Posts Tagged hippocampus

[Editorial] Functional Adult Neurogenesis – Neuroscience

Editorial on the Research Topic
Functional Adult Neurogenesis

In the adult brains of most mammalian species, new neurons are continuously generated from neural stem/progenitor cells in discrete regions, such as the subgranular zone (SGZ) in the hippocampal dentate gyrus and the subventricular zone (SVZ) along the lateral cerebral ventricles. This process is generally termed adult neurogenesis, which is important for the survival of an individual in the natural environment. Accumulating studies have shown that the continuous adding of new neurons to the adult brain plays essential roles in relevant brain functions, such as spatial and fear memories, pattern separation, stress resilience, etc. Abnormalities in the generation or integration of new neurons are often associated with a various of disorders, such as mental disorders, stress disorders, epilepsy, etc. On the other hand, adult neurogenesis is regulated by a combination of molecular, cellular and circuitry mechanisms. This Research Topic collected several interesting and exciting new findings in the field of adult neurogenesis, regarding its functional implications.

During the development of newborn neurons in the adult brain, the initial morphogenic stage is critical for the survival, development, and functional integration of these newborn neurons. Ahamad et al. investigated the regulation of early morphogenesis of newborn neurons by a cellular metabolism-linked gene, Four and a half LIM domain 2 (FHL2). By using engineered viral vectors for genetic manipulation of FHL2 in the adult-born dentate granule neurons, they found that overexpression of FHL2 during early DGC development resulted in marked sprouting and branching of dendrites, while silencing of FHL2 increased dendritic length. These results suggest that FHL2 is an important regulator of early dendritic morphogenesis in adult-born dentate granule neurons, thus providing evidence for potential biological relevance of FHL2 in brain development and functions.

Tonic and phasic GABA signals regulate the development and integration of newborn neurons. Due to high level of ionic cotransporter NKCC1 expression in early-stage young neurons, GABAergic inputs initially provide depolarizing signals. As new neurons develop, accompanied by increasing expression of KCC2 and decreasing expression of NKCC1, GABA responses transit to hyperpolarizing signals. Gómez-Correa and Zepeda chronically administrated NKCC1 blocker bumetanide to young-adult rats, and found that the number of DCX-positive young neurons decreased, associated with altered morphological development of these newborn neurons. However, the animals’ behavior was not affected in contextual fear conditioning and open field tests.

Evidence has shown that neurogenesis declines in the aging brain. Some of the most interesting questions arising from this observation are, how adult neurogenesis is affected by the microenvironment in the aging brain, and how adult neurogenesis may benefit the physiological functions of the aging brain. Trinchero et al. provided two studies related to adult neurogenesis in the aging brain. Their first study used whole-cell recordings in developing granule cells to characterize the time course of functional integration of adult-born granule neurons in aging mice, and found a later onset of functional excitatory synaptogenesis in aging mice than in young adult mice. Enriched environment significantly facilitated functional integration of newborn neurons in aging mice, indicating an experience-dependent structural plasticity and functional integration of newborn neurons in the aging brain. A second study from the same group showed long-term exercise accelerated the development of adult-generated dentate granule neurons. The accumulation of rapidly integrated newborn neurons generated under exercise are likely beneficial to hippocampus-dependent cognitive functions, possibly rejuvenating the hippocampal neural network in aging animals. These observations highlight how physical exercise could be a beneficial intervention to improve cognition in aging.

Early life stress affects the development of hippocampal neural circuits and postnatal behaviors. In a study by Daun et al., the authors utilized a maternal and social deprivation (MSD) model to investigate the effects of early life stress on neural stem cells and neurogenesis in the adult brain. They found that early life MSD enhanced neurogenesis not only in the dentate gyrus of the hippocampus, but also in the amygdala, such that the animals exposed to early life MSD exhibited a reduction in amygdala/hippocampus-dependent fear memory. This suggests that early life stress during a stress-hyporesponsive period may benefit the resilience to stress in adulthood.

Schizophrenia is a complex and serious mental disorder, and patients with schizophrenia are characterized by psychological hallucinations, deregulated emotionality, and cognitive impairment. Evidence indicated that postnatal neurogenesis in the hippocampus is profoundly impaired in schizophrenic individuals. As an extension of embryonic and early postnatal neurogenesis, adult neurogenesis in the hippocampus is susceptible to factors that are related to schizophrenia. Previous studies have shown that deficiency in schizophrenia-risk gene DISC1 results in deficits in the development of newborn neurons in the dentate gyrus and aberrant adult neurogenesis. Sheu et al. used a rodent model of schizophrenia through maternal immune activation of poly (I:C) injection, and found a delayed onset of schizophrenia-like pathology and the severity of the symptoms positively correlated with the aberrant dendritic phenotypes preferentially at 9-week-old of age for the animals. Temporal suppression of aberrant neurogenesis during such critical time period ameliorated the emergence of schizophrenia-like symptoms. These findings strongly suggest the aberrant dendritic growth of postnatal neurogenesis during a critical time window of development is essential for the pathophysiological progression of schizophrenia-like symptoms.

