Dentate Gyrus

Green tea is thought to have wide-ranging health benefits, especially in the prevention of cardiovascular disease, inflammatory diseases, and diabetes. These are all implicated in the development of age-related cognitive impairment, so it’s no surprise that regular drinking of green tea has been suggested as one way to help protect against age-related cognitive decline and dementia. A new mouse study adds to that evidence by showing how a particular compound in green tea promotes neurogenesis.

The chemical EGCG, (epigallocatechin-3 gallate) is a known anti-oxidant, but this study shows that it also has a specific benefit in increasing the production of neural progenitor cells. Like stem cells, these progenitor cells can become different types of cell.

Mice treated with EGCG displayed better object recognition and spatial memory than control mice, and this improved performance was associated with the number of progenitor cells in the dentate gyrus and increased activity in the sonic hedgehog signaling pathway (confirming the importance of this pathway in adult neurogenesis in the hippocampus).

The findings add to evidence that green tea may help protect against cognitive impairment and dementia.

Like us, guinea pigs can’t make vitamin C, but must obtain it from their diet. This makes them a good model for examining the effects of vitamin C deficiency.

In a recent study looking specifically at the effects of prenatal vitamin C deficiency, 80 pregnant guinea pigs were fed a diet that was either high or low in vitamin C. Subsequently, 157 of the newborn pups were randomly allocated to either a low or high vitamin C diet (after weaning), creating four conditions: high/high (controls); high/low (postnatal depletion); low/high (postnatal repletion); low/low (pre/postnatal deficiency). Only males experienced the high/low condition (postnatal depletion).

Only the postnatal depletion group showed any effect on body weight; no group showed an effect on brain weight.

Nevertheless, although the brain as a whole grew normally, those who had experienced a prenatal vitamin C deficiency showed a significantly smaller hippocampus (about 10-15% smaller). This reduction was not reversed by later repletion.

This reduction appeared to be related to a significant reduction in the migration of new neurons into the dentate gyrus. There was no difference in the creation or survival of new neurons in the hippocampus.

This finding suggests that marginal deficiency in vitamin C during pregnancy (a not uncommon occurrence) may have long-term effects on offspring.

Interpreting brain activity is a very tricky business. Even the most basic difference can be interpreted in two ways — i.e., what does it mean if a region is more active in one group of people compared to another? A new study not only indicates a new therapeutic approach to amnestic mild cognitive impairment, but also demonstrates the folly of assuming that greater activity is good.

Higher activity in the dentate gyrus/CA3 region of the hippocampus is often seen in disorders associated with an increased Alzheimer's risk, such as aMCI. It’s been thought, reasonably enough, that this might reflect compensatory activity, as the brain recruits extra resources in the face of memory loss. But rodent studies have suggested an alternative interpretation: that the increased activity might itself be part of the problem.

Following on from animal studies, this new study has investigated the effects of a drug that reduces hippocampal hyperactivity. The drug, levetiracetam, is used to treat epilepsy. The 17 patients with aMCI (average age 73) were given a placebo in the first two-week treatment phase and a low dose of the epilepsy drug during the second treatment phase, while 17 controls (average age 69) were given a placebo in both treatment phases. The treatments were separated by four weeks, and brain scans were given at the end of each phase. Participants carried out a cognitive task designed to assess memory errors attributable to a dysfunction in the dentate gyrus/CA3 region (note that these neighboring areas are not clearly demarcated from each other, and so are best analyzed as one).

As predicted, those with aMCI showed greater activity in this region, and treatment with the drug significantly reduced that activity. The drug treatment also significantly improved their performance on the three-choice recognition task, with a significant decrease in memory errors. It did not have a significant effect on general cognition or memory (as measured by delayed recall on the Verbal Paired Associates subtest of the Wechsler Memory Scale, the Benton Visual Retention Test, and the Buschke Selective Reminding Test).

These findings make it clear that the excess activity in the hippocampus is not compensatory, and also point to the therapeutic value of targeting this hyperactivity for those with aMCI. It also raises the possibility that other conditions might benefit from this approach. For example, those who carry the Alzheimer’s gene, APOE4, also show increased hippocampal activity.

Quarter of British children performing poorly due to family disadvantage

A British study involving over 18,000 very young children (aged 9 months to 5 years) has found that those exposed to two or more “disadvantages” (28% of the children) were significantly more likely to have impaired intellectual development, expressed in a significantly reduced vocabulary and behavioral problems.

These differences were significant at three, and for the most part tended to widen between ages three or five (cognitive development, hyperactivity, peer problems and prosocial behaviors; the gap didn’t change for emotional problems, and narrowed for conduct problems). However, only the narrowing of the conduct problem gap and the widening of the peer problem gap was statistically significant.

