Memory Consolidation for Contextual and Auditory Fear Conditioning Is Dependent on Protein Synthesis, PKA, and MAP Kinase

Fear conditioning has received extensive experimental attention. However, little is known about the molecular mechanisms that underlie fear memory consolidation. Previous studies have shown that long-term potentiation (LTP) exists in pathways known to be relevant to fear conditioning and that fear conditioning modifies neural processing in these pathways in a manner similar to LTP induction. The present experiments examined whether inhibition of protein synthesis, PKA, and MAP kinase activity, treatments that block LTP, also interfere with the consolidation of fear conditioning. Rats were injected intraventricularly with Anisomycin (100 or 300 μg), Rp-cAMPS (90 or 180 μg), or PD098059 (1 or 3 μg) prior to conditioning and assessed for retention of contextual and auditory fear memory both within an hour and 24 hr later. Results indicated that injection of these compounds selectively interfered with long-term memory for contextual and auditory fear, while leaving short-term memory intact. Additional control groups indicated that this effect was likely due to impaired memory consolidation rather than to nonspecific effects of the drugs on fear expression. Results suggest that fear conditioning and LTP may share common molecular mechanisms.

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Integrated Overview of the Memory System

International Journal for Research in Applied Science and Engineering Technology ◽

10.22214/ijraset.2021.35690 ◽

2021 ◽

Vol 9 (VI) ◽

pp. 3328-3338

Author(s):

Ishanee Das Sharma

Keyword(s):

Molecular Mechanisms ◽

Short Term Memory ◽

Long Term Potentiation ◽

Point Of View ◽

Memory Storage ◽

Long Term Memory ◽

Special Focus ◽

Term Memory ◽

Term Potentiation

This review aims to clarify and classify memory from psychological and neuroscientific point of view, delving into the molecular mechanisms taking place as well. The main forms of memory are sensory memory, short term memory and long-term memory. We also try to specify the flow of information through various memory models. The concept of synaptic plasticity and long-term potentiation is highlighted, with special focus on the physiological parts of the brain that are involved in memory storage. Overall, this study will help expand our knowledge on the intrinsic details of memory storage and the functioning of our brain.

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Modeling memory consolidation during posttraining periods in cerebellovestibular learning

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1413798112 ◽

2015 ◽

Vol 112 (11) ◽

pp. 3541-3546 ◽

Cited By ~ 35

Author(s):

Tadashi Yamazaki ◽

Soichi Nagao ◽

William Lennon ◽

Shigeru Tanaka

Keyword(s):

Memory Consolidation ◽

Short Term Memory ◽

Mossy Fiber ◽

Long Term Potentiation ◽

Memory Formation ◽

Experimental Results ◽

Long Term Memory ◽

Optokinetic Response ◽

Term Memory

Long-term depression (LTD) at parallel fiber–Purkinje cell (PF–PC) synapses is thought to underlie memory formation in cerebellar motor learning. Recent experimental results, however, suggest that multiple plasticity mechanisms in the cerebellar cortex and cerebellar/vestibular nuclei participate in memory formation. To examine this possibility, we formulated a simple model of the cerebellum with a minimal number of components based on its known anatomy and physiology, implementing both LTD and long-term potentiation (LTP) at PF–PC synapses and mossy fiber–vestibular nuclear neuron (MF–VN) synapses. With this model, we conducted a simulation study of the gain adaptation of optokinetic response (OKR) eye movement. Our model reproduced several important aspects of previously reported experimental results in wild-type and cerebellum-related gene-manipulated mice. First, each 1-h training led to the formation of short-term memory of learned OKR gain at PF–PC synapses, which diminished throughout the day. Second, daily repetition of the training gradually formed long-term memory that was maintained for days at MF–VN synapses. We reproduced such memory formation under various learning conditions. Third, long-term memory formation occurred after training but not during training, indicating that the memory consolidation occurred during posttraining periods. Fourth, spaced training outperformed massed training in long-term memory formation. Finally, we reproduced OKR gain changes consistent with the changes in the vestibuloocular reflex (VOR) previously reported in some gene-manipulated mice.