Resent observations have indicated that mating behavior may affect neurogenesis in the adult brain. In a study by Portillo et al., the authors investigated the effect of paced mating on adult neurogenesis in the olfactory bulb in female rats. They observed a significant increase in the percentage of new neurons in the granular and glomerular layers of the accessory olfactory bulb and granular layer of the main olfactory bulb in females that mated in four sessions, which paced sexual interaction, suggesting that repeated paced mating increases the percentage of new neurons that survive in the olfactory bulb of female rats.

The study of adult neurogenesis after injuries that affected the central nervous system has led to interesting observations suggesting that utilizing newly generated new neurons after injury may provide potential novel strategies for the functional recovery of impaired regions. The endogenous spinal cord ependymal cells, which form the central canal, represent a repair cell source in treating spinal cord injury. A study from Wang et al. showed that BAF45D, a member of the Brg1/Brm-associated factor (BAF) chromatin remodeling complex, is expressed in spinal cord ependymal cells, neurons, and oligodendrocytes but not astrocytes in rat spinal cord. After injury, the structure of central canal was disrupted and the BAF45D-positive spinal cord ependymal cell-derivatives were decreased. This study further highlighted the decreased expression of BAF45D in spinal cord ependymal cells in injured spinal cord, and the potential role of BAF45D downregulation in development of neuronal lesion after spinal cord injury. Their findings provided further understanding of the structural and biological roles of BAF45D in spinal cord ependymal cells after injury, and provided a potential target for spinal cord injury therapy via the manipulation of spinal cord ependymal cells.

Altogether, the articles included in this special Research Topic have identified novel mechanisms underlying the regulation of the generation, development, integration, and functions of newborn neurons in a variety of areas in the adult central nervous system, and provide meaningful insights for our understanding of functional neurogenesis in the adult nervous system.

Source: https://www.frontiersin.org/articles/10.3389/fnins.2020.00885/full

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[ARTICLE] Intermittent fasting increases adult hippocampal neurogenesis – Full Text

Abstract

Introduction

Intermittent fasting (IF) has been suggested to have neuroprotective effects through the activation of multiple signaling pathways. Rodents fasted intermittently exhibit enhanced hippocampal neurogenesis and long‐term potentiation (LTP) at hippocampal synapses compared with sedentary animals fed an ad libitum (AL) diet. However, the underlying mechanisms have not been studied. In this study, we evaluated the mechanistic gap in understanding IF‐induced neurogenesis.

Methods

We evaluated the impact of 3 months of IF (12, 16, and 24 hr of food deprivation on a daily basis) on hippocampal neurogenesis in C57BL/6NTac mice using immunoblot analysis.

Results

Three‐month IF significantly increased activation of the Notch signaling pathway (Notch 1, NICD1, and HES5), neurotrophic factor BDNF, and downstream cellular transcription factor, cAMP response element‐binding protein (p‐CREB). The expression of postsynaptic marker, PSD95, and neuronal stem cell marker, Nestin, was also increased in the hippocampus in response to 3‐month IF.

Conclusions

These findings suggest that IF may increase hippocampal neurogenesis involving the Notch 1 pathway.

1 INTRODUCTION

Dietary restriction (DR) is defined as a decrease in energy consumption without reducing nutritional value. This simple dietary intervention has been shown in a wide range of experimental animals to extend lifespan and decrease the incidence of several age‐related diseases. The definition of DR has been expanded from an alternative description of caloric restriction (CR) to also encompass a broader scope of interventions, including short‐term starvation, periodic fasting, fasting‐mimetic diets, and intermittent fasting (IF; Mattson & Arumugam, 2018). IF has been proven to be advantageous to various organ systems in the body and acts as a mild metabolic stressor. It has been postulated that IF is able to cause powerful changes in the metabolic pathways in the brain via an increase in stress resistance, and breakdown of ketogenic amino acids and fatty acids (Bruce‐Keller, Umberger, McFall, & Mattson, 1999; Kim et al., 2018). Experimental studies have also shown that IF is neuroprotective against acute brain injuries such as stroke, and neurodegenerative diseases (Arumugam et al., 2010; Halagappa et al., 2007; Manzanero et al., 2014). In addition, recent studies have also shown that IF can lead to an increase in neurogenesis levels in the hippocampus (Manzanero et al., 2014).

In the adult brain, the niches of neuronal stem cells (NSCs) are located specifically at the subventricular zone (SVZ) of the lateral ventricles, and in the subgranular zone (SGZ) of the hippocampus. The ability of NSCs to maintain cerebral neurogenesis is controlled by the tight regulation of balanced events commencing from stem cell maintenance, to stem cell division and proliferation, to its differentiation into mature neurons, and finally their survival and functional integration into the brain parenchyma (Lathia, Mattson, & Cheng, 2008; Lledo, Alonso, & Grubb, 2006). The process of adult neurogenesis is highly regulated and is adaptable to environmental, morphological, and physiological cues, whereby cerebral performance is suited to function at optimal levels for a given environment. Studies have demonstrated that the proliferation of neural stem cells can be modified through metabolic perturbations experienced during high temperatures (Matsuzaki et al., 2009), physical activity (Niwa et al., 2016), and a high‐fat diet (Kokoeva, Yin, & Flier, 2005). Experimental studies from our group have also shown that IF increases neurogenesis in the hippocampus as a form of neuroprotection following acute brain injury such as ischemic stroke. Moreover, we established that the number of BrdU‐labeled cells in the dentate gyrus of IF mice was elevated (Manzanero et al., 2014). To measure cell proliferation without the confound availability of an exogenous marker BrdU, we established increases in the number of Ki67‐labeled cells in the dentate gyrus of mice on the IF diet, indicating enhancement of cell proliferation in these mice (Manzanero et al., 2014). In addition to our findings, previous work similarly demonstrated that using the every other day (EOD) IF regimen also increased BrdU‐labeled cell number in the hippocampus (Lee, Duan, & Mattson, 2002).

