Akt signaling in fear memory processing and depression‐like behaviors

Abstract Background A core symptom of posttraumatic stress disorder is persistent fear memory, which can be defined as fear memory that is resistant to updating, inhibition, or extinction. posttraumatic stress disorder emerges after traumatic stress exposure, but neurobiological mechanisms via which traumatic stress leads to persistent fear memory are not well defined. Akt signaling within the amygdala (Amy) is enhanced with traumatic stress, and phosphatidylinositol kinase 3 (PI3K) activation of Akt within the basolateral Amy (BLA) has been implicated as critical to fear memory formation. These findings raise the possibility that traumatic stress enhances PI3K→Akt signaling in the BLA, which leads to persistent fear memory. Methods To test this hypothesis, rats were exposed to traumatic stress using the single prolonged stress model, and changes in Akt phosphorylation were assayed in the Amy at 0 and 30 minutes after fear conditioning (FC). In a separate experiment, we inhibited PI3K→Akt signaling in the BLA prior to FC and observed the effect this had on acquisition, expression, and extinction of FC in stressed and control rats. Results Enhanced Akt phosphorylation in the Amy at both time points was observed in stressed rats, but not in control rats. PI3K→Akt inhibition in the BLA had no effect on freezing in control rats but decreased freezing during extinction training and testing in stressed rats. Conclusion These findings suggest that PI3K→Akt signaling in the BLA could be a mechanism via which traumatic stress leads to fear memory that is resistant to extinction.

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Molecularly-Defined Hippocampal Inputs Regulate Population Dynamics in the Prelimbic Cortex to Suppress Context Fear Memory Recall

10.1101/802967 ◽

2019 ◽

Author(s):

Henry L. Hallock ◽

Henry M. Quillian ◽

Kristen R. Maynard ◽

Yishan Mai ◽

Huei-Ying Chen ◽

...

Keyword(s):

Hippocampal Neurons ◽

Molecular Mechanisms ◽

Fear Memory ◽

Fear Learning ◽

Memory Recall ◽

Post Traumatic Stress ◽

Memory Processing ◽

Expression Of Genes ◽

Post Traumatic ◽

Genetic Targeting

AbstractAssociating fearful events with the context in which they occur is critical for survival. Dysregulation of context-fear memory processing is a hallmark symptom of several neuropsychiatric disorders, including generalized anxiety disorder (GAD) and post-traumatic stress disorder (PTSD). Both the hippocampus and prelimbic subregion (PrL) of the medial prefrontal cortex (mPFC) have been linked with context fear memory recall in rodents, but the mechanisms by which hippocampal-prelimbic circuitry regulates this process remains poorly understood. Spatial and genetic targeting of this circuit in mice allowed us to use molecular profiling to show that hippocampal neurons with projections to the PrL (vHC-PrL projectors) are a transcriptomically-distinct sub-population that is enriched for expression of genes associated with both GAD and PTSD. We further show that stimulation of this population of vHC-PrL projectors suppresses context fear memory recall and impairs the ability of PrL neurons to dynamically distinguish between distinct phases of fear learning. Using transgenic and circuit-specific molecular targeting approaches, we demonstrate that unique patterns of activity-dependent gene transcription within vHC-PrL projectors causally regulate excitatory/inhibitory balance in the PrL during context fear memory recall. Together, our data illuminate the molecular mechanisms by which hippocampal-prelimbic circuitry regulates the retrieval of contextually-mediated fear memories.

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Metabolic fingerprints of fear memory consolidation during sleep

Molecular Brain ◽

10.1186/s13041-021-00733-6 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Iyo Koyanagi ◽

Kazuhiro Sonomura ◽

Toshie Naoi ◽

Takaaki Ohnishi ◽

Naoko Kaneko ◽

...

