Localization of a stable neural correlate of associative memory

Do learning and retrieval of a memory activate the same neurons? Does the number of reactivated neurons correlate with memory strength? We developed a transgenic mouse that enables the long-lasting genetic tagging of c-fos-active neurons. We found neurons in the basolateral amygdala that are activated during Pavlovian fear conditioning and are reactivated during memory retrieval. The number of reactivated neurons correlated positively with the behavioral expression of the fear memory, indicating a stable neural correlate of associative memory. The ability to manipulate these neurons genetically should allow a more precise dissection of the molecular mechanisms of memory encoding within a distributed neuronal network.     

Amygdalar and hippocampal theta rhythm synchronization during fear memory retrieval

The amygdalohippocampal circuit plays a pivotal role in Pavlovian fear memory. We simultaneously recorded electrical activity in the lateral amygdala (LA) and the CA1 area of the hippocampus in freely behaving fear-conditioned mice. Patterns of activity were related to fear behavior evoked by conditioned and indifferent sensory stimuli and contexts. Rhythmically synchronized activity at theta frequencies increased between the LA and the CA1 after fear conditioning and became significant during confrontation with conditioned fear stimuli and expression of freezing behavior. Synchronization of theta activities in the amygdalohippocampal network represents a neuronal correlate of conditioned fear, apt to improve neuronal communication during memory retrieval.     

Neuronal competition and selection during memory formation

Competition between neurons is necessary for refining neural circuits during development and may be important for selecting the neurons that participate in encoding memories in the adult brain. To examine neuronal competition during memory formation, we conducted experiments with mice in which we manipulated the function of CREB (adenosine 3',5'-monophosphate response element-binding protein) in subsets of neurons. Changes in CREB function influenced the probability that individual lateral amygdala neurons were recruited into a fear memory trace. Our results suggest a competitive model underlying memory formation, in which eligible neurons are selected to participate in amemorytrace as a function of their relative CREB activity at the time of learning.     

Postsynaptic receptor trafficking underlying a form of associative learning

To elucidate molecular, cellular, and circuit changes that occur in the brain during learning, we investigated the role of a glutamate receptor subtype in fear conditioning. In this form of learning, animals associate two stimuli, such as a tone and a shock. Here we report that fear conditioning drives AMPA-type glutamate receptors into the synapse of a large fraction of postsynaptic neurons in the lateral amygdala, a brain structure essential for this learning process. Furthermore, memory was reduced if AMPA receptor synaptic incorporation was blocked in as few as 10 to 20% of lateral amygdala neurons. Thus, the encoding of memories in the lateral amygdala is mediated by AMPA receptor trafficking, is widely distributed, and displays little redundancy.     

The neurobiology of learning and memory

Study of the neurobiology of learning and memory is in a most exciting phase. Behavioral studies in animals are characterizing the categories and properties of learning and memory; essential memory trace circuits in the brain are being defined and localized in mammalian models; work on human memory and the brain is identifying neuronal systems involved in memory; the neuronal, neurochemical, molecular, and biophysical substrates of memory are beginning to be understood in both invertebrate and vertebrate systems; and theoretical and mathematical analysis of basic associative learning and of neuronal networks in proceeding apace. Likely applications of this new understanding of the neural bases of learning and memory range from education to the treatment of learning disabilities to the design of new artificial intelligence systems.     

Neuroscience. Immune molecules prune neural links

In work described on page 2155, a team of neuroscientists suggests that the class I major histocompatibility complex proteins, previously known for their role in controlling immune responses, also play a role in the nervous system. They are necessary for the formation of normal neuronal connections in a visual area of the brain during development, and later in life, they're called into play in the hippocampus, a brain area involved in memory and learning. The work shows a completely unexpected function for the immune system molecules.     

The involvement of the anterior cingulate cortex in remote contextual fear memory

Although the molecular, cellular, and systems mechanisms required for initial memory processing have been intensively investigated, those underlying permanent memory storage remain elusive. We present neuroanatomical, pharmacological, and genetic results demonstrating that the anterior cingulate cortex plays a critical role in remote memory for contextual fear conditioning. Imaging of activity-dependent genes shows that the anterior cingulate is activated by remote memory and that this activation is impaired by a null alpha-CaMKII mutation that blocks remote memory. Accordingly, reversible inactivation of this structure in normal mice disrupts remote memory without affecting recent memory.     

