Cortisol Suppression in the Early Morning Enhances Memory Reconsolidation

Post by Andrew Vo

What's the science?

Our memories are not concrete, they are malleable and susceptible to change through a process known as reconsolidation. It has been proposed that manipulations of sleep and levels of the stress hormone cortisol can modulate reconsolidation and alter reactivated memories, however the direction of such effects is still unclear. Cortisol levels normally decrease during the evening but rise in the early morning and can also be manipulated pharmacologically. This week in The Journal of Neuroscience, Antypa et al. examine the effects of pharmacological cortisol suppression following memory reactivation on later memory retrieval.

How did they do it?

A group of healthy young adults participated in two experimental conditions (i.e., drug and placebo) spaced a minimum of 10 days apart. In each condition, participants completed (1) an encoding session, (2) a reactivation session, and (3) a retrieval session. In the encoding session, they were presented with two stories, each composed of visual slides and auditory narration. In the reactivation session that took place 2 days after encoding, participants slept in the lab from 11:00 p.m. until 3:55 a.m. when they were awakened, and one of the two encoded stories was reactivated through a cueing procedure. At 4:00 a.m., they were administered either metyrapone (a cortisol synthesis inhibitor) or a placebo before returning to bed until a 6:45 a.m. awakening. Salivary cortisol samples were collected immediately before drug intake as well as in 15-minute intervals for 3 hours after the second awakening (i.e., 6:45 a.m. to 9:45 a.m.). In the retrieval session that took place 4 days after reactivation, participants completed a multiple-choice recognition memory test on both the reactivated and non-reactivated stories. Finally, a subset of participants completed whole night polysomnography (PSG) recording for both experimental conditions.

What did they find?

Cortisol suppression via metyrapone administration just after memory reactivation enhanced performance on the multiple-choice recognition memory test in the retrieval session. This effect was not only greater for the reactivated relative to the non-reactivated story in the drug condition, but also in comparison to both reactivated and non-reactivated memories under placebo. Memory enhancement for the reactivated versus non-reactivated story negatively correlated with metyrapone-associated cortisol suppression during but not after sleep. That is, the more cortisol levels were suppressed, the more memory for the reactivated story was enhanced.

Analysis of salivary cortisol samples revealed that baseline levels (at 3:55 a.m.) did not differ between the two experimental conditions. These levels gradually lowered after awakening (6:45 to 9:45 a.m.) following metyrapone administration. Examining PSG recordings in a subset of participants, metyrapone affected subsequent sleep by increasing awake time, altering the proportion of time spent in different sleep stages, reducing total sleep time, and decreasing sleep efficiency. These metyrapone-associated changes in sleep correlated with cortisol decrease but not memory enhancement for the reactivated versus non-reactivated story because of metyrapone intake.

What's the impact?

In summary, this study demonstrated that metyrapone-mediated cortisol suppression immediately following memory reactivation enhanced reconsolidation and later recall of that memory. These findings demonstrate a cognitive (reconsolidation), physiological (sleep and cortisol levels), and pharmacological (metyrapone intake) mechanism through which episodic memories may be manipulated. Understanding of these processes holds potential clinical implications for the treatment of individuals with disease, trauma, or stress-related memory impairment.

Antypa et al. Suppressing the Morning Cortisol Rise After Memory Reactivation at 4 A.M. Enhances Episodic Memory Reconsolidation in Humans. The Journal of Neuroscience (2021). Access the original scientific publication here.

The Role of Astrocyte-Derived Cholesterol in Alzheimer’s Disease

Post by Ifrah Khanyaree

What's the science?

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of beta-amyloid (Aß) plaques in the brain and cognitive impairment. AD is estimated to affect over 20 million people worldwide. This week in PNAS, Wang and colleagues used super-resolution imaging to show that astrocyte cholesterol synthesis and its transport controls Aß accumulation and hence plaque formation in AD.                                                

How did they do it?

For the first experiment, the authors wanted to establish astrocytes as a key cholesterol source. They took a control cell culture and looked at a specific lipid cluster. They compared the size of this lipid cluster to the size of the same lipid cluster in neurons co-cultured with cholesterol-deficient astrocytes. As a second experiment, to establish the integral role of Apolipoprotein E, apoE (which is a cholesterol transport protein produced by astrocytes), they compared two cultures of cells — one loaded with apoE and a cholesterol source and the other only with apoE.

