Scientists could manipulate your brain to enhance or suppress memories


What if scientists could manipulate your brain so that a traumatic memory lost its emotional power over your psyche?

Steve Ramirez, a Boston University neuroscientist fascinated by memory, believes that a small structure in the brain could hold the keys to future therapeutic techniques for treating depression, anxiety, and PTSD, someday allowing clinicians to enhance positive memories or suppress negative ones.

Inside our brains, a cashew-shaped structure called the hippocampus stores the sensory and emotional information that makes up memories, whether they be positive or negative ones.

No two memories are exactly alike, and likewise, each memory we have is stored inside a unique combination of brain cells that contain all the environmental and emotional information associated with that memory.

The hippocampus itself, although small, comprises many different subregions all working in tandem to recall the elements of a specific memory.

Now, in a new paper in Current Biology, Ramirez and a team of collaborators have shown just how pliable memory is if you know which regions of the hippocampus to stimulate – which could someday enable personalized treatment for people haunted by particularly troubling memories.

Risultati immagini per hippocampus

“Many psychiatric disorders, especially PTSD, are based on the idea that after there’s a really traumatic experience, the person isn’t able to move on because they recall their fear over and over again,” says Briana Chen, first author of the paper, who is currently a graduate researcher studying depression at Columbia University.

In their study, Chen and Ramirez, the paper’s senior author, show how traumatic memories -such as those at the root of disorders like PTSD – can become so emotionally loaded.

By artificially activating memory cells in the bottom part of the brain’s hippocampus, negative memories can become even more debilitating.

In contrast, stimulating memory cells in the top part of the hippocampus can strip bad memories of their emotional oomph, making them less traumatic to remember.

Well, at least if you’re a mouse.

Using a technique called optogenetics, Chen and Ramirez mapped out which cells in the hippocampus were being activated when male mice made new memories of positive, neutral, and negative experiences.

A positive experience, for example, could be exposure to a female mouse.

In contrast, a negative experience could be receiving a startling but mild electrical zap to the feet.

Then, identifying which cells were part of the memory-making process (which they did with the help of a glowing green protein designed to literally light up when cells are activated), they were able to artificially trigger those specific memories again later, using laser light to activate the memory cells.

Their studies reveal just how different the roles of the top and bottom parts of the hippocampus are.

Activating the top of the hippocampus seems to function like effective exposure therapy, deadening the trauma of reliving bad memories.

But activating the bottom part of the hippocampus can impart lasting fear and anxiety-related behavioral changes, hinting that this part of the brain could be overactive when memories become so emotionally charged that they are debilitating.

That distinction, Ramirez says, is critical.

He says that it suggests suppressing overactivity in the bottom part of the hippocampus could potentially be used to treat PTSD and anxiety disorders.

It could also be the key to enhancing cognitive skills, “like Limitless,” he says, referencing the 2011 film starring Bradley Cooper in which the main character takes special pills that drastically improve his memory and brain function.

“The field of memory manipulation is still young….

It sounds like sci-fi but this study is a sneak preview of what’s to come in terms of our abilities to artificially enhance or suppress memories,” says Ramirez, a BU College of Arts & Sciences assistant professor of psychological and brain sciences. Although the study got its start while Chen and Ramirez were both doing research at Massachusetts Institute of Technology, its data has been the backbone of the first paper to come out of the new laboratory group that Ramirez established at BU in 2017.

“We’re a long way from being able to do this in humans, but the proof of concept is here,” Chen says. “As Steve likes to say, ‘never say never.’ Nothing is impossible.”

“This is the first step in teasing apart what these [brain] regions do to these really emotional memories….

The first step toward translating this to people, which is the holy grail,” says memory researcher Sheena Josselyn, a University of Toronto neuroscientist who was not involved in this study. “[Steve’s] group is really unique in trying to see how the brain stores memories with the goal being to help people… they’re not just playing around but doing it for a purpose.”

