Dynamics of a hippocampal neuronal ensemble encoding trace fear memory revealed by in vivo Ca2+ imaging

Although fear memory formation is essential for survival and fear-related mental disorders, the neural circuitry and mechanism are incompletely understood. Here, we utilized trace fear conditioning to study the formation of trace fear memory in mice. We identified the entorhinal cortex (EC) as a critical component of sensory signaling to the amygdala. We adopted both loss-of-function and gain-of-function experiments to demonstrate that release of the cholecystokinin (CCK) from the EC is required for trace fear memory formation. We discovered that CCK-positive neurons project from the EC to the lateral nuclei of the amygdala (LA), and inhibition of CCK-dependent signaling in the EC prevented long-term potentiation of the auditory response in the LA and formation of trace fear memory. In summary, high-frequency activation of EC neurons triggers the release of CCK in their projection terminals in the LA, potentiating auditory response in LA neurons. The neural plasticity in the LA leads to trace fear memory formation.

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ERK phosphorylation is required for retention of trace fear memory

Neurobiology of Learning and Memory ◽

10.1016/j.nlm.2005.08.005 ◽

2006 ◽

Vol 85 (1) ◽

pp. 44-57 ◽

Cited By ~ 26

Author(s):

Julissa S. Villarreal ◽

Edwin J. Barea-Rodriguez

Keyword(s):

Fear Memory ◽

Erk Phosphorylation ◽

Trace Fear

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Deficits in Trace Fear Memory and Long-Term Potentiation in a Mouse Model for Fragile X Syndrome

Journal of Neuroscience ◽

10.1523/jneurosci.1520-05.2005 ◽

2005 ◽

Vol 25 (32) ◽

pp. 7385-7392 ◽

Cited By ~ 188

Author(s):

M.-G. Zhao

Keyword(s):

Mouse Model ◽

Fragile X Syndrome ◽

Fragile X ◽

Long Term Potentiation ◽

Fear Memory ◽

Term Potentiation ◽

Trace Fear

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Genetically targeted reporter imaging of deep neuronal network in the mammalian brain

10.1101/2020.04.08.032870 ◽

2020 ◽

Author(s):

Masafumi Shimojo ◽

Maiko Ono ◽

Hiroyuki Takuwa ◽

Koki Mimura ◽

Yuji Nagai ◽

...

Keyword(s):

Dihydrofolate Reductase ◽

Self Assembly ◽

Emission Tomography ◽

Mammalian Brain ◽

Neuronal Ensemble ◽

Positron Emission ◽

Mouse Hippocampus ◽

Brain Circuit ◽

Human Primate

AbstractPositron Emission Tomography (PET) allows biomolecular tracking, while PET monitoring of brain networks has been hampered by the lack of a suitable reporter. Here, we describe in vivo brain imaging that takes advantage of bacterial dihydrofolate reductase, ecDHFR, and its unique antagonist, TMP. In mice, peripheral administration of radiofluorinated and fluorescent TMP analogs enabled PET and intravital microscopy, respectively, of neuronal ecDHFR expressions. This technique is applicable to the visualization of neuronal ensemble activities elicited by chemogenetic manipulation in the mouse hippocampus. Notably, ecDHFR-PET offers mapping of neuronal projections in non-human primate brains, indicating the availability of ecDHFR-based tracking technologies for network monitoring. Finally, we demonstrate the utility of TMP analogs for PET assays of turnover and self-assembly of proteins tagged with ecDHFR mutants. Our findings may facilitate a broad spectrum of PET analyses of a mammalian brain circuit at molecular levels that were not previously applicable for technical reasons.

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Immediate early gene expression dynamics in vivo segregates neuronal ensemble of multiple memories

10.1101/2020.12.17.423270 ◽

2020 ◽

Author(s):

P. Meenakshi ◽

S. Kumar ◽

J. Balaji

Keyword(s):

Retrosplenial Cortex ◽

Contextual Fear Conditioning ◽

Early Gene ◽

Immediate Early ◽

Temporal Expression ◽

Contextual Fear ◽

Two Photon ◽

Neuronal Ensemble ◽

Gene Expression Dynamics

AbstractImmediate early genes (IEGs) are widely used as a marker for neuronal plasticity. Here, we model the dynamics of IEG expression as a consecutive, irreversible first order reaction with a limiting substrate. We show that such a model, together with two-photon in vivo imaging of IEG expression, can be used to identify distinct neuronal subsets representing multiple memories. We image retrosplenial cortex (RSc) of cFOS-GFP transgenic mice to follow the dynamics of cellular changes resulting from both seizure and contextual fear conditioning behaviour. The analytical expression allowed us to segregate the neurons based on their temporal response to one specific behavioural event, thereby improving the sensitivity of detecting plasticity related neurons. This enables us to establish representation of context in RSc at the cellular scale following memory acquisition. Thus, we obtain a general method which distinguishes neurons that took part in multiple temporally separated events, by measuring fluorescence from individual neurons in live mice.SummaryIdentifying neuronal ensemble associated with different memories is vital in modern neuroscience. Meenakshi et al model and use the temporal expression dynamics of IEGs rather than thresholded intensities of the probes to identify the neurons encoding different memory in vivo.Graphical abstract

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The entorhinal cortex modulates trace fear memory formation and neuroplasticity in the lateral amygdala via cholecystokinin

