I HDAC inhibition appears to engage A1 plasticity that enables additional acoustic features to become encoded in memory. Thus, epigenetic mechanisms act to regulate sensory cortical plasticity, which offers an information processing mechanism for gating what and how much is encoded to produce exceptionally persistent and vivid memories. Significance statement: Here we provide evidence of an epigenetic mechanism for information processing. The study reveals that a class I HDAC inhibitor (Malvaez et al., 2013; Rumbaugh et al., 2015; RGFP966, chemical formula C21H19FN4O) alters the formation of auditory memory by enabling more acoustic information to become encoded into memory. Moreover, RGFP966 appears to affect cortical plasticity: the primary auditory cortex reorganized in a manner that was unusually "tuned-in" to the specific sound cues and acoustic features that were related to reward and subsequently remembered. We propose that HDACs control "informational capture" at a systems level for what and how much information is encoded by gating sensory cortical plasticity that underlies the sensory richness of newly formed memories.

Extracellular ATP modulates synaptic plasticity induced by activation of metabotropic glutamate receptors in the hippocampus.

Synaptic plasticity is believed to be a cellular mechanism for memory formation in the brain. It has been known that the metabotropic glutamate receptor (mGluR) is required for persistent forms of memory and induction of synaptic plasticity. Application of mGluR agonists induces synaptic plasticity in the absence of electrical conditioning stimulation, such as high or low frequency stimulation. The direction of the mGluR-induced synaptic plasticity, i.e., either long-term potentiation (LTP) or long-term-depression (LTD), is dependent on whether N-methyl-D-aspartate receptors (NMDARs) are co-activated with mGluRs. ATP has modulatory effects on neuronal functions and, in particular, there is increasing evidence that it plays a crucial role in synaptic plasticity. LTP can be induced by application of ATP, and this effect is inhibited by NMDAR antagonist. Although cooperative effects of NMDARs and mGluRs and of NMDARs and extracellular ATP in synaptic plasticity have been revealed, the effect of extracellular ATP on mGluR-induced synaptic plasticity is unknown. In this article, we summarize published data on mGluR- and ATP-induced synaptic plasticity, and present new data showing that extracellular ATP facilitates both the LTP and LTD induced by mGluR activation.

The role of γ-secretase in hippocampal synaptic transmission and activity-dependent synaptic plasticity

γ-Secretase plays an important role in the generation of amyloid beta and the activation of Notch receptors. In the hope that the reduction of amyloid production can help to battle Alzheimer's disease (AD) secretases were suggested to represent a potential therapeutic targets. However, the role of γ-secretase in cellular mechanisms of memory formation under physiological conditions remained to be clarified. To this end, γ-secretase was inhibited by bath-application of DAPT or Compound E and the effects on activity-dependent hippocampal synaptic plasticity and basal synaptic transmission in acute hippocampal slices from Wistar rats were examined. Bath application of DAPT or Compound E over the whole recording period of field excitatory postsynaptic potential (fEPSP) caused a reduction of synaptic potentiation within 1h after 3×1s 100Hz/10min stimulation (HFS) of Schaffer-collateral CA1 synapses. Notably, DAPT and Compound E inhibited effectively long-term potentiation (LTP) of fEPSPs when it was applied after HFS, but not if applied only during the tetanization paradigm. Compounds did not affect basal synaptic transmission, paired-pulse facilitation and NMDA mediated fEPSPs. Our data thus imply that γ-secretase plays a role in LTP and most notably for the persistence of activity dependent synaptic plasticity, presumably through the reduction of endogenous amyloid beta and/or Notch receptor activation. Targeting of γ-secretase to prevent the onset of AD might by itself alter memory formation.

