scholarly journals Fear Learning Induces Long-Lasting Changes in Gene Expression and Pathway Specific Presynaptic Growth

2019 ◽  
Author(s):  
Blythe C. Dillingham ◽  
Peter Cameron ◽  
Simon Pieraut ◽  
Leonardo M. Cardozo ◽  
Eun J. Yoo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Basolateral Amygdala ◽  
Contextual Fear Conditioning ◽  
Fear Learning ◽  
Neural Ensembles ◽  
Examine Gene Expression ◽  
Initial Learning ◽  
Long Time ◽  
Transcriptional Changes ◽  
New Gene

AbstractThe stabilization or consolidation of long-term memories lasting more than a few hours requires new gene expression. While neural activity has been shown to induce expression of a variety of genes within several hours of learning, whether this leads to persistent changes in gene expression that lasts for days or weeks remains unclear. We developed a novel mouse line which expresses Cre recombinase in an inducible manner and used it to examine gene expression in learning-activated neurons of the medial prefrontal cortex (mPFC) one month following contextual fear conditioning. The mPFC is not required for the initial retrieval of contextual memory but becomes necessary after one month, suggesting a slowly developing plasticity. We found a variety of changes in gene expression in learning-activated neural ensembles that were specific to the mPFC. One group of transcriptional changes observed was the coordinated upregulation of presynaptic proteins suggesting a potential learning-induced elaboration of presynaptic terminals. We tested this idea by labeling the projections of mPFC neurons active during initial learning and found an increase in the number of terminals in neurons projecting to the basolateral amygdala at 1 month following training. These results suggest a presynaptic growth mechanism that could account for the enhanced role of the mPFC in fear memory retrieval at long time points after learning.

scholarly journals Fear Memory

2016 ◽  
Vol 96 (2) ◽  
pp. 695-750 ◽  
Author(s):  
Ivan Izquierdo ◽  
Cristiane R. G. Furini ◽  
Jociane C. Myskiw
Keyword(s):  
Fear Conditioning ◽  
Basolateral Amygdala ◽  
Inhibitory Avoidance ◽  
Long Term Potentiation ◽  
Fear Memory ◽  
Contextual Fear Conditioning ◽  
Fear Learning ◽  
Term Potentiation ◽  
Mechanisms Of Memory

Fear memory is the best-studied form of memory. It was thoroughly investigated in the past 60 years mostly using two classical conditioning procedures (contextual fear conditioning and fear conditioning to a tone) and one instrumental procedure (one-trial inhibitory avoidance). Fear memory is formed in the hippocampus (contextual conditioning and inhibitory avoidance), in the basolateral amygdala (inhibitory avoidance), and in the lateral amygdala (conditioning to a tone). The circuitry involves, in addition, the pre- and infralimbic ventromedial prefrontal cortex, the central amygdala subnuclei, and the dentate gyrus. Fear learning models, notably inhibitory avoidance, have also been very useful for the analysis of the biochemical mechanisms of memory consolidation as a whole. These studies have capitalized on in vitro observations on long-term potentiation and other kinds of plasticity. The effect of a very large number of drugs on fear learning has been intensively studied, often as a prelude to the investigation of effects on anxiety. The extinction of fear learning involves to an extent a reversal of the flow of information in the mentioned structures and is used in the therapy of posttraumatic stress disorder and fear memories in general.

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 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.

Stage 1 Registered Report Manuscript - Transcriptional Correlates of Savings Memory: Is Forgetting Due to Decay or Retrieval Failure?

2020 ◽  
Author(s):  
Robert Calin-Jageman ◽  
Irina Calin-Jageman ◽  
Tania Rosiles ◽  
Melissa Nguyen ◽  
Annette Garcia ◽  
...  
Keyword(s):  
Gene Expression ◽  
Memory Trace ◽  
Aplysia Californica ◽  
Retrieval Failure ◽  
Initial Learning ◽  
Rigorous Test ◽  
Regulated Gene Expression ◽  
Stage 1 ◽  
Weak Similarity

