Stereological Study Reveals Neuron and Glia Proliferation in Hippocampus of Lithium-Treated Mice

Dentate gyruspilot

The optical fractionator probe was used to quantify the number of neurons and glia in the dentate gyrus

Doctors have used lithium to treat patients with bipolar disorder since the 1970s. Known for its efficacy in stabilizing patients’ moods by regulating manic episodes, lithium is also associated with a decreased risk of suicide. But while this naturally occurring element is the most widely prescribed medication for those suffering from bipolar disorder, scientists still have much to learn about how lithium physically affects the brain.

A recent study published in the journal Bipolar Disorders adds to the growing body of evidence that says lithium contributes to cell proliferation in parts of the brain. Conducted by scientists at the University of Mississippi and the VU University Medical Center in Amsterdam, the study revealed an increased number of neurons and glia, and increased astrocyte density in the dentate gyrus of lithium-treated mice versus controls treated with a placebo.

Using the optical fractionator probe in Stereo Investigator, the researchers quantified the number of Nissl stained neurons and glial cells, and calculated astrocyte density. The results showed twenty-five percent more neurons and twenty-one percent more glia in the denate gyrus of lithium-treated mice. They also performed a stereological examination of another brain region – the medial prefrontal cortex (mPFC), but did not witness significant differences between lithium-treated and control mice in this area.

“In this study, particular cortical regions, ie. the fascia dentata in the hippocampus and the mPFC in the cerebral cortex needed to be selected in histological sections of the mice brains,” explained Dr. Harry B.M. Uylings, “therefore the stereological counting procedure applied was the best one. Stereo Investigator greatly assisted in the counting of cells, and the software’s excel data-output was especially beneficial.”

According to the paper, the findings present a more detailed picture of lithium-induced alterations in the dentate gyrus cellular phenotype than previously available, and provide the first evidence for lithium-induced increases in glia and astrocytes.

The authors also explain that while cell number increased in the dentate gyrus of lithium-treated mice, the region’s overall volume as well as that of the greater hippocampus was unaffected by the element. The volume of the dentate gyrus and the hippocampus as a whole was measured with the Cavalieri method in Stereo Investigator.  The researchers describe the dissociation between cell proliferation and volume as “an interesting observation that warrants further investigation.”

Rajkowska, G., Clarke, G., Mahajan, G., Licht, C.M., van de Werd, H.J., Yuan, P., Stockmeier, C.A., Maji, H.K., Uylings, H.B., Differential effect of lithium on cell number in the hippocampus and prefrontal cortex in adult mice: a stereological study. Bipolar Disord. 2016 Feb;18(1):41-51. doi: 10.1111/bdi.12364.

Genetic Mutation Accelerates CTE Pathology

Phosphorylated tau pS422 immunoreactive profiles in the cortex of P301Smice after repetitive mild TBI. Image courtesy of Dr. Leyan Xu.

Phosphorylated tau pS422 immunoreactive profiles (dark brown) in the cortex of P301S mice after repetitive mild TBI. Image courtesy of Dr. Leyan Xu, Department of Pathology, Johns Hopkins University.

Over the course of a football game or a boxing match, athletes may experience a series of mild concussions. Some of these athletes develop a condition known as chronic traumatic encephalopathy (CTE), a neurodegenerative disease characterized by the build-up of abnormal tau protein that eventually leads to dementia. But not every athlete develops CTE after repetitive mild traumatic brain injury, and scientists think genetic factors are involved.

In a recent study, researchers at the Johns Hopkins University School of Medicine found that the density of abnormal tau protein increased exponentially in mice that had a genetic mutation thought to cause neurodegenerative diseases. Their findings contrast with previous studies of mice without genetic mutation, where abnormal tau protein build-up did not occur. This evidence leads the scientists to infer that genetic factors play a role in the onset of CTE.

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New Neurons Erase Memories

Dentate gyrus

Neurogenesis occurs in the dentate gyrus, pictured here, from birth through adulthood.