However, the molecular process involved in IF‐induced neurogenesis is not well understood. The Notch signaling pathway that is intricately involved in the determination of cell fate during brain development and adult neurogenesis may be a possible molecular process involved in IF‐induced neurogenesis (Lathia et al., 2008). In this study, we investigated the expression levels of molecular and cellular components of the hippocampal region, focusing specifically on Notch activation and associated proteins that are known to promote hippocampal neurogenesis such as brain‐derived neurotrophic factor (BDNF) and cAMP response element‐binding protein (CREB).[…]

Continue —-> https://onlinelibrary.wiley.com/doi/10.1002/brb3.1444?fbclid=IwAR0qkXNad-QtdS13s8RImgOnFHLelYIZ9JJx5fM7PuwCLnjzE0AJstUoeB4#.XtKGYmljNQc.facebook

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Figure 4Open in figure viewerPowerPoint
Schematic diagram of intermittent fasting‐mediated pathways that induce adult hippocampal neurogenesis. Intermittent fasting was shown to activate the Notch 1 signaling pathway, which caused the transcription factor, HES5, to induce an upregulation of Nestin, a marker of neuronal stem cells that led to increased neurogenesis. In addition, intermittent fasting was shown to activate the CREB signaling pathway, which caused an upregulation of neurotrophic factor, BDNF, that led to increased levels of Nestin and neurogenesis. BDNF, brain‐derived neurotrophic factor; CREB, cAMP response element‐binding protein; NeuN, neuronal nuclei

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[WEB SITE] The Adult Brain Does Grow New Neurons After All, Study Says

Study points toward lifelong neuron formation in the human brain’s hippocampus, with implications for memory and disease

The Adult Brain Does Grow New Neurons After All, Study Says

Cerebral cortical neuron. Credit: Getty Images

If the memory center of the human brain can grow new cells, it might help people recover from depression and post-traumatic stress disorder (PTSD), delay the onset of Alzheimer’s, deepen our understanding of epilepsy and offer new insights into memory and learning. If not, well then, it’s just one other way people are different from rodents and birds.

For decades, scientists have debated whether the birth of new neurons—called neurogenesis—was possible in an area of the brain that is responsible for learning, memory and mood regulation. A growing body of research suggested they could, but then a Nature paper last year raised doubts.

Now, a new study published today in another of the Nature family of journals—Nature Medicine—tips the balance back toward “yes.” In light of the new study, “I would say that there is an overwhelming case for the neurogenesis throughout life in humans,” Jonas Frisén, a professor at the Karolinska Institute in Sweden, said in an e-mail. Frisén, who was not involved in the new research, wrote a News and Views about the study in the current issue of Nature Medicine.

Not everyone was convinced. Arturo Alvarez-Buylla was the senior author on last year’s Nature paper, which questioned the existence of neurogenesis. Alvarez-Buylla, a professor of neurological surgery at the University of California, San Francisco, says he still doubts that new neurons develop in the brain’s hippocampus after toddlerhood.

“I don’t think this at all settles things out,” he says. “I’ve been studying adult neurogenesis all my life. I wish I could find a place [in humans] where it does happen convincingly.”

For decades, some researchers have thought that the brain circuits of primates—including humans—would be too disrupted by the growth of substantial numbers of new neurons. Alvarez-Buylla says he thinks the scientific debate over the existence of neurogenesis should continue. “Basic knowledge is fundamental. Just knowing whether adult neurons get replaced is a fascinating basic problem,” he said.

New technologies that can locate cells in the living brain and measure the cells’ individual activity, none of which were used in the Nature Medicinestudy, may eventually put to rest any lingering questions.

A number of researchers praised the new study as thoughtful and carefully conducted. It’s a “technical tour de force,” and addresses the concerns raised by last year’s paper, says Michael Bonaguidi, an assistant professor at the University of Southern California Keck School of Medicine.

The researchers, from Spain, tested a variety of methods of preserving brain tissue from 58 newly deceased people. They found that different methods of preservation led to different conclusions about whether new neurons could develop in the adult and aging brain.

Brain tissue has to be preserved within a few hours after death, and specific chemicals used to preserve the tissue, or the proteins that identify newly developing cells will be destroyed, said Maria Llorens-Martin, the paper’s senior author. Other researchers have missed the presence of these cells, because their brain tissue was not as precisely preserved, says Llorens-Martin, a neuroscientist at the Autonomous University of Madrid in Spain.

Jenny Hsieh, a professor at the University of Texas San Antonio who was not involved in the new research, said the study provides a lesson for all scientists who rely on the generosity of brain donations. “If and when we go and look at something in human postmortem, we have to be very cautious about these technical issues.”