[[This is a Stage 1 Registered Report manuscript. The project was submitted for review to eNeuro. Upon revision and acceptance, this version of the manuscript was pre-registered on the OSF (9/11/2019, https://osf.io/fqh8j) (but due to an oversight not posted as a preprint until July 2020). A Stage 2 manuscript is now posted as a pre-print (https://psyarxiv.com/h59jv) and is under review at eNeuro. A link to the final Stage 2 manuscript will be added when available.]]There is fundamental debate about the nature of forgetting: some have argued that it represents the decay of the memory trace, others that the memory trace persists but becomes inaccessible due to retrieval failure. These different accounts of forgetting make different predictions about savings memory, the rapid re-learning of seemingly forgotten information. If forgetting is due to decay then savings requires re-encoding and should thus involve the same mechanisms as initial learning. If forgetting is due to retrieval-failure then savings should be mechanistically distinct from encoding. In this registered report we conducted a pre-registered and rigorous test between these accounts of forgetting. Specifically, we used microarray to characterize the transcriptional correlates of a new memory (1 day from training), a forgotten memory (8 days from training), and a savings memory (8 days from training but with a reminder on day 7 to evoke a long-term savings memory) for sensitization in Aplysia californica (n = 8 samples/group). We find that the transcriptional correlates of savings are [highly similar / somewhat similar / unique] relative to new (1-day-old) memories. Specifically, savings memory and a new memory share [X] of [Y] regulated transcripts, show [strong / moderate / weak] similarity in sets of regulated transcripts, and show [r] correlation in regulated gene expression, which is [substantially / somewhat / not at all] stronger than at forgetting. Overall, our results suggest that forgetting represents [decay / retrieval-failure / mixed mechanisms].

Stop the new gene, the alien: Predicted breakdown of MYB overexpression by ncRNA mediated gene regulations

2017 ◽  
Vol 4 (2) ◽  
Author(s):  
NEHA SINGH ◽  
INDERJEET BHOGAL ◽  
ABHISHEK KUMAR ◽  
PUNIT TYAGI ◽  
GIRIJA SIKARWAR ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Gene ◽  
Neutral Theory ◽  
Poor Performance ◽  
Warning Sign ◽  
Cellular Mechanisms ◽  
Constitutive Overexpression ◽  
New Gene ◽  
Altered Gene ◽  
Growing Conditions

Acclimatization is a process that occurs in individual cells to a drastic change in micro and macro environments. When an organism is subjected to a new environment or a change in its normal growing conditions, the cellular mechanisms initiate a warning sign and over a period of time or over generations the acquired, modified traits are being communicated and fixed as a new trait. If there is lack of equilibrium within the cell due to over expression of a single gene or network of associated genes either manmade or due to mutations, the organism or plant tries to fix it by initiating gene regulatory mechanisms. According to our neutral theory of gene expression, always a cell tries to maintain its pH by modifying its cytosol through altered gene expression. In the present investigation, 198 AtMYB genes were analyzed and found to play an intrinsic photosystem linked network of 38 nodes where MYB being regulated by a set of 48 miRNAs. Members of the network have evidence-based link to energy related mechanisms. Altering gene expression to an extent where, the cell may not be able to fix it or a trait, which requires excessive energy loss escorts the organism’s gene regulation by breakdown of the introduced sequence over few generations. Events with constitutive overexpression may suffer poor performance over the years based on gene network prevailing in the crop of interest. Hence, network rewiring with minimal energy expenses is concerned.

scholarly journals High-throughput transcriptomic analysis of human primary hepatocyte spheroids exposed to per- and polyfluoroalkyl substances (PFAS) as a platform for relative potency characterization

2021 ◽  
Author(s):  
A Rowan-Carroll ◽  
A Reardon ◽  
K Leingartner ◽  
R Gagné ◽  
A Williams ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cholesterol Biosynthesis ◽  
Health Hazard ◽  
Biological Responses ◽  
Similar Gene Expression Profile ◽  
Transcriptional Changes ◽  
Hazard And Risk ◽  
Hepatocyte Spheroids ◽  
Similar Gene ◽  
Identify Gene Expression

Abstract Per- and poly-fluoroalkyl substances (PFAS) are widely found in the environment because of their extensive use and persistence. Although several PFAS are well studied, most lack toxicity data to inform human health hazard and risk assessment. This study focussed on four model PFAS: perfluorooctanoic acid (PFOA; 8 carbon), perfluorobutane sulfonate (PFBS; 4 carbon), perfluorooctane sulfonate (PFOS; 8 carbon), and perfluorodecane sulfonate (PFDS; 10 carbon). Human primary liver cell spheroids (pooled from 10 donors) were exposed to 10 concentrations of each PFAS and analyzed at four time-points. The approach aimed to: (1) identify gene expression changes mediated by the PFAS; (2) identify similarities in biological responses; (3) compare PFAS potency through benchmark concentration analysis; and (4) derive bioactivity exposure ratios (ratio of the concentration at which biological responses occur, relative to daily human exposure). All PFAS induced transcriptional changes in cholesterol biosynthesis and lipid metabolism pathways, and predicted PPARα activation. PFOS exhibited the most transcriptional activity and had a highly similar gene expression profile to PFDS. PFBS induced the least transcriptional changes and the highest benchmark concentration (i.e., was the least potent). The data indicate that these PFAS may have common molecular targets and toxicities, but that PFOS and PFDS are the most similar. The transcriptomic bioactivity exposure ratios derived here for PFOA and PFOS were comparable to those derived using rodent apical endpoints in risk assessments. These data provide a baseline level of toxicity for comparison with other known PFAS using this testing strategy.

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