The clock gene Per1 may exert diurnal control over hippocampal memory consolidation

Bellfy, Lauren; Smies, Chad W.; Bernhardt, Alicia R.; Bodinayake, Kasuni K.; Sebastian, Aswathy; Stuart, Emily M.; Wright, Destiny S.; Lo, Chen-Yu; Murakami, Shoko; Boyd, Hannah M.; Abo, Megan J. von; Albert, István; Kwapis, Janine L.

doi:10.1038/s41386-023-01616-1

Cited by 8 publications

(7 citation statements)

References 45 publications

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“…Major depressive disorder, seasonal affective disorder, and bipolar disorder have all been tied to disruptions in circadian cycles (Dollish et al, 2024). Metabolic side effects, such as abnormal glucose metabolism and lower insulin sensitivity, are also well-established consequences of circadian rhythm disruption (Potter et al, 2016), as are memory impairments (Bellfy et al, 2023; Smies et al, 2022). In short, biological rhythms in the brain likely regulate mood and cognition.…”

Section: Discussionmentioning

confidence: 99%

Circadian rhythms tied to changes in brain morphology in a densely-sampled male

Murata,

Pritschet,

Grotzinger

et al. 2024

Preprint

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Circadian, infradian, and seasonal changes in steroid hormone secretion have been tied to changes in brain volume in several mammalian species. However, the relationship between circadian changes in steroid hormone production and rhythmic changes in brain morphology in humans is largely unknown. Here, we examined the relationship between diurnal fluctuations in steroid hormones and multiscale brain morphology in a precision imaging study of a male who completed forty MRI and serological assessments at 7 A.M. and 8 P.M. over the course of a month, targeting hormone concentrations at their peak and nadir. Diurnal fluctuations in steroid hormones were tied to pronounced changes in global and regional brain morphology. From morning to evening, total brain volume, gray matter volume, and cortical thickness decreased, coincident with decreases in steroid hormone concentrations (testosterone, estradiol, and cortisol). In parallel, cerebrospinal fluid and ventricle size increased from A.M. to P.M. Global changes were driven by decreases within the occipital and parietal cortices. These findings highlight natural rhythms in brain morphology that keep time with the diurnal ebb and flow of steroid hormones.

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Section: Discussionmentioning

confidence: 99%

Circadian rhythms tied to changes in brain morphology in a densely-sampled male

Murata,

Pritschet,

Grotzinger

et al. 2024

Preprint

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“…All animals were maintained in a temperature (68-79°C) and humidity-controlled (30-70%) environment under a 12-hour light/dark cycle (lights on at 7A, lights off at 7P). Behavior was conducted during the light phase, when we observe peak spatial memory performance (Bellfy et al, 2023; Brunswick et al, 2023; Urban et al, 2021). Mice had access to food and water ad libitum .…”

Section: Methodsmentioning

confidence: 99%

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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“…Interestingly, CREB initiates Per1 transcription independently of the canonical TTFL that induces Per1 transcription via the E-box element ( Travnickova-Bendova et al, 2002 ). This secondary mechanism for transcriptional control of Per1 may enable it to function in roles outside of the circadian system, including in long-term memory formation across a variety of memory-relevant brain regions ( Bellfy et al, 2023 ; Jilg et al, 2010 ; Kwapis et al, 2018 ; Rawashdeh et al, 2014 ; Urban et al, 2021 ; Woodruff et al, 2018 ). The SCN, as well as many of its direct afferent targets, expresses both estrogen and progestin receptors, indicating that ovarian hormones likely act through multiple brain regions to regulate circadian gene expression and circadian behavior.…”

Section: Evidence For Sex Hormone Control Of the Circadian Clockmentioning

confidence: 99%

“…Within memory-relevant brain regions, sex hormones induce rapid biochemical changes that influence cell-signaling cascades (for review see Frick et al, 2020 ), changes in gene expression (for review see Fortress and Frick, 2014 ), neuron morphology (for review see Murakami et al, 2018 ), and neuronal excitability (for review see Ooishi et al, 2012 ; Smith and Woolley, 2004 ). This review will focus on the role of sex hormones in memory consolidation, since this phase of memory is intricately linked to dynamic changes in gene expression, including the transcription of clock genes ( Bellfy et al, 2023 ; Guzowski et al, 2000 ; Hall et al, 2000 ; Linnarsson et al, 1997 ; Rawashdeh et al, 2014 ). The consolidation phase of memory is a common target for sex hormone manipulations because sex hormones can be manipulated immediately after memory acquisition to affect consolidation without interfering with the learning event itself.…”

Section: Sex Hormones Modulate Learning and Memorymentioning

confidence: 99%

“…Recent work has suggested that clock genes may modulate memory formation directly within memory-relevant brain regions, suggesting that clock gene oscillations and their modulation via sex hormone action may play a key role in regulating memory. Notably, hippocampal memory is tightly controlled by the circadian system, with memory formation oscillating over the 24-h day/night cycle in both animal models and humans ( Bellfy et al, 2023 ; Chaudhury and Colwell, 2002 ; Eckel-Mahan et al, 2008 ; Evans et al, 2017 ; Goode et al, 2022 ; Groeger et al, 2008 ; Harrison et al, 2007 ; Rawashdeh et al, 2014 ). Furthermore, long-term memory requires expression of at least one of the core clock components, Per1 ( Rawashdeh et al, 2016 ), and bidirectional manipulation of Per1 in the hippocampus can modulate memory; local knockdown in young mice impairs spatial memory, whereas overexpression in old mice ameliorates age-related memory impairments ( Kwapis et al, 2018 ).…”

Section: Intersection Between Sex Hormones and Circadian Regulators I...mentioning

confidence: 99%

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Connecting the Dots: Potential Interactions Between Sex Hormones and the Circadian System During Memory Consolidation

2023

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Both the circadian clock and sex hormone signaling can strongly influence brain function, yet little is known about how these 2 powerful modulatory systems might interact during complex neural processes like memory consolidation. Individually, the molecular components and action of each of these systems have been fairly well-characterized, but there is a fundamental lack of information about how these systems cooperate. In the circadian system, clock genes function as timekeeping molecules that convey time-of-day information on a well-stereotyped cycle that is governed by the suprachiasmatic nucleus. Keeping time is particularly important to synchronize various physiological processes across the brain and body, including those that regulate memory consolidation. Similarly, sex hormones are powerful modulators of memory, with androgens, estrogens, and progestins, all influencing memory consolidation within memory-relevant brain regions like the hippocampus. Despite clear evidence that each system can influence memory individually, exactly how the circadian and hormonal systems might interact to impact memory consolidation remains unclear. Research investigating either sex hormone action or circadian gene function within memory-relevant brain regions has unveiled several notable places in which the two systems could interact to control memory. Here, we bring attention to known interactions between the circadian clock and sex hormone signaling. We then review sex hormone–mediated control of memory consolidation, highlighting potential nodes through which the circadian system might interact during memory formation. We suggest that the bidirectional relationship between these two systems is essential for proper control of memory formation based on an animal’s hormonal and circadian state.

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The clock gene Per1 may exert diurnal control over hippocampal memory consolidation

Cited by 8 publications

References 45 publications

Circadian rhythms tied to changes in brain morphology in a densely-sampled male

Circadian rhythms tied to changes in brain morphology in a densely-sampled male

Pharmacological HDAC3 inhibition alters memory updating in young and old mice

Connecting the Dots: Potential Interactions Between Sex Hormones and the Circadian System During Memory Consolidation

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