Peroxiredoxin 6 Knockout Mice Demonstrate Anxiety Behavior and Attenuated Contextual Fear Memory after Receiving Acute Immobilization Stress

Stress can elicit glucocorticoid release to promote coping mechanisms and influence learning and memory performance. Individual memory performance varies in response to stress, and the underlying mechanism is not clear yet. Peroxiredoxin 6 (PRDX6) is a multifunctional enzyme participating in both physiological and pathological conditions. Several studies have demonstrated the correlation between PRDX6 expression level and stress-related disorders. Our recent finding indicates that lack of the Prdx6 gene leads to enhanced fear memory. However, it is unknown whether PRDX6 is involved in changes in anxiety response and memory performance upon stress. The present study reveals that hippocampal PRDX6 level is downregulated 30 min after acute immobilization stress (AIS) and trace fear conditioning (TFC). In human retinal pigment epithelium (ARPE-19) cells, the PRDX6 expression level decreases after being treated with stress hormone corticosterone. Lack of PRDX6 caused elevated basal H2O2 levels in the hippocampus, basolateral amygdala, and medial prefrontal cortex, brain regions involved in anxiety response and fear memory formation. Additionally, this H2O2 level was still high in the medial prefrontal cortex of the knockout mice under AIS. Anxiety behavior of Prdx6−/− mice was enhanced after immobilization for 30 min. After exposure to AIS before a contextual test, Prdx6−/− mice displayed a contextual fear memory deficit. Our results showed that the memory performance of Prdx6−/− mice was impaired when responding to AIS, accompanied by dysregulated H2O2 levels. The present study helps better understand the function of PRDX6 in memory performance after acute stress.

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Enhanced contextual fear memory in peroxiredoxin 6 knockout mice is associated with hyperactivation of MAPK signaling pathway

Molecular Brain ◽

10.1186/s13041-021-00754-1 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Sarayut Phasuk ◽

Tanita Pairojana ◽

Pavithra Suresh ◽

Chee-Hing Yang ◽

Sittiruk Roytrakul ◽

...

Keyword(s):

Knockout Mice ◽

Redox Regulation ◽

Mapk Pathway ◽

Fear Memory ◽

Mapk Signaling ◽

Intraventricular Injection ◽

Fear Response ◽

Peroxiredoxin 6 ◽

Contextual Fear ◽

Contextual Fear Memory

AbstractFear dysregulation is one of the symptoms found in post-traumatic stress disorder (PTSD) patients. The functional abnormality of the hippocampus is known to be implicated in the development of such pathology. Peroxiredoxin 6 (PRDX6) belongs to the peroxiredoxin family. This antioxidant enzyme is expressed throughout the brain, including the hippocampus. Recent evidence reveals that PRDX6 plays an important role in redox regulation and the modulation of several signaling molecules involved in fear regulation. Thus, we hypothesized that PRDX6 plays a role in the regulation of fear memory. We subjected a systemic Prdx6 knockout (Prdx6−/−) mice to trace fear conditioning and observed enhanced fear response after training. Intraventricular injection of lentivirus-carried mouse Prdx6 into the 3rd ventricle reduced the enhanced fear response in these knockout mice. Proteomic analysis followed by validation of western blot analysis revealed that several proteins in the MAPK pathway, such as NTRK2, AKT, and phospho-ERK1/2, cPLA2 were significantly upregulated in the hippocampus of Prdx6−/− mice during the retrieval stage of contextual fear memory. The distribution of PRDX6 found in the astrocytes was also observed throughout the hippocampus. This study identifies PRDX6 as a participant in the regulation of fear response. It suggests that PRDX6 and related molecules may have important implications for understanding fear-dysregulation associated disorders like PTSD.

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Torpor enhances synaptic strength and restores memory performance in a mouse model of Alzheimer’s disease

Scientific Reports ◽

10.1038/s41598-021-94992-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Christina F. de Veij Mestdagh ◽

Jaap A. Timmerman ◽

Frank Koopmans ◽

Iryna Paliukhovich ◽

Suzanne S. M. Miedema ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Memory Performance ◽

Long Term Potentiation ◽

Fear Memory ◽

Contextual Fear ◽

Contextual Fear Memory ◽

Model Of Alzheimer’S Disease ◽

Term Potentiation

AbstractHibernation induces neurodegeneration-like changes in the brain, which are completely reversed upon arousal. Hibernation-induced plasticity may therefore be of great relevance for the treatment of neurodegenerative diseases, but remains largely unexplored. Here we show that a single torpor and arousal sequence in mice does not induce dendrite retraction and synapse loss as observed in seasonal hibernators. Instead, it increases hippocampal long-term potentiation and contextual fear memory. This is accompanied by increased levels of key postsynaptic proteins and mitochondrial complex I and IV proteins, indicating mitochondrial reactivation and enhanced synaptic plasticity upon arousal. Interestingly, a single torpor and arousal sequence was also sufficient to restore contextual fear memory in an APP/PS1 mouse model of Alzheimer’s disease. Our study demonstrates that torpor in mice evokes an exceptional state of hippocampal plasticity and that naturally occurring plasticity mechanisms during torpor provide an opportunity to identify unique druggable targets for the treatment of cognitive impairment.

