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.

 

Stereo Investigator Helps Harvard Scientists Study Social Isolation’s Effects on the Brain

Some children raised in orphanages grow up to develop social disorders, and there’s not all that much modern medicine can do about it. But scientists at Harvard Medical School are working on gaining a better understanding of how early isolation affects a developing brain. Their research gives new insight into the mechanisms at play, and indicates that timing and healthy myelination are crucial.

“Social isolation from P21 to P35 alters [medial Prefrontal Cortex] oligodendrocyte morphology, myelination, and mPFC-mediated behaviors,” the authors say in their paper, published in Science. “These effects persist even when isolated mice are re-exposed to social interactions, which suggests a link between the quality of mPFC myelination established during the juvenile period and adult behaviors.”

Led by Dr. Manabu Makinodan, the research team studied three groups of male mice. At 21-days-old, the mice were caged according to different scenarios: isolated environment (alone),  regular environment (with three other mice), or enriched environment (with seven other mice and a selection of toys). Four weeks later, testing showed deficits in social behavior and memory in the isolated mice.

To determine what went wrong in the brains of the isolated mice, the researchers examined the oligodendrocyte neurons in the prefrontal cortex, a brain region integral to social behavior. They determined that the density of oligodendrocytes was the same in all three groups, by using Stereo Investigator with the optical disector to perform a stereological count. Although density was consistent, the morphology of oligodendrocytes in the brains of the isolated mice was remarkably different. These mice displayed a simpler morphology that included “shorter processes, less branching, and fewer internodes.” Their myelin sheaths were thinner, resulting in decreased signaling between neurons and altered information processing.

Further trials showed that mice isolated later in life, after 35 days of age, showed the same morphology as normally reared mice, indicating that the critical period for development is before 35 days. They also noticed that mice isolated from 21 days, and which were later returned to normal environments, still showed abnormal morphology, implying that the detrimental effects of isolation could not be reversed.

“Our findings indicate that the effects of childhood isolation and neglect on adult mental health might be caused, at least in part, by alterations in oligodendrocytes and myelin development. Furthermore, we provide a cellular and/or molecular context and genetic models in which to begin to understand the effects of juvenile social experience on brain development in general and myelin maturation in particular. Our results also may be relevant to neuropsychiatric disorders such as schizophrenia and mood disorders” (Makinodan, et al, 2012).

Access the paper “A Critical Period for Social Experience–Dependent Oligodendrocyte Maturation and Myelination” at ScienceMag.org.

Manabu Makinodan, Kenneth M. Rosen, Susumu Ito, and Gabriel Corfas. “A Critical Period for Social Experience–Dependent Oligodendrocyte Maturation and Myelination.” Science, 2012; 337 (6100): 1357-1360 DOI: 10.1126/science.1220845

Image of Oligodendrocyte courtesy of Harvard Medical School.