Ten disadvantages were identified: living in overcrowded housing; having a teenage mother; having one or more parents with depression, parent with a physical disability; parent with low basic skills; maternal smoking during pregnancy; excessive alcohol intake; financial stress, unemployment; domestic violence..

Around 41% of the children did not face any of these disadvantages, and 30% faced only one of these disadvantages. Of those facing two or more, half of those (14%) only had two, while 7% of the total group experienced three risk factors, and fewer than 2% had five or more.

There was no dominant combination of risks, but parental depression was the most common factor (19%), followed by parental disability (15%). Violence was present in only 4% of families, and both parents unemployed in only 5.5%. While there was some correlation between various risk factors, these correlations were relatively modest for the most part. The highest correlations were between unemployment and disability; violence and depression; unemployment and overcrowding.

There were ethnic differences in rate: at 48%, Bangladeshi children were most likely to be exposed to multiple disadvantages, followed by Pakistani families (34%), other (including mixed) (33%), black African (31%), black Caribbean (29%), white (28%) and Indian (20%).

There were also differences depending on family income. Among those in the lowest income band (below £10,400 pa) — into which 21% of the families fell, the same proportion as is found nationally — nearly half had at least two risk factors, compared to 27% of those in families above this threshold. Moreover, children in families with multiple risk factors plus low income showed the lowest cognitive development (as measured by vocabulary).

Childhood maltreatment reduces size of hippocampus

In this context, it is interesting to note a recent finding that three key areas of the hippocampus were significantly smaller in adults who had experienced maltreatment in childhood. In this study, brain scans were taken of nearly 200 young adults (18-25), of whom 46% reported no childhood adversity and 16% reported three or more forms of maltreatment. Maltreatment was most commonly physical and verbal abuse from parents, but also included corporal punishment, sexual abuse and witnessing domestic violence.

Reduced volume in specific hippocampus regions (dentate gyrus, cornu ammonis, presubiculum and subiculum) was still evident after such confounding factors as a history of depression or PTSD were taken into account. The findings support the theory that early stress affects the development of subregions in the hippocampus.

While mother’s nurturing grows the hippocampus

Supporting this, another study, involving 92 children aged 7 to 10 who had participated in an earlier study of preschool depression, has found that those children who received a lot of nurturing from their parent (generally mother) developed a larger hippocampus than those who didn’t.

‘Nurturing’ was assessed in a videotaped interaction at the time of the preschool study. In this interaction, the parent performed a task while the child waited for her to finish so they could open an attractive gift. How the parent dealt with this common scenario — the degree to which they helped the child through the stress — was evaluated by independent raters.

Brain scans revealed that children who had been nurtured had a significantly larger hippocampus than those whose mothers were not as nurturing, and (this was the surprising bit), this effect was greater among the healthy, non-depressed children. Among this group, those with a nurturing parent had hippocampi which were on average almost 10% larger than those whose parent had not been as nurturing.

First study:
Sabates, R., Dex, S., Sabates, R., & Dex, S. (2012). Multiple risk factors in young children’s development. CLS Cohort Studies Working paper 2012/1.
Full text available at http://www.cls.ioe.ac.uk/news.aspx?itemid=1661&itemTitle=More+than+one+i...

Second study:
[2741] Teicher MH, Anderson CM, Polcari A. Childhood maltreatment is associated with reduced volume in the hippocampal subfields CA3, dentate gyrus, and subiculum. Proceedings of the National Academy of Sciences [Internet]. 2012 . Available from: http://www.pnas.org/content/early/2012/02/07/1115396109.abstract?sid=f7347fbd-20b6-429c-a0b4-c3d666c460cd
Full text available at http://www.pnas.org/content/early/2012/02/07/1115396109.abstract?sid=f73...

Third study:
[2734] Luby JL, Barch DM, Belden A, Gaffrey MS, Tillman R, Babb C, Nishino T, Suzuki H, Botteron KN. Maternal support in early childhood predicts larger hippocampal volumes at school age. Proceedings of the National Academy of Sciences [Internet]. 2012 . Available from: http://www.pnas.org/content/early/2012/01/24/1118003109

As we get older, when we suffer memory problems, we often laughingly talk about our brain being ‘full up’, with no room for more information. A new study suggests that in some sense (but not the direct one!) that’s true.

To make new memories, we need to recognize that they are new memories. That means we need to be able to distinguish between events, or objects, or people. We need to distinguish between them and representations already in our database.

We are all familiar with the experience of wondering if we’ve done something. Is it that we remember ourselves doing it today, or are we remembering a previous occasion? We go looking for the car in the wrong place because the memory of an earlier occasion has taken precedence over today’s event. As we age, we do get much more of this interference from older memories.