A baby laughs at an elephant at the zoo. A toddler runs across a beach. Small children make memories all the time, but how many will they recall as the years pass? Maybe none at all. The phenomenon is called “infantile amnesia,” and scientists may have pinpointed a reason for why it occurs – neurogenesis.

Researchers at the Hospital for Sick Children in Toronto say that when new brain cells integrate into existing circuitry, they remodel the structure of networks already in place, wiping out the information previously stored there. This process is prevalent in infancy and early childhood because this is the time when new brain cells are being generated faster and more frequently than at any other time in a human being’s life. Humans and other mammals spawn new neurons throughout their lifespans, although the rate of neurogenesis decreases significantly with age.

In their paper, published in Science, the researchers explain how recent studies have focused on how new brain cells can lead to new memories, but the Toronto team speculated that neurogenesis could also wipe away memories. To test their hypothesis, they conducted a series of studies on populations of newborn and adult mice. Neuron development in mice occurs in much the same way as in humans, with rapid cell genesis in infancy that tapers off with age.

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Scientists Use Stereo Investigator in Spinal Cord Injury Study

Stereo Investigator Graphic

After an initial spinal cord injury, a cascading series of secondary events continues to do damage to the nervous system. One particularly damaging event is the death of oligodendrocytes—neuroglial cells that help protect and support the central nervous system. Scientists are learning more about the mechanisms involved in this process in the hope that their research may lead to the development of new therapeutic treatments for stopping some of the secondary damage before it occurs.

Researchers at the Miami Project to Cure Paralysis previously found that astrocytes play a role in oligodendrocyte death after spinal cord injury, but they weren’t quite sure how. Their new study identifies a culprit – an enzyme called NADPH oxidase. According to their paper, published in PLOS One, astrocytes activate NADPH oxidase within oligodendrocytes after an injury, triggering a toxic effect in the tiny neural cells.

In their study, the researchers set out to see what would happen if they could prevent post-trauma NADPH oxidase activation. Their results proved promising, with both in vitro and in vivo experiments resulting in lower oligodendrocyte death.

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Scientists Map Photoreceptor Cells of Deep-Sea Sharks

Topographic mapping of photoreceptor cells. a Scleral eyecup with the retina uppermost, where peripheral slits have been made to allow flattening. The retina is then carefully removed from the sclera, freed of the underlying choroidal tapetum lucidum and wholemounted onto a non-subbed slide. Scale bar = 1 cm. b Screen shot taken from Stereo Investigator showing the green inclusion line and the red exclusion line overlaid on the rod photoreceptor array, viewed here on the axial plane. Colors are visible online only. Scale bar = 10 μm. c Optic nerve head as seen under a light microscope. Note the fascicles or bundles of ganglion cell axons converging on the optic nerve head. Scale bar = 200 μm.

a. Topographic mapping of photoreceptor cells. a Scleral eyecup with the retina uppermost, where peripheral slits have been made to allow flattening. The retina is then carefully removed from the sclera, freed of the underlying choroidal tapetum lucidum and wholemounted onto a non-subbed slide. Scale bar = 1 cm. b. Screen shot taken from Stereo Investigator showing the green inclusion line and the red exclusion line overlaid on the rod photoreceptor array, viewed here on the axial plane. Colors are visible online only. Scale bar = 10 μm. c. Optic nerve head as seen under a light microscope. Note the fascicles or bundles of ganglion cell axons converging on the optic nerve head. Scale bar = 200 μm.

The deepest parts of the ocean are dark. For marine animals living one thousand feet below sea level and lower, the absence of light makes it challenging to find food, attract a mate, and identify predators.

Some animals make their own light through a process called bioluminescence. Others have adapted in ways that help them detect light in an environment beyond the reach of the sun’s rays.

In the first stereological study of the eyes of deep sea sharks, scientists in Queensland, Australia quantified photoreceptor cell populations and mapped their topography in the retina of five different species of deep sea sharks.