Although mouse brains and human brains are very different, Ramirez, who is also a member of the BU Center for Systems Neuroscience and the Center for Memory and Brain, says that learning how these fundamental principles play out in mice is helping his team map out a blueprint of how memory works in people.

Being able to activate specific memories on demand, as well as targeted areas of the brain involved in memory, allows the researchers to see exactly what side effects come along with different areas of the brain being overstimulated.

“Let’s use what we’re learning in mice to make predictions about how memory functions in humans,” he says.

“If we can create a two-way street to compare how memory works in mice and in humans, we can then ask specific questions [in mice] about how and why memories can have positive or negative effects on psychological health.”

This is what a bad memory looks like in a mouse brain. The cells glowing green indicate that they are being activated in storing a fear memory. Credit: The Ramirez Group, Boston University

Our memories define us.

They feed our grandest ambitions, lie at the root of our darkest fears, and allow us to travel in our mind from the present to the past.

The idea that our precious memories might be susceptible to manipulation via external stimuli, such as leading questions in an interview, has long been known (Loftus and Palmer, 1974).

However, a variety of technical advances have enabled researchers to manipulate memories more precisely and in new and innovative ways.

Enhancing recall, deleting knowledge of the past and implanting fictitious memories – once the preserve of Hollywood blockbusters – are now becoming a reality.

Being able to manipulate memories has many potential benefits.

Enhancing memory in patients afflicted with diseases such as Alzheimer’s dementia opens a pathway to a substantially increased quality of life.

as post-traumatic stress disorder (PTSD), phobias or anxiety disorders may provide a powerful means of potential treatment. Despite this, memory manipulation also has a dark-side. Films such as InceptionThe Eternal Sunshine of the Spotless Mind, Limitless, Total Recall and The Manchurian Candidate provide prophetic warnings of the dangers of recklessly tampering with memories (see Appendix).

While the ethics of memory manipulation are hotly debated (Liao and Sandberg, 2008; Mohamed and Sahakian, 2012; Ragan et al., 2013) research continues to advance at an ever-increasing pace.

Here we provide a brief overview of recent research on memory manipulation.

We focus primarily on memories for which the hippocampus is thought to be required due to its central importance in the study of memory (Eichenbaum, 2004; Moscovitch et al., 2006; Squire et al., 2004; Spiers, 2012).

The repertoire of methods employed is expanding and includes optogenetics (e.g. Ramirez et al., 2013), transcranial stimulation (e.g. Marshall et al., 2006), deep brain stimulation (e.g. Laxton et al., 2010), cued reactivation during sleep (e.g. Rasch et al., 2007; Rudoy et al., 2009) and the use of pharmacological agents (e.g. Steckler and Risbrough, 2012; De Kleine et al., 2013).

In addition, the possible mechanisms underlying these memory changes have been investigated using techniques such as single unit recording (e.g. Bendor and Wilson, 2012) and functional magnetic resonance imaging (fMRI) (e.g. Hauner et al., 2013).Go to:

If only I could remember…

We all want to have a better memory.

Why spend hours or even days studying for an exam, if with a photographic memory we could store this information almost instantaneously.

While research has explored the enhancement of memory consolidation by the administration of putative ‘cognitive enhancers’ (e.g. Kaplan and Moore, 2011; Rodríguez et al., 2013) recent interest has focused on manipulating memories during sleep, tapping into the brain’s normal memory consolidation process.

Our brain processes a high volume of information every day, and to avoid being overwhelmed with the storage of all of this information, our brain must retain only a subset of our experiences.

Each memory’s storage must be prioritized according to its importance (e.g. your baby’s first laugh should hopefully outrank the sound of the fan in the background).

This process of selectively stabilizing specific memories is thought to occur most effectively during sleep (Stickgold and Walker, 2013).

