Positive memory engrams & depression

Activating positive memory engrams suppresses depression-like behaviour
Nature 522, 335–339 (18 June 2015)
Steve Ramirez, … & Susumu Tonegawa

Here we acutely rescue stress-induced depression-related behaviours in mice by optogenetically reactivating dentate gyrus cells that were previously active during a positive experience. A brain-wide histological investigation, coupled with pharmacological and projection-specific optogenetic blockade experiments, identified glutamatergic activity in the hippocampus–amygdala–nucleus-accumbens pathway as a candidate circuit supporting the acute rescue.

dentate gyrus engram cells as potential therapeutic nodes for intervening with maladaptive behavioural states.
Subject terms: Hippocampus, Stress and resilience, Emotion

Activating happy memories cheers moody mice
17 June 2015

The work has grown out of studies … aimed to locate the memory engram — the physical trace of a memory, thought to be encoded in an ensemble of neurons.

More recently, the researchers used variations of the engram method to create false memories in mice, trigger lost memories and even retrain engram cells to encode a positive memory instead of a negative one.

By the sixth day, the previously stressed-out animals showed improved motivation and pleasure-seeking behaviours even after the light was turned off. “We were able to cure the animals’ depression,” …

the gap between simple animal models of depression and the complex human condition. “Depression in humans is a very heterogeneous clinical state. Some people have problems with motivation and experiencing reward, and other people don’t. … Optogenetic stimulation is not feasible in people, and deep-brain-stimulating implants, which involve invasive surgery, are used only as a last resort.


Neuroscience: The power of positivity
Alex Dranovsky & E. David Leonardo
Nature 522, 294–295 (18 June 2015)
Understanding how emotion-laden memories affect behaviour forms the bedrock of psychotherapy treatments, but the biology of this process is poorly understood.


Localization of a stable neural correlate of associative memory.
Science. 2007 Aug 31;317(5842):1230-3.
Reijmers LG1, Perkins BL, Matsuo N, Mayford M.
Do learning and retrieval of a memory activate the same neurons? Does the number of reactivated neurons correlate with memory strength? We developed a transgenic mouse that enables the long-lasting genetic tagging of c-fos-active neurons. We found neurons in the basolateral amygdala that are activated during Pavlovian fear conditioning and are reactivated during memory retrieval. The number of reactivated neurons correlated positively with the behavioral expression of the fear memory, indicating a stable neural correlate of associative memory. The ability to manipulate these neurons genetically should allow a more precise dissection of the molecular mechanisms of memory encoding within a distributed neuronal network.

BMC Biol. 2016 May 19;14(1):40. doi: 10.1186/s12915-016-0261-6.
What is memory? The present state of the engram.
Poo MM, et al.
The mechanism of memory remains one of the great unsolved problems of biology. Grappling with the question more than a hundred years ago, the German zoologist Richard Semon formulated the concept of the engram, lasting connections in the brain that result from simultaneous “excitations”, whose precise physical nature and consequences were out of reach of the biology of his day. Neuroscientists now have the knowledge and tools to tackle this question, however, and this Forum brings together leading contemporary views on the mechanisms of memory and what the engram means today.
Which Neurons Will Be the Engram – Activated Neurons and/or More Excitable Neurons?
Exp Neurobiol. 2016 Apr;25(2):55-63.
Kim JI, et al.
During past decades, the formation and storage principle of memory have received much attention in the neuroscience field. Although some studies have attempted to demonstrate the nature of the engram, elucidating the memory engram allocation mechanism was not possible because of the limitations of existing methods, which cannot specifically modulate the candidate neuronal population. Recently, the development of new techniques, which offer ways to mark and control specific populations of neurons, may accelerate solving this issue. Here, we review the recent advances, which have provided substantial evidence showing that both candidates (neuronal population that is activated by learning, and that has increased CREB level/excitability at learning) satisfy the criteria of the engram, which are necessary and sufficient for memory expression.
CREB; Memory allocation; Memory engram; Review; excitability
Neuronal Allocation to a Hippocampal Engram.
Neuropsychopharmacology. 2016 May 17.
Park S, et al
The dentate gyrus (DG) is important for encoding contextual memories, but little is known about how a population of DG neurons comes to encode and support a particular memory. One possibility is that recruitment into an engram depends on a neuron’s excitability (Han et al, 2009; Zhou et al, 2009; Choi et al, 2011; Sano et al, 2014). Here we manipulated excitability by overexpressing CREB in a random population of DG neurons and examined whether this biased their recruitment to an engram supporting a contextual fear memory. To directly assess whether neurons overexpressing CREB at the time of training became critical components of the engram, we examined memory expression while the activity of these neurons was silenced. Chemogenetically (hM4Di, an inhibitory DREADD receptor) or optogenetically (iC++, a light-activated chloride channel) silencing the small number of CREB-overexpressing DG neurons attenuated memory expression, while silencing a similar number of random neurons not overexpressing CREB at the time of training did not. As post-encoding reactivation of the activity patterns present during initial experience is thought to be important in memory consolidation, we investigated whether post-training silencing of neurons allocated to an engram disrupted subsequent memory expression. We found that silencing neurons 5 min (but not 24 h) following training disrupted memory expression. Together these results indicate that the rules of neuronal allocation to an engram originally described in the lateral amygdala are followed in different brain regions including DG, and moreover, that disrupting the post-training activity pattern of these neurons prevents memory consolidation.
Still searching for the engram.
Learn Behav. 2016 Mar 4.
Eichenbaum H1.
For nearly a century, neurobiologists have searched for the engram-the neural representation of a memory. Early studies showed that the engram is widely distributed both within and across brain areas and is supported by interactions among large networks of neurons. Subsequent research has identified engrams that support memory within dedicated functional systems for habit learning and emotional memory, but the engram for declarative memories has been elusive. Nevertheless, recent years have brought progress from molecular biological approaches that identify neurons and networks that are necessary and sufficient to support memory, and from recording approaches and population analyses that characterize the information coded by large neural networks. These new directions offer the promise of revealing the engrams for episodic and semantic memories.
Comparative cognition; Episodic memory; Memory; Rat; Spatial learning

Web-Based Intervention for Depression

Effect of a Web-Based Guided Self-help Intervention for Prevention of Major Depression in Adults With Subthreshold Depression
A Randomized Clinical Trial
Claudia Buntrock, MSc, et al.
JAMA. 2016;315(17):1854-1863.

