(Figure 1: A magnified image of a mouse brain showing memory cells (red) that can be turned ‘on’ and ‘off’ using light delivered by a fiber optic cable (black). Credit: © Susumu Tonegawa)

Memories get the emotional switch

Memories of experiences are encoded in the brain along with contextual and emotional information such as where the experience took place and whether it was positive or negative. This allows for the formation of memory associations that might assist in survival. Just how this positive and negative encoding occurs, however, has remained unclear.

Susumu Tonegawa and colleagues from the RIKEN–MIT Center for Neural Circuit Genetics have now discovered that neurons in the hippocampus region of the brain can be artificially switched to encode memories as either positive or negative regardless of the original experience.

Tonegawa’s research team used genetic techniques to mark neurons in the dorsal dentate gyrus region of the hippocampus and the basolateral complex of the amygdala (BLA) in male mice. Memories are encoded in both these regions as specific groups of activated cells called ‘engrams’, but each region encodes the memory in slightly different ways: the BLA encodes positive and negative memory ‘valence’, while the dorsal dentate gyrus encodes contextual information such as emotion.

The genetic labeling, which involved using a light-sensitive ion channel called channelrhodopsin, was activated by the formation of either a positive memory, in this case exposure to females, or a negative memory associated with a foot shock. The cells that expressed this channel could be subsequently activated by exposure to light (Fig. 1); doing so induced aversive responses in mice that had experienced foot shocks, and appetitive responses in those that had experienced female interactions.

The researchers then used light to activate the hippocampal or BLA neurons that had been labeled during the formation of a positive memory while exposing the mice to foot shocks. The next time the animals were tested, light activation of those hippocampal neurons that had initially induced appetitive responses instead led the mice to exhibit aversive responses. However, BLA neurons could not be switched in this way, indicating that only neurons in the hippocampus have plasticity in their encoding of positive or negative memories.

The valence of hippocampal neurons, the researchers found, could be switched from both good to bad and bad to good using this technique, with the switch attributed to a change in the strength of connections between the hippocampal and BLA neurons of each engram.

The findings provide new insight into how memories can be altered after they are formed. The possibility of inducing similar changes to memory valence in humans could also offer hope of a treatment for those suffering from conditions such as post-traumatic stress disorder.

(Image caption: This image depicts the injection sites and the expression of the viral constructs in the two areas of the brain studied: the Dentate Gyrus of the hippocampus (middle) and the Basolateral Amygdala (bottom corners). Image courtesy of the researchers)

Neuroscientists reverse memories’ emotional associations

Most memories have some kind of emotion associated with them: Recalling the week you just spent at the beach probably makes you feel happy, while reflecting on being bullied provokes more negative feelings.

A new study from MIT neuroscientists reveals the brain circuit that controls how memories become linked with positive or negative emotions. Furthermore, the researchers found that they could reverse the emotional association of specific memories by manipulating brain cells with optogenetics — a technique that uses light to control neuron activity.

The findings, described in the Aug. 27 issue of Nature, demonstrated that a neuronal circuit connecting the hippocampus and the amygdala plays a critical role in associating emotion with memory. This circuit could offer a target for new drugs to help treat conditions such as post-traumatic stress disorder, the researchers say.

“In the future, one may be able to develop methods that help people to remember positive memories more strongly than negative ones,” says Susumu Tonegawa, the Picower Professor of Biology and Neuroscience, director of the RIKEN-MIT Center for Neural Circuit Genetics at MIT’s Picower Institute for Learning and Memory, and senior author of the paper.

The paper’s lead authors are Roger Redondo, a Howard Hughes Medical Institute postdoc at MIT, and Joshua Kim, a graduate student in MIT’s Department of Biology.

Shifting memories

Memories are made of many elements, which are stored in different parts of the brain. A memory’s context, including information about the location where the event took place, is stored in cells of the hippocampus, while emotions linked to that memory are found in the amygdala.

Previous research has shown that many aspects of memory, including emotional associations, are malleable. Psychotherapists have taken advantage of this to help patients suffering from depression and post-traumatic stress disorder, but the neural circuitry underlying such malleability is not known.

In this study, the researchers set out to explore that malleability with an experimental technique they recently devised that allows them to tag neurons that encode a specific memory, or engram. To achieve this, they label hippocampal cells that are turned on during memory formation with a light-sensitive protein called channelrhodopsin. From that point on, any time those cells are activated with light, the mice recall the memory encoded by that group of cells.

