Muscarinic receptor activation promotes destabilization and updating of object location memories in mice

Huff, Andrew Ethan; O’Neill, Olivia S.; Messer, William S.; Winters, Boyer D.

doi:10.1016/j.bbr.2024.114847

Cited by 3 publications

(3 citation statements)

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“…Next, we wanted to see if post-update RGFP966 had any effect on young mice. As young mice successfully learn both the training and the updated information (Huff et al, 2024; Kwapis et al, 2020; Wright et al, 2020), we expected to observe no effect of post-update RGFP966. Here, young mice given one day of training were given a 5-minute memory update followed by systemic injections of RGFP966 or vehicle ( FIG 2A ).…”

Section: Resultsmentioning

confidence: 97%

“…OUL, therefore, appears to drive reconsolidation-based updating in the original neuronal ensemble. Recent work has demonstrated that muscarinic acetylcholine receptors (mAChRs) are required for the original memory to destabilize during updating; blocking mAChRs with scopolamine before updating prevented mice from learning the updated location A3 without affecting memory for the original locations A1 and A2 (Huff et al, 2024). Finally, exposing mice to galactic cosmic radiation (intended to mimic space radiation for astronauts traveling to Mars) disrupts memory updating even when initial memory formation is intact (Alaghband et al, 2023; Keiser et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

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Pharmacological HDAC3 inhibition alters memory updating in young and old mice

Smies,

Bellfy,

Wright

et al. 2024

Preprint

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Long-term memories are not stored in a stable state but must be flexible and dynamic to maintain relevance in response to new information. Existing memories are thought to be updated through the process of reconsolidation, in which memory retrieval initiates destabilization and updating to incorporate new information. Memory updating is impaired in old age, yet little is known about the mechanisms that go awry. One potential mechanism is the repressive histone deacetylase 3 (HDAC3), which is a powerful negative regulator of memory formation that contributes to age-related impairments in memory formation. Here, we tested whether HDAC3 also contributes to age-related impairments in memory updating using the Objects in Updated Locations (OUL) paradigm. We show that blocking HDAC3 immediately after updating with the pharmacological inhibitor RGFP966 ameliorated age-related impairments in memory updating in 18-m.o. mice. Surprisingly, we found that post-update HDAC3 inhibition in young (3-m.o.) mice had no effect on memory updating but instead impaired memory for the original information, suggesting that the original and updated information may compete for expression at test and HDAC3 helps regulate which information is expressed. To test this idea, we next assessed whether HDAC3 inhibition would improve memory updating in young mice given a weak, subthreshold update. Consistent with our hypothesis, we found that HDAC3 blockade strengthened the subthreshold update without impairing memory for the original information, enabling balanced expression of the original and updated information. Together, this research suggests that HDAC3 may contribute to age-related impairments in memory updating and may regulate the strength of a memory update in young mice, shifting the balance between the original and updated information at test.

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Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Pharmacological HDAC3 inhibition alters memory updating in young and old mice

Smies,

Bellfy,

Wright

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Next, we wanted to see if post-update RGFP966 had any effect on young mice. As young mice successfully learn both the training and the updated information ( Kwapis et al, 2020 ; Wright et al, 2020 ; Huff et al, 2024 ), we expected to observe no effect of post-update RGFP966. Here, young male mice given one day of training were given a 5-min memory update followed by systemic injections of RGFP966 or vehicle ( Figure 2A ).…”

Section: Resultsmentioning

confidence: 97%

Pharmacological HDAC3 inhibition alters memory updating in young and old male mice

Smies,

Bellfy,

Wright

et al. 2024

Front. Mol. Neurosci.

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Long-term memories are not stored in a stable state but must be flexible and dynamic to maintain relevance in response to new information. Existing memories are thought to be updated through the process of reconsolidation, in which memory retrieval initiates destabilization and updating to incorporate new information. Memory updating is impaired in old age, yet little is known about the mechanisms that go awry. One potential mechanism is the repressive histone deacetylase 3 (HDAC3), which is a powerful negative regulator of memory formation that contributes to age-related impairments in memory formation. Here, we tested whether HDAC3 also contributes to age-related impairments in memory updating using the Objects in Updated Locations (OUL) paradigm. We show that blocking HDAC3 immediately after updating with the pharmacological inhibitor RGFP966 ameliorated age-related impairments in memory updating in 18-m.o. male mice. Surprisingly, we found that post-update HDAC3 inhibition in young (3-m.o.) male mice had no effect on memory updating but instead impaired memory for the original information, suggesting that the original and updated information may compete for expression at test and HDAC3 helps regulate which information is expressed. To test this idea, we next assessed whether HDAC3 inhibition would improve memory updating in young male mice given a weak, subthreshold update. Consistent with our hypothesis, we found that HDAC3 blockade strengthened the subthreshold update without impairing memory for the original information, enabling balanced expression of the original and updated information. Together, this research suggests that HDAC3 may contribute to age-related impairments in memory updating and may regulate the strength of a memory update in young mice, shifting the balance between the original and updated information at test.

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Muscarinic Receptors and Alzheimer’s Disease: New Perspectives and Mechanisms

Monaco,

Trebesova,

Grilli

2024

CIMB

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Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases on a global scale. Historically, this pathology has been linked to cholinergic transmission, and despite the scarcity of effective therapies, numerous alternative processes and targets have been proposed as potential avenues for comprehending this complex illness. Nevertheless, the fundamental pathophysiological mechanisms underpinning AD remain largely enigmatic, with a growing body of evidence advocating for the significance of muscarinic receptors in modulating the brain’s capacity to adapt and generate new memories. This review summarizes the current state of the art in the field of muscarinic receptors’ involvement in AD. A specific key factor was the relationship between comorbidity and the emergence of new mechanisms.

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Muscarinic receptor activation promotes destabilization and updating of object location memories in mice

Cited by 3 publications

References 50 publications

Pharmacological HDAC3 inhibition alters memory updating in young and old mice

Pharmacological HDAC3 inhibition alters memory updating in young and old mice

Pharmacological HDAC3 inhibition alters memory updating in young and old male mice

Muscarinic Receptors and Alzheimer’s Disease: New Perspectives and Mechanisms

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