For decades researchers thought that the production of neurons stopped early in life, leaving the adult brain with a finite number of neurons. The discovery of neural stem cells with self-renewing capacity and multi-potency has radically changed this view, and it is now well accepted that the birth of new neurons continues throughout adulthood. Adult neurogenesis occurs in two primary locations: the olfactory bulb and the central part of the hippocampus, called the dendate gyrus (shown at the left). Image: Widefield multi-photon fluorescence image of a rat hippocampus stained to reveal the distribution of glia (cyan), neurofilaments (green) and cell nuclei (yellow). The image was produced as part of an ongoing brain mapping project for the Whole Brain Catalog.
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For decades researchers thought that the production of neurons stopped early in life, leaving the adult brain with a finite number of neurons. The discovery of neural stem cells with self-renewing capacity and multi-potency has radically changed this view, and it is now well accepted that the birth of new neurons continues throughout adulthood. Adult neurogenesis occurs in two primary locations: the olfactory bulb and the central part of the hippocampus, called the dendate gyrus (shown at the left).

Image: Widefield multi-photon fluorescence image of a rat hippocampus stained to reveal the distribution of glia (cyan), neurofilaments (green) and cell nuclei (yellow). The image was produced as part of an ongoing brain mapping project for the Whole Brain Catalog.

Source: download.cell.com

Peering deeply – and quite literally – into the intact brain: A video fly-through

CLARITY, pioneered by Stanford psychiatrist/bioengineer Karl Deisseroth, MD, PhD, renders intact tissue samples transparent. Above is a video clip showing off the new method’s capabilities. First you’ll witness a “fly-through” of a complete mouse brain using fluorescent imaging. The immediately following clip – it’s spectacular! – provides a three-dimensional view of a mouse hippocampus (the brain’s brain’s memory hub), with projecting neurons depicted in green, connecting interneurons in red, and layers of support cells, or glia, in blue.

Note that in both cases, there was no need to slice the tissue into ultra-thin sections, analyze them chemically and/or optically and then laboriously “sew” them back together via computer algorithms in order to reconstruct a 3-D virtual image of the biological sample. All that was required, after performing the necessary hocus-pocus, was to ”send in the stain” (i.e., use histochemical means to paint different cell types different colors) and move the sample or camera lens or shift the latter’s focal length. Nice trick. With big implications for biomedical research.

Purkinje neurons play an essential role in motor function. Here the Purkinje neurons reach their arbor-like dendrites into the molecular layer of the developing cerebellum of a mouse. The mostly green cells at the bottom left are cerebellar granule cells, which relay information from the nervous system to the Purkinje neurons.
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Purkinje neurons play an essential role in motor function. Here the Purkinje neurons reach their arbor-like dendrites into the molecular layer of the developing cerebellum of a mouse. The mostly green cells at the bottom left are cerebellar granule cells, which relay information from the nervous system to the Purkinje neurons.

Source: download.cell.com

The Human Brain in cross section (near the midline) The following structures can be located here: Cerebellum, 4th ventricle, Superior colliculus, Inferior colliculus, Periaqueductal gray, Pons, Dorsal funiculus, MLF, Medial lemniscus, Red nucleus, Mammillary body, Pineal body, Posterior commissure, Anterior commissure, Thalamus, and Fornix.
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The Human Brain in cross section (near the midline)

The following structures can be located here:

Cerebellum, 4th ventricle, Superior colliculus, Inferior colliculus, Periaqueductal gray, Pons, Dorsal funiculus, MLF, Medial lemniscus, Red nucleus, Mammillary body, Pineal body, Posterior commissure, Anterior commissure, Thalamus, and Fornix.

Source: medicine.creighton.edu

In the hippocampus, neural stem cells (green) sit in a layer below their progeny, the granule neurons (red). When activated by extrinsic stimuli, they enter mitosis and generate neuron progenitor cells, which eventually mature into neurons and migrate into the layer above. The number of neural stem cells in the hippocampus decreases over time, possibly contributing to the cognitive impairment associated with aging. One hypothesis is that, after a rapid series of divisions, these neural stem cells disappear via their conversion into astrocytes. Image: Section of a mouse hippocampus imaged with Zeiss LSM 50 confocal microscope with a 40X C-Apochromat water-immersion objective lens (N.A. value 1.2, working distance 220 microns) at 62x magnification. Brain slices were fixed in 4% paraformaldehyde, immunolabeled, and then cleared in FocusClear (CelExplorer, Taiwan).
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In the hippocampus, neural stem cells (green) sit in a layer below their progeny, the granule neurons (red). When activated by extrinsic stimuli, they enter mitosis and generate neuron progenitor cells, which eventually mature into neurons and migrate into the layer above. The number of neural stem cells in the hippocampus decreases over time, possibly contributing to the cognitive impairment associated with aging. One hypothesis is that, after a rapid series of divisions, these neural stem cells disappear via their conversion into astrocytes.

