At the sleep research meeting in San Antonio this year, there were signs of an impending pharmaceutical arms race in the realm of narcolepsy.
The big fish in a small pond, Jazz Pharmaceuticals, was preparing to market its recently FDA-approved medication: Sunosi/solriamfetol. Startup Harmony Biosciences was close behind with pitolisant, already approved in Europe. On the horizon are experimental drugs designed to more precisely target the neuropeptide deficiency in people with classic narcolepsy type 1 Read more
A region of the brain called the hippocampus is known for its role in memory formation. Scientists at Yerkes National Primate Research Center, Emory University are learning more about another facet of hippocampal function: its importance in the regulation and expression of emotions, particularly during early development.
Using a nonhuman primate model, their findings provide insight into the mechanisms of human psychiatric disorders associated with emotion dysregulation, such as PTSD (post-traumatic stress disorder) and schizophrenia. The results were published online recently by the journal Psychoneuroendocrinology.
“Our findings demonstrate that damage to the hippocampus early in life leads to increased anxiety-like behaviors in response to an unfamiliar human,” says research associate Jessica Raper, PhD, first author of the paper. “However, despite heightened anxious behavior, cortisol responses to the social stress were dampened in adulthood.”
The hormone cortisol modulates metabolism, the immune system and brain function in response to stress. Reduced hippocampal volume and lower cortisol response to stressors have been demonstrated as features of and risk factors for PTSD, Raper says. Also, the dampened daily rhythms of cortisol seen in the nonhuman primates with hippocampal damage resemble those reported in first-episode schizophrenia patients.
Follow-up studies could involve temporary interference with hippocampus function using targeted genetic techniques, she says. Read more
As part of reporting on neurosurgeon Robert Grossâ€™s work with patients who have drug-resistant epilepsy, I interviewed a remarkable woman, Barbara Olds. She had laser ablation surgery for temporal lobe epilepsy in 2012, which drastically reduced her seizures and relieved her epilepsy-associated depression.
Emory Medicineâ€™s editor decided to focus on deep brain stimulation, rather than ablative surgery, so Ms. Oldsâ€™ experiences were not part of the magazine feature. Still, talking with her highlighted some interesting questions for me.
Everything is connected, especially in the brain. A protein called BAI1 involved in limiting the growth of brain tumors is also critical for spatial learning and memory, researchers have discovered.
Mice missing BAI1 have trouble learning and remembering where they have been. Because of the loss of BAI1, their neurons have changes in how they respond to electrical stimulation, and subtle alterations in parts of the cell needed for information processing.
Erwin Van Meir, PhD, and his colleagues at Winship Cancer Institute of Emory University have been studying BAI1 (brain-specific angiogenesis inhibitor 1) for several years. Part of the BAI1 protein can stop the growth of new blood vessels, which growing cancers need. Normally highly active in the brain, the BAI1 gene is lost or silenced in brain tumors, suggesting that it acts as a tumor suppressor.
The researchers were surprised to find that the brains of mice lacking the BAI1 gene looked normal anatomically. They didnâ€™t develop tumors any faster than normal, and they didnâ€™t have any alterations in their blood vessels, which the researchers had anticipated based on BAI1â€™s role in regulating blood vessel growth. What they did have was problems with spatial memory.
Methylation, an epigenetic modification to DNA, can be thought of as a highlighting pen applied to DNAâ€™s text, adding information but not changing the actual letters of the text.
Are you still with me on the metaphors? If so, consider this wrinkle. (If not, more explanation here.)
Emory geneticist Peng Jin and his colleagues have been a key part of the discovery in the last few years that methylation comes in several colors. His lab has been mapping where 5-hydroxymethylcytosine or 5hmC appears in the genome and inferring how it functions. 5-hmC is particularly abundant in the brain.
Methylation, in the form of 5-methylcytosine or 5mC, is both a control button for turning genes off and a sign of their off state. 5hmC looks like 5mC, except it has an extra oxygen. That could be a tag for a removal, or a signal that aÂ gene is poised to be turned on.
Two recent papers on this topic:
Please recall that an enriched environment (exercise and mental stimulation) is good for learning and memory, for young and old. In the journalÂ Genomics, Jin and his team show that exposing mice to an enriched environmentÂ — a running wheel and a variety of toys — leads to a 60 percent reduction in 5hmC in the hippocampus, a region of the brain critical for learning and memory. Â The changes in 5hmC were concentratedÂ in genes having to do with axon guidance. Hat tip to the all-things-epigenetic site Epigenie.
In Genes and Development, structural biologist Xiaodong Cheng and colleagues demonstrateÂ that two regulatory proteins that bind DNA (Egr1 and WT1) respond primarily to oxidation of their target sequences rather than methylation. These proteins like plain old C and 5mC equally, but they donâ€™t like 5hmC or other oxidized forms of 5mC. â€œGene activity could plausibly be controlled on a much finer scale by these modifications than simply â€˜on or â€˜offâ€™,â€ the authors write.