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Perineuronal nets protect long-term memory by limiting activity-dependent inhibition from parvalbumin interneurons

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1902680116 ◽

2019 ◽

Vol 116 (52) ◽

pp. 27063-27073 ◽

Cited By ~ 7

Author(s):

Wei Shi ◽

Xiangbo Wei ◽

Xiaofei Wang ◽

Shuwen Du ◽

Weixuan Liu ◽

...

Keyword(s):

Memory Consolidation ◽

Long Term Potentiation ◽

Fear Memory ◽

Anterior Cingulate ◽

Long Term Memory ◽

Projection Neurons ◽

Perineuronal Nets ◽

Term Memory ◽

Memory Consolidation And Reconsolidation

Perineuronal nets (PNNs), a complex of extracellular matrix molecules that mostly surround GABAergic neurons in various brain regions, play a critical role in synaptic plasticity. The function and cellular mechanisms of PNNs in memory consolidation and reconsolidation processes are still not well understood. We hypothesized that PNNs protect long-term memory by limiting feedback inhibition from parvalbumin (PV) interneurons to projection neurons. Using behavioral, electrophysiological, and optogenetic approaches, we investigated the role of PNNs in fear memory consolidation and reconsolidation and GABAergic long-term potentiation (LTP). We made the discovery that the formation of PNNs was promoted by memory events in the hippocampus (HP), and we also demonstrated that PNN formation in both the HP and the anterior cingulate cortex (ACC) is essential for memory consolidation and reconsolidation of recent and remote memories. Removal of PNNs resulted in evident LTP impairments, which were rescued by acute application of picrotoxin, a GABAAreceptor blocker, indicating that enhanced inhibition was the cause of the LTP impairments induced by PNN removal. Moreover, removal of PNNs switched GABAAreceptor-mediated long-term depression to LTP through a presynaptic mechanism. Furthermore, the reduced activity of PV interneurons surrounded by PNNs regulated theta oscillations during fear memory consolidation. Finally, optogenetically suppressing PV interneurons rescued the memory impairment caused by removal of PNNs. Altogether, these results unveil the function of PV interneurons surrounding PNNs in protecting recent and remote contextual memory through the regulation of PV neuron GABA release.

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The amnestic agent anisomycin disrupts intrinsic membrane properties of hippocampal neurons via a loss of cellular energetics

Journal of Neurophysiology ◽

10.1152/jn.00370.2019 ◽

2019 ◽

Vol 122 (3) ◽

pp. 1123-1135 ◽

Cited By ~ 1

Author(s):

C. J. Scavuzzo ◽

M. J. LeBlancq ◽

F. Nargang ◽

H. Lemieux ◽

T. J. Hamilton ◽

...

Keyword(s):

Protein Synthesis ◽

Mitochondrial Function ◽

Neural Activity ◽

Memory Consolidation ◽

Hippocampal Neurons ◽

Membrane Properties ◽

Long Term Memory ◽

Term Memory ◽

Cellular Energetics

The nearly axiomatic idea that de novo protein synthesis is necessary for long-term memory consolidation is based heavily on behavioral studies using translational inhibitors such as anisomycin. Although inhibiting protein synthesis has been shown to disrupt the expression of memory, translational inhibitors also have been found to profoundly disrupt basic neurobiological functions, including the suppression of ongoing neural activity in vivo. In the present study, using transverse hippocampal brain slices, we monitored the passive and active membrane properties of hippocampal CA1 pyramidal neurons using intracellular whole cell recordings during a brief ~30-min exposure to fast-bath-perfused anisomycin. Anisomycin suppressed protein synthesis to 46% of control levels as measured using incorporation of radiolabeled amino acids and autoradiography. During its application, anisomycin caused a significant depolarization of the membrane potential, without any changes in apparent input resistance or membrane time constant. Anisomycin-treated neurons also showed significant decreases in firing frequencies and spike amplitudes, and showed increases in spike width across spike trains, without changes in spike threshold. Because these changes indicated a loss of cellular energetics contributing to maintenance of ionic gradients across the membrane, we confirmed that anisomycin impaired mitochondrial function by reduced staining with 2,3,5-triphenyltetrazolium chloride and also impaired cytochrome c oxidase (complex IV) activity as indicated through high-resolution respirometry. These findings emphasize that anisomycin-induced alterations in neural activity and metabolism are a likely consequence of cell-wide translational inhibition. Critical reevaluation of studies using translational inhibitors to promote the protein synthesis dependent idea of long-term memory is absolutely necessary. NEW & NOTEWORTHY Memory consolidation is thought to be dependent on the synthesis of new proteins because translational inhibitors produce amnesia when administered just after learning. However, these agents also disrupt basic neurobiological functions. We show that blocking protein synthesis disrupts basic membrane properties of hippocampal neurons that correspond to induced disruptions of mitochondrial function. It is likely that translational inhibitors cause amnesia through their disruption of neural activity as a result of dysfunction of intracellular energetics.