Image: Section of a mouse hippocampus imaged with Zeiss LSM 50 confocal microscope with a 40X C-Apochromat water-immersion objective lens (N.A. value 1.2, working distance 220 microns) at 62x magnification. Brain slices were fixed in 4% paraformaldehyde, immunolabeled, and then cleared in FocusClear (CelExplorer, Taiwan).

Source: download.cell.com

Stem cells grow to become human neurons“In neurodegenerative disorders, such as Parkinson’s and Huntington’s disease, selective loss of some 500,000 cells in critical brain regions can lead to devastating symptoms,” writes Dr. Ole Isacson, Director of the Neuroregeneration Laboratory at McLean Hospital.Our understanding of regeneration and plasticity in the mammalian nervous system has developed greatly through basic research following implantation of fetal stem or genetically engineered cells into the adult brain. While the adult brain previously was thought of as a non-regenerative system for pathway formation, recent studies show how dissociated primordial neurons and stem cells implanted into the adult central nervous system can grow to reconnect neuronal pathways and integrate in a molecular and physiological fashion.Neurodegenerative diseases have very few effective treatments, which is why the laboratory’s research team is working towards a new understanding of these diseases by studying the regenerative properties of stem cells.
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Stem cells grow to become human neurons

“In neurodegenerative disorders, such as Parkinson’s and Huntington’s disease, selective loss of some 500,000 cells in critical brain regions can lead to devastating symptoms,” writes Dr. Ole Isacson, Director of the Neuroregeneration Laboratory at McLean Hospital.

Our understanding of regeneration and plasticity in the mammalian nervous system has developed greatly through basic research following implantation of fetal stem or genetically engineered cells into the adult brain. While the adult brain previously was thought of as a non-regenerative system for pathway formation, recent studies show how dissociated primordial neurons and stem cells implanted into the adult central nervous system can grow to reconnect neuronal pathways and integrate in a molecular and physiological fashion.

Neurodegenerative diseases have very few effective treatments, which is why the laboratory’s research team is working towards a new understanding of these diseases by studying the regenerative properties of stem cells.

Source: mclean.harvard.edu

Scientists probe the source of a pulsing signal in the sleeping brain New findings clarify where and how the brain’s “slow waves” originate. These rhythmic signal pulses, which sweep through the brain during deep sleep at the rate of about one cycle per second, are assumed to play a role in processes such as consolidation of memory. For the first time, researchers have shown conclusively that slow waves start in the cerebral cortex, the part of the brain responsible for cognitive functions. They also found that such a wave can be set in motion by a tiny cluster of neurons. “The brain is a rhythm machine, producing all kinds of rhythms all the time,” says Prof. Arthur Konnerth of the Technische Universitaet Muenchen (TUM). “These are clocks that help to keep many parts of the brain on the same page.” One such timekeeper produces the so-called slow waves of deep sleep, which are thought to be involved in transmuting fragments of a day’s experience and learning into lasting memory. They can be observed in very early stages of development, and they may be disrupted in diseases such as Alzheimer’s. Previous studies, relying mainly on electrical measurements, have lacked the spatial resolution to map the initiation and propagation of slow waves precisely. But using light, Konnerth’s Munich-based team – in collaboration with researchers at Stanford and the University of Mainz – could both stimulate slow waves and observe them in unprecedented detail. One key result confirmed that the slow waves originate only in the cortex, ruling out other long-standing hypotheses. “The second major finding,” Konnerth says, “was that out of the billions of cells in the brain, it takes not more than a local cluster of fifty to one hundred neurons in a deep layer of the cortex, called layer 5, to make a wave that extends over the entire brain.” New light on a fundamental neural mechanism Despite considerable investigation of the brain’s slow waves, definitive answers about the underlying circuit mechanism have remained elusive. Where is the pacemaker for this rhythm? Where do the waves start, and where do they stop? This study – based on optical probing of intact brains of live mice under anesthesia – now provides the basis for a detailed, comprehensive view. “We implemented an optogenetic approach combined with optical detection of neuronal activity to explore causal features of these slow oscillations, or Up-Down state transitions, that represent the dominating network rhythm in sleep,” explains Prof. Albrecht Stroh of the Johannes Gutenberg University Mainz. Optogenetics is a novel technique that enabled the researchers to insert light-sensitive channels into specific kinds of neurons, to make them responsive to light stimulation. This allowed for selective and spatially defined stimulation of small numbers of cortical and thalamic neurons. Access to the brain via optical fibers allowed for both microscopic recording and direct stimulation of neurons. Flashes of light near the mouse’s eyes were also used to stimulate neurons in the visual cortex. By recording the flux of calcium ions, a chemical signal that can serve as a more spatially precise readout of the electric activity, the researchers made the slow waves visible. They also correlated optical recordings with more conventional electrical measurements. As a result, it was possible to watch individual wave fronts spread – like ripples from a rock thrown into a quiet lake – first through the cortex and then through other brain structures. A new picture begins to emerge: Not only is it possible for a tiny local cluster of neurons to initiate a slow wave that will spread far and wide, recruiting multiple regions of the brain into a single event – this appears to be typical. “In spontaneous conditions,” Konnerth says, “as it happens with you and me and everyone else every night in deep sleep, every part of the cortex can be an initiation site.” Furthermore, a surprisingly simple communication protocol can be seen in the slow wave rhythm. During each one-second cycle a single neuron cluster sends its signal and all others are silenced, as if they are taking turns bathing the brain in fragments of experience or learning, building blocks of memory. The researchers view these findings as a step toward a better understanding of learning and memory formation, a topic Konnerth’s group is investigating with funding from the European Research Council. They also are testing how the slow waves behave during disease.
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Scientists probe the source of a pulsing signal in the sleeping brain