The sharks, including the Borneo catshark, the longsnout dogfish, the prickly dogfish, the beige catshark, and McMillan’s catshark, were caught in the nets of deep-sea fishermen off the coast of New Zealand. Each type of shark featured large, round pupils and a tapetum lucidum, a reflective structure at the back of the eye – two common adaptations deep-sea animals use to enhance sensitivity in environments where bioluminescence is the only available light source, according to the paper.

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Exercise Heals the Brain After Binge Drinking

The granule cell layer of the dentate gyrus captured using a 100x objective. Image provided by Mark Maynard.

The granule cell layer of the dentate gyrus. Image provided by Mark Maynard.

Binge drinking damages brain regions responsible for memory, decision-making, and behavioral control. After a binge, the brain begins to heal itself but not much is known about this self-repair process. In a study published in PLoS ONE, researchers used rats to find that binge drinking damages the hippocampus, and exercise reverses this damage.

The study found that excessive ethanol killed granule neurons in the dentate gyrus (DG), a part of the hippocampus, and significantly decreased the volume of the DG. Rats that exercised after binging had more DG granule neurons and a larger DG than rats that did not exercise after a binge. In fact, rats that exercised after binging had a similar number of DG neurons and a similar DG volume to that of controls, indicating that exercise almost fully reversed damaged to the DG caused by binge drinking.

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Researchers from Quebec Delay Symptoms of Huntington’s Disease in Mouse Model

Neuron_with_mHtt_inclusionA montage of three images of single striatal neurons transfected with a disease-associated version of huntingtin, the protein that causes Huntington’s disease; By: Dr. Steven Finkbeiner, Gladstone Institute of Neurological Disease, The Taube-Koret Center for Huntington’s Disease Research, and the University of California San Francisco; licensed under the Creative Commons Attribution 3.0 Unported license.

Patients with Huntington’s disease deteriorate physically, cognitively, and emotionally. There is no cure for the inherited illness, but scientists may have found a way to slow down the onset of symptoms. Researchers in Quebec increased the expression of a molecule known as pre-enkephalin (pENK) in a mouse model of Huntington’s disease (HD) and saw promising results.

Since reduced expression of pENK is a hallmark of the disease, and neurons containing this molecule are some of the first cells to die in the brains of HD patients, the researchers hypothesized that an HD brain over-expressing pENK might have beneficial results. Their study offers the first evidence that increased pENK expression leads to a delay in muscle dysfunction, improved motor activity, memory, and lower anxiety in early-onset HD. Continue reading “Researchers from Quebec Delay Symptoms of Huntington’s Disease in Mouse Model” »

Hawaii Scientists Measure Density of Parvalbumin-Interneurons With Stereo Investigator

Reduced density of PV-interneurons in Sepp1-/- mice. (A) Representative images showing PV expression in the hippocampus (left column) and inferior colliculus (middle and right columns) of WT Sepp1+/+ (top row) and Sepp1-/- (bottom row) mice. Higher magnification images of the inferior colliculus (far right) (B), Mean density of PV-interneurons per mm3 (+-SEM, n=6 per genotype) in brain regions investigated: SC; MS; DG, CA1, and CA2/3 of the hippocampus; IC. * P<0.01. Figure courtesy of Matthew W. Pitts, Ph.D.

Reduced density of PV-interneurons in Sepp1-/- mice. (A) Representative images showing PV expression in the hippocampus (left column) and inferior colliculus (middle and right columns) of WT Sepp1+/+ (top row) and Sepp1-/- (bottom row) mice. Higher magnification images of the inferior colliculus (far right) (B), Mean density of PV-interneurons per mm3 (+-SEM, n=6 per genotype) in brain regions investigated: SC; MS; DG, CA1, and CA2/3 of the hippocampus; IC. * P<0.01. Figure courtesy of Matthew W. Pitts, Ph.D.

Foods like tuna fish and Brazil nuts are rich in selenium, a mineral that scientists say has antioxidant effects, keeping the brain healthy and free of clutter so cells can work smoothly together. A key element of this process is Selenoprotein P (Sepp1) – a protein that delivers selenium to neurons by binding with another protein – ApoER2. Neuroscientists at the University of Hawaii say Sepp1 plays a critical role in brain function, and deficits may play a part in mental illnesses like schizophrenia.

