Posts tagged nerve cells

The Who asked “who are you?” but Dartmouth neurobiologist Jeffrey Taube asks “where are you?” and “where are you going?” Taube is not asking philosophical or theological questions. Rather, he is investigating nerve cells in the brain that function in establishing one’s location and direction.

Taube, a professor in the Department of Psychological and Brain Sciences, is using microelectrodes to record the activity of cells in a rat’s brain that make possible spatial navigation — how the rat gets from one place to another — from “here” to “there.” But before embarking to go “there,” you must first define “here.”

Survival Value

"Knowing what direction you are facing, where you are, and how to navigate are really fundamental to your survival," says Taube. "For any animal that is preyed upon, you’d better know where your hole in the ground is and how you are going to get there quickly. And you also need to know direction and location to find food resources, water resources, and the like."

Not only is this information fundamental to your survival, but knowing your spatial orientation at a given moment is important in other ways, as well. Taube points out that it is a sense or skill that you tend to take for granted, which you subconsciously keep track of. “It only comes to your attention when something goes wrong, like when you look for your car at the end of the day and you can’t find it in the parking lot,” says Taube.

Perhaps this is a momentary lapse, a minor navigational error, but it might also be the result of brain damage due to trauma or a stroke, or it might even be attributable to the onset of a disease such as Alzheimer’s. Understanding the process of spatial navigation and knowing its relevant areas in the brain may be crucial to dealing with such situations.

The Cells Themselves

One critical component involved in this process is the set of neurons called “head direction cells.” These cells act like a compass based on the direction your head is facing. They are located in the thalamus, a structure that sits on top of the brainstem, near the center of the brain.

He is also studying neurons he calls “place cells.” These cells work to establish your location relative to some landmarks or cues in the environment. The place cells are found in the hippocampus, part of the brain’s temporal lobe. They fire based not on the direction you are facing, but on where you are located.

Studies were conducted using implanted microelectrodes that enabled the monitoring of electrical activity as these different cell types fired.

Taube explains that the two populations — the head direction cells and the place cells — talk to one another. “They put that information together to give you an overall sense of ‘here,’ location wise and direction wise,” he says. “That is the first ingredient for being able to ask the question, ‘How am I going to get to point B if I am at point A?’ It is the starting point on the cognitive map.”

The Latest Research

Taube and Stephane Valerio, his postdoctoral associate for the last four years, have just published a paper in the journal Nature Neuroscience, highlighting the head direction cells. Valerio has since returned to the Université Bordeaux in France.

The studies described in Nature Neuroscience discuss the responses of the spatial navigation system when an animal makes an error and arrives at a destination other than the one targeted — its home refuge, in this case. The authors describe two error-correction processes that may be called into play — resetting and remapping — differentiating them based on the size of error the animal makes when performing the task.

When the animal makes a small error and misses the target by a little, the cells will reset to their original setting, fixing on landmarks it can identify in its landscape. “We concluded that this was an active behavioral correction process, an adjustment in performance,” Taube says. “However, if the animal becomes disoriented and makes a large error in its quest for home, it will construct an entirely new cognitive map with a permanent shift in the directional firing pattern of the head direction cells.” This is the “remapping.”

Taube acknowledges that others have talked about remapping and resetting, but they have always regarded them as if they were the same process. “What we are trying to argue in this paper is that they are really two different, separate brain processes, and we demonstrated it empirically,” he says. “To continue to study spatial navigation, in particular how you correct for errors, you have to distinguish between these two qualitatively different responses.”

Taube says other investigators will use this distinction as a basis for further studies, particularly in understanding how people correct their orientation when making navigational errors.

(Source: sciencedaily.com)

Scientists studying a rare genetic disorder have identified a molecular pathway that may play a role in schizophrenia, according to new research in the Oct. 10 issue of The Journal of Neuroscience. The findings may one day guide researchers to new treatment options for people with schizophrenia — a devastating disease that affects approximately 1 percent of the world’s population.