In particular, memory consolidation (Dudai, 2004; Frankland and Bontempi, 2005; Squire and Alvarez, 1995) for hippocampus-dependent learning (e.g. spatial association and word pairings) benefits specifically from the non-REM stage of sleep (Diekelmann and Born, 2010).

While getting a good night of sleep will improve your memory, further memory enhancement is potentially possible if we can modify this sleep-consolidation process, and direct it towards specific memories.

To do this, we can take advantage of the fact that non-REM sleep has a number of signature rhythmic components that distinguish it from both an awake/active state and a REM sleep state (Buzsaki, 2009).

The first rhythmic component is a slow wave oscillation – a large amplitude and low frequency (<1 Hz) variation in the local field potential (LFP) generated by the alternation between up and down states in neocortex (Buzsáki et al., 2012).

The second rhythmic component is a spindle – a brief thalamocortical oscillation (7–14 Hz) – generated by the thalamic reticular nucleus (Steriade et al., 1993). Both of these non-REM sleep specific brain rhythms have been postulated to be important for memory consolidation, and therefore based on this idea, boosting the strength or increasing the amount of these oscillations could lead to memory enhancement.

To boost slow wave oscillations, Marshall et al. (2006) applied a low frequency time-varying transcranial stimulation (0.75 Hz) to the frontal cortex of human subjects during early non-REM sleep. Interestingly, as a consequence of this low frequency transcranial stimulation, spindle power also increased.

After being trained on a hippocampus-dependent task (word-pair associations), subjects went to sleep while receiving transcranial stimulation. When the subjects woke up, they were tested on the task, and the subjects that had received low frequency stimulation during sleep had better task performance (compared to control subjects that had received a sham stimulation).

As this method boosted both slow-wave oscillations and spindles, both could potentially linked to this memory enhancement.

More recently, optogenetics has been used to artificially induce spindles in rodents (Halassa et al., 2011), potentially providing a more effective (albeit invasive) method of boosting spindle production during sleep.

Whether this methodology can be used during sleep to boost memory has not yet been demonstrated, nor is optogenetics currently viable for humans. Nonetheless, some traction has been achieved from invasive deep brain stimulation (DBS) in humans.

DBS typically involves placing electrodes in deep neural structures for the treatment of severe dementias or obesity. In this method a continual stream of stimulation is applied to the nuclei or fibre tracks targeted.

Electrodes stimulating the fornix and hypothalamus (Hamani et al., 2008; Laxton et al., 2010) or entorhinal cortex (Suthana et al., 2012) have been found to provide memory enhancement, perhaps paving the way for enhanced treatment. Whether stimulating during sleep has an added benefit over awake-stimulation has not yet been explored.

Another signature oscillation produced during non-REM sleep is the sharp-wave ripple, a 100–300 Hz brief oscillation generated within the hippocampus, and temporally correlated with spindle oscillations in prefrontal cortex (Siapas and Wilson, 1998).

One interesting phenomenon related to sharp-wave ripples is replay, where sequential neural patterns associated to a previous behavioural episode spontaneously reactivate in the hippocampus and neocortex during a sharp-wave ripple event (Wilson and McNaughton, 1994; Lee and Wilson, 2002; Ji and Wilson, 2006).

Replay events are a memory trace of a previous experience; replaying a memory trace again and again is a potential mechanism by which this memory could be reinforced and gradually consolidated.

Blocking hippocampal sharp waves (which in turn silences replay events) leads to a memory impairment (Girardeau et al., 2009; Ego-Stengel and Wilson, 2010), which suggests that sharp wave ripple events and/or replay events may be important for memory consolidation.

In order to improve specific memories using sharp wave ripples, can we manipulate the hippocampus to control what is getting replayed in the brain?

One approach that has been used is pairing a sensory cue with a task, and then repeating this cue to the sleeping subject.

When rats are trained on an auditory-spatial association task (each sound is associated with a particular reward location), playing these cues bias replay events towards replaying the experience associated with the cue (Bendor and Wilson, 2012). So if we can bias replay towards a particular memory when we sleep, can we use this to boost memories?

