Posted on by Dr. Francis Collins
All of us make many decisions every day. For most things, such as which jacket to wear or where to grab a cup of coffee, there’s usually no right answer, so we often decide using values rooted in our past experiences. Now, neuroscientists have identified the part of the mammalian brain that stores information essential to such value-based decision making.
Researchers zeroed in on this particular brain region, known as the retrosplenial cortex (RSC), by analyzing movies—including the clip shown about 32 seconds into this video—that captured in real time what goes on in the brains of mice as they make decisions. Each white circle is a neuron, and the flickers of light reflect their activity: the brighter the light, the more active the neuron at that point in time.
All told, the NIH-funded team, led by Ryoma Hattori and Takaki Komiyama, University of California at San Diego, La Jolla, made recordings of more than 45,000 neurons across six regions of the mouse brain . Neural activity isn’t usually visible. But, in this case, researchers used mice that had been genetically engineered so that their neurons, when activated, expressed a protein that glowed.
Their system was also set up to encourage the mice to make value-based decisions, including choosing between two drinking tubes, each with a different probability of delivering water. During this decision-making process, the RSC proved to be the region of the brain where neurons persistently lit up, reflecting how the mouse evaluated one option over the other.
The new discovery, described in the journal Cell, comes as something of a surprise to neuroscientists because the RSC hadn’t previously been implicated in value-based decisions. To gather additional evidence, the researchers turned to optogenetics, a technique that enabled them to use light to inactivate neurons in the RSC’s of living animals. These studies confirmed that, with the RSC turned off, the mice couldn’t retrieve value information based on past experience.
The researchers note that the RSC is heavily interconnected with other key brain regions, including those involved in learning, memory, and controlling movement. This indicates that the RSC may be well situated to serve as a hub for storing value information, allowing it to be accessed and acted upon when it is needed.
The findings are yet another amazing example of how advances coming out of the NIH-led Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative are revolutionizing our understanding of the brain. In the future, the team hopes to learn more about how the RSC stores this information and sends it to other parts of the brain. They note that it will also be important to explore how activity in this brain area may be altered in schizophrenia, dementia, substance abuse, and other conditions that may affect decision-making abilities. It will also be interesting to see how this develops during childhood and adolescence.
 Area-Specificity and Plasticity of History-Dependent Value Coding During Learning. Hattori R, Danskin B, Babic Z, Mlynaryk N, Komiyama T. Cell. 2019 Jun 13;177(7):1858-1872.e15.
Komiyama Lab (UCSD, La Jolla)
NIH Support: National Institute of Neurological Disorders and Stroke; National Eye Institute; National Institute on Deafness and Other Communication Disorders
Posted on by Dr. Francis Collins
A few weeks ago, I was pleased to take part in the announcement of NIH’s HEALing Communities Study in four states hard hit by the opioid epidemic. This study will test a comprehensive, evidence-based approach—which includes the wide distribution of naloxone to reverse overdoses—with the aim of reducing opioid-related deaths in selected communities by 40 percent over three years.
That’s a very ambitious goal. So, I was encouraged to read about new findings that indicate such reductions may be within our reach if society implements a number of key changes. Among those is the need to arm friends, family members, and others with the ability to save lives from opioid overdoses. Between 2013 and 2016, nine states instituted laws that give pharmacists direct authority to dispense naloxone to anyone without a prescription. However, the impact of such changes has remained rather unclear. Now, an NIH-funded analysis has found that within a couple of years of these new laws taking effect, fatal opioid overdoses in these states fell significantly .
The misuse and overuse of opioids, which include heroin, fentanyl, and prescription painkillers, poses an unprecedented public health crisis. Every day, more than 130 people in the United States die from opioid overdoses . Not only are far too many families losing their loved ones, this crisis is costing our nation tens of billions of dollars a year in lost productivity and added expenses for healthcare, addiction treatment, and criminal justice.
Opioid overdoses lead to respiratory arrest. If not reversed in a few minutes, this will be fatal. In an effort to address this crisis, the federal government and many states have pursued various strategies to increase access to naloxone, which is a medication that can quickly restore breathing in a person overdosing on opioids. Naloxone, which can be delivered via nasal spray or injection, works by binding opioid receptors to reverse or block the effect of opioids. The challenge is to get naloxone to those who need it before it’s too late.
In some states, a physician still must prescribe naloxone. In others, naloxone access laws (NALs) have given pharmacists the authority to supply naloxone without a doctor’s orders. But not all NALs are the same.
Some NALs, including those in Alaska, California, Connecticut, Idaho, New Mexico, North Dakota, Oklahoma, Oregon, and South Carolina, give pharmacists direct authority to dispense naloxone to anyone who requests it. But NALs in certain other states only give pharmacists indirect authority to dispense naloxone to people enrolled in certain treatment programs, or who meet other specific criteria.
In the new analysis, published in JAMA Internal Medicine, a team that included Rahi Abouk, William Paterson University, Wayne, NJ, and Rosalie Liccardo Pacula and David Powell, RAND Corp., Arlington, VA, asked: Do state laws to improve naloxone access lead to reductions in fatal overdoses involving opioids? The answer appears to be “yes,” but success seems to hinge on the details of those laws.
The evidence shows that states allowing pharmacists direct authority to dispense naloxone to anyone have seen large increases in the dispensing of the medication. In contrast, states granting pharmacists’ only indirect authority to dispense naloxone have experienced little change.
Most importantly, the research team found that states that adopted direct authority NALs experienced far greater reductions in opioid-related deaths than states with indirect authority NALs or no NALs. Specifically, the analysis showed that in the year after direct authority NALs were enacted, fatal opioid overdoses in those states fell an average of 27 percent, with even steeper declines in ensuing years. Longer-term data are needed, and, as in all observational studies of this sort, one must be careful not to equate correlation with causation. But these findings are certainly encouraging.