Llorens-Martin said she began carefully collecting and preserving brain samples in 2010, when she realized that many brains stored in brain banks were not adequately preserved for this kind of research. In their study, she and her colleagues examined the brains of people who died with their memories intact, and those who died at different stages of Alzheimer’s disease. She found that the brains of people with Alzheimer’s showed few if any signs of new neurons in the hippocampus—with less signal the further along the people were in the course of the disease. This suggests that the loss of new neurons—if it could be detected in the living brain—would be an early indicator of the onset of Alzheimer’s, and that promoting new neuronal growth could delay or prevent the disease that now affects more than 5.5 million Americans.

Rusty Gage, president of the Salk Institute for Biological Studies and a neuroscientist and professor there, says he was impressed by the researchers’ attention to detail. “Methodologically, it sets the bar for future studies,” says Gage, who was not involved in the new research but was the senior author in 1998 of a paper that found the first evidence for neurogenesis. Gage says this new study addresses the concerns raised by Alvarez-Buylla’s research. “From my view, this puts to rest that one blip that occurred,” he says. “This paper in a very nice way… systematically evaluates all the issues that we all feel are very important.”

Neurogenesis in the hippocampus matters, Gage says, because evidence in animals shows that it is essential for pattern separation, “allowing an animal to distinguish between two events that are closely associated with each other.” In people, Gage says, the inability to distinguish between two similar events could explain why patients with PTSD keep reliving the same experiences, even though their circumstances have changed. Also, many deficits seen in the early stages of cognitive decline are similar to those seen in animals whose neurogenesis has been halted, he says.

In healthy animals, neurogenesis promotes resilience in stressful situations, Gage says. Mood disorders, including depression, have also been linked to neurogenesis.

Hsieh says her research on epilepsy has found that newborn neurons get miswired, disrupting brain circuits and causing seizures and potential memory loss. In rodents with epilepsy, if researchers prevent the abnormal growth of new neurons, they prevent seizures, Hsieh says, giving her hope that something similar could someday help human patients. Epilepsy increases someone’s risk of Alzheimer’s as well as depression and anxiety, she says. “So, it’s all connected somehow. We believe that the new neurons play a vital role connecting all of these pieces,” Hsieh says.

In mice and rats, researchers can stimulate the growth of new neurons by getting the rodents to exercise more or by providing them with environments that are more cognitively or socially stimulating, Llorens-Martin says. “This could not be applied to advanced stages of Alzheimer’s disease. But if we could act at earlier stages where mobility is not yet compromised,” she says, “who knows, maybe we could slow down or prevent some of the loss of plasticity [in the brain].”


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The Adult Brain Does Grow New Neurons After All, Study Says – Scientific American

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[NEWS] Vitamin D Deficiency Linked to Loss in Brain Plasticity

Feb 21, 2019 | Original Press Release from the University of Queensland

Vitamin D Deficiency Linked to Loss in Brain Plasticity

Perineuronal nets (bright green) surround particular neurons (blue). Fluorescence labelling reveals just how detailed these structures are. Credit: Phoebe Mayne, UQ

University of Queensland research may explain why vitamin D is vital for brain health, and how deficiency leads to disorders including depression and schizophrenia.

 

via Vitamin D Deficiency Linked to Loss in Brain Plasticity | Technology Networks

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[News] Hope for epileptics as scientists discover device implanted in the brain cuts seizures by 93% – Daily Mail Online

  • Unnamed ‘chip’ gives out the proteins GDNFs in the hippocampus in the brain
  • GDNFs help produce dopamine, with low levels being associated with seizures
  • When implanted in epileptic rats, they were protected even once it was removed 

Scientists have raised hope for epileptics after creating a ‘chip’ that cuts seizures by 93 per cent over three months.

The device, which has not been named, continuously gives out the protein GDNF in an area of the brain known as the hippocampus, which is associated with epilepsy.

GDNF is critical to the production of the chemical messenger dopamine, with low levels being linked to seizures.

When the chip was implanted in the brains of epileptic rats, the rodents experienced 75 per cent fewer seizures after just two weeks.

And the animals continued to be protected even once the chip was removed, suggesting it modified the cells of the rodents’ brains, safeguarding them against epilepsy.

Scientists have raised hope for epileptics after creating a 'chip' that cuts seizures by 93 per cent over three months (stock image is a depiction of a patient after having a seizure)

Scientists have raised hope for epileptics after creating a ‘chip’ that cuts seizures by 93 per cent over three months (stock image is a depiction of a patient after having a seizure)

The research was carried out by the University of Ferrara, Italy, and Gloriana Therapeutics – the non-profit biotech company behind the chip.

It was led by Giovanna Paolone, a research assistant in the department of pharmacology at the university.

Around one in 100 people in the UK have epilepsy, which is defined as seizures that start in the brain, Epilepsy Society statistics reveal.

And in the US, 1.2 per cent of the population have the condition, according to the Centers for Disease Control and Prevention.

Targeting nerve tissue growth has been suggested as a way of treating epilepsy, however, getting the right concentration of drugs in the correct area of the brain has always been a challenge.

But scientists may have overcome this by developing a chip that continuously delivers GDNF (glial cell line-derived neurotrophic factor) where it needs to go. GDNF is expressed within the cells of the hippocampus.

The hippocampus – which stores memories – degrades following continued epileptics seizures, however, its exact role in the disease is unclear.

A third of patients with a form of epilepsy that affects the hippocampus are immune to treatment, which causes their condition to become more severe over time.


WHAT IS EPILEPSY?