Learning to learn – Intrinsic plasticity as a metaplasticity mechanism for memory formation

“Use it or lose it” is a popular adage often associated with use-dependent enhancement of cognitive abilities. Much research has focused on understanding exactly how the brain changes as a function of experience. Such experience-dependent plasticity involves both structural and functional alterations that contribute to adaptive behaviors, such as learning and memory, as well as maladaptive behaviors, including anxiety disorders, phobias, and posttraumatic stress disorder. With the advancing age of our population, understanding how use-dependent plasticity changes across the lifespan may also help to promote healthy brain aging. A common misconception is that such experience-dependent plasticity (e.g., associative learning) is synonymous with synaptic plasticity. Other forms of plasticity also play a critical role in shaping adaptive changes within the nervous system, including intrinsic plasticity – a change in the intrinsic excitability of a neuron. Intrinsic plasticity can result from a change in the number, distribution or activity of various ion channels located throughout the neuron. Here, we review evidence that intrinsic plasticity is an important and evolutionarily conserved neural correlate of learning. Intrinsic plasticity acts as a metaplasticity mechanism by lowering the threshold for synaptic changes. Thus, learning-related intrinsic changes can facilitate future synaptic plasticity and learning. Such intrinsic changes can impact the allocation of a memory trace within a brain structure, and when compromised, can contribute to cognitive decline during the aging process. This unique role of intrinsic excitability can provide insight into how memories are formed and, more interestingly, how neurons that participate in a memory trace are selected. Most importantly, modulation of intrinsic excitability can allow for regulation of learning ability – this can prevent or provide treatment for cognitive decline not only in patients with clinical disorders but also in the aging population.

Sleep for Preserving and Transforming Episodic Memory

Sleep is known to support memory consolidation. Here we review evidence for an active system consolidation occurring during sleep. At the beginning of this process is sleep's ability to preserve episodic experiences preferentially encoded in hippocampal networks. Repeated neuronal reactivation of these representations during slow-wave sleep transforms episodic representations into long-term memories, redistributes them toward extrahippocampal networks, and qualitatively changes them to decontextualized schema-like representations. Electroencephalographic (EEG) oscillations regulate the underlying communication: Hippocampal sharp-wave ripples coalescing with thalamic spindles mediate the bottom-up transfer of reactivated memory information to extrahippocampal regions. Neocortical slow oscillations exert a supraordinate top-down control to synchronize hippocampal reactivations of specific memories to their excitable up-phase, thus allowing plastic changes in extrahippocampal regions. We propose that reactivations during sleep are a general mechanism underlying the abstraction of temporally stable invariants from a flow of input that is solely structured in time, thus representing a basic mechanism of memory formation.

