Biology subjects

Bellfy, L.

Publications and source records attributed to Bellfy, L..

5 recordsLinked to original sources

bioRxiv2025

Age and Sex Influence Diurnal Memory Oscillations, Circadian Rhythmicity, and Per1 Expression

BackgroundThe circadian system influences many different biological processes across the lifespan, including memory performance and daily activity patterns. The biological process of aging causes decreased control of the circadian system that is accompanied by a decline in memory performance, suggesting that these two processes may be linked. Indeed, our previous work has shown that in male mice, the clock gene Per1 functions within the dorsal hippocampus to exert diurnal control over memory and repression of Per1 in the old hippocampus contributes to age-related impairments in spatial memory. Although it is clear that Per1 may be a key molecular link between memory and the circadian rhythm, next to nothing is known about how sex impacts this role in the young or old brain. Here, we are interested in understanding how the factors of sex and age impact memory performance, circadian activity patterns, sleep behavior, and hippocampal Per1 expression. MethodsWe used a combination of spatial memory (Object Location Memory (OLM)) and circadian activity monitoring to determine how male and female mice change across the lifespan. In addition, we used RT-qPCR to quantify the change in Per1 levels in response to learning in young and old, male and female mice. ResultsYoung female mice resist diurnal oscillations in memory, showing robust spatial memory across the diurnal cycle. In contrast, old female mice show an emergence of diurnal memory oscillations, with better memory during the day than at night (similar to what we observed previously in young male mice). In contrast, old male mice showed better memory performance during the night than the day, suggesting that their peak memory performance is drastically shifted compared to young males. We also measured activity patterns and sleep behavior across the diurnal cycle and found that sex was more of an influence than age in multiple analyses, but age did have an impact, with old male mice showing stronger circadian rhythm disruptions than any other cohort. Finally, we investigated whether the circadian clock gene Per1 plays a role in these sex- and age-dependent effects in diurnal memory performance. We found that, in general, learning- induced Per1 and memory performance peaked at similar times of day in each group, consistent with our hypothesis that Per1 exerts diurnal control over memory performance. ConclusionsThis work supports a role for Per1 in exerting diurnal control over memory and suggests that Per1 may be an appealing therapeutic target to improve memory and circadian dysfunction in old age. HighlightsO_LIDiurnal oscillations in spatial memory are sex- and age-dependent in mice C_LIO_LIPer1 learning-induced expression matches diurnal memory patterns C_LIO_LICircadian rhythm patterns are sex- and age-dependent in mice C_LIO_LIYoung females show good memory across the diurnal cycle C_LIO_LIDiurnal memory oscillations reemerge in old female mice C_LI Plain language summaryMemory is an integral part of everyday functioning, and one that is known to decline with aging. Our lab has previously shown that the clock gene Period1 (Per1) regulates spatial memory performance in young males, establishing a molecular link between circadian rhythms and memory. Young adult male mice show diurnal oscillations in memory consolidation, with the best memory occurring at midday, and the worst memory occurring at midnight. In the current study, we wanted to expand our work to young adult females, as well as an aged population of male and female mice. Using a simple spatial memory task, we measured diurnal changes in both memory performance and Per1 gene expression within the dorsal hippocampus (a brain region necessary for spatial memory). We found that old mice (both male and female) showed a correlation between high Per1 levels and better memory, as we have previously seen. Conversely, young female mice performed well on the memory task at every timepoint but didnt have a significant change in Per1, indicating that they may be using some different mechanism to modulate memory performance. Finally, we used infrared activity monitoring to investigate several circadian rhythm related measures in young and old, male and female mice. We found that sex influenced the circadian rhythm more than age, and the group with the largest circadian disruption was aged males. Overall, this research provides new information about how both sex and age impact diurnal oscillations in both memory and activity, fundamental knowledge that has been lacking in the field.

animal behavior and cognition↗

bioRxiv2025

Alcohol consumption drives sex- and region- specific disruption of somatostatin signaling in mice

The prefrontal cortex (PFC), which is thought to be disrupted early in the cycle of substance use and addiction [1], is comprised of a complex microcircuit of long-range glutamatergic pyramidal neurons controlled by GABAergic-expressing local inhibitory neurons [2, 3]. Somatostatin (SST)-expressing neurons are a subpopulation of these local GABAergic inhibitory cells and provide both peptidergic and GABAergic control over these PFC circuits [3, 4], and are disturbed following alcohol consumption in humans [5] and in rodent models [6, 7]. However, little is known about how endogenous SST peptide signaling is affected by alcohol. Using ex vivo electrophysiology, immunohistochemistry, in situ hybridization, and behavior, we demonstrate robust down-regulation of SST control over pyramidal output activity in the prelimbic (PL), but not infralimbic (IL), PFC after alcohol exposure. We also show this is likely mediated by changes in SST receptor expression levels and not disrupted expression or capacity for release of SST peptide, suggesting postsynaptic homeostatic changes to SST signaling following binge alcohol consumption in mice that may underlie post-alcohol dysregulation in mood. This provides insight into how voluntary alcohol consumption disrupts PFC peptide signaling and suggests a potential therapeutic target for the treatment of alcohol use disorder (AUD).

