May 31

Of mice and NREM: In this brain circuit, memories depend on sleep

A coronal view of a mouse brain. Image: Wellcome Images, CC BY-NC-ND 2.0

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This post originally appeared on Medium

Like many people, mice are suckers for novelty. They will explore new environments and objects more than familiar ones, and this preference for novelty is the basis for memory testing in mice. Given the choice, if mice spend more time examining new surroundings, the reasoning goes, it’s because they remember places and things they’ve already been exposed to. But if the right neurons don’t get turned on during sleep, mice don’t remember what they’ve experienced and treat the familiar as if it were new. The parts of the brain responsible for creating the memory itself — the sensory and motor cortex areas that mediate the feeling of exploration — must be re-activated during a specific part of the sleep cycle for the mouse to remember.

It’s no surprise that, for both humans and mice, sleep is pretty important for learning and remembering. What wasn’t known was that higher brain regions, as opposed to canonical memory areas like the hippocampus, participate in consolidating memories. In an intricate set of experiments, researchers in Japan either activated or silenced motor and sensory cortical areas in mice and then looked at how well they remembered.

tactile memory task

A mouse exploring the two floor textures during the experiment. Image: Masanori Murayama/RIKEN Brain Science Institute

The study started with mice experiencing a new environment with either smooth or grooved floors. Not surprisingly, when mice were given a choice one day later, they preferred the previously unexplored texture. The brain areas mediating the mouse’s feeling of the floor and the associated movement are reciprocally connected: touch input from the paw goes from primary somatosensory cortex (S1) to secondary motor cortex (M2), which in turn projects ‘top-down’ back to S1. This sensorimotor circuit was the target of a memory manipulation, achieved using optogenetics (here’s a simple intro to this method of controlling neurons with light).

After 10 minutes of exploring, mice took a rest, and this is where the optogenetics comes in. The researchers independently turned off M2 or S1 with light during different brain states corresponding to wakefulness or non-REM (rapid eye movement) sleep. If the top-down signal from M2 was silenced, in a later memory test mice had ‘forgotten’ the learned environment, but only if M2 was turned off early in the sleep cycle during the non-REM phase. Switching off M2 while the mouse was awake and resting, or switching off S1 during non-REM sleep, did not have any impact on mouse memory.

The authors were able to achieve even more potent control of memory, again with optogenetics. The memories of mice could effectively be wiped out in a day, or prolonged for up to four days, depending on the synchrony of light stimulation to S1 and M2. Simultaneous stimulation caused neurons in the two cortical areas to activate more during non-REM sleep. The optogenetic control of neurons created a synchrony of slow brain wave activity between S1 and M2 that is typical of deep, non-REM sleep. Even sleep-deprived mice retained their memory of the explored environment when they were given simultaneous light stimulation to both S1 and M2.

Turning on the same neurons that were active during the memory formation, when the mouse was exploring, thus seems to be important for retaining the memory in mice, at least for this texture learning task. The fact that this consolidation happens during sleep means brain stimulation techniques like transcranial magnetic stimulation or transcranial direct current stimulation applied at the right time could rescue memories in sleep disordered individuals, a direction the researchers are pursuing next.

This post originally appeared on Medium

Like many people, mice are suckers for novelty. They will explore new environments and objects more than familiar ones, and this preference for novelty is the basis for memory testing in mice. Given the choice, if mice spend more time examining new surroundings, the reasoning goes, it’s because they remember places and things they’ve already been exposed to. But if the right neurons don’t get turned on during sleep, mice don’t remember what they’ve experienced and treat the familiar as if it were new. The parts of the brain responsible for creating the memory itself — the sensory and motor cortex areas that mediate the feeling of exploration — must be re-activated during a specific part of the sleep cycle for the mouse to remember.

It’s no surprise that, for both humans and mice, sleep is pretty important for learning and remembering. What wasn’t known was that higher brain regions, as opposed to canonical memory areas like the hippocampus, participate in consolidating memories. In an intricate set of experiments, researchers in Japan either activated or silenced motor and sensory cortical areas in mice and then looked at how well they remembered.

tactile memory task

A mouse exploring the two floor textures during the experiment. Image: Masanori Murayama/RIKEN Brain Science Institute

The study started with mice experiencing a new environment with either smooth or grooved floors. Not surprisingly, when mice were given a choice one day later, they preferred the previously unexplored texture. The brain areas mediating the mouse’s feeling of the floor and the associated movement are reciprocally connected: touch input from the paw goes from primary somatosensory cortex (S1) to secondary motor cortex (M2), which in turn projects ‘top-down’ back to S1. This sensorimotor circuit was the target of a memory manipulation, achieved using optogenetics (here’s a simple intro to this method of controlling neurons with light).