Schizophrenia is characterized by a multitude of symptoms, including hallucinations, social withdrawal, and learning and memory deficits, which usually appear during late adolescence or early adulthood. Efforts to identify disease causes have been complicated by the fact that no single genetic mutation is strongly associated with the disease. By studying a rare genetic disorder that increases the risk of schizophrenia, Laurie Earls, PhD, and colleagues in the laboratory of Stanislav Zakharenko, MD, PhD, at St. Jude Children’s Research Hospital identified molecular changes that affect memory and are also present in people with schizophrenia.

Approximately 30 percent of people with a genetic disorder known as 22q11 deletion syndrome develop schizophrenia, making it one of the strongest risk factors for the disease. In previous studies of mice with the 22q11 deletion, Zakharenko’s group identified changes in nerve cells leading to deficits in the hippocampus — the brain’s learning and memory center — that appear with age. In the current study, the group confirmed similar molecular changes occur in people with schizophrenia. They also zeroed in on the gene contributing to the nerve cell changes.

"This study makes some very important discoveries about the precise mechanisms underlying the learning and memory deficits seen in the genetic mouse model — problems that are a central part of the human disease," said Carrie Bearden, PhD, an expert on 22q11 deletion syndrome at the University of California, Los Angeles, who was not involved in the study. "Pinpointing the specific gene involved is the first step toward developing targeted therapies that could reverse the cognitive deficits associated with schizophrenia, both in the context of this genetic mutation and the broader population," she added.

In previous studies, Zakharenko’s group found that abnormal nerve cell communication and cognitive dysfunction was associated with elevated levels of a protein that regulates calcium in certain nerve cells known as Serca2. These abnormalities are only detectable with age in mice with the 22q11 deletion.

In the current study, the researchers identified the gene Dgcr8 as the source of the changes.It produces molecules called microRNAs that normally keep Serca2 in check. Without them, the protein becomes elevated.By adding these molecules back into the hippocampus of animals with the 22q11 deletion, the researchers were able to reduce elevated Serca2 levels and reduce the cellular deficits associated with this genetic defect.

To assess whether the findings from these genetic mouse studies might translate to schizophrenia, the authors analyzed post-mortem brain tissue from people with schizophrenia. The researchers discovered that Serca2 was elevated even in patients with schizophrenia who did not have the 22q11 deletion.

"These data suggest a link between the nerve cell changes in patients with the 22q11 deletion syndrome and those that occur in patients with schizophrenia," Zakharenko said. "Serca2 regulation represents a novel therapeutic target for schizophrenia."

(Source: sott.net)

Results may help improve drugs for neurological disorders

Researchers have published the first highly detailed description of how neurotensin, a neuropeptide hormone which modulates nerve cell activity in the brain, interacts with its receptor. Their results suggest that neuropeptide hormones use a novel binding mechanism to activate a class of receptors called G-protein coupled receptors (GPCRs). 

“The knowledge of how the peptide binds to its receptor should help scientists design better drugs,” said Dr. Reinhard Grisshammer, a scientist at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and an author of the study published in Nature.

Binding of neurotensin initiates a series of reactions in nerve cells. Previous studies have shown that neurotensin may be involved in Parkinson’s disease, schizophrenia, temperature regulation, pain, and cancer cell growth.

Dr. Grisshammer and his colleagues used X-ray crystallography to show what the receptor looks like in atomic detail when it is bound to neurotensin. Their results provide the most direct and detailed views describing this interaction which may change the way scientists develop drugs targeting similar neuropeptide receptors.

X-ray crystallography is a technique in which scientists shoot X-rays at crystallized molecules to determine a molecule’s shape and structure. The X-rays change directions, or diffract, as they pass through the crystals before hitting a detector where they form a pattern that is used to calculate the atomic structure of the molecule. These structures guide the way scientists think about how proteins work.

Neurotensin receptors and other GPCRs belong to a large class of membrane proteins which are activated by a variety of molecules, called ligands. Previous X-ray crystallography studies showed that smaller ligands, such as adrenaline and retinal, bind in the middle of their respective GPCRs and well below the receptor’s surface.  In contrast, Dr. Grisshammer’s group found that neurotensin binds to the outer part of its receptor, just at the receptor surface. These results suggest that neuropeptides activate GPCRs in a different way compared to the smaller ligands.