Keyword(s):

Dentate Gyrus ◽

Memory Consolidation ◽

Conditioned Fear ◽

Fear Memory ◽

State Transitions ◽

Contextual Fear ◽

Memory Processing ◽

Contextual Fear Memory ◽

Purine Metabolites ◽

Wake State

AbstractMetabolites underlying brain function and pathology are not as well understood as genes. Here, we applied a novel metabolomics approach to further understand the mechanisms of memory processing in sleep. As hippocampal dentate gyrus neurons are known to consolidate contextual fear memory, we analyzed real-time changes in metabolites in the dentate gyrus in different sleep–wake states in mice. Throughout the study, we consistently detected more than > 200 metabolites. Metabolite profiles changed dramactically upon sleep–wake state transitions, leading to a clear separation of phenotypes between wakefulness and sleep. By contrast, contextual fear memory consolidation induced less obvious metabolite phenotypes. However, changes in purine metabolites were observed upon both sleep–wake state transitions and contextual fear memory consolidation. Dietary supplementation of certain purine metabolites impaired correlations between conditioned fear responses before and after memory consolidation. These results point toward the importance of purine metabolism in fear memory processing during sleep.

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Ex vivo and in vivo imaging of mouse parietal association cortex activity in episodes of cued fear memory formation and retrieval

10.1101/863589 ◽

2019 ◽

Author(s):

Olga I. Ivashkina ◽

Anna M. Gruzdeva ◽

Marina A. Roshchina ◽

Ksenia A. Toropova ◽

Konstantin V. Anokhin

Keyword(s):

Parietal Cortex ◽

Ex Vivo ◽

Anterior Part ◽

Fear Memory ◽

Memory Formation ◽

Movement Planning ◽

Association Cortex ◽

Memory Processing ◽

Two Photon

AbstractThe parietal cortex in rodents has an integrative function and participates in sensory and spatial processing, movement planning and decision-making. However, much less is known about its functions in associative memory processing. Here using Fos immunohistochemical mapping of neuronal activity and two-photon imaging in Fos-eGFP mice we show an involvement of anterior part of the parietal cortex (PtA) in the formation and retrieval of recent fear memory in mice. Using ex vivo c-fos imaging we demonstrate the specific activation of the PtA during recent memory retrieval. In vivo two-photon c-fos imaging confirms these results as well as establishes the activation of the PtA neurons during fear memory formation. Additionally, we describe a design of Fos-Cre-GCaMP transgenic mice to investigate long-term changes of calcium dynamics in neurons captured with Fos-TRAP technique during fear conditioning training.

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Prelimbic proBDNF facilitates memory destabilization by regulation of neuronal function in juveniles

10.1101/2021.12.30.474526 ◽

2022 ◽

Author(s):

Wei Sun ◽

Xiao Chen ◽

Yazi Mei ◽

Yang Yang ◽

Xiaoliang Li ◽

...

Keyword(s):

Fear Memory ◽

Suppressive Effect ◽

Synaptic Function ◽

Juvenile Period ◽

Memory Processing ◽

Memory Extinction ◽

High Level ◽

Neuronal Functions ◽

Neurodevelopment Disorders ◽

Regulation Changes

Fear regulation changes as a function of age and adolescence is a key developmental period for the continued maturation of fear neural circuitry. The involvement of prelimbic proBDNF in fear memory extinction and its mediated signaling were reported previously. Given the inherent high level of proBDNF during juvenile period, we tested whether prelimbic proBDNF regulated synaptic and neuronal functions allowing to influencing retrieval-dependent memory processing. By examining freezing behavior of auditory fear conditioned rats, we found high levels of prelimbic proBDNF in juvenile rats enhanced destabilization of the retrieval-dependent weak but not strong fear memory through activating p75NTR-GluN2B signaling. This modification was attributed to the increment in proportion of thin type spine and promotion in synaptic function, as evidence by facilitation of NMDA-mediated EPSCs and GluN2B-dependent synaptic depression. The strong prelimbic theta- and gamma-oscillation coupling predicted the suppressive effect of proBDNF on the recall of post-retrieval memory. Our results critically emphasize the importance of developmental proBDNF for modification of retrieval-dependent memory and provide a potential critical targeting to inhibit threaten memories associated with neurodevelopment disorders.