Synaptic protein degradation underlies destabilization of retrieved fear memory

Reactivated memory undergoes a rebuilding process that depends on de novo protein synthesis. This suggests that retrieval is dynamic and serves to incorporate new information into preexisting memories. However, little is known about whether or not protein degradation is involved in the reorganization of retrieved memory. We found that postsynaptic proteins were degraded in the hippocampus by polyubiquitination after retrieval of contextual fear memory. Moreover, the infusion of proteasome inhibitor into the CA1 region immediately after retrieval prevented anisomycin-induced memory impairment, as well as the extinction of fear memory. This suggests that ubiquitin- and proteasome-dependent protein degradation underlies destabilization processes after fear memory retrieval. It also provides strong evidence for the existence of reorganization processes whereby preexisting memory is disrupted by protein degradation, and updated memory is reconsolidated by protein synthesis.     

Glucocorticoids can induce PTSD-like memory impairments in mice

Posttraumatic stress disorder (PTSD) is characterized by a hypermnesia of the trauma and by a memory impairment that decreases the ability to restrict fear to the appropriate context. Infusion of glucocorticoids in the hippocampus after fear conditioning induces PTSD-like memory impairments and an altered pattern of neural activation in the hippocampal-amygdalar circuit. Mice become unable to identify the context as the correct predictor of the threat and show fear responses to a discrete cue not predicting the threat in normal conditions. These data demonstrate PTSD-like memory impairments in rodents and identify a potential pathophysiological mechanism of this condition.     

Calcium-permeable AMPA receptor dynamics mediate fear memory erasure

Traumatic fear memories can be inhibited by behavioral therapy for humans, or by extinction training in rodent models, but are prone to recur. Under some conditions, however, these treatments generate a permanent effect on behavior, which suggests that emotional memory erasure has occurred. The neural basis for such disparate outcomes is unknown. We found that a central component of extinction-induced erasure is the synaptic removal of calcium-permeable α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) in the lateral amygdala. A transient up-regulation of this form of plasticity, which involves phosphorylation of the glutamate receptor 1 subunit of the AMPA receptor, defines a temporal window in which fear memory can be degraded by behavioral experience. These results reveal a molecular mechanism for fear erasure and the relative instability of recent memory.     

Spine-type-specific recruitment of newly synthesized AMPA receptors with learning

The stabilization of long-term memories requires de novo protein synthesis. How can proteins, synthesized in the soma, act on specific synapses that participate in a given memory? We studied the dynamics of newly synthesized AMPA-type glutamate receptors (AMPARs) induced with learning using transgenic mice expressing the GluR1 subunit fused to green fluorescent protein (GFP-GluR1) under control of the c-fos promoter. We found learning-associated recruitment of newly synthesized GFP-GluR1 selectively to mushroom-type spines in adult hippocampal CA1 neurons 24 hours after fear conditioning. Our results are consistent with a "synaptic tagging" model to allow activated synapses to subsequently capture newly synthesized receptor and also demonstrate a critical functional distinction in the mushroom spines with learning.     

Generation of a synthetic memory trace

We investigated the effect of activating a competing, artificially generated, neural representation on encoding of contextual fear memory in mice. We used a c-fos-based transgenic approach to introduce the hM(3)D(q) DREADD receptor (designer receptor exclusively activated by designer drug) into neurons naturally activated by sensory experience. Neural activity could then be specifically and inducibly increased in the hM(3)D(q)-expressing neurons by an exogenous ligand. When an ensemble of neurons for one context (ctxA) was artificially activated during conditioning in a distinct second context (ctxB), mice formed a hybrid memory representation. Reactivation of the artificially stimulated network within the conditioning context was required for retrieval of the memory, and the memory was specific for the spatial pattern of neurons artificially activated during learning. Similar stimulation impaired recall when not part of the initial conditioning.     

Oxytocin selectively gates fear responses through distinct outputs from the central amygdala

Central amygdala (CeA) projections to hypothalamic and brain stem nuclei regulate the behavioral and physiological expression of fear, but it is unknown whether these different aspects of the fear response can be separately regulated by the CeA. We combined fluorescent retrograde tracing of CeA projections to nuclei that modulate fear-related freezing or cardiovascular responses with in vitro electrophysiological recordings and with in vivo monitoring of related behavioral and physiological parameters. CeA projections emerged from separate neuronal populations with different electrophysiological characteristics and different response properties to oxytocin. In vivo, oxytocin decreased freezing responses in fear-conditioned rats without affecting the cardiovascular response. Thus, neuropeptidergic signaling can modulate the CeA outputs through separate neuronal circuits and thereby individually steer the various aspects of the fear response.     