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Role of amygdala–prefrontal cortex circuitry in regulating the expression of contextual fear memory

Neurobiology of Learning and Memory ◽

10.1016/j.nlm.2011.06.005 ◽

2011 ◽

Vol 96 (2) ◽

pp. 315-323 ◽

Cited By ~ 21

Author(s):

Carl W. Stevenson

Keyword(s):

Prefrontal Cortex ◽

Fear Memory ◽

Contextual Fear ◽

Contextual Fear Memory

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Hippocampus and Prefrontal Cortex Modulation of Contextual Fear Memory Is Dissociated by Inhibiting De Novo Transcription During Late Consolidation

Molecular Neurobiology ◽

10.1007/s12035-018-1463-4 ◽

2019 ◽

Vol 56 (8) ◽

pp. 5507-5519 ◽

Cited By ~ 3

Author(s):

Luciana M. Pereira ◽

Caio M. de Castro ◽

Lorena T. L. Guerra ◽

Thaís M. Queiroz ◽

João T. Marques ◽

...

Keyword(s):

Prefrontal Cortex ◽

De Novo ◽

Fear Memory ◽

Contextual Fear ◽

Contextual Fear Memory

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Hippocampus and medial prefrontal cortex contributions to trace and contextual fear memory expression over time

Learning & Memory ◽

10.1101/lm.031161.113 ◽

2013 ◽

Vol 20 (6) ◽

pp. 336-343 ◽

Cited By ~ 30

Author(s):

C. L. Beeman ◽

P. S. Bauer ◽

J. L. Pierson ◽

J. J. Quinn

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Fear Memory ◽

Contextual Fear ◽

Contextual Fear Memory ◽

Over Time

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Sevoflurane anesthesia induces neither contextual fear memory impairment nor alterations in local population connectivity of medial prefrontal cortex local field potentials networks in aged rats

Fundamental and Clinical Pharmacology ◽

10.1111/fcp.12194 ◽

2016 ◽

Vol 30 (4) ◽

pp. 338-346 ◽

Cited By ~ 2

Author(s):

Xinyu Xu ◽

Qian Zhang ◽

Xin Tian ◽

Guolin Wang

Keyword(s):

Prefrontal Cortex ◽

Memory Impairment ◽

Local Population ◽

Fear Memory ◽

Population Connectivity ◽

Aged Rats ◽

Sevoflurane Anesthesia ◽

Field Potentials ◽

Contextual Fear ◽

Contextual Fear Memory

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Parvalbumin-positive interneurons mediate neocortical-hippocampal interactions that are necessary for memory consolidation

eLife ◽

10.7554/elife.27868 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 56

Author(s):

Frances Xia ◽

Blake A Richards ◽

Matthew M Tran ◽

Sheena A Josselyn ◽

Kaori Takehara-Nishiuchi ◽

...

Keyword(s):

Prefrontal Cortex ◽

Fear Conditioning ◽

Medial Prefrontal Cortex ◽

Memory Consolidation ◽

Fear Memory ◽

Contextual Fear Conditioning ◽

Contextual Fear ◽

Contextual Fear Memory ◽

Spiking Activity

Following learning, increased coupling between spindle oscillations in the medial prefrontal cortex (mPFC) and ripple oscillations in the hippocampus is thought to underlie memory consolidation. However, whether learning-induced increases in ripple-spindle coupling are necessary for successful memory consolidation has not been tested directly. In order to decouple ripple-spindle oscillations, here we chemogenetically inhibited parvalbumin-positive (PV+) interneurons, since their activity is important for regulating the timing of spiking activity during oscillations. We found that contextual fear conditioning increased ripple-spindle coupling in mice. However, inhibition of PV+ cells in either CA1 or mPFC eliminated this learning-induced increase in ripple-spindle coupling without affecting ripple or spindle incidence. Consistent with the hypothesized importance of ripple-spindle coupling in memory consolidation, post-training inhibition of PV+ cells disrupted contextual fear memory consolidation. These results indicate that successful memory consolidation requires coherent hippocampal-neocortical communication mediated by PV+ cells.

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