Conclusions and Relevance  Among patients with subthreshold depression, the use of a web-based guided self-help intervention compared with enhanced usual care reduced the incidence of MDD over 12 months. Further research is needed to understand whether the effects are generalizable to both first onset of depression and depression recurrence as well as efficacy without the use of an online trainer.
depressive disorders ;  follow-up ;  internet ;  major depressive disorder ;  guided self-help ;  prevention ;  symptom onset

journalistic version:

Computerised cognitive behaviour therapy (cCBT) as treatment for depression in primary care (REEACT trial): large scale pragmatic randomised controlled trial
BMJ 2015; 351

Depression & stroke risk 2 years after mood improves

Changes in Depressive Symptoms and Incidence of First Stroke Among Middle‐Aged and Older US Adults
Paola Gilsanz, et al.
Conclusions: persistently high depressive symptoms were associated with increased stroke risk. Risk remained elevated even if depressive symptoms remitted over a 2‐year period, suggesting cumulative etiologic mechanisms linking depression and stroke.

journalistic version:
Long-Term Depression May Boost Stroke Risk Long After Mood Improves
May 14, 2015

Computerized cognitive behavioral therapy

Tapping into Digitized Behavioral Therapy: Lessons from the Safety Net
November 2015
Patients with depression or chronic pain may be helped by computerized cognitive behavioral therapy. Two pilot tests in safety-net clinics point to both barriers and solutions.

Californians with chronic pain or depression are frequently seen in safety-net clinics. Cognitive behavioral therapy has been shown to be effective with both conditions, but a shortage of behavioral health providers is a significant barrier to timely treatment in these settings.

Digital programs that provide computerized cognitive behavioral therapy (CCBT) may hold promise for these patients. Such programs can be used on computers and handheld devices. To find out what the barriers are and how they might be overcome, the California HealthCare Foundation funded two pilot tests, one focused on depression and one on chronic pain.

Perfect depression care: zero suicides

What Happens If You Try To Prevent Every Single Suicide?
November 02, 2015

Each year, nearly three times as many Americans die from suicide as from homicide. More Americans kill themselves than die from breast cancer.

As Dr.Thomas Insel, longtime head of the National Institute of Mental Health, prepared to step down from his job in October, he cited the lack of progress in reducing the number of suicides as his biggest disappointment. While the homicide rate in the U.S. has dropped 50 percent since the early 1990s, the suicide rate is higher than it was a decade ago.

In 2003, the suicide rate was 10.8 per 100,000 people.
In 2013, it was 12.6.

something they called “perfect depression care” for the 200,000 patients in the health system. The goal: zero suicides.

LYNN: When I was in the depths, the very depths of depression, I was being pulled and sucked into this black tunnel that was just pulling me and pulling me. And I was desperately trying to grab onto something to stop being sucked in.

SILBERNER: Others have spoken and written about the deep pain Lynn felt. Author William Styron once described his own depression as the pain of drowning.

Night Falls Fast

Kay Redfield Jamison

Depression: ketamine gains traction

Club Drug Ketamine Gains Traction As A Treatment For Depression
September 28, 2015

in 2006, a team from the National Institute of Mental Health published a landmark study showing that a single intra venous dose of ketamine produced “robust and rapid antidepressant effects” within a couple of hours.

Since then, thousands of depressed patients have received “off-label” treatment with ketamine.

A major study on antidepressant medication published in 2008 seemed to confirm his suspicions. It found that current antidepressants really aren’t much better than a placebo.

Many psychiatrists criticized that study. But not Feifel. “I was kind of like, I’m not surprised,” he says. “These really don’t seem like powerful tools.”
He knew the drug had risks. It could be abused. It could produce hallucinations.

“There are a lot of pundits who remain skeptical or feel we need to research this ad infinitum before it’s ready, which doesn’t make sense to me,” Feifel says. It’s hard to take the wait-and-see approach when you’re treating patients who are desperate for help, he adds.

For the past year, Paul has been getting ketamine every four to six weeks. He feels an altered sense of reality for an hour or two after getting the drug. The effect on depression and anxiety, though, lasts more than a month.

One is that its ability to keep depression at bay can fade pretty quickly. Feifel recalls one patient whose depression would disappear like magic after a dose of ketamine. But “we could never get it to sustain beyond maybe a day,” he says.

Also, ketamine treatment is expensive because patients need to be monitored so closely. Feifel charges about $500 for each injection and $1,000 for an intra venous infusion, which takes effect more quickly. Insurers don’t cover the cost because the treatment is still considered experimental.

Even so, ketamine clinics are popping up around the country and they have already treated thousands of patients willing and able to pay out of pocket. Some of the clinics are run by psychiatrists. Others have been started by entrepreneurial anesthesiologists and emergency room doctors, who are familiar with ketamine but may not know much about depression.

Director’s Blog: Ketamine
By Thomas Insel on October 1, 2014