Truncating neurotrypsin mutation in autosomal recessive nonsyndromic mental retardation

A 4-base pair deletion in the neuronal serine protease neurotrypsin gene was associated with autosomal recessive nonsyndromic mental retardation (MR). In situ hybridization experiments on human fetal brains showed that neurotrypsin was highly expressed in brain structures involved in learning and memory. Immuno-electron microscopy on adult human brain sections revealed that neurotrypsin is located in presynaptic nerve endings, particularly over the presynaptic membrane lining the synaptic cleft. These findings suggest that neurotrypsin-mediated proteolysis is required for normal synaptic function and suggest potential insights into the pathophysiological bases of mental retardation.     

Electroconvulsive shock effects on a reactivated memory trace: further examination

Rats showed amnesia for conditioned fear training if given an electroconvulsive shock immediately after training. Retention was unimpaired, however, when the electroconvulsive shock treatment was given 1 day after training immediately after the presentation of the stimulus used in the fear conditioning training. These results support the view that electroconvulsive shock disrupts memory trace consolidation but does not disrupt a recently reactivated memory trace.     

Fear erasure in mice requires synergy between antidepressant drugs and extinction training

Antidepressant drugs and psychotherapy combined are more effective in treating mood disorders than either treatment alone, but the neurobiological basis of this interaction is unknown. To investigate how antidepressants influence the response of mood-related systems to behavioral experience, we used a fear-conditioning and extinction paradigm in mice. Combining extinction training with chronic fluoxetine, but neither treatment alone, induced an enduring loss of conditioned fear memory in adult animals. Fluoxetine treatment increased synaptic plasticity, converted the fear memory circuitry to a more immature state, and acted through local brain-derived neurotrophic factor. Fluoxetine-induced plasticity may allow fear erasure by extinction-guided remodeling of the memory circuitry. Thus, the pharmacological effects of antidepressants need to be combined with psychological rehabilitation to reorganize networks rendered more plastic by the drug treatment.     

Vasopressin and oxytocin excite distinct neuronal populations in the central amygdala

Vasopressin and oxytocin strongly modulate autonomic fear responses, through mechanisms that are still unclear. We describe how these neuropeptides excite distinct neuronal populations in the central amygdala, which provides the major output of the amygdaloid complex to the autonomic nervous system. We identified these two neuronal populations as part of an inhibitory network, through which vasopressin and oxytocin modulate the integration of excitatory information from the basolateral amygdala and cerebral cortex in opposite manners. Through this network, the expression and endogenous activation of vasopressin and oxytocin receptors may regulate the autonomic expression of fear.     

Aversive learning enhances perceptual and cortical discrimination of indiscriminable odor cues

Learning to associate sensory cues with threats is critical for minimizing aversive experience. The ecological benefit of associative learning relies on accurate perception of predictive cues, but how aversive learning enhances perceptual acuity of sensory signals, particularly in humans, is unclear. We combined multivariate functional magnetic resonance imaging with olfactory psychophysics to show that initially indistinguishable odor enantiomers (mirror-image molecules) become discriminable after aversive conditioning, paralleling the spatial divergence of ensemble activity patterns in primary olfactory (piriform) cortex. Our findings indicate that aversive learning induces piriform plasticity with corresponding gains in odor enantiomer discrimination, underscoring the capacity of fear conditioning to update perceptual representation of predictive cues, over and above its well-recognized role in the acquisition of conditioned responses. That completely indiscriminable sensations can be transformed into discriminable percepts further accentuates the potency of associative learning to enhance sensory cue perception and support adaptive behavior.     

Building neural representations of habits

Memories for habits and skills ("implicit or procedural memory") and memories for facts ("explicit or episodic memory") are built up in different brain systems and are vulnerable to different neurodegenerative disorders in humans. So that the striatum-based mechanisms underlying habit formation could be studied, chronic recordings from ensembles of striatal neurons were made with multiple tetrodes as rats learned a T-maze procedural task. Large and widely distributed changes in the neuronal activity patterns occurred in the sensorimotor striatum during behavioral acquisition, culminating in task-related activity emphasizing the beginning and end of the automatized procedure. The new ensemble patterns remained stable during weeks of subsequent performance of the same task. These results suggest that the encoding of action in the sensorimotor striatum undergoes dynamic reorganization as habit learning proceeds.     

英语词汇记忆之研究

词汇是语言的基本组成部分。扩大词汇量、提高运用词汇的能力是学好外语的重要环节。本文从语言学、心理学、认知学和教育学的角度分别阐述一些词汇记忆的方法和技巧。词汇记忆需要一定的外语基础和知识面。它不是死记硬背,而是一种艺术