neuroscience↗

bioRxiv2024

Pharmacological HDAC3 inhibition alters memory updating in young and old mice

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.

neuroscience↗

bioRxiv2022

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

The circadian system influences many different biological processes, including memory performance. While the suprachiasmatic nucleus (SCN) functions as the brains central pacemaker, satellite clocks have also been identified in other brain regions, such as the memory-relevant dorsal hippocampus. Although it is unclear how these satellite clocks contribute to brain function, one possibility is that they may serve to exert diurnal control over local processes. Within the hippocampus, for example, the local clock may contribute to time-of-day effects on memory. Here, we used the hippocampus-dependent Object Location Memory task to determine how memory is regulated across the day/night cycle in mice. First, we systematically determined which phase of memory (acquisition, consolidation, or retrieval) is modulated across the 24h day. We found that mice show better long-term memory performance during the day than at night, an effect that was specifically attributed to diurnal changes in memory consolidation, as neither memory acquisition nor memory retrieval fluctuated across the day/night cycle. Using RNA-sequencing we identified the circadian clock gene Period1 (Per1) as a key mechanism capable of supporting this diurnal fluctuation in memory consolidation, as Per1 oscillates in tandem with memory performance. We then show that local knockdown of Per1 within the dorsal hippocampus has no effect on either the circadian rhythm or sleep behavior, although previous work has shown this manipulation impairs memory. Thus, Per1 may independently function within the dorsal hippocampus to regulate memory in addition to its known role in regulating the circadian rhythm within the SCN. Per1 may therefore exert local diurnal control over memory consolidation within the dorsal hippocampus.

neuroscience↗

bioRxiv2019

TeXP: Deconvolving the effects of pervasive and autonomous transcription of transposable elements

Long interspersed nuclear element 1 (LINE-1) is a primary source of genetic variation in humans and other mammals. Despite its importance, LINE-1 activity remains difficult to study because of its highly repetitive nature. Here, we developed and validated a method called TeXP to gauge LINE-1 activity accurately. TeXP builds mappability signatures from LINE-1 subfamilies to deconvolve the effect of pervasive transcription from autonomous LINE-1 activity. In particular, it apportions the multiple reads aligned to the many LINE-1 instances in the genome into these two categories. Using our method, we evaluated well-established cell lines, cell-line compartments and healthy tissues and found that the vast majority (91.7%) of transcriptome reads overlapping LINE-1 derive from pervasive transcription. We validated TeXP by independently estimating the levels of LINE-1 autonomous transcription using ddPCR, finding high concordance. Next, we applied our method to comprehensively measure LINE-1 activity across healthy somatic cells, while backing out the effect of pervasive transcription. Unexpectedly, we found that LINE-1 activity is present in many normal somatic cells. This finding contrasts with earlier studies showing that LINE-1 has limited activity in healthy somatic tissues, except for neuroprogenitor cells. Interestingly, we found that the amount of LINE-1 activity was associated with the with the amount of cell turnover, with tissues with low cell turnover rates (e.g. the adult central nervous system) showing lower LINE-1 activity. Altogether, our results show how accounting for pervasive transcription is critical to accurately quantify the activity of highly repetitive regions of the human genome.\n\nAuthor SummaryRepetitive sequences, such as LINEs, comprise more than half of the human genome. Due to their repetitive nature, LINEs are hard to grasp. In particular, we find that pervasive transcription is a major confounding factor in transcriptome data. We observe that, on average, more than 90% of LINE signal derives from pervasive transcription. To investigate this issue, we developed and validated a new method called TeXP. TeXP accounts and removes the effects of pervasive transcription when quantifying LINE activity. Our method uses the broad distribution of LINEs to estimate the effects of pervasive transcription. Using TeXP, we processed thousands of transcriptome datasets to uniformly, and unbiasedly measure LINE-1 activity across healthy somatic cells. By removing the pervasive transcription component, we find that (1) LINE-1 is broadly expressed in healthy somatic tissues; (2) Adult brain show small levels of LINE transcription and; (3) LINE-1 transcription level is correlated with tissue cell turnover. Our method thus offers insights into how repetitive sequences and influenced by pervasive transcription. Moreover, we uncover the activity of LINE-1 in somatic tissues at an unmatched scale.

bioinformatics↗