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Ablation of STAT3 in Purkinje Cells Reorganizes Cerebellar Synaptic Plasticity in Long-Term Fear Memory Network

10.1101/2020.09.14.286765 ◽

2020 ◽

Author(s):

Jeong-Kyu Han ◽

Sun-Ho Kwon ◽

Yong Gyu Kim ◽

Jaeyong Choi ◽

Jong-Il Kim ◽

...

Keyword(s):

Purkinje Cells ◽

Long Term Potentiation ◽

Fear Memory ◽

Emotional Memory ◽

Brain Regions ◽

Parallel Fiber ◽

Wild Type ◽

Memory Processing ◽

Memory Network

Emotional memory processing, such as fear memory, engages a large neuronal network of brain regions including the cerebellum. However, the molecular and cellular mechanisms of the cerebellar cortex modulating the fear memory network is largely unknown. Here, we illustrate a novel mechanism by which synaptic signaling in cerebellar Purkinje cells (PCs) via STAT3 regulates long-term fear memory. Firstly, we generated PC-specific STAT3 knockout (STAT3PKO) mice. Transcriptome analyses revealed that STAT3 deletion results in transcriptional changes that lead to an increase in the expression of glutamate receptors. The amplitude of AMPA receptor-mediated excitatory postsynaptic currents at parallel fiber to PC synapses was larger in STAT3PKO mice than in wild-type littermates. Conditioning at the parallel fiber induced long-term depression of parallel fiber-PC synapses in STAT3PKO mice while the same manipulation induced long-term potentiation in wild-type littermates. Interestingly, STAT3PKO mice showed an aberrantly enhanced long-term fear memory. Neuronal activity in fear-related regions increased in fear-conditioned STAT3PKO mice. Our data suggest that STAT3-dependent molecular regulation in PCs is indispensable for proper expression of fear memory processing.

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Exploring Refinement Strategies for Single Housing of Male C57BL/6JRj Mice: Effect of Cage Divider on Stress-Related Behavior and Hypothalamic-Pituitary-Adrenal-Axis Activity

Frontiers in Behavioral Neuroscience ◽

10.3389/fnbeh.2021.743959 ◽

2021 ◽

Vol 15 ◽

Author(s):

An Buckinx ◽

Andries Van Schuerbeek ◽

Jo Bossuyt ◽

Wissal Allaoui ◽

Yana Van Den Herrewegen ◽

...

Keyword(s):

Working Memory ◽

Hpa Axis ◽

Spontaneous Alternation ◽

Fear Memory ◽

Exploratory Activity ◽

Physical Contact ◽

Intermale Aggression ◽

Memory Processing ◽

Hypothalamic Pituitary Adrenal ◽

Y Maze

Introduction: Single housing of laboratory mice is a common practice to meet experimental needs, or to avoid intermale aggression. However, single housing is considered to negatively affect animal welfare and may compromise the scientific validity of experiments. The aim of this study was to investigate whether the use of a cage with a cage divider, which avoids physical contact between mice while maintaining sensory contact, may be a potential refinement strategy for experiments in which group housing of mice is not possible.Methods: Eight-week-old male C57BL/6JRj mice were single housed, pair housed or pair housed with a cage divider for four (experiment 1) or ten (experiment 2) weeks, after which we performed an open field test, Y-maze spontaneous alternation test, elevated plus maze test, an auditory fear conditioning task, and assessed responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis.Results: Housing conditions did not affect body weight, exploratory activity, anxiety, working memory, fear memory processing or markers for HPA-axis functioning in either experiment 1 or experiment 2. There was an increased distance traveled in mice housed with a cage divider compared to pair housed mice after 4 weeks, and after 10 weeks mice housed with a cage divider made significantly more arm entries in the Y-maze spontaneous alternation test.Conclusion: Taken together, our study did not provide evidence for robust differences in exploratory activity, anxiety, working memory and fear memory processing in male C57BL/6JRj mice that were single housed, pair housed or pair housed with a cage divider.

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