10.1101/2021.04.18.440346 ◽

2021 ◽

Author(s):

Hemin Feng ◽

Junfeng Su ◽

Wei Fang ◽

Xi Chen ◽

Jufang He

Keyword(s):

Entorhinal Cortex ◽

Neural Plasticity ◽

Long Term Potentiation ◽

Fear Memory ◽

Memory Formation ◽

Loss Of Function ◽

Sensory Stimuli ◽

Sensory Signals ◽

Term Potentiation ◽

Trace Fear

Although the neural circuitry underlying fear memory formation is important in fear-related mental disorders, it is incompletely understood. Here, we utilized trace fear conditioning to study the formation of trace fear memory. We identified the entorhinal cortex (EC) as a critical component of sensory signaling to the amygdala. Moreover, we used the loss of function and rescue experiments to demonstrate that release of the neuropeptide cholecystokinin (CCK) from the EC is required for trace fear memory formation. We discovered that CCK-positive neurons extend from the EC to the lateral nuclei of the amygdala (LA), and inhibition of CCK21 dependent signaling in the EC prevented long-term potentiation of sensory signals to the LA and formation of trace fear memory. Altogether, we suggest a model where sensory stimuli trigger the release of CCK from EC neurons, which potentiates sensory signals to the LA, ultimately influencing neural plasticity and trace fear memory formation.

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Activation of astrocytes in hippocampus decreases fear memory through adenosine A1 receptors

eLife ◽

10.7554/elife.57155 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 1

Author(s):

Yulan Li ◽

Lixuan Li ◽

Jintao Wu ◽

Zhenggang Zhu ◽

Xiang Feng ◽

...

Keyword(s):

Therapeutic Strategy ◽

Fear Memory ◽

In Vivo Microdialysis ◽

Astrocyte Activation ◽

Temporal Window ◽

Contextual Fear ◽

Adenosine A1 ◽

Memory Acquisition ◽

Anxiety Behavior

Astrocytes respond to and regulate neuronal activity, yet their role in mammalian behavior remains incompletely understood. Especially unclear is whether, and if so how, astrocyte activity regulates contextual fear memory, the dysregulation of which leads to pathological fear-related disorders. We generated GFAP-ChR2-EYFP rats to allow the specific activation of astrocytes in vivo by optogenetics. We found that after memory acquisition within a temporal window, astrocyte activation disrupted memory consolidation and persistently decreased contextual but not cued fear memory accompanied by reduced fear-related anxiety behavior. In vivo microdialysis experiments showed astrocyte photoactivation increased extracellular ATP and adenosine concentrations. Intracerebral blockade of adenosine A1 receptors (A1Rs) reversed the attenuation of fear memory. Furthermore, intracerebral or intraperitoneal injection of A1R agonist mimicked the effects of astrocyte activation. Therefore, our findings provide a deeper understanding of the astrocyte-mediated regulation of fear memory and suggest a new and important therapeutic strategy against pathological fear-related disorders.

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A time-dependent role for the transcription factor CREB in neuronal allocation to an engram underlying a fear memory revealed using a novel in vivo optogenetic tool to modulate CREB function

Neuropsychopharmacology ◽

10.1038/s41386-019-0588-0 ◽

2019 ◽

Vol 45 (6) ◽

pp. 916-924 ◽

Cited By ~ 5

Author(s):

Albert Park ◽

Alexander D. Jacob ◽

Brandon J. Walters ◽

Sungmo Park ◽

Asim J. Rashid ◽

...

Keyword(s):

Transcription Factor ◽

Fear Memory ◽

Time Dependent

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Interplay of Amygdala and Cingulate Plasticity in Emotional Fear

Neural Plasticity ◽

10.1155/2011/813749 ◽

2011 ◽

Vol 2011 ◽

pp. 1-9 ◽

Cited By ~ 28

Author(s):

Hiroki Toyoda ◽

Xiang-Yao Li ◽

Long-Jun Wu ◽

Ming-Gao Zhao ◽

Giannina Descalzi ◽

...

Keyword(s):

Synaptic Plasticity ◽

Emotional Disorders ◽

Cortical Neurons ◽

Fear Memory ◽

Anterior Cingulate ◽

Cortical Areas ◽

Freely Moving ◽

Plastic Changes ◽

Trace Fear ◽

Synaptic Level

The amygdala is known to be a critical brain region for emotional fear. It is believed that synaptic plasticity within the amygdala is the cellular basis of fear memory. Recent studies demonstrate that cortical areas such as the prefrontal cortex (PFC) and anterior cingulate cortex (ACC) may also contribute to the formation of fear memory, including trace fear memory and remote fear memory. At synaptic level, fear conditioning also triggers plastic changes within the cortical areas immediately after the condition. These results raise the possibility that certain forms of synaptic plasticity may occur within the cortex while synaptic potentiation takes place within synapses in the hippocampus and amygdala. This hypothesis is supported by electrophysiological evidence obtained from freely moving animals that neurons in the hippocampus/amygdala fire synchronous activities with cortical neurons during the learning. To study fear-related synaptic plasticity in the cortex and its functional connectivity with neurons in the amygdala and hippocampus will help us understand brain mechanisms of fear and improve clinical treatment of emotional disorders in patients.

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