Memory updating tends to decline as we age, but the precise mechanisms behind this issue are not thoroughly understood. A research team discovered that inhibiting a certain enzyme known as histone deacetylase 3 leads to improved memory updating in aging mice.
It’s common to experience forgetfulness occasionally, particularly as we grow older. However, older adults face more than just challenges with remembering new information; they also struggle to adjust their existing memories when new information becomes available. The underlying mechanisms of memory updating and the changes that occur with aging remain largely unknown.
A research group from Penn State has pinpointed an enzyme that plays a role in the decline of memory updating as we age. By blocking this enzyme, older mice were able to embrace new information better, performing comparably to younger mice. These findings, published in Frontiers in Molecular Neuroscience, could open up avenues for potential treatments aimed at enhancing cognitive flexibility in the elderly.
“Understanding the molecular processes involved in memory updating is crucial because most of our memories as humans are actually updates. We continuously build on our prior knowledge and modify what we remember,” stated Janine Kwapis, an assistant professor of biology and the lead author of the study. “However, very few have investigated whether the mechanisms for forming memories are the same as those for updating them, or if they’re distinct. This research helps clarify that distinction.”
When a new memory is formed, the brain undergoes a process known as consolidation to establish that memory. This involves the expression of proteins at synapses, which are the spaces where neurons communicate, linking together the cells activated during memory creation. When it’s time to recall the memory, those connected cells activate simultaneously.
“When you receive new information, you need to retrieve the existing memory and weaken it to be receptive to the new data. After processing this new information, the updated memory is then strengthened and saved once more,” Kwapis explained. She emphasized that this process, known as reconsolidation, becomes less efficient with age.
The research team aimed to uncover why updating memories becomes challenging with normal aging. They wondered if enhancing gene expression during reconsolidation could potentially improve memory updating.
To investigate this, they targeted histone deacetylase 3 (HDAC3), an enzyme that influences gene transcription—the procedure of transcribing information from a DNA segment into RNA, which eventually synthesizes a functional protein. While HDAC3 has been linked to negative impacts on memory formation and gene expression during consolidation, its role in memory reconsolidation had not been explored before.
“HDAC3 generally compresses chromatin, a complex of DNA and proteins, making transcription more difficult,” explained Chad Smies, a doctoral student in biology and the primary author. “By inhibiting this enzyme, we can maintain a more accessible chromatin state, thus enhancing gene expression.”
When HDAC3 inhibition occurred during the reconsolidation phase of memory, it countered the usual age-related memory updating deficits. Older mice showed performance on memory update tasks that was on par with that of younger mice.
The research team utilized a method known as the objects in updated locations paradigm, developed by Kwapis specifically to evaluate memory updating. This approach consists of three phases: a training session where mice familiarize themselves with two locations containing identical objects; an update session wherein one object is relocated; and a testing session where objects are presented in four different spots—the initial two training locations, the updated site, and a brand-new location.
“Mice are naturally attracted to novelty, so if they remember well from training or updating, they’ll explore the novel object location more,” noted Smies. “Conversely, if their memory is weak, they will wander equally among the previously learned sites and the new one.”
By investigating molecular mechanisms like HDAC3, the researchers aim to propose possible therapeutic strategies for enhancing cognitive flexibility in older individuals.
“If these mechanisms can improve memory in healthy aging, they might also aid in addressing conditions like Alzheimer’s disease and dementia,” Kwapis added.
Other contributors to the paper from Penn State included Lauren Bellfy, a doctoral student in molecular, cellular and integrative biosciences, and Chad Brunswick, a doctoral student in neuroscience. Additionally, undergraduate students Destiny Wright and Sofia Bennetts, postdoctoral scholar Mark Urban, and Guanhua Shu, a graduate student from Harvard University at the time of the study, also contributed to this research.
This study was supported by funding from the National Institute on Aging, Hevolution/American Federation for Aging Research, and the Penn State Paul Berg Early Career Professorship.