Last year, Tonegawa’s lab used this technique to implant, or “incept,” false memories in mice by reactivating engrams while the mice were undergoing a different experience. In the new study, the researchers wanted to investigate how the context of a memory becomes linked to a particular emotion. First, they used their engram-labeling protocol to tag neurons associated with either a rewarding experience (for male mice, socializing with a female mouse) or an unpleasant experience (a mild electrical shock). In this first set of experiments, the researchers labeled memory cells in a part of the hippocampus called the dentate gyrus.

Two days later, the mice were placed into a large rectangular arena. For three minutes, the researchers recorded which half of the arena the mice naturally preferred. Then, for mice that had received the fear conditioning, the researchers stimulated the labeled cells in the dentate gyrus with light whenever the mice went into the preferred side. The mice soon began avoiding that area, showing that the reactivation of the fear memory had been successful.

The reward memory could also be reactivated: For mice that were reward-conditioned, the researchers stimulated them with light whenever they went into the less-preferred side, and they soon began to spend more time there, recalling the pleasant memory.

A couple of days later, the researchers tried to reverse the mice’s emotional responses. For male mice that had originally received the fear conditioning, they activated the memory cells involved in the fear memory with light for 12 minutes while the mice spent time with female mice. For mice that had initially received the reward conditioning, memory cells were activated while they received mild electric shocks.

Next, the researchers again put the mice in the large two-zone arena. This time, the mice that had originally been conditioned with fear and had avoided the side of the chamber where their hippocampal cells were activated by the laser now began to spend more time in that side when their hippocampal cells were activated, showing that a pleasant association had replaced the fearful one. This reversal also took place in mice that went from reward to fear conditioning.

Altered connections

The researchers then performed the same set of experiments but labeled memory cells in the basolateral amygdala, a region involved in processing emotions. This time, they could not induce a switch by reactivating those cells — the mice continued to behave as they had been conditioned when the memory cells were first labeled.

This suggests that emotional associations, also called valences, are encoded somewhere in the neural circuitry that connects the dentate gyrus to the amygdala, the researchers say. A fearful experience strengthens the connections between the hippocampal engram and fear-encoding cells in the amygdala, but that connection can be weakened later on as new connections are formed between the hippocampus and amygdala cells that encode positive associations.

“That plasticity of the connection between the hippocampus and the amygdala plays a crucial role in the switching of the valence of the memory,” Tonegawa says.

These results indicate that while dentate gyrus cells are neutral with respect to emotion, individual amygdala cells are precommitted to encode fear or reward memory. The researchers are now trying to discover molecular signatures of these two types of amygdala cells. They are also investigating whether reactivating pleasant memories has any effect on depression, in hopes of identifying new targets for drugs to treat depression and post-traumatic stress disorder.

David Anderson, a professor of biology at the California Institute of Technology, says the study makes an important contribution to neuroscientists’ fundamental understanding of the brain and also has potential implications for treating mental illness.

“This is a tour de force of modern molecular-biology-based methods for analyzing processes, such as learning and memory, at the neural-circuitry level. It’s one of the most sophisticated studies of this type that I’ve seen,” he says.

Self-repairing mechanism helps to preserve brain function in neurodegenerative diseases

New research, led by scientists at the University of Southampton, has found that neurogenesis, the self-repairing mechanism of the adult brain, can help to preserve brain function in neurodegenerative diseases such as Alzheimer’s, Prion or Parkinson’s.

The progressive degeneration and death of the brain, occurring in many neurodegenerative diseases, is often seen as an unstoppable and irrevocable process. However, the brain has some self-repairing potential that accounts for the renewal of certain neuronal populations living in the dentate gyrus, a simple cortical region that is part of the larger functional brain system controlling learning and memory, the hippocampus. This process is known as neurogenesis.

While increased neurogenesis has been reported in neurodegenerative diseases in the past, its significance is unclear. Now a research team, led by Dr Diego Gomez-Nicola from the Centre for Biological Sciences at the University of Southampton, has detected increased neurogenesis in the dentate gyrus that partially counteracts neuronal loss.

Using a model of prion disease from mice, the research identified the time-course of the generation of these newborn neurons and how they integrate into the brain circuitry. While this self-repairing mechanism is effective in maintaining some neuronal functions at early and mid-stages of the disease, it fails at more advanced phases. This highlights a temporal window for potential therapeutic intervention, in order to preserve the beneficial effects of enhanced neurogenesis.