Next, the authors wanted to confirm whether astrocytes directly control Aβ peptide production (which leads to Aβ plaques). For this, only neurons were isolated from other cortical cells in one culture and, for a second mixed culture, both neurons and astrocytes were used. These cell cultures were treated with or without apoE, labelled, and then imaged with super-resolution microscopy. Finally, to confirm astrocyte-derived cholesterol as the regulator of amyloid precursor protein or APP (which generates Aß peptides) they knocked out the main transcriptional regulator of enzymes involved in cholesterol synthesis.

What did they find?

The authors found that without astrocyte derived cholesterol, the size of the lipid cluster in primary neurons was significantly smaller, suggesting that astrocytes are needed for the transport of cholesterol to neurons. This was confirmed in their second experiment, where they observed cells loaded with apoE and a cholesterol source increased in cluster diameter and those without cholesterol actually decreased in size as well as number.

They were also able to confirm the role of astrocytes in APP regulation and Aß production. The authors observed a decrease in APP and lipid cluster association in a cell culture containing only neurons and apoE. The opposite effect was seen in a mixed culture with astrocytes with neurons. There was a 2.5x increase in APP association with lipid clusters. This demonstrates that astrocytes are necessary for synthesizing the cholesterol that is then shuttled to neuronal membranes. The more cholesterol that is loaded into neuronal membranes, the more APP interacts with enzymes that cleave it to make Aß peptides. 

What's the impact?

This study found that astrocyte-derived cholesterol tightly regulates the formation of beta-amyloid plaques in AD. Before this, the role of astrocytes in AD pathogenesis was not well understood. In this study, Wang and colleagues establish a molecular pathway that defines the role of astrocytes in plaque formation by the production and distribution of cholesterol to neurons.

Wang et al. Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol. PNAS (2021). Access the original scientific publication here.

How Has COVID-19 Impacted Neuroscience Research?

Post by Anastasia Sares

Science interrupted

The effects of the pandemic have been felt in every sector of life across the globe since the beginning of 2020, and neuroscience research is no different. This week in Neuron, Joy Snider and David Holtzman—one a laboratory scientist and the other a clinical researcher—narrate their own experiences and the influence of the pandemic on their fields.

Empty labs, full screens

Most in-person data collection and lab work was quickly deemed “nonessential” and placed under heavy restrictions, slowing progress to a crawl. Longitudinal studies (where people come in multiple times to be tested) that were begun before the pandemic were often unable to stay on schedule, compromising their original plans and possibly leading to data loss. MRI studies were especially risky if the imaging facility was connected to a hospital where COVID patients were treated, so many of these were put on hold as well.

On the other hand, forcing talks and conferences to move online, often at a reduced cost of attendance, removed barriers to these events and increased scholarly communication. The increase in participation was sometimes two- to three-fold, and people from around the world were able to dialogue. In addition, for some people, the lack of daily distractions at the lab was exactly what they needed to do in-depth analyses or writing, and paper submissions rose substantially.

A changed future

The setbacks caused by the pandemic will change the course of research long after. In animal research, the death of animals with highly specific genetics means starting back at square one, setting projects back years. Human clinical and preclinical studies also take years to approve, set up, and administer— some may need to go through these processes again and could lose participants. Fewer volunteering opportunities, projects on hold, and school closures impact careers across the board but disproportionately affect students, early-career scientists, and parents of young children who had to switch to virtual schooling at home. However, despite these difficulties, the push for remote communication and even remote testing could reduce the cost of scientific activities. 

What’s the bottom line?

The pandemic certainly presented challenges to researchers that may take years to recover from. However, it also led to surprising benefits, like the democratization of scientific events and more efficient remote testing. This could mean permanent changes to the way we conduct research moving forward.

Snider & Holtzman. Effects of COVI9-19 on preclinical and clinical research in Neurology: Examples from research on neurodegeneration and Alzheimer’s disease. Neuron (2021). Access the original scientific publication here.