In a new study, the brains of 40 college students and older adults (60-80) were scanned while they viewed pictures of everyday objects and classified them as either "indoor" or "outdoor." Some of the pictures were similar but not identical, and others were very different. It was found that while the hippocampus of young students treated all the similar pictures as new, the hippocampus of older adults had more difficulty with this, requiring much more distinctiveness for a picture to be classified as new.

Later, the participants were presented with completely new pictures to classify, and then, only a few minutes later, shown another set of pictures and asked whether each item was "old," "new" or "similar." Older adults tended to have fewer 'similar' responses and more 'old' responses instead, indicating that they could not distinguish between similar items.

The inability to recognize information as "similar" to something seen recently is associated with “representational rigidity” in two areas of the hippocampus: the dentate gyrus and CA3 region. The brain scans from this study confirm this, and find that this rigidity is associated with changes in the dendrites of neurons in the dentate/CA3 areas, and impaired integrity of the perforant pathway — the main input path into the hippocampus, from the entorhinal cortex. The more degraded the pathway, the less likely the hippocampus is to store similar memories as distinct from old memories.

Apart from helping us understand the mechanisms of age-related cognitive decline, the findings also have implications for the treatment of Alzheimer’s. The hippocampus is one of the first brain regions to be affected by the disease. The researchers plan to conduct clinical trials in early Alzheimer's disease patients to investigate the effect of a drug on hippocampal function and pathway integrity.

Older news items (pre-2010) brought over from the old website

December 2009

Nerve-cell transplants help brain-damaged rats recover lost ability to learn

After destroying neurons in the subiculum of 48 adult rats, some were given hippocampal cells taken from newborn transgenic mice. On spatial memory tests two months later, the rats given cell transplants performed as well as rats which had not had their subiculums damaged; however, those without transplants had significantly impaired performance. The new cells were found to have mainly settled in the dentate gyrus, where they appeared to promote the secretion of two types of growth factors, namely BDNF and basic fibroblast growth factor (bFGF).

Rekha, J. et al. 2009. Transplantation of hippocampal cell lines restore spatial learning in rats with ventral subicular lesions. Behavioral Neuroscience, 123(6), 1197-1217.

http://www.eurekalert.org/pub_releases/2009-12/apa-nth120909.php

January 2009

Baby neurons time-stamp new memories

Since its discovery ten years, adult neurogenesis has been a fruitful area of research, but although we know it’s important for learning and memory, we’re still a little vague on how. Now a new computational model suggests that immature cells are very excitable, easily provoked into firing, while older neurons are more discriminating. The dentate gyrus is designed to separate new memories into separate events (pattern separation), but the indiscriminate excitability of newborn neurons means they link events and memories that happen around the same time (pattern integration) instead. As the brain cells mature, they settle down and join established neural circuits, taking on their proper role, but clusters of neurons that "grew up" around the same time still retain the memories forged in their youth. Which is why independent events that have nothing in common but the fact that they occurred at the same time are connected in our minds: baby neurons have ‘time-stamped’ them.

Aimone, J.B., Wiles, J. & Gage, F.H. 2009. Computational Influence of Adult Neurogenesis on Memory Encoding. Neuron, 61 (2), 187-202.

http://www.the-scientist.com/blog/display/55385/
http://www.eurekalert.org/pub_releases/2009-01/si-nbc012209.php

December 2008

Blood sugar linked to normal cognitive aging

Following research showing that decreasing brain function in the area of the hippocampus called the dentate gyrus is a main contributor of normal age-related cognitive decline, an imaging study has been investigating the cause of this decreasing function by looking at measures that typically change during aging, like rising blood sugar, body mass index, cholesterol and insulin levels. The study of 240 community-based nondemented elders (average age 80 years), of whom 60 had type 2 diabetes, found that decreasing activity in the dentate gyrus only correlated with levels of blood glucose. The same association was also found in aging rhesus monkeys and in mice. The finding suggests that maintaining blood sugar levels, even in the absence of diabetes, could help maintain aspects of cognitive health. It also suggests that one reason why physical exercise benefits memory may be its effect on lowering glucose levels.

Wu, W. et al. 2008. The brain in the age of old: The hippocampal formation is targeted differentially by diseases of late life. Annals of Neurology, 64 (6), 698-706.

http://www.eurekalert.org/pub_releases/2008-12/cumc-rac121508.php

August 2008

New brain cells are essential for learning

It was only a short time ago that it was accepted wisdom that new neurons were only created during childhood and that being an adult meant facing the gradual death, without replacement, of those neurons. Then, nearly a decade ago, it was discovered that adult brains could create new brain cells, albeit in a very limited way. However, it still hasn’t been clear how important adult neurogenesis is for learning and memory. Now a mouse study makes it clear that in one of the two regions in which neurogenesis takes place, it really is necessary. The study is the first to simultaneously study the two brain regions that produce new neurons, the subventricular zone and the dentate gyrus. Continual cell death was observed in the olfactory bulb, suggesting that newly born neurons (from the subventricular zone) are necessary to take their place. Neurons in the dentate gyrus, however, did not die regularly. However, when neurogenesis was knocked out in the olfactory bulb, no deficits occurred in smell memory, while the same action in the dentate gyrus did result in problems with spatial memory. The findings perhaps open up more questions than they answer — such as how odor memory is maintained when neurons in the olfactory bulb are being continuously replaced.

