scholarly journals Differential behavioral, stress, and sleep responses in mice with different delays of fear extinction

SLEEP ◽  
2019 ◽  
Vol 42 (10) ◽  
Author(s):  
Mayumi Machida ◽  
Amy M Sutton ◽  
Brook L Williams ◽  
Laurie L Wellman ◽  
Larry D Sanford
Keyword(s):  
Body Temperature ◽  
Stress Responses ◽  
Dark Period ◽  
Contextual Fear Conditioning ◽  
Fear Learning ◽  
Contextual Fear ◽  
Behavioral Stress ◽  
And Behavior ◽  
Sleep Amount ◽  
Shock Training

Abstract Study Objectives Sleep, in particular rapid eye movement (REM), has been linked to fear learning and extinction; however, their relationship is poorly understood. We determined how different delays of extinction training (ET) impact fear-conditioned behaviors, changes in sleep, and stress responses. Methods EEG activity, movement, and body temperature in mice were monitored via telemetry. Following contextual fear conditioning (shock training [ST]), separate groups of mice were reexposed to the context at 24-hour post-ST (24h ET-1) and at 48-hour post-ST (48h ET-1). Post-ET sleep amount and sleep-associated EEG (delta and theta) activity were compared to baseline and to post-ST sleep. Freezing, locomotion, grooming, and rearing were monitored to determine effects of ET on fear behaviors. Body temperature immediately after ET was monitored to assess stress-induced hyperthermia (SIH). Results 24h ET-1 and 48h ET-1 produced similar freezing and REM reductions, but dissimilar rearing activity and SIH. 24h ET-1 was followed by periods of suppressed REM-associated theta (REM-θ) activity, immediately after ET and during the subsequent dark period. Suppressed REM-θ was specific to sleep after 24h ET-1, and did not occur after ST, nor after 48h ET-1. Conclusions ET-1 at 24 and 48 hours after ST was associated with similar freezing and REM amounts, but with differences in other overt behaviors, in REM-θ, and in SIH. Freezing was not predictive of changes in other fear-associated responses. This study demonstrated that consideration of time delay from fear acquisition to extinction is important when assessing the relationships between extinction and behavior, sleep, and stress responses.

scholarly journals Npas4a expression in the teleost forebrain is associated with stress coping style differences in fear learning

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Matthew R. Baker ◽  
Ryan Y. Wong
Keyword(s):  
Neural Plasticity ◽  
Coping Style ◽  
Molecular Mechanisms ◽  
Conditioned Fear ◽  
Coping Styles ◽  
Brain Regions ◽  
Contextual Fear Conditioning ◽  
Fear Learning ◽  
Stress Coping ◽  
Contextual Fear

AbstractLearning to anticipate potentially dangerous contexts is an adaptive behavioral response to coping with stressors. An animal’s stress coping style (e.g. proactive–reactive axis) is known to influence how it encodes salient events. However, the neural and molecular mechanisms underlying these stress coping style differences in learning are unknown. Further, while a number of neuroplasticity-related genes have been associated with alternative stress coping styles, it is unclear if these genes may bias the development of conditioned behavioral responses to stressful stimuli, and if so, which brain regions are involved. Here, we trained adult zebrafish to associate a naturally aversive olfactory cue with a given context. Next, we investigated if expression of two neural plasticity and neurotransmission-related genes (npas4a and gabbr1a) were associated with the contextual fear conditioning differences between proactive and reactive stress coping styles. Reactive zebrafish developed a stronger conditioned fear response and showed significantly higher npas4a expression in the medial and lateral zones of the dorsal telencephalon (Dm, Dl), and the supracommissural nucleus of the ventral telencephalon (Vs). Our findings suggest that the expression of activity-dependent genes like npas4a may be differentially expressed across several interconnected forebrain regions in response to fearful stimuli and promote biases in fear learning among different stress coping styles.