Epilepsy is a condition that affects the brain and leaves patients at risk of seizures.

Around one in 100 people in the UK have epilepsy, Epilepsy Society statistics reveal.

And in the US, 1.2 per cent of the population have the condition, according to the Centers for Disease Control and Prevention.

Anyone can have a seizure, which does not automatically mean they have epilepsy.

Usually more than one episode is required before a diagnosis.

Seizures occur when there is a sudden burst of electrical activity in the brain, which causes a disruption to the way it works.

Some seizures cause people to remain alert and aware of their surroundings, while others make people lose consciousness.

Some also make patients experience unusual sensations, feelings or movement, or go stiff and fall to the floor where they jerk.

Epilepsy can be brought on at any age by a stroke, brain infection, head injury or problems at birth that lead to lack of oxygen.

But in more than half of cases, a cause is never found.

Anti-epileptic drugs do not cure the condition but help to stop or reduce seizures.

If these do not work, brain surgery can be effective.

Source: Epilepsy Action


The researchers genetically-modified cells found in the retina, known as ARPE-19, to produce high levels of GDNF before enclosing them in a semi-permeable membrane.  This allowed oxygen and nutrients in, while letting GDNF out.

To test the chip, scientists implanted it into the hippocampus of 37 rats. The rodents were made to be epileptic by injecting them with the drug pilocarpine, which is used to treat dry mouth and relieves pressure in the eyes.

Results revealed the chip reduced the number of motor seizures – when the muscles go stiff or weaken temporarily – by 75 per cent within two weeks and 93 per cent after three months.

The researchers then staggered the removal of the chips from rats by between one week and six months after they were implanted.

Even once the device was removed, the animals continued to experience less seizures, which suggests the device modified their disease.

They also showed decreased anxiety – a key complication of epilepsy. Anxiety was measured by the time the rats spent in the open area of a maze over ‘hiding’ in corners or close to the walls.

When the rats were put down and their brains examined, the scientists even found the chip reduced the degradation of their hippocampus.

Overall, the researchers claim their chip delivers GDNF in a ‘sustained, targeted, and efficacious manner’.

They hope the device will be tested in further animal studies and eventually in patients.

Ley Sander, medical director at Epilepsy Society and professor of neurology at University College London, told MailOnline: ‘Targeted treatments that go straight to the source of a seizure are offering real hope for the future in the treatment of epilepsy.

‘The hippocampus is a key area in the brain for generating seizures and for many with this type of epilepsy, their seizures are not controlled with conventional medications.

‘At Epilepsy Society our genomic research is trying to understand at an individual level what causes a person’s epilepsy. We believe this will enable us to deliver far more personalised medicines in the future.

‘Hopefully, the work of these scientists at the University of Ferrara in Italy may be a future option for some.’

via Hope for epileptics as scientists discover device implanted in the brain cuts seizures by 93% | Daily Mail Online

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[WEB SITE] A New Research for a better epilepsy treatment

A New Research for a better epilepsy treatment

About 1.2 percent of the population have active epilepsy. Although the majority of the people respond to anti-seizure medications, these medications may not work for every person. They may come with a risk of side effects. About 20 to 40 percent of patients with epilepsy continue to have seizures even after various anti-seizure medications.

Even when the drugs work, individuals may develop memory difficulties and depression. It may be due to the combination of the underlying seizure disorder and the drugs used to treat it.

A research team was led by Ashok K. Shetty. He is a Ph.D. professor at the Texas A&M College of Medicine. He is working on a permanent and better treatment for epilepsy. Their findings were published in the Proceedings of the National Academy of Sciences (PNAS).

“This publication by Dr. Shetty and his team is a step forward in treating incurable diseases of the brain,” said Darwin J. Prockop. He is an MD, Ph.D., the Stearman Chair in Genomic Medicine, director of the Texas A&M Institute for Regenerative Medicine and professor at the Texas A&M College of Medicine.

Working of excitatory and inhibitory neurons

Seizures are caused by the over-excitation of the excitatory neurons in the brain. Due to this overexcitation, they fire too much. And inhibitory neurons aren’t as abundant or aren’t effective at their optimum level.

Inhibitory neurons are required to stop the firing of excitatory neurons. Thus, the chief inhibitory neurotransmitter present in the brain is GABA, short for gamma-Aminobutyric acid.

Over the last decade, researchers have learned to generate induced pluripotent stem cells from normal adult cells, like a skin cell. Therefore, these stem cells can develop into nearly any type of cells in the body, including neurons which use GABA, called GABAergic interneurons.

“For this, transplant human induced pluripotent stem cell-derived GABAergic progenitor cells into the hippocampus in an animal model of early temporal lobe epilepsy,” Shetty said.

The hippocampus is an area in the brain where seizures originate in temporal lobe epilepsy. It is also important for learning, mood, and memory. “Also, this region of brain functioned very well to overwhelm seizures. It even improves mental as well as mood functioning in the chronic epilepsy phase.”

Outcomes of the research

Additional testing exposed that the transplanted human neurons formed synapses with the excitatory neurons of the host. “They were also helpful for GABA and other markers of specific subclasses of inhibitory interneurons,” Shetty said.

“Another captivating aspect of this research is that transplanted human GABAergic neurons were found to be involved directly in controlling seizures. As silencing the transplanted GABAergic neurons caused an increased number of seizures.”