Big answers from a small fly with a cultured brain

Anyone who has swatted flies buzzing over their food knows how deftly they manoeuvre their bodies in the air, and how quickly they learn, forcing you to readjust your striking strategy. Their intelligence is almost humbling for humans. Flies display their learning abilities in various contexts, and a well-studied example is their memory linking odours to noxious stimuli. The fruit fly Drosophila can associate conditioned stimuli (such as odour) with unconditioned stimuli (a foot shock) and learn to increase avoidance with the presentation of odour. The association between odour and shock can be retained over a long period. In order to understand how such memories in a classical conditioning paradigm are formed at the cellular level, delineating the neural networks responsible is critical. Over the years, the anatomical basis of such learning processes has been studied, and the critical role of the brain structure known as the mushroom body has been established (de Belle & Heisenberg, 1994). In this issue of The Journal of Physiology, an article by Ueno et al. (2012), using an innovative, state of the art technique, examined how information is integrated at synapses in the mushroom body. The authors isolated fly brains and cultured them in vitro, even over a week in some experiments. Using genetically encoded Ca2+ indicators in the cultured brain preparation, the authors showed that information encoding odour and shock, transmitted through distinct pathways, is integrated in specific areas of the mushroom body. The pathways for odour and shock are antennal lobes (AL) and ascending fibres of the ventral nerve cord (AFV), respectively. The use of cultured brains enabled the direct stimulation of AL and AFV in a mechanically stable condition, emulating odour and shock input. Simultaneous stimulation of both pathways led to long-term enhancement of the odour-induced response, persisting over 2 h. The authors went further and elucidated the neurotransmitters and their receptors playing roles in the memory formation. The input of odour information to the mushroom body is mediated by nicotinic acetylcholine receptors, while that of shock information is mediated by NMDA receptors. Moreover, D1 dopamine receptors, which are not required for individual AL- or AFV-mediated Ca2+ responses, are necessary during the simultaneous stimulation for establishing long-term enhancement. Importantly, the properties of long-term enhancement, both in terms of physiology and genetics, resembled those of memory formation at the behavioural level, suggesting that the revealed network underlies the behaviour. An intriguing aspect of Drosophila neurons, highlighted in the cultured brain preparation, is the surprisingly high concentration of Mg2+, above 20 mm, in the haemolymph. In a paper recently published in Neuron, the same group reported that the Mg2+ block of NMDA receptors, which occurs only in high Mg2+ concentrations, plays a critical role in the formation of long-term memory (Miyashita et al. 2012). Twenty millimolar Mg2+ in the semi-intact cultured brain system revealed physiologically relevant areas in the mushroom body for signal transduction. The synaptic basis of olfactory aversive conditioning and the receptors involved in the process pose interesting questions for synapse physiology. In particular, interactions of the dopaminergic and cholinergic systems have been implicated in the mushroom body (Tsydzik & Wright, 2009), and the role of D1 dopamine receptors in the memory circuit is highly intriguing. The region-specific rescue experiment suggests that dopamine receptors expressed in the mushroom body are critical. Do they modify postsynaptic nicotinic acetylcholine receptors, or do they regulate release of acetylcholine vesicles in a retrograde fashion? How are they activated and modified in the learning process? The mechanism of memory formation is a hotly studied area of neuroscience, and researchers use different models. Thanks to a plethora of available genetic tools, Drosophila provides valuable information to advance the field. With newly developed experimental techniques, Drosophila neuroscientists will continue to explore the physiological basis of memory. In the meantime, based on their efforts, we can envision a neural circuit taking shape in the brains of tiny insects the next time we narrowly miss a fly hovering over our meal!

Reward Value Determines Memory Consolidation in Parasitic Wasps

Animals can store learned information in their brains through a series of distinct memory forms. Short-lasting memory forms can be followed by longer-lasting, consolidated memory forms. However, the factors determining variation in memory consolidation encountered in nature have thus far not been fully elucidated. Here, we show that two parasitic wasp species belonging to different families, Cotesia glomerata (Hymenoptera: Braconidae) and Trichogramma evanescens (Hymenoptera; Trichogrammatidae), similarly adjust the memory form they consolidate to a fitness-determining reward: egg-laying into a host-insect that serves as food for their offspring. Protein synthesis-dependent long-term memory (LTM) was consolidated after single-trial conditioning with a high-value host. However, single-trial conditioning with a low-value host induced consolidation of a shorter-lasting memory form. For Cotesia glomerata, we subsequently identified this shorter-lasting memory form as anesthesia-resistant memory (ARM) because it was not sensitive to protein synthesis inhibitors or anesthesia. Associative conditioning using a single reward of different value thus induced a physiologically different mechanism of memory formation in this species. We conclude that the memory form that is consolidated does not only change in response to relatively large differences in conditioning, such as the number and type of conditioning trials, but is also sensitive to more subtle differences, such as reward value. Reward-dependent consolidation of exclusive ARM or LTM provides excellent opportunities for within-species comparison of mechanisms underlying memory consolidation.

About similar characteristics of visual perceptual learning and LTP

Perceptual learning is an implicit form of learning which induces long-lasting perceptual enhancements. Perceptual learning shows intriguing characteristics. For example, a minimal number of trials per session is needed for learning and the interleaved presentation of more than one stimulus type can hinder learning. Here, we show that these and other characteristics of perceptual learning are very similar to characteristics of long-term potentiation (LTP), the basic mechanism of memory formation. We outline these characteristics and discuss results of electrophysiological experiments which indirectly link LTP and perceptual learning.