Dr Gomez-Nicola says: “This study highlights the latent potential of the brain to orchestrate a self-repairing response. The continuation of this line of research is opening new avenues to identify what specific signals are used to promote this increased neurogenic response, with views focused in targeting neurogenesis as a therapeutic approach to promote the regeneration of lost neurons.”

Rescue of Alzheimer’s Memory Deficit Achieved by Reducing ‘Excessive Inhibition’

A new drug target to fight Alzheimer’s disease has been discovered by a research team led by Gong Chen, a Professor of Biology and the Verne M. Willaman Chair in Life Sciences at Penn State University. The discovery also has potential for development as a novel diagnostic tool for Alzheimer’s disease, which is the most common form of dementia and one for which no cure has yet been found. A scientific paper describing the discovery will be published in Nature Communications on 13 June 2014. 

Chen’s research was motivated by the recent failure in clinical trials of once-promising Alzheimer’s drugs being developed by large pharmaceutical companies. “Billions of dollars were invested in years of research leading up to the clinical trials of those Alzheimer’s drugs, but they failed the test after they unexpectedly worsened the patients’ symptoms,” Chen said. The research behind those drugs had targeted the long-recognized feature of Alzheimer’s brains: the sticky buildup of the amyloid protein known as plaques, which can cause neurons in the brain to die. “The research of our lab and others now has focused on finding new drug targets and on developing new approaches for diagnosing and treating Alzheimer’s disease,” Chen explained.

"We recently discovered an abnormally high concentration of one inhibitory neurotransmitter in the brains of deceased Alzheimer’s patients," Chen said. He and his research team found the neurotransmitter, called GABA (gamma-aminobutyric acid), in deformed cells called "reactive astrocytes" in a structure in the core of the brain called the dentate gyrus. This structure is the gateway to hippocampus, an area of the brain that is critical for learning and memory.  

Chen’s team found that the GABA neurotransmitter was drastically increased in the deformed versions of the normally large, star-shaped “astrocyte” cells which, in a healthy individual, surround and support individual neurons in the brain. “Our research shows that the excessively high concentration of the GABA neurotransmitter in these reactive astrocytes is a novel biomarker that we hope can be targeted in further research as a tool for the diagnosis and treatment of Alzheimer’s disease,” Chen said. 

Chen’s team developed new analysis methods to evaluate neurotransmitter concentrations in the brains of normal and genetically modified mouse models for Alzheimer’s disease (AD mice). “Our studies of AD mice showed that the high concentration of the GABA neurotransmitter in the reactive astrocytes of the dentate gyrus correlates with the animals’ poor performance on tests of learning and memory,” Chen said. His lab also found that the high concentration of the GABA neurotransmitter in the reactive astrocytes is released through an astrocyte-specific GABA transporter, a novel drug target found in this study, to enhance GABA inhibition in the dentate gyrus. With too much inhibitory GABA neurotransmitter, the neurons in the dentate gyrus are not fired up like they normally would be when a healthy person is learning something new or remembering something already learned.

Importantly, Chen said, “After we inhibited the astrocytic GABA transporter to reduce GABA inhibition in the brains of the AD mice, we found that they showed better memory capability than the control AD mice. We are very excited and encouraged by this result because it might explain why previous clinical trials failed by targeting amyloid plaques alone. One possible explanation is that while amyloid plaques may be reduced by targeting amyloid proteins, the other downstream alterations triggered by amyloid deposits, such as the excessive GABA inhibition discovered in our study, cannot be corrected by targeting amyloid proteins alone. Our studies suggest that reducing the excessive GABA inhibition to the neurons in the brain’s dentate gyrus may lead to a novel therapy for Alzheimer’s disease. An ultimate successful therapy may be a cocktail of compounds acting on several drug targets simultaneously.”

Learning Early in Life May Help Keep Brain Cells Alive

Using your brain – particularly during adolescence – may help brain cells survive and could impact how the brain functions after puberty.

According to a recently published study in Frontiers in Neuroscience, Rutgers behavioral and systems neuroscientist Tracey Shors, who co-authored the study, found that the newborn brain cells in young rats that were successful at learning survived while the same brain cells in animals that didn’t master the task died quickly.

“In those that didn’t learn, three weeks after the new brain cells were made, nearly one-half of them were no longer there,” said Shors, professor in the Department of Psychology and Center for Collaborative Neuroscience at Rutgers. “But in those that learned, it was hard to count. There were so many that were still alive.”