“One central aspect of the effort is that the similar cells can be attained from a patient.” This process, called autologous transplant, is patient specific. It means that there would be no rejection risk of the new neurons. And the person would not need anti-rejection drugs.

“However, we should make sure that we’re doing more good than harm,” Shetty said. “Going onward, we need to be certain that all the transplanted cells have turned into neurons. Because putting undifferentiated pluripotent stem cells could lead to tumors and other problems in the body.”

The epilepsy development often occurs after a head injury. That is why the Department of Defense is involved in funding the development of improved treatment and prevention options.

Treatment of other disorders

“Therefore, good research is essential before patients can be treated safely,” Prockop said. “But this study shows a technique through which patients can someday be treated with their own cells for the shocking epilepsy effects but possibly also other disorders like Parkinsonism and Alzheimer’s disease.”

Hence, Shetty advised that these tests were early interferences after the initial brain injury caused by status epilepticus. This is a state of continuous seizures in humans lasting more than five minutes.

The next phase is to understand if similar transplants would work for chronic epilepsy cases, mainly drug-resistant epilepsy. “Presently, there is no effective treatment for drug-resistant epilepsy. It is associated with memory problems, depression, and a death rate 5 to 10 times that of the general population,” he said.

“Hence, our findings propose that induced pluripotent stem cell-derived GABAergic cell therapy has the potential for providing a lifelong seizure control and releasing co-morbidities associated with epilepsy.”

 

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[TED Talk] The Brain-Changing Effects of Exercise

What’s the most transformative thing that you can do for your brain today? Exercise! says neuroscientist Wendy Suzuki. Get inspired to go to the gym as Suzuki discusses the science of how working out boosts your mood and memory — and protects your brain against neurodegenerative diseases like Alzheimer’s.

This talk was presented at an official TED conference, and was featured by our editors on the home page.

ABOUT THE SPEAKER
Wendy Suzuki · Neuroscientist, author Wendy Suzuki is researching the science behind the extraordinary, life-changing effects that physical activity can have on the most important organ in your body: your brain.

Transcript

03:54
05:02
07:13
09:41
11:13
12:12
12:43
12:46
12:47

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[WEB SITE] Neuroscientists unravel how two different types of brain plasticity work on synapses

 

The brain’s crucial function is to allow organisms to learn and adapt to their surroundings. It does this by literally changing the connections, or synapses, between neurons, strengthening meaningful patterns of neural activity in order to store information. The existence of this process – brain plasticity – has been known for some time.

But actually, there are two different types of brain plasticity at work on synapses. One is “Hebbian plasticity”; it is the one which effectively allows for the recording of information in the synapses, named after pioneering neuroscientist Donald Hebb. The other, more recently discovered, is “homeostatic synaptic plasticity” (HSP), and, like other “homeostatic” processes in the body such as maintaining a constant body temperature, its purpose is to keep things stable. In this case, HSP ensures that the brain doesn’t build up too much activity (as is the case in epilepsy) or become too quiet (as can happen when you lose synapses in Alzheimer’s Disease).

However, little is known about how these two types of plasticity actually interact in the brain. Now, a team of neuroscientists at the Champalimaud Centre for the Unknown, in Lisbon, Portugal, has begun to unravel the fundamental processes that happen in the synapse when the two mechanisms overlap. Their results were published in the journal iScience.

“In theory, the two types of plasticity act as opposing forces”, says Anna Hobbiss, first author of the new study, which was led by Inbal Israely. “Hebbian plasticity reacts to activity at the synapses by inciting them to get stronger while HSP reacts to it by making them weaker. We wanted to understand, on a cellular and molecular level, how the synapse deals with these two forces when they are present at the same time.”

In so doing, the authors have surprisingly shown that, contrary to what might be expected, HSP facilitates Hebbian plasticity, and thus influences memory formation and learning. This means that these two types of plasticity “may actually not be such distinct processes, but instead work together at the same synapses”, says Israely.

The team’s goal was to determine the changes in size of minute structures called dendritic spines, which are the “receiving end” of the synapse. The size of these spines changes to reflect the strength of the synaptic connection.

For this, they studied cells from the mouse hippocampus, a part of the brain which is crucial for learning. In their experiments, they blocked activity in the cells by introducing a potent neurotoxin called tetrodotoxin, thus simulating the loss of input to a certain part of the brain (“think about a person suddenly becoming blind, which leads to loss of input from the eyes to the brain”, says Hobbiss).

Forty eight hours later, they mimicked a small recovery of activity at only one synapse by releasing a few molecules of a neurotransmitter called glutamate on single spines of single neurons. This was possible thanks to a very high resolution, state-of-the-art laser technology, called two-photon microscopy, which allowed the scientists to very precisely visualize and target individual dendritic spines.

As this process evolved, the team closely watched what was happening to the spines – and they saw various anatomical changes. First, the silencing of all neural activity made the spines grow in size. “The spines are like little microphones, which, when there is silence, ramp up the ‘volume’ to try and catch even the faintest noise”, Hobbiss explains.

The scientists then activated individual spines with pulses of glutamate and watched them for two hours. One of the things they thought could happen was that the size of the spines would not grow further, since they had already turned up their ‘volume’ as far is it would go. But the opposite happened: the spines grew even more, with the smaller spines showing the biggest growth.

