Ripples During Slow-Wave Sleep Re-balance Neurons

What's the science?

Synapses in the brain are strengthened while awake and synaptic depression (weakening of the synapses) occurs during slow-wave sleep to rebalance synapses. This synaptic depression may help to selectively preserve memories, however, how it occurs during sleep is unclear. During slow-wave sleep, the hippocampus emits high frequency oscillations called “sharp-wave ripples” which reactivate the neurons involved in recent memories. Ripples could be required for synaptic depression during sleep, making “room” for new memories to form. This week in Science, Norimoto and colleagues test whether ripples are required for synaptic depression and subsequent memory formation in mice.

How did they do it?

They silenced sharp-wave ripple events during slow-wave sleep using optogenetic-feedback (i.e. every time a ripple event was detected, they inhibited the hippocampal neurons to reduce firing) in a group of test mice. They then recorded excitatory postsynaptic potentials (activity in the postsynaptic neurons) during slow-wave sleep and compared the test mice to control mice to determine whether synaptic depression during sleep was affected in the test mice. Mice then underwent a spatial object-recognition task. First, they explored an area containing two new objects, and then returned to the same location 2 hours later where one of the objects had moved. The authors compared the memory performance between test and control mice to determine whether disrupting the ripples had an effect on new memory acquisition.

What did they find?

The authors were able to successfully reduce almost all of the ripple events in the test mice. Control mice experienced depressed postsynaptic activity representing the expected synaptic depression that occurs during slow-wave sleep, while mice with the impaired ripple events did not show synaptic depression. Control mice showed normal memory performance, while mice with impaired ripple events were unable to identify a moved object in the spatial object recognition task, suggesting that they could not form new memories. The authors were also able to replicate the lack of synaptic depression by testing the effects of disrupting ripples in hippocampal tissue slices. They used in vitro and in vivo experiments to show that synaptic depression occurring during slow-wave sleep is mediated by NMDA receptors.

What's the impact?

This is the first study to link sharp-wave ripples during slow-wave sleep with synaptic depression and memory performance. Before this study, we did not understand the mechanism through which synaptic depression occurred during slow-wave sleep. We now know that ripples during slow-wave sleep are critical for balancing of synapses and for new memory formation.

H. Norimoto et al., Hippocampal ripples down-regulate synapses. Science (2018). Access the original scientific publication here.

Plasticity in Neural Genomes During Early Life Experiences

What's the science?

The brain undergoes changes (i.e. plasticity) during early development, and these are thought to be due to gene-environment interactions. Retrotransposons are segments of DNA that are mobile and can essentially “jump” and insert themselves throughout the genome, and could be one way that DNA is modified by interactions with the environment. Currently, we don’t know whether retrotransposons play a role in changing DNA during early life. This week in Science, Bedrosian and colleagues observe the effects of early maternal care on retrotransposon levels in mouse DNA.

How did they do it?

Mice were divided into two groups: high and low maternal care (as evidenced by median natural levels of grooming and nursing over 2 weeks). They used droplet digital Polymerase Chain Reaction (ddPCR) to quantify the number of retrotransposons (‘L1’ retrotransposons, making up 17% of the mouse genome) in mice DNA from brain (hippocampus and frontal cortex) and heart tissue between the high and low care groups. They also manipulated the level of maternal care to test how this affected the number of retrotransposons over time.

What did they find?

There were more retrotransposons in the hippocampus in mice with low maternal care (but not in the heart or frontal cortex). When they manipulated the levels of maternal care by separating the mother and pup, retrotransposon levels also varied. They then tested what causes retrotransposon levels to change. They measured neurogenesis (the formation of new neurons) by staining hippocampal neurons, and found no differences (i.e. neurogenesis was not responsible for changes in retrotransposon levels). They also used bisulfite sequencing to measure the level of methylation of DNA (a DNA modification that affects gene expression). The retrotransposon regions in hippocampal DNA showed less methylation in mice with low maternal care (who have higher retrotransposon levels), suggesting that methylation is responsible for changes in retrotransposon levels with maternal care.

What's the impact?

This is the first study to show that maternal care alters retrotransposon (i.e. jumping gene) activity in early life. Before, we did not understand exactly how early life experience can change the structure of DNA. Now we know that retrotransposons are one of the ways that DNA plasticity (i.e. changes) occurs in response to early life experiences.

T. Bedrosian et al., Early life experience drives structural variation of neural genomes in mice. Science (2018). Access the original scientific publication here.

A Model for the Spread of Tau through Connected Tracts in the Human Brain

What's the science?

In Alzheimer’s disease, tau proteins accumulate in the hippocampus resulting in neurofibrillary tangles. Beta-amyloid plaques, another form of protein aggregation, are thought to help tau proteins spread. One way that tau may spread from neuron to neuron is through neural connections, while another possibility is that it simply spreads to neurons located close by. This week in Nature Neuroscience, Jacobs and colleagues used brain imaging to ask: ‘How does  tau spread?’

How did they do it?

Healthy older participants from the Harvard Aging and Brain Study were scanned over several years with positron emission tomography (PET) imaging to measure tau and beta-amyloid in the brain, and diffusion tensor imaging (DTI) to measure connectivity (of white matter tracts) in the brain. They tested whether beta-amyloid in the brain at baseline predicts hippocampal volume loss. They then measured whether this volume loss predicts abnormalities in the hippocampal cingulum bundle (a white matter tract that innervates the hippocampus and connects it with the posterior cingulate cortex) and in turn, whether these abnormal connections predict the accumulation of tau in the posterior cingulate cortex. They ran control analyses with another tract (that does not innervate the hippocampus) and another close by region. Associations with memory and executive functions were also assessed to understand the clinical relevance. 

What did they find?

Brain beta-amyloid level at baseline predicted hippocampal volume loss. The hippocampal volume loss also predicted abnormal white matter tract connectivity over time in the hippocampal cingulum bundle, but not in other white matter tracts close by that do not directly connect with the hippocampus. The abnormal connectivity in this tract predicted the accumulation of tau in a connected region called the posterior cingulate cortex, but not in another adjacent control region. Collectively, these changes were associated with memory decline over time. This means that early Alzheimer’s pathology (beta-amyloid) initiates a cascade of hippocampal volume loss followed by abnormal tract connectivity and the spreading of tau along this tract. 

What's the impact?

This is the first study to confirm that tau likely spreads via neural connections (rather than just to regions close by) from the hippocampus, facilitated by beta-amyloid in the brain. Clarifying the order in which Alzheimer’s pathology spreads, as well as the mechanism through which it spreads is critical for helping to target the advancement of Alzheimer’s disease.

You can reach out to her about her work at @DrHeidiJacobs on Twitter.

H. I. L. Jacobs et al., Structural tract alterations predict down-stream tau accumulation in amyloid positive older individuals. Nat. Neurosci. (2018). Access the original scientific publication here.