Imayoshi, I. et al. 2008. Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain.  Nature Neuroscience, Published online: 31 August 2008; doi:10.1038/nn.2185

http://www.the-scientist.com/blog/display/54993/
http://www.newscientist.com/channel/being-human/dn14630-new-brain-cells-are-essential-for-learning.html

February 2008

REM sleep deprivation reduces neurogenesis

And in another sleep study, rats deprived of REM sleep for four days showed reduced cell proliferation in the dentate gyrus of the hippocampus, where most adult neurogenesis takes place. The finding indicates that REM sleep is important for brain plasticity.

Guzman-Marin, R. et al. 2008. Rapid Eye Movement Sleep Deprivation Contributes to Reduction of Neurogenesis in the Hippocampal Dentate Gyrus of the Adult Rat. SLEEP, 31(2), 167-175.

http://www.eurekalert.org/pub_releases/2008-02/aaos-fdo012808.php

May 2007

Natural compound and exercise boost memory in mice

The flavanol epicatechin, found in blueberries, tea, grapes, and cocoa, has been found to enhance memory in mice. Moreover, this effect increased when mice also exercised regularly. The combination of exercise and a diet with epicatechin also promoted structural and functional changes in the dentate gyrus.

Praag, H. et al. 2007. Plant-Derived Flavanol (–)Epicatechin Enhances Angiogenesis and Retention of Spatial Memory in Mice. Journal of Neuroscience, 27, 5869-5878.

http://www.eurekalert.org/pub_releases/2007-05/sfn-nca052907.php

October 2005

Wnt signaling vital for adult neurogenesis

Neurogenesis (the birth of new neurons) only occurs in adult brains in two areas: the lateral ventricle, and the dentate gyrus (in the hippocampus). New neurons are spawned from the division of stem cells — but how do they decide whether to remain a stem cell, turn into a neuron, or a support cell (an astrocyte or oligodendrocyte)? A new study has pinpointed the protein that provides a vital chemical signal that helps this decision in the hippocampus. When Wnt3 proteins were blocked in the brains of adult mice, neurogenesis decreased dramatically; when additional Wnt3 was introduced, neurogenesis increased. Wnt3 molecules are secreted by astrocytes.

Lie, D-C., Colamarino, S.A., Song, H-J., Désiré, L., Mira, H., Consiglio, A., Lein, E.S., Jessberger, S., Lansford, H., Dearie, A.R. & Gage, F.H. 2005. Wnt signalling regulates adult hippocampal neurogenesis. Nature, 437, 1370-1375.

http://www.eurekalert.org/pub_releases/2005-10/si-wsc102405.php

July 2004

Social status influences brain structure

A rat study has found that dominant rats have more new nerve cells in the hippocampus than their subordinates, suggesting that social hierarchies can influence brain structure. Seven colonies of 6 rats (4 male and 2 female) established their pecking order within three days, and were tested two weeks later. The dominant males had some 30% more neurons in their dentate gyrus than both the subordinate rats and controls. The increase seems to be because the new cells constantly being born in this area of the brain (most of which usually die within a week) were surviving longer. Hippocampal neurons have already been shown to be responsive to negative factors such as stress, and positive factors such as exercise and environmental enrichment. The increase in neurons was maintained when the rats were removed from the social setting.

Kozorovitskiy, Y. & Gould, E.J. 2004. Dominance Hierarchy Influences Adult Neurogenesis in the Dentate Gyrus. The Journal of Neuroscience,24 (30), 6755-6759.

http://www.nature.com/news/2004/040802/full/040802-18.html

January 2003

More details about how memories are formed in the hippocampus

We know how important the hippocampus is in forming memories, but now, using newly developed imaging techniques, researchers have managed to observe how activity patterns within specific substructures of the hippocampus change during learning. The study identified areas within the hippocampus (the cornu ammonis and the dentate gyrus) as highly active during encoding of face-name pairs. This activity decreased as the associations were learned. A different area of the hippocampus (the subiculum) was active primarily during the retrieval of the face-name associations. Activity in the subiculum also decreased as retrieval became more practiced.

Zeineh, M.M., Engel, S.A., Thompson, P.M. & Bookheimer, S.Y. 2003. Dynamics of the Hippocampus During Encoding and Retrieval of Face-Name Pairs, Science, 299, 577-580.

http://www.eurekalert.org/pub_releases/2003-01/uoc--som012303.php