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Meningeal γδ T cell–derived IL-17 controls synaptic plasticity and short-term memory

Science Immunology ◽

10.1126/sciimmunol.aay5199 ◽

2019 ◽

Vol 4 (40) ◽

pp. eaay5199 ◽

Cited By ~ 28

Author(s):

Miguel Ribeiro ◽

Helena C. Brigas ◽

Mariana Temido-Ferreira ◽

Paula A. Pousinha ◽

Tommy Regen ◽

...

Keyword(s):

T Cell ◽

Short Term Memory ◽

Long Term Potentiation ◽

Long Term Memory ◽

Interleukin 17 ◽

Γδ T Cell ◽

Short Term ◽

Functional Link ◽

Term Memory

The notion of “immune privilege” of the brain has been revised to accommodate its infiltration, at steady state, by immune cells that participate in normal neurophysiology. However, the immune mechanisms that regulate learning and memory remain poorly understood. Here, we show that noninflammatory interleukin-17 (IL-17) derived from a previously unknown fetal-derived meningeal-resident γδ T cell subset promotes cognition. When tested in classical spatial learning paradigms, mice lacking γδ T cells or IL-17 displayed deficient short-term memory while retaining long-term memory. The plasticity of glutamatergic synapses was reduced in the absence of IL-17, resulting in impaired long-term potentiation in the hippocampus. Conversely, IL-17 enhanced glial cell production of brain-derived neurotropic factor, whose exogenous provision rescued the synaptic and behavioral phenotypes of IL-17–deficient animals. Together, our work provides previously unknown clues on the mechanisms that regulate short-term versus long-term memory and on the evolutionary and functional link between the immune and nervous systems.

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Auditory Fear Conditioning and Long-Term Potentiation in the Lateral Amygdala Require ERK/MAP Kinase Signaling in the Auditory Thalamus: A Role for Presynaptic Plasticity in the Fear System

Journal of Neuroscience ◽

10.1523/jneurosci.0096-05.2005 ◽

2005 ◽

Vol 25 (24) ◽

pp. 5730-5739 ◽

Cited By ~ 62

Author(s):

A. M. Apergis-Schoute

Keyword(s):

Map Kinase ◽

Fear Conditioning ◽

Long Term Potentiation ◽

Kinase Signaling ◽

Lateral Amygdala ◽

Auditory Thalamus ◽

Term Potentiation ◽

Presynaptic Plasticity ◽

Map Kinase Signaling

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Long-Term Memory Deficits in Pavlovian Fear Conditioning in Ca2+/Calmodulin Kinase Kinase α-Deficient Mice

Molecular and Cellular Biology ◽

10.1128/mcb.01452-06 ◽

2006 ◽

Vol 26 (23) ◽

pp. 9105-9115 ◽

Cited By ~ 28

Author(s):

Frank Blaeser ◽

Matthew J. Sanders ◽

Nga Truong ◽

Shanelle Ko ◽

Long Jun Wu ◽

...