Forming well-diffracting neuropeptide-bound GPCR crystals is very difficult. Dr. Grisshammer and his colleagues spent many years obtaining the results on the neurotensin receptor. During that time Dr. Grisshammer started collaborating with a group led by Dr. Christopher Tate, Ph.D. at the MRC Laboratory of Molecular Biology, Cambridge, England. Dr. Tate’s lab used recombinant gene technology to create a stable version of the neurotensin receptor which tightly binds neurotensin. Meanwhile Dr. Grisshammer’s lab employed the latest methods to crystallize the receptor bound to a short version of neurotensin.

The results published today are the first X-ray crystallography studies showing how a neuropeptide agonist binds to neuropeptide GPCRs. Nonetheless, more work is needed to fully understand the detailed signaling mechanism of this GPCR, said Dr. Grisshammer.

(Source: ninds.nih.gov)

Researchers from the University of Utah have gained new insight into the regulation of adult nerve cell generation in the hypothalamus, the part of the brain that regulates many aspects of behavior, mood, and metabolism. In the Sept. 10, 2012, issue of Developmental Cell they report that a cell-to-cell communication network known as the Wnt signaling pathway plays an important role in both the production and specialization of nerve cell precursors in the hypothalamus.

The hypothalamus is a highly complex region of the brain that controls hunger, thirst, fatigue, body temperature, and sleep. It also links the central nervous system to the body system that regulates hormone levels. Recent studies have shown that the hypothalamus is one of the parts of the brain in which neurogenesis, the birth of new nerve cells, continues throughout adulthood.

“In our earlier work, we discovered that Wnt signaling was required for neurogenesis in the embryonic zebrafish hypothalamus,” says Richard Dorsky, Ph.D., associate professor of neurobiology and anatomy at the University of Utah School of Medicine and senior author on the study. “We also found that, in zebrafish, both Wnt signaling and hypothalamic neurogenesis continue into adulthood. The goal of this study was to define specific roles for Wnt signaling in neurogenesis.”

The Wnt signaling pathway is a network of proteins that transmits signals from the cell surface to DNA in the cell nucleus to regulate gene expression, and it is known to play a critical role in cell-to-cell communication in both embryos and adults. In this study, Dorsky and his colleagues demonstrated that in zebrafish embryos Wnt signaling is present in progenitor cells that are actively multiplying in the hypothalamus. Progenitor cells have the potential to divide and differentiate into a variety of specialized cell types. Dorsky and his colleagues also found that Wnt signaling continues to be required for hypothalamic neurogenesis throughout life.

Neural progenitor cells arise from neural stem cells, and retain the capacity to develop into more specialized types of nerve cells. After the embryo is formed, some neural stem cells lie dormant in the brain and spinal cord until they are activated to serve as a repair system. When tissue damage or death occurs, chemical substances trigger these neural stem cells to make neural progenitor cells that assist in tissue recovery. Recent research suggests that other neural progenitor cells continue to make new nerve cells in the uninjured brain and contribute to the plasticity of the brain in response to changes in the environment.

“From a functional standpoint, it is not yet clear why the ability to continuously produce hypothalamic nerve cells is important in adult zebrafish,” says Dorsky. “However, in adult mice, hypothalamic neurogenesis seems to be significant in the regulation of feeding behaviors due to environmental changes.”

Dorsky and his colleagues discovered that the role of the Wnt signaling pathway differs between embryos and adults. In zebrafish embryos, activation of Wnt signaling is required for proliferation of progenitor cells contributing to growth of brain structures. However, at later stages of development including adulthood, Wnt signaling must be active for neural progenitor cells to commit to becoming nerve cells, but then must be inhibited for these cells to complete the differentiation process. Significantly, Dorsky and his colleagues also found that mice displayed a similar pattern of Wnt activity.

“Compared to other regions of the brain, the hypothalamus is relatively unstudied as a model of post-embryonic neurogenesis,” says Dorsky. “Our research represents a significant contribution to the field because it establishes the vertebrate hypothalamus as a model of Wnt-regulated neural progenitor differentiation that can be used to shed light on the plasticity of the adult brain.”

(Source: newswise.com)