In humans, if the same sensory cue (olfactory or auditory) is present during the training and afterwards during non-REM sleep, task performance is enhanced during the post-nap test (i.e. less forgetting) (Rasch et al., 2007; Rudoy et al., 2009; Diekelmann et al., 2011; Antony et al., 2012; Rolls et al., 2013).

This method of targeted memory reactivation (Oudiette and Paller, 2013) only works during non-REM sleep; no memory improvement occurs for cue presentation during the awake state or during REM sleep (Rasch et al., 2007; Diekelmann et al., 2011).

Thus far, we have discussed three methods (transcranial stimulation, deep brain stimulation and targeted memory reactivation) that have the potential to enhance the strength of memories or bias the memory trace content during non-REM sleep specific brain rhythms.

While these methods lead to a memory boost, it is important to note that the effect, while statistically significant, is typically mild (∼10% improvement). The ability to manipulate multiple brain rhythms together (ripple–spindle interactions) and more precisely target the neural circuits of a particular memory (Liu et al., 2012) may produce a larger memory boost.Go to:

If only I could forget…

While a method for enhancing memories would seem an asset, a procedure for deleting memories comes laden with more nefarious connotations. The disastrous consequences of erasing memories from a broken relationship are played out in the film The Eternal Sunshine of the Spotless Mind (see Appendix). Amnesia for personally known individuals can occur in cases of semantic dementia (Thompson et al., 2004). However, given that semantic memories appear to be widely distributed in the neocortex (Martin and Chao, 2001; McClelland and Rogers, 2003) it is highly questionable that it would be possible to erase all the memories associated with a single individual. By contrast, disrupting memory for a single event, or learned association is not so far flung. Rather than something to be feared, memory disruption may prove substantially beneficial for the treatment of disorders such as PTSD, phobias and anxiety disorders.

While the brain may have developed specific mechanisms for modulating which memories are to be degraded (Frankland et al., 2013; Hardt et al., 2013), researchers have sought to improve this via the application of selected drugs. Pharmacological treatment of the persistent involuntary memory retrieval that accompanies PTSD has been explored in numerous studies (see e.g. Steckler and Risbrough, 2012; De Kleine et al., 2013 for reviews). In both clinical and laboratory settings, a wide variety of pharmacological agents have been used to modifying memories, with particular emphasis on disrupting fear-related memories (Kaplan and Moore, 2011). These have included targeting glucocorticoid (e.g. De Bitencourt et al., 2013), glutamtergic (Kuriyama et al., 2013), GABAergic (Rodríguez et al., 2013) adrenergic (Kindt et al., 2009), cannabinoid (Rabinak et al., 2013), serotonergic (Zhang et al., 2013) and glycine (File et al., 1999) receptors.

Research on disrupting memory derives predominately from studying Pavlovian fear conditioning using an electrical shock. In “auditory fear conditioning” a rodent is initially exposed to repeated pairings of an electrical shock with a neutral tone. This leads to the tone alone evoking a fearful memory of getting shocked, which results in freezing behaviour in the rodent (Maren, 2001). In a variant of this method, contextual fear conditioning, the animal is exposed to a novel environment, during which it receives one or more electric shocks resulting in a learned hippocampus-dependent association between the environmental context (instead of an auditory cue) and the potential for more shocks (Kim and Fanselow, 1992). With repeated exposure to the tone or the context alone the animal will eventually stop freezing. This is referred to as extinction. Infusion of fibroblast growth factor 2 (an agent affecting neural cell development and neurogenesis) into the amygdala immediately after extinction strongly increases the chance that this memory will not re-surface at a later time point (Graham and Richardson, 2011). Whether a similar approach targeting the hippocampus can be used to enhance contextual fear conditioning remains to be determined. Recent work has revealed that extinction of conditioned fear memories can be enhanced via re-activation of the memories during non-REM sleep. Hauner et al. (2013) conditioned humans to expect a shock when viewing certain faces. The presentation of the shocked faces was paired with certain odours. Later during non-REM sleep subjects were re-exposed to the odours associated with some of the feared faces. Conditioned responses to the faces associated with the odours that were re-presented during sleep were significantly less than those faces paired with odours not presented. The impact of the odour presentation was apparent in the reduction of hippocampal activity and re-organization of activity patterns in the amygdala when pre- and post-sleep conditioning periods were examined with fMRI, further highlighting the importance of these brain regions. Although these results appear to be contradictory to the memory-enhancing results obtained using cued-reactivation during non-REM sleep (Rasch et al., 2007; Rudoy et al., 2009; Rolls et al., 2013), the extinction of a fear memory is not necessarily caused by memory deletion. Rather, extinction likely involves the active suppression of a still intact fear memory by regions of the brain distinct from where the original fear memory is stored (Milad and Quirk, 2002).