Congratulations to John O’Keefe, May-Britt Moser and Edvard Moser for receiving the 2014 Nobel Prize in Medicine. The prize is for discovering “the brain’s navigation system”: place cells, cells in the hippocampus which are active whenever a rat is in a particular place, and grid cells, cells in the entorhinal cortex which are active when the animal is at multiple locations in a grid pattern.
Former Yerkes researcher Beth Buffalo and herÂ graduate studentÂ Nathan KillianÂ were the first to directly detect, via electrode recordings, grid cells in the brains of non-human primates. Buffalo is now at the University of WashingtonÂ and Killian is at Harvard Medical School.
A significant difference about theirÂ experiments was that theyÂ could identify grid cellsÂ when monkeys were moving their eyes, suggesting that primates don’t have to actually visit a place to construct the same kind of mental map. Another aspect of grid cells in non-human primates not previously seen with rodents is that the cells’ responses change when monkeys are seeing an image for the second time.
Following that report, grid cells were also directlyÂ detected inÂ human epilepsy patients. The Mosers themselves notedÂ in a 2014Â review, “It will be interesting to see whether the same cells that respond to visual movement in monkeys also respond to locomotion, or whether there is a separate system of grid cells that is responsive to locomotion.”
The epilepsy patient Henry Molaison, known for most of the 20th century as H.M., is one of the most famous in neuroscience. His case played an important role in telling scientists about structures of the brain that are important for forming short-term and long-term memories.
To control H.M.â€™s epilepsy, neurosurgeon William Scoville http://www.raybandasoleit.com/ removed much of the hippocampi, amygdalae and nearby regions on both sides of his brain. After the surgery, H.M. suffered from severe anterograde amnesia, meaning that he could not commit new events to explicit memory. However, other forms of his memory were intact, such as short-term working memory and motor skills.
This classic case helps us understand the advances that neurosurgeons at Emory are achieving today. The surgeries now used to treat some medication-resistant forms of epilepsy are similar to what was performed on H.M., although they are considerably less drastic. Usually tissue on only one side of the brain is removed. Still, there can be cognitive side effects: loss of visual or verbal memory abilities, and deficiencies in the ability to name or recognize objects, places or people.
When processing what the eyes see, the brains of primates don’t use square grids, but instead use triangles, research from Yerkes neuroscientist Beth Buffalo’s lab suggests.
Elizabeth Buffalo, PhD
She and graduate student Nathan Killian recently published (in Nature) their description of grid cells, neurons in the entorhinal cortex that fire when the eyes focus on particular locations.
Their findings broaden our understanding of how visual information makes its way into memory. It also helps us grasp why deterioration of the entorhinal cortex, a region of the brain often affected early by Alzheimer’s disease, produces disorientation.
The amazing thing about grid cells is that the multiple place fields are in precise geometric relation to each other and form a tessellated array of equilateral triangles, a â€˜gridâ€™ that tiles the entire environment. A spatial autocorrelation of the grid field map produces a hexagonal structure, with 60Âº rotational symmetry. In 2008, grid cells were identified Gafas Ray Ban outlet in mice, in bats in 2011, and now our work has shown that grid cells are also present in the primate brain.
Please read the whole thing!
Grid cells fire at different rates depending on where the eyes are focused. Mapping that activity across the visual field produces triangular patterns.
Mice with a disabled RGS14 gene remembered objects in their cages more easily and learned to navigate water mazes better, pharmacologist John Hepler and his colleagues found.Â Since the presence of a functional RGS14 gene holds mice back mentally, Hepler and his colleagues have been jokingly calling it “the Homer Simpson gene.”
This description struck a chord; the Atlantic magazine even embellished the story with a video showing the “D’oh”-ey cartoon character evolving from a single cell into a human couch potato.
One important difference: the Doogie mice had all their normal genes, and were overproducing a NMDA receptor gene involved in helping neurons communicate. Still, as a helpful 2009 round-up in Nature Reviews Neuroscience explains, scientists have found several single-gene knock-out mice that do better on tests of learning and memory. Many of these genetic alterations affect the process of long term potentiation, a process where neurons that get stimulated at the same time have the connections between them grow stronger.
RGS14 is turned on primarily in the CA2 region of the hippocampus
What makes the RGS14 gene an intriguing case is that it’s primarily turned on in the enigmatic CA2 region of the hippocampus. The CA2 region is normally relatively resistant to long-term potentiation and is also more hardy in situations of stroke or seizure.
Hepler observes that the vasopressin receptor 1b gene is also turned on predominantly in the CA2 region, and seems to be involved in aggression and social memory. He and his colleagues are planning to examine whether the RGS14-disabled mice have altered capabilities in those areas. Conveniently, Larry Young’s laboratory at Yerkes National Primate Research Center has been investigating the functions of vasopressin receptors in voles.
One last note: scientists in Spain have reported in Science that they can generate a variety of smart mice by putting the RGS14 gene on overdrive in a part of the brain where it’s not usually turned on. So whatever precise function RGS14 has, it doesn’t always dumb things down.