ANTS SYNTHESISE PROTEINS FOR LONG-TERM MEMORY

Foraging insects need to exploit every available cue to track down food fast. This is why many insects associate certain scents with food in order to home in on tasty treats. They can also be trained to associate specific odours with sweet or bitter tastes, and scientists have taken advantage of this skill to learn about the mechanisms of memory formation. ‘They learn simple and complex associations and possess a relatively simple nervous system that allows retracing associative phenomena to the cellular and molecular level,’ explain Fernando Guerrieri and his colleagues from the University of Copenhagen, Denmark and the University of Toulouse, France. According to the team, the strength of a memory depends on the way the ants were trained, with short memories lasting no more than an hour and long-term memories holding for days. Also, new proteins have to be synthesised in the brain for a memory to be truly long term. Knowing that Camponotus fellah ants seem to be able to retain memories for at least 3 days, Guerrieri and his colleagues Patrizia d'Ettorre, Jean-Marc Devaud and Martin Giurfa decided to find out whether the memories were genuinely long term by testing to see if ants' brains synthesise new proteins after long-term memory training (p. 3300).‘A hungry harnessed ant extends its maxilla-labium [mouth parts] when its antennae are stimulated with a sucrose solution,’ the team explains, and adds, ‘the maxilla-labium extension reflex can also be elicited by odours if these are appropriately paired with sucrose solution.’ Training ants to associate sweet sucrose with the scent of the hydrocarbon docosane – extending their mouth parts when presented with the odour – the team also trained the ants to associated bitter-tasting quinine with another hydrocarbon, octacosane, to keep their mouths immobile in response to the scent. Next, they tested the insects' memories 1 h, 12 h and 3 days after training to see if the insects remembered when to extend their mouthparts and when to keep them retracted. Sure enough, the ants remembered to extend their mouthparts in response to docosane while remaining immobile when their antennae picked up octacosane. Their long-term memory seemed to be primed, but had they consolidated the memory by synthesising new proteins in their brains?The team repeated the experiment, training another group of ants to associate the odours and hydrocarbons, but this time they fed the ants a chemical, cycloheximide, before training to prevent them from synthesising new proteins. If the 72-h-old memories were genuinely long term, the ants that had been fed cycloheximide would be unable to distinguish between the two odours 3 days later: and they didn't. However, the ants had no problem forming short- and mid-term memories. They still remembered the odours 1 h and 12 h after testing; they just couldn't consolidate their long-term memories by synthesising proteins.So, having shown that protein synthesis is the key to ants' long-term memories, the team is keen to find out whether ants use the same memory structures and circuits as that other champion of insect memory, the bee, and to learn more about how insects use their memories to navigate their complex environments in search of food.

Circuit Mechanisms of Memory Formation

Memory formation is one of the most fascinating and complex brain functions. A large body of research over the last decades has drastically increased our understanding of the molecular and cellular processes underlying learning, most notably through a detailed investigation of synaptic plasticity. This reductionist approach, typically involving in vitro experiments, has been tremendously successful in providing a mechanistic framework for learning at the level of single neurons. However, real-life memories are formed through dynamic interactions of many neurons embedded in large networks. Investigating the mechanisms and consequences of learning at the level of neuronal circuits is technically much more demanding, and we are only beginning to understand this important topic. This special issue presents recent progress in illuminating the most exciting issues in the field of circuit mechanisms of memory formation. The contributing articles cover essential concepts and hypotheses underlying memory formation ranging from synaptic mechanisms of plasticity in neuronal microcircuits to circuit reorganizations in response to physiological and pathological influences.