Neonatal Handling Enhances Contextual Fear Conditioning and Alters Corticosterone Stress Responses in Young Rats

2002 ◽  
Vol 41 (1) ◽  
pp. 33-40 ◽  
Author(s):  
Melinda L. Beane ◽  
Michael A. Cole ◽  
Robert L. Spencer ◽  
Jerry W. Rudy
Keyword(s):  
Fear Conditioning ◽  
Stress Responses ◽  
Contextual Fear Conditioning ◽  
Contextual Fear ◽  
Neonatal Handling ◽  
Young Rats

scholarly journals Matrix Metalloproteinase (MMP) 9 Transcription in Mouse Brain Induced by Fear Learning

2013 ◽  
Vol 288 (29) ◽  
pp. 20978-20991 ◽  
Author(s):  
Krishnendu Ganguly ◽  
Emilia Rejmak ◽  
Marta Mikosz ◽  
Evgeni Nikolaev ◽  
Ewelina Knapska ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Prefrontal Cortex ◽  
Matrix Metalloproteinase ◽  
Gene Promoter ◽  
Brain Structures ◽  
Contextual Fear Conditioning ◽  
Fear Learning ◽  
Contextual Fear ◽  
The Brain

Memory formation requires learning-based molecular and structural changes in neurons, whereas matrix metalloproteinase (MMP) 9 is involved in the synaptic plasticity by cleaving extracellular matrix proteins and, thus, is associated with learning processes in the mammalian brain. Because the mechanisms of MMP-9 transcription in the brain are poorly understood, this study aimed to elucidate regulation of MMP-9 gene expression in the mouse brain after fear learning. We show here that contextual fear conditioning markedly increases MMP-9 transcription, followed by enhanced enzymatic levels in the three major brain structures implicated in fear learning, i.e. the amygdala, hippocampus, and prefrontal cortex. To reveal the role of AP-1 transcription factor in MMP-9 gene expression, we have used reporter gene constructs with specifically mutated AP-1 gene promoter sites. The constructs were introduced into the medial prefrontal cortex of neonatal mouse pups by electroporation, and the regulation of MMP-9 transcription was studied after contextual fear conditioning in the adult animals. Specifically, −42/-50- and −478/-486-bp AP-1 binding motifs of the mouse MMP-9 promoter sequence have been found to play a major role in MMP-9 gene activation. Furthermore, increases in MMP-9 gene promoter binding by the AP-1 transcription factor proteins c-Fos and c-Jun have been demonstrated in all three brain structures under investigation. Hence, our results suggest that AP-1 acts as a positive regulator of MMP-9 transcription in the brain following fear learning.

scholarly journals Understanding the contributions of visual stimuli to contextual fear conditioning: a proof-of-concept study using LCD screens

2016 ◽  
Author(s):  
Nathen J. Murawski ◽  
Arun Asok
Keyword(s):  
Fear Conditioning ◽  
Visual Information ◽  
Visual Image ◽  
Contextual Fear Conditioning ◽  
Fear Learning ◽  
Proof Of Concept ◽  
Facilitation Effect ◽  
Simple Modification ◽  
Conditioning Paradigm ◽  
Contextual Fear

AbstractThe precise contribution of visual information to contextual fear-learning and discrimination has remained elusive. To better understand this contribution, we coupled the context pre-exposure facilitation effect (CPFE) fear conditioning paradigm with presentations of distinct visual scenes displayed on 4 LCD screens surrounding a conditioning chamber. Adult male Long-Evans rats received non-reinforced context pre-exposure on Day 1, an immediate 1.5 mA foot shock on Day 2, and a non-reinforced context test on Day 3. Rats were pre-exposed to either digital Context (dCtx) A, dCtx B, a distinct Context C, or no context on Day 1. Context A and B were identical except for the visual image displayed on the LCD monitors. Immediate shock and retention testing occurred in dCtx A. Rats pre-exposed dCtx A showed the CPFE with significantly higher levels of freezing compared to learning controls. Rats pre-exposed to Context B failed to show the CPFE, with freezing that did not differ significantly from any group. The results suggest that 1) visual information contributes to contextual fear learning in rats and that 2) visual components of the context can be parametrically controlled via LCD screens. Our approach offers a simple modification to contextual fear conditioning whereby the visual features of a context can be precisely controlled to better understand how rodents discriminate and generalize fear across environments.

scholarly journals Network supporting contextual fear learning after dorsal hippocampal damage has increased dependence on retrosplenial cortex

2017 ◽  
Author(s):  
Cesar A.O. Coelho ◽  
Tatiana L. Ferreira ◽  
Juliana C.K. Soares ◽  
João R. Sato ◽  
Maria Gabriela M. Oliveira
Keyword(s):  
Fear Conditioning ◽  
Correlation Coefficients ◽  
Brain Regions ◽  
Memory System ◽  
Retrosplenial Cortex ◽  
Contextual Fear Conditioning ◽  
Fear Learning ◽  
Hippocampal Damage ◽  
Contextual Fear ◽  
Dorsal Hippocampal