In their study published in Neuroscience, the researchers investigate the relationship between Sepp1 and parvalbumin (PV)-interneurons – a class of brain cell that controls firing rates and synchronizes spiking activity among other groups of neurons. Previous research shows that these cells need selenium to develop properly, so the scientists set out to find out what affect a Sepp1 deficit would have on the mouse brain.

Led by Dr. Matthew W. Pitts, the research team compared the brains of wild type mice with Sepp1 deficient mice. They used a Zeiss Axioskop microscope equipped with Stereo Investigator to conduct a stereological analysis of PV-interneurons in several different regions of the mouse brain. Using Stereo Investigator’s optical fractionator probe, they observed reduced numbers of PV-interneurons along with elevated oxidative stress in the inferior colliculus of Sepp1 deficient mice, a region involved in processing auditory information.

“Stereo Investigator was particularly useful for estimating cell density in larger brain structures, such as the inferior colliculus,” said Dr. Pitts.

Since scientists speculate that dysfunctional PV-interneuron networks may be involved in neuropsychiatric conditions, the researchers conducted behavioral tests that showed impairments in contextual fear extinction, latent inhibition, and sensorimotor gating in the Sepp1 deficient mice – behaviors observed in some mental illnesses.

“Previous studies (Valentine et al., 2008) and our findings together indicate that ApoER2- mediated uptake of Sepp1 serves an important neuroprotective role in the inferior colliculus,” the authors say in their paper. “These findings may have relevance to neuropsychiatric conditions in which dysfunc- tional PV-interneuron networks have been implicated, such as epilepsy and schizophrenia.”

Pitts M.W., Raman A.V., Hashimoto A.C., Todorovic C., Nichols R.A., Berry M.J. Deletion of selenoprotein P results in impaired function of parvalbumin interneurons and alterations in fear learning and sensorimotor gating. Neuroscience. 2012 Apr 19;208:58-68. doi: 10.1016/j.neuroscience.2012.02.017.

 

New Zealand Scientists Use Stereo Investigator to Develop a New Model for Human Extreme Prematurity

675px-Oligodendrocyte

Oligodendrocytes, pictured here with a green fluorescent protein, form a myelin sheath – the insulation around axons. The extremely premature brain features a lower number of pre-oligodendrocytes, thereby decreasing myelination, a characteristic which has been associated with ADHD. Image courtesy of Wikimedia Commons.

Each year, nearly ninety thousand children are born extremely premature in the United States – that is, before 28 weeks gestation. Most of them survive, but about half the survivors suffer from severe health problems throughout their childhood and into adulthood, including learning and behavioral disorders such as ADHD.

“Treatment options are clearly urgently required to prevent the brain damage and associated memory deficits that follow extremely premature birth,” say the authors of a study published last month in the Journal of Neuroscience.

Treatment options are limited, the authors say, because current small animal models fall short in their mimicry of the extremely premature human brain. However, the researchers from the University of Otago in New Zealand have come up with a new animal model for human extreme prematurity, which they say more closely resembles the pathological and behavioral deficits seen among this population.

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Stereo Investigator Helps Scientists Assess Damage in Rat Model of Ischemic Stroke

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A stroke patient is rushed to the hospital. Deprived of oxygen-rich blood, brain cells have already died, and more damage will probably occur in the hours and days to come. But researchers at the University of South Florida and the University of Padova in Italy say a two-part package administered through the body, rather than directly into the brain, may be the key to staving off some of the cell death that takes place after a stroke.

In their study, published in the Journal of Enzyme Inhibition and Medicinal Chemistry, the scientists saw a smaller region of damage in a rat model of focal cerebral ischemia, when the rats were treated with a combination of an anesthetic and a Caspase-3 inhibitor – a drug that suppresses a protein involved in brain cell death.

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