Protein Kinase C Phosphorylation Regulates Membrane Insertion of GABAA Receptor Subtypes That Mediate Tonic Inhibition

Tonic inhibition in the brain is mediated largely by specialized populations of extrasynaptic receptors, γ-aminobutyric acid receptors (GABA(A)Rs). In the dentate gyrus region of the hippocampus, tonic inhibition is mediated primarily by GABA(A)R subtypes assembled from α4β2/3 with or without the δ subunit. Although the gating of these receptors is subject to dynamic modulation by agents such as anesthetics, barbiturates, and neurosteroids, the cellular mechanisms neurons use to regulate their accumulation on the neuronal plasma membrane remain to be determined. Using immunoprecipitation coupled with metabolic labeling, we demonstrate that the α4 subunit is phosphorylated at Ser(443) by protein kinase C (PKC) in expression systems and hippocampal slices. In addition, the β3 subunit is phosphorylated on serine residues 408/409 by PKC activity, whereas the δ subunit did not appear to be a PKC substrate. We further demonstrate that the PKC-dependent increase of the cell surface expression of α4 subunit-containing GABA(A)Rs is dependent on Ser(443). Mechanistically, phosphorylation of Ser(443) acts to increase the stability of the α4 subunit within the endoplasmic reticulum, thereby increasing the rate of receptor insertion into the plasma membrane. Finally, we show that phosphorylation of Ser(443) increases the activity of α4 subunit-containing GABA(A)Rs by preventing current run-down. These results suggest that PKC-dependent phosphorylation of the α4 subunit plays a significant role in enhancing the cell surface stability and activity of GABA(A)R subtypes that mediate tonic inhibition.

Epigenetic mechanisms in memory formation

International Journal of Developmental NeuroscienceVolume 28, Issue 8 p. 639-639 Article [PL1]: Epigenetic mechanisms in memory formation J.D. Sweatt, J.D. Sweatt UAB School of Medicine, USASearch for more papers by this author J.D. Sweatt, J.D. Sweatt UAB School of Medicine, USASearch for more papers by this author First published: 01 November 2010 https://doi.org/10.1016/j.ijdevneu.2010.07.003Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume28, Issue8Abstracts to the 18th Biennial Meeting of the International Society for Developmental Neuroscience, 6-9 June 2010, Estoril, PortugalDecember 2010Pages 639-639 RelatedInformation

Myosin IIb Regulates Actin Dynamics during Synaptic Plasticity and Memory Formation

Reorganization of the actin cytoskeleton is essential for synaptic plasticity and memory formation. Presently, the mechanisms that trigger actin dynamics during these brain processes are poorly understood. In this study, we show that myosin II motor activity is downstream of LTP induction and is necessary for the emergence of specialized actin structures that stabilize an early phase of LTP. We also demonstrate that myosin II activity contributes importantly to an actin-dependent process that underlies memory consolidation. Pharmacological treatments that promote actin polymerization reversed the effects of a myosin II inhibitor on LTP and memory. We conclude that myosin II motors regulate plasticity by imparting mechanical forces onto the spine actin cytoskeleton in response to synaptic stimulation. These cytoskeletal forces trigger the emergence of actin structures that stabilize synaptic plasticity. Our studies provide a mechanical framework for understanding cytoskeletal dynamics associated with synaptic plasticity and memory formation.

An Animal Model for the Treatment of Alzheimer's Disease: Potential for a New Direction in Therapies that Enhance the Epigenic Mechanisms of Memory Formation

An Animal Model for the Treatment of Alzheimer's Disease: Potential for a New Direction in Therapies that Enhance the Epigenic Mechanisms of Memory Formation

Dendritic Spines: The Stuff That Memories Are Made Of?

Two new studies explore structural changes of nerve cells as a potential mechanism for memory formation by studying synaptic reorganization associated with motor learning.

Forgetting Is Regulated through Rac Activity in Drosophila

Initially acquired memory dissipates rapidly if not consolidated. Such memory decay is thought to result either from the inherently labile nature of newly acquired memories or from interference by subsequently attained information. Here we report that a small G protein Rac-dependent forgetting mechanism contributes to both passive memory decay and interference-induced forgetting in Drosophila. Inhibition of Rac activity leads to slower decay of early memory, extending it from a few hours to more than one day, and to blockade of interference-induced forgetting. Conversely, elevated Rac activity in mushroom body neurons accelerates memory decay. This forgetting mechanism does not affect memory acquisition and is independent of Rutabaga adenylyl cyclase-mediated memory formation mechanisms. Endogenous Rac activation is evoked on different time scales during gradual memory loss in passive decay and during acute memory removal in reversal learning. We suggest that Rac's role in actin cytoskeleton remodeling may contribute to memory erasure.