ABSTRACTHippocampal damage results in profound retrograde, but no anterograde amnesia in contextual fear conditioning (CFC). Although the content learned in the latter have been discussed, the compensating regions were seldom proposed and never empirically addressed. Here, we employed network analysis of pCREB expression quantified from brain slices of rats with dorsal hippocampal lesion (dHPC) after undergoing CFC session. Using inter-regional correlations of pCREB-positive nuclei between brain regions, we modelled functional networks using different thresholds. The dHPC network showed small-world topology, equivalent to SHAM (control) network. However, diverging hubs were identified in each network. In a direct comparison, hubs in both networks showed consistently higher centrality values compared to the other network. Further, the distribution of correlation coefficients was different between the groups, with most significantly stronger correlation coefficients belonging to the SHAM network. These results suggest that dHPC network engaged in CFC learning is partially different, and engage alternative hubs. We next tested if pre-training lesions of dHPC and one of the new dHPC network hubs (perirhinal, Per; or disgranular retrosplenial, RSC, cortices) would impair CFC. Only dHPC-RSC, but not dHPC-Per, impaired CFC. Interestingly, only RSC showed a consistently higher centrality in the dHPC network, suggesting that the increased centrality reflects an increased functional dependence on RSC. Our results provide evidence that, without hippocampus, the RSC, an anatomically central region in the medial temporal lobe memory system might support CFC learning and memory.AUTHOR SUMMARYWhen determined cognitive performances are not affected by brain lesions of regions generally involved in that performance, the interpretation is that the remaining regions can compensate the damaged one. In contextual fear conditioning, a memory model largely used in laboratory rodents, hippocampal lesions produce amnesia for events occurred before, but not after the lesion, although the hippocampus is known to be important for new learning. Addressing compensation in animal models has always been challenging as it requires large-scale brain mapping. Here, we quantified 30 brain regions and used mathematical tools to model how a brain network can compensate hippocampal loss and learn contextual fear. We described that the damaged network preserved general interactivity characteristics, although different brain regions were identified as highly important for the network (e.g. highly connected). Further, we empirically validated our network model by performing double lesions of the hippocampus and the alternative hubs observed in the network models. We verified that double lesion of the hippocampus and retrosplenial cortex, one of the hubs, impaired contextual fear learning. We provide evidence that without hippocampus, the remaining network relies on alternative important regions from the memory system to coordinate contextual fear learning.

scholarly journals Hippocampal Regulation of Postsynaptic Density Homer1 by Associative Learning

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Nicholas E. Clifton ◽  
Darren Cameron ◽  
Simon Trent ◽  
Lucy H. Sykes ◽  
Kerrie L. Thomas ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Learning And Memory ◽  
Novelty Detection ◽  
Postsynaptic Density ◽  
Fear Memory ◽  
Contextual Fear Conditioning ◽  
Fear Learning ◽  
Contextual Fear ◽  
Postsynaptic Density Proteins ◽  
Genes Encoding

Genes involved in synaptic plasticity, particularly genes encoding postsynaptic density proteins, have been recurrently linked to psychiatric disorders including schizophrenia and autism. Postsynaptic density Homer1 proteins contribute to synaptic plasticity through the competing actions of short and long isoforms. The activity-induced expression of shortHomer1isoforms,Homer1aandAnia-3, is thought to be related to processes of learning and memory. However, the precise regulation ofHomer1aandAnia-3with different components of learning has not been investigated. Here, we used in situ hybridization to quantify short and longHomer1expression in the hippocampus following consolidation, retrieval, and extinction of associative fear memory, using contextual fear conditioning in rats.Homer1aandAnia-3, but not longHomer1, were regulated by contextual fear learning or novelty detection, although their precise patterns of expression in hippocampal subregions were dependent on the isoform. We also show for the first time that the two short Homer1 isoforms are regulated after the retrieval and extinction of contextual fear memory, albeit with distinct temporal and spatial profiles. These findings support a role of activity-induced Homer1 isoforms in learning and memory processes in discrete hippocampal subregions and suggest that Homer1a and Ania-3 may play separable roles in synaptic plasticity.

scholarly journals Profiling DNA break sites and transcriptional changes in response to contextual fear learning

2021 ◽  
Author(s):  
Ryan Stott ◽  
Oleg Kritsky ◽  
Li-Huei Tsai
Keyword(s):  
Neuronal Activity ◽  
Early Response ◽  
Contextual Fear Conditioning ◽  
Fear Learning ◽  
Dna Breaks ◽  
Learning Behaviors ◽  
Contextual Fear ◽  
Transcriptional Changes ◽  
The Brain