There were some other intriguing trends. For instance, the researchers found that states that allow pharmacists to dispense naloxone without a prescription also saw an increase in the number of patients treated at emergency departments for nonfatal overdoses. This finding highlights the importance of combining strategies to improve naloxone access with other proven interventions and access to medications aimed to treat opioid addiction. Integration of all possible interventions is exactly the goal of the HEALing Communities Study mentioned above.
Successfully tackling the opioid epidemic will require a multi-pronged approach, including concerted efforts and research advances in overdose reversal, addiction treatment, and non-addictive pain management . As I’ve noted before, we cannot solve the opioid addiction and overdose crisis without finding innovative new ways to treat pain. The NIH is partnering with pharmaceutical industry leaders to accelerate this process, but it will take time. The good news based on this new study is that, with thoughtful strategies and policies in place, many of the tools needed to help address this epidemic and save lives may already be at our disposal.
 Association Between State Laws Facilitating Pharmacy Distribution of Naloxone and Risk of Fatal Overdose. Abouk R, Pacula RL, Powell D. JAMA Intern Med. 2019 May 6
 Opioid Overdose Crisis. National Institute on Drug Abuse/NIH. Updated January 2019.
Naloxone for Opioid Overdose (National Institute on Drug Abuse/NIH)
NIH Support: National Institute on Drug Abuse
Posted on by Dr. Francis Collins
Serotonin is best known for its role as a chemical messenger in the brain, helping to regulate mood, appetite, sleep, and many other functions. It exerts these influences by binding to its receptor on the surface of neural cells. But startling new work suggests the impact of serotonin does not end there: the molecule also can enter a cell’s nucleus and directly switch on genes.
While much more study is needed, this is a potentially groundbreaking discovery. Not only could it have implications for managing depression and other mood disorders, it may also open new avenues for treating substance abuse and neurodegenerative diseases.
To understand how serotonin contributes to switching genes on and off, a lesson on epigenetics is helpful. Keep in mind that the DNA instruction book of all cells is essentially the same, yet the chapters of the book are read in very different ways by cells in different parts of the body. Epigenetics refers to chemical marks on DNA itself or on the protein “spools” called histones that package DNA. These marks influence the activity of genes in a particular cell without changing the underlying DNA sequence, switching them on and off or acting as “volume knobs” to turn the activity of particular genes up or down.
The marks include various chemical groups—including acetyl, phosphate, or methyl—which are added at precise locations to those spool-like proteins called histones. The addition of such groups alters the accessibility of the DNA for copying into messenger RNA and producing needed proteins.
In the study reported in Nature, researchers led by Ian Maze and postdoctoral researcher Lorna Farrelly, Icahn School of Medicine at Mount Sinai, New York, followed a hunch that serotonin molecules might also get added to histones . There had been hints that it might be possible. For instance, earlier evidence suggested that inside cells, serotonin could enter the nucleus. There also was evidence that serotonin could attach to proteins outside the nucleus in a process called serotonylation.
These data begged the question: Is serotonylation important in the brain and/or other living tissues that produce serotonin in vivo? After a lot of hard work, the answer now appears to be yes.
These NIH-supported researchers found that serotonylation does indeed occur in the cell nucleus. They also identified a particular enzyme that directly attaches serotonin molecules to histone proteins. With serotonin attached, DNA loosens on its spool, allowing for increased gene expression.
The team found that histone serotonylation takes place in serotonin-producing human neurons derived from induced pluripotent stem cells (iPSCs). They also observed this process occurring in the brains of developing mice.
In fact, the researchers found evidence of those serotonin marks in many parts of the body. They are especially prevalent in the brain and gut, where serotonin also is produced in significant amounts. Those marks consistently correlate with areas of active gene expression.
The serotonin mark often occurs on histones in combination with a second methyl mark. The researchers suggest that this double marking of histones might help to further reinforce an active state of gene expression.
This work demonstrates that serotonin can directly influence gene expression in a manner that’s wholly separate from its previously known role in transmitting chemical messages from one neuron to the next. And, there are likely other surprises in store.
The newly discovered role of serotonin in modifying gene expression may contribute significantly to our understanding of mood disorders and other psychiatric conditions with known links to serotonin signals, suggesting potentially new targets for therapeutic intervention. But for now, this fundamental discovery raises many more intriguing questions than it answers.
Science is full of surprises, and this paper is definitely one of them. Will this kind of histone marking occur with other chemical messengers, such as dopamine and acetylcholine? This unexpected discovery now allows us to track serotonin and perhaps some of the brain’s other chemical messengers to see what they might be doing in the cell nucleus and whether this information might one day help in treating the millions of Americans with mood and behavioral disorders.
 Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Farrelly LA, Thompson RE, Zhao S, Lepack AE, Lyu Y, Bhanu NV, Zhang B, Loh YE, Ramakrishnan A, Vadodaria KC, Heard KJ, Erikson G, Nakadai T, Bastle RM, Lukasak BJ, Zebroski H 3rd, Alenina N, Bader M, Berton O, Roeder RG, Molina H, Gage FH, Shen L, Garcia BA, Li H, Muir TW, Maze I. Nature. 2019 Mar 13. [Epub ahead of print]
Any Mood Disorder (National Institute of Mental Health/NIH)
Drugs, Brains, and Behavior: The Science of Addiction (National Institute on Drug Abuse/NIH)
Epigenomics (National Human Genome Research Institute/NIH)
Maze Lab (Icahn School of Medicine at Mount Sinai, New York, NY)
NIH Support: National Institute on Drug Abuse; National Institute of Mental Health; National Institute of General Medical Sciences; National Cancer Institute