The study is important, Shors says, because it suggests that the massive proliferation of new brain cells most likely helps young animals leave the protectiveness of their mothers and face dangers, challenges and opportunities of adulthood.

Scientists have known for years that the neurons in adult rats, which are significant but fewer in numbers than during puberty, could be saved with learning, but they did not know if this would be the case for young rats that produce two to four times more neurons than adult animals.

By examining the hippocampus – a portion of the brain associated with the process of learning – after the rats learned to associate a sound with a motor response, scientists found that the new brain cells injected with dye a few weeks earlier were still alive in those that had learned the task while the cells in those who had failed did not survive.

“It’s not that learning makes more cells,” says Shors. “It’s that the process of learning keeps new cells alive that are already present at the time of the learning experience.”

Since the process of producing new brain cells on a cellular level is similar in animals, including humans, Shors says ensuring that adolescent children learn at optimal levels is critical.

“What it has shown me, especially as an educator, is how difficult it is to achieve optimal learning for our students. You don’t want the material to be too easy to learn and yet still have it too difficult where the student doesn’t learn and gives up,” Shors says.

So, what does this mean for the 12-year-old adolescent boy or girl?

While scientists can’t measure individual brain cells in humans, Shors says this study, on the cellular level, provides a look at what is happening in the adolescent brain and provides a window into the amazing ability the brain has to reorganize itself and form new neural connections at such a transformational time in our lives.

“Adolescents are trying to figure out who they are now, who they want to be when they grow up and are at school in a learning environment all day long,” says Shors. “The brain has to have a lot of strength to respond to all those experiences.”

Preparing for adulthood: thousands upon thousands of new cells are born in the hippocampus during puberty, and most survive with effortful learning

The dentate gyrus of the hippocampal formation generates new granule neurons throughout life. The number of neurons produced each day is inversely related to age, with thousands more produced during puberty than during adulthood, and many fewer produced during senescence. In adulthood, approximately half of these cells undergo apoptosis shortly after they are generated. Most of these cells can be rescued from death by effortful and successful learning experiences (Gould et al., 1999; Waddell and Shors, 2008; Curlik and Shors, 2011). Once rescued, the newly-generated cells differentiate into neurons, and remain in the hippocampus for at least several months (Leuner et al., 2004). Here, we report that many new hippocampal cells also undergo cell death during puberty. Because the juvenile brain is more plastic than during adulthood, and because many experiences are new, we hypothesized that a great number of cells would be rescued by learning during puberty. Indeed, adolescent rats that successfully acquired the trace eyeblink response retained thousands more cells than animals that were not trained, and those that failed to learn. Because the hippocampus generates thousands more cells during puberty than during adulthood, these results support the idea that the adolescent brain is especially responsive to learning. This enhanced response can have significant consequences for the functional integrity of the hippocampus. Such a massive increase in cell proliferation is likely an adaptive response as the young animal must emerge from the care of its mother to face the dangers, challenges, and opportunities of adulthood.

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(Figure 1: Fluorescent labeling reveals mossy fibers (red) projecting from the dentate gyrus (green) into the CA2 subregion (orange). Credit: Keigo Kohara, RIKEN–MIT Center for Neural Circuit Genetics)

Novel combination of techniques reveals new details about the neuronal networks for memory

Learning and memory are believed to occur as a result of the strengthening of synaptic connections among neurons in a brain structure called the hippocampus. The hippocampus consists of five subregions, and a circuit formed between four of these is thought to be particularly important for memory formation. Keigo Kohara and colleagues from the RIKEN–MIT Center for Neural Circuit Genetics and RIKEN BioResource Center have now identified a previously unknown circuit involving the fifth subregion.

For a hundred years, memory research has typically focused on the main circuit, which projects from layer II of the entorhinal cortex via the dentate gyrus to subregion CA3 and then CA1. Subregion CA2 lies between CA3 and CA1 but its cells are less elaborate than those of its neighbors and were thought not to receive inputs from the dentate gyrus.

Kohara and his colleagues combined anatomical, genetic and physiological techniques to analyze the connections formed by neurons in the CA2 subregion of the hippocampus in unprecedented detail. First, they identified the CA2 subregion by examining the expression of three genes that encode proteins called RGS14, PCP4 and STEP using a fluorescent marker to label nerve fibers—a technique called fluorescent immunohistochemistry. They were surprised to discover that, contrary to expectations, CA2 neurons receive extensive inputs from cells in the dentate gyrus (Fig.1).

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