Finally, the authors also saw growth in neighboring spines, even though the experiment only targeted one spine. “We found that after a lack of activity, other spines in the vicinity also grew, further enhancing the cell’s sensitivity to restored neural transmission”, says Hobbiss. “The cells become more sensitive, more susceptible to encode information. It is as though the ‘gain’ has been turned up”, she adds.

“The fact that neighboring spines grew together with an active spine signifies that homeostatic plasticity changes one of the hallmark features of information storage, which is that plasticity is limited to the site of information entry”, Israely explains. “So, in this sense, the different plasticity mechanisms which are at work in the neuron can cooperate to change which and how many inputs respond to a stimulus. I think this is an exciting finding of our study.”

Taken together, these results show that homeostatic plasticity can actually rev up Hebbian plasticity, the type required for storing information. “Our work adds a piece to the puzzle of how the brain performs one of its fundamental tasks: being able to encode information while still keeping a stable level of activity”, concludes Hobbiss.

The misregulation of homeostatic plasticity – the stabilizing one – has started to be implicated in human health, specifically neurodevelopmental disorders such as Fragile X syndrome and Rett syndrome as well as neurodegenerative ones such as Alzheimer’s Disease. “Perhaps this balance is what allows us to be able to learn new information while retaining stability of that knowledge over a lifetime”, says Israely.

 

via Neuroscientists unravel how two different types of brain plasticity work on synapses

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[WEB PAGE] Study offers possibility of squelching a focal epilepsy seizure before symptoms appear

Patients with focal epilepsy that does not respond to medications badly need alternative treatments.

In a first-in-humans pilot study, researchers at the University of Alabama at Birmingham have identified a sentinel area of the brain that may give an early warning before clinical seizure manifestations appear. They have also validated an algorithm that can automatically detect that early warning.

These two findings offer the possibility of squelching a focal epilepsy seizure — before the patient feels any symptoms — through neurostimulation of the sentinel area of the brain. This is somewhat akin to the way an implantable defibrillator in the heart can staunch heart arrhythmias before they injure the heart.

In the pilot study, three epilepsy patients undergoing brain surgery to map the source of their focal epilepsy seizures also gave consent to add an investigational aspect to their planned surgeries.

As neurosurgeons inserted long, thin, needle-like electrodes into the brain to map the location of the electrical storm that initiates an epileptic seizure, they also carefully positioned the electrodes to add one more task — simultaneously record the electrical activity at the anterior nucleus of the thalamus.

The thalamus is a structure sitting deep in the brain that is well connected with other parts of the brain. The thalamus controls sleep and wakefulness, so it often is called the “pacemaker” of the brain. Importantly, preclinical studies have shown that focal sources of seizures in the cortex can recruit other parts of the brain to help generate a seizure. One of these recruited areas is the anterior thalamic nucleus.

The UAB team led by Sandipan Pati, M.D., assistant professor of neurology, found that nearly all of the epileptic seizures detected in the three patients — which began in focal areas of the cortex outside of the thalamus — also recruited seizure-like electrical activity in the anterior thalamic nucleus after a very short time lag. Importantly, both of these initial electrical activities appeared before any clinical manifestations of the seizures.

The UAB researchers also used electroencelphalography, or EEG, brain recordings from the patients to develop and validate an algorithm that was able to automatically detect initiation of that seizure-like electrical activity in the anterior thalamic nucleus.

“This exciting finding opens up an avenue to develop brain stimulation therapy that can alter activities in the cortex by stimulating the thalamus in response to a seizure,” Pati said. “Neurostimulation of the thalamus, instead of the cortex, would avoid interference with cognition, in particular, memory.”

“In epilepsy, different aspects of memory go down,” Pati explained. “Particularly long-term memory, like remembering names, or remembering events. The common cause is that epilepsy affects the hippocampus, the structure that is the brain’s memory box.”

Pati said these first three patients were a feasibility study, and none of the patients had complications from their surgeries. The UAB team is now extending the study to another dozen patients to confirm the findings.

“Hopefully, after the bigger group is done, we can consider stimulating the thalamus,” Pati said. That next step would have the goals of improved control of seizures and improved cognition, vigilance and memory for patients.

For epilepsy patients where medications have failed, the surgery to map the source of focal seizures is a prelude to two current treatment options — epilepsy surgery to remove part of the brain or continuous, deep-brain stimulation. If the UAB research is successful, deep brain stimulation would be given automatically, only as the seizure initiates, and it would be targeted at the thalamus, where the stimulation might interfere less with memory.

 

via Study offers possibility of squelching a focal epilepsy seizure before symptoms appear

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[BLOG POST] Do Older Brains Make New Neurons or Not?

Neurons in the brain. (Credit: Andrii Vodolazhskyi/Shutterstock)

Neurons in the brain. (Credit: Andrii Vodolazhskyi/Shutterstock)

One of the most basic things our bodies do is make new cells. It’s what allows tissues to grow and heal, and allows our bodies to continually rejuvenate themselves.

When it comes to cellular replenishment, one of the places researchers are most interested in is the brain. The formation of new brain cells is of critical interest to researchers studying everything from brain injuries to aging to mental illnesses like depression.

New Neurons Or No?