Aiding in the evolution of translational medicine: “Bridging Academia and Industry” in the field of neuroscience

Aiding in the evolution of translational medicine: “Bridging Academia and Industry” in the field of neuroscience

Short Trains of Theta Frequency Stimulation Enhance CA1 Pyramidal Neuron Excitability in the Absence of Synaptic Potentiation

Although plasticity at excitatory synapses is widely studied as a mechanism for memory formation, less is known about the properties and mechanisms underlying activity-dependent changes in excitability. Using extracellular and intracellular recordings in hippocampal slices, we find that short trains (2-3 s) of Schaffer collateral fiber stimulation delivered at 5 Hz induce a robust and persistent increase in the excitability of CA1 pyramidal cells in the absence of synaptic potentiation. This change in excitability is input specific, NMDA receptor dependent, and is not accompanied by lasting changes in either inhibitory synaptic transmission or somatic excitability. Although many of these properties are similar to those seen in synaptic long-term potentiation (LTP), the increase in CA1 pyramidal cell excitability was not blocked by inhibitors of several protein kinases required for the induction of LTP by theta frequency stimulation. Instead, 5 Hz stimulation-induced changes in neuronal excitability were blocked by inhibitors of the protein phosphatase calcineurin. Together, our results suggest that very brief bouts of theta frequency synaptic activity induce a selective, persistent, and dendritically localized increase in CA1 pyramidal cell excitability that might have an important role in both information storage and metaplasticity.

Olfactory host finding, intermediate memory and its potential ecological adaptation in Nasonia vitripennis

Associative learning of host-associated chemical cues was studied in Nasonia vitripennis, a parasitoid of fly pupae in nests of hole-nesting birds. When females encountered a fly pupa and performed one sequence of host recognition behaviour including drilling the ovipositor into the host in the presence of the artificial odour furfurylheptanoate (FFH), they were afterwards arrested by FFH in olfactometer experiments. The response vanished after 4 days and could be blocked after 3 days by feeding wasps with ethacrynic acid prior and after the training. This indicates the formation of an intermediate form of memory by one host experience in N. vitripennis. Interestingly, the trained wasps avoided odours that were not present during the host encounter, although naive wasps did not react to these odours. This unique behaviour probably causes wasps to focus during host searching on those chemical cues they have experienced in the host environment. Studies in nests of hole-nesting birds revealed that about 30% of all nests contained only one fly pupa, and laboratory studies showed that N. vitripennis females are able to parasitise around 100 fly pupae in their life. It is discussed that under these conditions, the formation of a non-permanent intermediate memory for host-associated odours after one host encounter is adaptive to avoid costs involved with formation and maintenance of memory for misleading cues. The demonstration of associative olfactory learning in N. vitripennis, the first parasitoid species with sequenced genome, opens the gate to study molecular mechanisms of memory formation and its ecological adaptation in parasitoids.

Altered gene expression of histone deacetylases in mood disorder patients

While the aging of the population is a sign of progress for societies, it also carries its load of negative aspects. Among them, cognitive decline and in particular memory loss is a common feature of non-pathological aging. Autobiographical memories, which rely on the hippocampus, are a primary target of age-related cognitive decline. Here, focusing on the neurobiological mechanisms of memory formation and storage, we describe how hippocampal functions are altered across time in non-pathological mammalian brains. Several hallmarks of aging have been well described over the last decades; among them, we consider altered synaptic communication and plasticity, reduction of adult neurogenesis and epigenetic alterations. Building on the neurobiological processes of cognitive aging that have been identified to date, we review some of the strategies based on lifestyle manupulation allowing to address age-related cognitive deficits.