Keyword(s):

Fear Conditioning ◽

Long Term Potentiation ◽

Long Term Memory ◽

Term Memory ◽

Calmodulin Kinase ◽

Element Binding Protein ◽

Long Term Follow Up ◽

Responsive Element ◽

Deficient Mice

ABSTRACT Signaling by the Ca2+/calmodulin kinase (CaMK) cascade has been implicated in neuronal gene transcription, synaptic plasticity, and long-term memory consolidation. The CaM kinase kinase α (CaMKKα) isoform is an upstream component of the CaMK cascade whose function in different behavioral and learning and memory paradigms was analyzed by targeted gene disruption in mice. CaMKKα mutants exhibited normal long-term spatial memory formation and cued fear conditioning but showed deficits in context fear during both conditioning and long-term follow-up testing. They also exhibited impaired activation of the downstream kinase CaMKIV/Gr and its substrate, the transcription factor cyclic AMP-responsive element binding protein (CREB) upon fear conditioning. Unlike CaMKIV/Gr-deficient mice, the CaMKKα mutants exhibited normal long-term potentiation and normal levels of anxiety-like behavior. These results demonstrate a selective role for CaMKKα in contextual fear memory and suggest that different combinations of upstream and downstream components of the CaMK cascade may serve distinct physiological functions.

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Drug inhibition of memory formation in chickens II. Short-term memory

Proceedings of the Royal Society of London Series B Biological Sciences ◽

10.1098/rspb.1971.0075 ◽

1971 ◽

Vol 178 (1053) ◽

pp. 455-464 ◽

Cited By ~ 32

Keyword(s):

Protein Synthesis ◽

Sodium Pump ◽

Short Term Memory ◽

Memory Loss ◽

Protein Synthesis Inhibitor ◽

Protein Synthesis Inhibitors ◽

Short Term ◽

Synthesis Inhibitor ◽

Term Memory

1. Memory in day-old-chickens during the first few hours after learning can be made to decline by the prior intracranial injection of two classes of drugs. 2. Sodium pump inhibitors in increasing doses cause increasingly rapid loss of memory. 3. Protein synthesis inhibitors in increasing doses attain a maximum potency in causing memory decline and the rate may not be further accelerated by higher doses. 4. Adding a sodium pump inhibitor to the inhibition of protein synthesis increases memory loss. 5. Adding a protein synthesis inhibitor to a sodium pump inhibitor causes no further loss. 6. Therefore within a few minutes of learning a short-term memory of limited time span but independent of protein synthesis becomes supplemented and eventually replaced by a long-term storage requiring protein synthesis. The amount of long-term store is set by the amount of short-term memory. 7. The short-term store could be directly dependent on post-activation enhancement of Na + extrusion from neurons. Some physiological mechanisms by which this could be achieved and how this might activate protein synthesis are discussed.

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An NMDA-R mediated short-term memory resistant to anesthesia in adult Danio rerio

10.1101/795351 ◽

2019 ◽

Author(s):

Gokul Rajan ◽

Joby Joseph

Keyword(s):

Fear Conditioning ◽

Danio Rerio ◽

Early Phase ◽

Short Term Memory ◽

Green Light ◽

Long Term Memory ◽

Adult Zebrafish ◽

Term Memory ◽

Vertebrate Model

ABSTRACTMemory in animals is labile in the early phase post-training. Memory in the early phase has been shown to be disrupted by treatments such as electroconvulsive shock or cold-shock (Quinn and Dudai, 1976). Using hypothermic shock and other pharmacological interventions, the various underlying memory pathways in Drosophila can be identified as an immediate short-lasting anesthesia sensitive memory and a delayed anesthesia resistant memory which is followed by a more stable protein synthesis dependent long-term memory (Margulies et al., 2005). In another ectothermic animal, Danio rerio, a popular vertebrate model, we ask if such a memory component exists which is sensitive to hypothermic disruption. To test this, we developed a fear conditioning assay with a green light at the bottom of the tank as the conditioned stimulus (CS) and electric shock as the unconditioned stimulus (US). We also standardized a cold anesthesia protocol in adult zebrafish to induce stage V anesthesia. The learning/memory was found to be NMDA-R mediated. Cold anesthesia as well as tricaine mediated anesthesia did not significantly affect the early-acting memory trace induced by a fear-conditioning protocol in adult zebrafish. We suggest future directions to tease out the underlying memory components in the early phase of memory in zebrafish.

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