But researchers might be experiencing a bit of whiplash right now. Two papers, published just under a month apart, stand at odds with each other. One, led by researchers from the University of California, San Francisco, and published in Nature in early March, suggests that the hippocampus, a brain region important in the formation of memories, learning and emotional regulation, stops making new neurons after childhood, something that contradicts most previous research. The second, from Columbia University researchers out today in Cell Stem Cell, and using a very similar method, says that’s not true at all — the hippocampus does in fact make new cells throughout our lifespan.

It’s enough to tangle your neurons. But, it’s really a reminder that science is driven by debate and disagreement. It takes time and effort to arrive at a true consensus, and researchers can’t answer questions as definitively as we might wish.

In this case, the confusion seems to come down to methodology. Finding evidence of newly-formed neurons isn’t as simple as putting samples of brain tissue under a microscope. In fact, there are few direct ways of searching for neurogenesis. Instead, most researchers use indirect approaches, like searching for marker proteins involved in the maturation of new cells or other molecules somehow involved with cell development.

Though the way both teams of researchers looked for marker proteins differed slightly, both essentially involved highlighting cells expressing various marker proteins. They looked to see whether any cells “lit up”, and if so, checked to make sure they were actual new neurons.

What Do You See?

If both teams used the similar methods, how did they come to such different conclusions? Maura Boldrini, the author of the most recent paper who found the hippocampus continues to make new neurons throughout our lives, thinks it came down to the samples each team used.

“It’s not that they did something different from what we are doing substantially, I think it’s more a matter of what kind of tissue they had available,” she says. Boldrini studies how neurogenesis in the brain is related to things like depression and suicide. Over the years, she and others at Columbia University have built a large collection of brain tissue samples. Most importantly, she says, they had samples from people with healthy brains.

“As we started going on, we started having people with no psychiatric or neurological disease, no treatment, no history of drug abuse; spanning a big lifespan,” Boldrini says. “So we thought we had the right collection of brains to be able to look at the effects of aging, per se, without having these confounding factors … not too many brain collections in the world actually have information about this.”

The California researchers, says Sorrell, didn’t know the exact diagnosis of each brain sample, and had no toxicology reports for them. Drug use or psychological conditions like depression could affect the brain’s ability to make new neurons, potentially throwing the results off. In addition, some marker proteins begin to disappear soon after death, so if the samples aren’t preserved quickly, evidence of neurogenesis could be wiped away.

Another factor, Boldrini says, is the method of preservation. Some fixatives can obscure researchers’ ability to see certain types of cells. She encountered this problem during the course of her previous work, and that helped her choose the right fixatives to use. The California researchers used different fixatives than Boldrini did, and she thinks it’s another reason they might have come to different conclusions.

Counterpoint

Though Boldrini’s work agrees with the bulk of prior research into the subject, she and her team are still relying on an indirect method of imaging neurons, and it makes it difficult at the moment to close the book on the subject.

And not every researcher is convinced. Arturo Alvarez-Buylla is a neuroscientist at UC, San Francisco and a co-author of the paper that found no evidence of adult neurogenesis in the hippocampus. While he says more work needs to be done, he thinks Boldrini’s work may be misinterpreting some evidence, specifically the cells they label as new neurons.

“I believe what they are calling dividing cells and what they are calling new neurons, they may be [those things], but the evidence is not there,” Alvarez-Buylla says.

He points to a marker protein both his team and Boldrini’s use to search for developing cells, called Ki-67. Boldrini’s team likely misread figures showing the protein, Alvarez-Buylla thinks, leading them to falsely conclude that new neurons existed.

As for his own research, he says the fact they identified new neurons in samples of young tissue proves that his team’s methodology was solid, and that his results weren’t simply the result of poor sampling or fixing. They watched those cells dwindle and disappear as they looked at samples from progressively older people, which is evidence that neurogenesis does stop.

In fact, their method did turn up similar structures in adults as Boldrini did, Alvarez-Buylla says, but their interpretation differs.

“So, we did see the same cells that they do see in our post-mortem material, it’s just that we do not agree that they are young neurons,” he says.

Where Do We Stand?

Jonas Frisen, a stem cell researcher at Sweden’s Karolinska Institutet who was not involved with either study, agrees that the reason both teams got such different answers most likely lies in how they went about collecting and analyzing samples. Furthermore, drawing conclusions from negative data, as Alvarez-Buylla’s team did, is difficult.

“The commonly used quote, ‘Absence of evidence is not evidence of absence,’ summarizes that,” Frisen says in an email. “An analogy to the current situation is that you send 10 people into the woods to search for blueberries. Nine come back with blueberries and one not—are there blueberries in that forest?”

The method that both teams relied on has its drawbacks as well. There is a poor signal-to-noise ratio when searching for marker proteins in the brain, Frisen says, and much of the evidence that it works is based on animal studies — which may not fully translate to humans.

In the end, he agrees with Boldrini that humans probably continue to make neurons throughout the course of their lives. It would be good news for those of us worried about cracking our heads one too many times, though it obviously doesn’t change how our brains actually behave. The real benefit would be to researchers studying how the formation of new neurons relates to depression and other mental disorders, as well as how we make new memories and regulate emotions.

These past few weeks have been a case study in the machinations of science, and it serves as a solid reminder that there aren’t many hard-and-fast truths in science. And, new neurons or not, it’s another piece of the puzzle of how our brains work. In the end, that’s good for all of us.

via Do Older Brains Make New Neurons or Not?

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