After 10 minutes of exploring, mice took a rest, and this is where the optogenetics comes in. The researchers independently turned off M2 or S1 with light during different brain states corresponding to wakefulness or non-REM (rapid eye movement) sleep. If the top-down signal from M2 was silenced, in a later memory test mice had ‘forgotten’ the learned environment, but only if M2 was turned off early in the sleep cycle during the non-REM phase. Switching off M2 while the mouse was awake and resting, or switching off S1 during non-REM sleep, did not have any impact on mouse memory.

The authors were able to achieve even more potent control of memory, again with optogenetics. The memories of mice could effectively be wiped out in a day, or prolonged for up to four days, depending on the synchrony of light stimulation to S1 and M2. Simultaneous stimulation caused neurons in the two cortical areas to activate more during non-REM sleep. The optogenetic control of neurons created a synchrony of slow brain wave activity between S1 and M2 that is typical of deep, non-REM sleep. Even sleep-deprived mice retained their memory of the explored environment when they were given simultaneous light stimulation to both S1 and M2.

Turning on the same neurons that were active during the memory formation, when the mouse was exploring, thus seems to be important for retaining the memory in mice, at least for this texture learning task. The fact that this consolidation happens during sleep means brain stimulation techniques like transcranial magnetic stimulation or transcranial direct current stimulation applied at the right time could rescue memories in sleep disordered individuals, a direction the researchers are pursuing next.

Reference:

Miyamoto, D., Hirai, D., Fung, C., Inutsuka, A., Odagawa, M., Suzuki, T., Boehringer, R., Adaikkan, C., Matsubara, C., Matsuki, N., Fukai, T., McHugh, T., Yamanaka, A., & Murayama, M. (2016). Top-down cortical input during NREM sleep consolidates perceptual memory. Science. DOI: 10.1126/science.aaf0902
neuroamanda

neuroamanda

Science writer at the RIKEN Brain Science Institute in Japan

Blogging about brains on Medium

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8 Comments

  1. To my understanding, NREM is stages 1-3 of the sleep cycle; each cycle lasting about 90 minutes before REM is reached. NREM is typically where sleep walkers become active because the muscles do not paralyze. It is also explained that any “dreaming” during NREM is more “thought-like,” than dreaming as we know it, which is a result of REM sleep. Thus, NREM is also crucial for memory consolidation. Am I correct to say, In this case NREM was inhibited when S1 & M2 were manipulated. Therefore, prohibiting NREM and ultimately rejected the mice to enter successfully NREM; because of sleep deprivation?

    Reply
    • adam phillips

      I think when the signals from M2 to S1 (top-down) were blocked during nREM sleep, it prevented memory consolidation. Conversely, if the M2➜S1 path was stimulated, it improved memories even if mice were sleep deprived.

      Reply
    • neuroamanda

      Adam’s reply is correct, but to add a bit more detail: in one experiment, the M2S1 circuit was either stimulated or inhibited during NREM sleep, which either strengthened or abolished the learned memory. In another experiment (not discussed in detail in this blog post), mice were actually sleep deprived so they didn’t experience NREM sleep. In that case, the memories were ‘rescued’ by optogenetically stimulating the M2S1 circuit.

      Reply
  2. Some suggest the main purpose of sleep, originally, was to save energy. Obviously still an important function today, it makes sense that we strengthen our memories when we sleep. This explanation is also the reason why professors advise against cramming for the tests the day of the test. Our mind does not have adequate time to absorb the information for us to remember.

    Reply
  3. I have always heard that sleeping has been very important in retaining memories, and I have recently learned a lot more about how it is a necessity to function correctly. After reading about the studies done with mice it now makes even more sense to me why running on little sleep or none at all can be very detrimental to someone.

    Reply
  4. NREM sleep is characterized by the first four stages of the sleep cycle. While sleeping is an extremely important facet of memory and energy levels in general, it’s kind of cool knowing that studying (not cramming!) before bed will make our recall better in the long run. Who knew weakened synapses could maybe help us test better?

    Reply
  5. To my understanding, sleep is divided into various stages before REM (rapid eye movement can be achieved by an individual. During sleep, we are able to archive our memories of events for each day as a librarian organizes important literature on a shelf. However, in this experiment, the mice were robbed of memories of the textured floor by optogenetics, the controlling neurons with stimulation to light. It’s scary to realize that when a person is still in the stages 1, 2, and 3 that the stimulation by optogenetics to the M2 or S1 could wipe a day of memories away.

    Reply
    • adam phillips

      I would just point out two things that might have gotten overlooked. The optogenetic manipulation that prevented consolidation was actually inhibition of that M2 to S1 pathway. Stimulating it strengthened the memories so that they lasted longer (twice as long actually). Also, the M2 to S1 pathway wouldn’t be related to all memories for the day. S1 is somatosensory cortex, which is activated by tactile stimulation from the different textured floors. When a visually-based task was used instead, inhibiting the M2 to S1 circuit had no effect on consolidation (that point might not have been in this post, but it’s in the paper itself). So, what seems important is that the same circuit that is activated during an experience is reactivated during sleep, helping it get consolidated as memory.

      Reply

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