Neuronal activity generates DNA double-strand breaks (DSBs) at specific loci in vitro and this facilitates the rapid transcriptional induction of early response genes (ERGs). Physiological neuronal activity, including exposure of mice to learning behaviors, also cause the formation of DSBs, yet the distribution of these breaks and their relation to brain function remains unclear. Here, following contextual fear conditioning (CFC) in mice, we profiled the locations of DSBs genome-wide in the medial prefrontal cortex and hippocampus using γH2AX ChIP-Seq. Remarkably, we found that DSB formation is widespread in the brain compared to cultured primary neurons and they are predominately involved in synaptic processes. We observed increased DNA breaks at genes induced by CFC in neuronal and non-neuronal nuclei. Activity-regulated and proteostasis-related transcription factors appear to govern some of these gene expression changes across cell types. Finally, we find that glia but not neurons have a robust transcriptional response to glucocorticoids, and many of these genes are sites of DSBs. Our results indicate that learning behaviors cause widespread DSB formation in the brain that are associated with experience-driven transcriptional changes across both neuronal and glial cells.

scholarly journals Profiling DNA break sites and transcriptional changes in response to contextual fear learning

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0249691
Author(s):  
Ryan T. Stott ◽  
Oleg Kritsky ◽  
Li-Huei Tsai
Keyword(s):  
Neuronal Activity ◽  
Early Response ◽  
Contextual Fear Conditioning ◽  
Fear Learning ◽  
Dna Breaks ◽  
Learning Behaviors ◽  
Contextual Fear ◽  
Transcriptional Changes ◽  
The Brain

Neuronal activity generates DNA double-strand breaks (DSBs) at specific loci in vitro and this facilitates the rapid transcriptional induction of early response genes (ERGs). Physiological neuronal activity, including exposure of mice to learning behaviors, also cause the formation of DSBs, yet the distribution of these breaks and their relation to brain function remains unclear. Here, following contextual fear conditioning (CFC) in mice, we profiled the locations of DSBs genome-wide in the medial prefrontal cortex and hippocampus using γH2AX ChIP-Seq. Remarkably, we found that DSB formation is widespread in the brain compared to cultured primary neurons and they are predominately involved in synaptic processes. We observed increased DNA breaks at genes induced by CFC in neuronal and non-neuronal nuclei. Activity-regulated and proteostasis-related transcription factors appear to govern some of these gene expression changes across cell types. Finally, we find that glia but not neurons have a robust transcriptional response to glucocorticoids, and many of these genes are sites of DSBs. Our results indicate that learning behaviors cause widespread DSB formation in the brain that are associated with experience-driven transcriptional changes across both neuronal and glial cells.

scholarly journals Npas4a expression in the teleost forebrain is associated with stress coping style differences in fear learning

2020 ◽  
Author(s):  
Matthew R Baker ◽  
Ryan Y Wong
Keyword(s):  
Neural Plasticity ◽  
Coping Style ◽  
Molecular Mechanisms ◽  
Conditioned Fear ◽  
Coping Styles ◽  
Brain Regions ◽  
Contextual Fear Conditioning ◽  
Fear Learning ◽  
Stress Coping ◽  
Contextual Fear

AbstractLearning to anticipate potentially dangerous contexts is an adaptive behavioral response to coping with stressors. An animal’s stress coping style (e.g. proactive-reactive axis) is known to influence how it encodes salient events. However, the neural and molecular mechanisms underlying these stress coping style differences in learning are unknown. Further, while a number of neuroplasticity-related genes have been associated with alternative stress coping styles, it is unclear if these genes may bias the development of conditioned behavioral responses to stressful stimuli, and if so, which brain regions are involved. Here, we trained adult zebrafish to associate a naturally aversive olfactory cue with a given context. Next, we investigated if expression of two neural plasticity and neurotransmission-related genes (npas4a and gabbr1a) were associated with the contextual fear conditioning differences between proactive and reactive stress coping styles. Reactive zebrafish developed a stronger conditioned fear response and showed significantly higher npas4a expression in the medial and lateral zones of the dorsal telencephalon (Dm, Dl), and the supracommissural nucleus of the ventral telencephalon (Vs). Our findings suggest that the magnitude of expression of activity-dependent genes like npas4a may be differentially expressed across several interconnected forebrain regions in response to fearful stimuli and promote biases in fear learning among different stress coping styles.

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