While enhancing extinction is one means of suppressing a memory, another method is to manipulate the brain at a time point many weeks later when a stored memory has been re-activated and requires stabilizing, a process known as reconsolidation (Misanin et al., 1968; Sara, 2010; Dudai, 2004). Infusion of protein synthesis inhibitors during periods after re-activation of memory has been shown to strongly disrupt future memory expression (Nader et al., 2000). Studies investigated manipulating reconsolidation in humans have focused on the effects of the adrenergic modulator propranolol (Brunet et al., 2011a; Kindt et al., 2009). Because propranolol must be administered before the re-activation to have an effect, it has been debated as to whether reconsolidation processes have been specifically targeted (Brunet et al., 2011b) or not (Schiller and Phelps, 2011).

The maintenance of long-term potentiation (LTP), an activity-dependent, persistent form of synaptic plasticity, is a key model for memory storage at a cellular level (Malenka and Bear, 2004). LTP is a complex and heterogeneous phenomenon (beyond the scope of this review), however in a simplified model of LTP, synapses that have been active during an experience become strengthened to form a memory of that experience; The persistence of this memory then depends on the continued maintenance of LTP in these synapses. Previous work has suggested that persistent phosphorylation by PKMζ (protein kinase M zeta) is required for this maintenance (Ling et al., 2002), and the injection of ZIP (a synthetic ζ-pseudosubstrate inhibitory peptide) can inhibit PKMζ and disrupt LTP (Serrano et al., 2005). Injecting ZIP in the hippocampus of rats, one day after they are trained in an active place avoidance task, can permanently delete the spatial memory related to this task (Pastalkova et al., 2006). The ability of ZIP to delete a memory also extends to other brain regions outside of the hippocampus, including the deletion of a taste-aversion memory stored in the insula (Shema et al., 2007). As an alternative to using ZIP, a lentivirus-induced overexpression of a dominant-negative PKMζ mutation in insular cortex can also be used to block a taste-aversion memory (Shema et al., 2011). Interestingly, if a normal version of PKMζ is overexpressed in insular cortex (using the same lentiviral approach), this leads to a general enhancement in taste aversion memories (Shema et al., 2011). However, more recent evidence suggests that the relationship between ZIP, PKMζ, and maintenance of LTP may be more complicated. Transgenic mice lacking PKMζ have normal memory function, suggesting that PKMζ, however, may not be the only kinase involved in LTP maintenance (Volk et al., 2013; Lee et al., 2013). As ZIP is still effective in erasing memories in PKMζ null mice, ZIP does not require PKMζ to function, and the mechanism by which ZIP can erase memories remains an open question (Volk et al., 2013; Lee et al., 2013).

More information: Briana K. Chen et al, Artificially Enhancing and Suppressing Hippocampus-Mediated Memories, Current Biology (2019).DOI: 10.1016/j.cub.2019.04.065

Journal information: Current Biology
Provided by Boston University


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