New findings clarify where and how the brain’s “slow waves” originate. These rhythmic signal pulses, which sweep through the brain during deep sleep at the rate of about one cycle per second, are assumed to play a role in processes such as consolidation of memory. For the first time, researchers have shown conclusively that slow waves start in the cerebral cortex, the part of the brain responsible for cognitive functions. They also found that such a wave can be set in motion by a tiny cluster of neurons.

“The brain is a rhythm machine, producing all kinds of rhythms all the time,” says Prof. Arthur Konnerth of the Technische Universitaet Muenchen (TUM). “These are clocks that help to keep many parts of the brain on the same page.” One such timekeeper produces the so-called slow waves of deep sleep, which are thought to be involved in transmuting fragments of a day’s experience and learning into lasting memory. They can be observed in very early stages of development, and they may be disrupted in diseases such as Alzheimer’s.

Previous studies, relying mainly on electrical measurements, have lacked the spatial resolution to map the initiation and propagation of slow waves precisely. But using light, Konnerth’s Munich-based team – in collaboration with researchers at Stanford and the University of Mainz – could both stimulate slow waves and observe them in unprecedented detail. One key result confirmed that the slow waves originate only in the cortex, ruling out other long-standing hypotheses. “The second major finding,” Konnerth says, “was that out of the billions of cells in the brain, it takes not more than a local cluster of fifty to one hundred neurons in a deep layer of the cortex, called layer 5, to make a wave that extends over the entire brain.”

New light on a fundamental neural mechanism

Despite considerable investigation of the brain’s slow waves, definitive answers about the underlying circuit mechanism have remained elusive. Where is the pacemaker for this rhythm? Where do the waves start, and where do they stop? This study – based on optical probing of intact brains of live mice under anesthesia – now provides the basis for a detailed, comprehensive view.

“We implemented an optogenetic approach combined with optical detection of neuronal activity to explore causal features of these slow oscillations, or Up-Down state transitions, that represent the dominating network rhythm in sleep,” explains Prof. Albrecht Stroh of the Johannes Gutenberg University Mainz. Optogenetics is a novel technique that enabled the researchers to insert light-sensitive channels into specific kinds of neurons, to make them responsive to light stimulation. This allowed for selective and spatially defined stimulation of small numbers of cortical and thalamic neurons.

Access to the brain via optical fibers allowed for both microscopic recording and direct stimulation of neurons. Flashes of light near the mouse’s eyes were also used to stimulate neurons in the visual cortex. By recording the flux of calcium ions, a chemical signal that can serve as a more spatially precise readout of the electric activity, the researchers made the slow waves visible. They also correlated optical recordings with more conventional electrical measurements. As a result, it was possible to watch individual wave fronts spread – like ripples from a rock thrown into a quiet lake – first through the cortex and then through other brain structures.

A new picture begins to emerge: Not only is it possible for a tiny local cluster of neurons to initiate a slow wave that will spread far and wide, recruiting multiple regions of the brain into a single event – this appears to be typical. “In spontaneous conditions,” Konnerth says, “as it happens with you and me and everyone else every night in deep sleep, every part of the cortex can be an initiation site.” Furthermore, a surprisingly simple communication protocol can be seen in the slow wave rhythm. During each one-second cycle a single neuron cluster sends its signal and all others are silenced, as if they are taking turns bathing the brain in fragments of experience or learning, building blocks of memory. The researchers view these findings as a step toward a better understanding of learning and memory formation, a topic Konnerth’s group is investigating with funding from the European Research Council. They also are testing how the slow waves behave during disease.