Lately I’ve been looking at HA and how its development and course may be altered by psychological stress, but I’ve already written about that in a term paper, so instead I’m going to write a bit about HA and energy deficiency. As suggested, the menstrual cycle often stops in the face of severe energy deficit, or as a result of strenuous exercise. Not surprisingly, the condition is seen from time to time in female athletes. Many, but not all cases of HA have hypoestrogenemia as a symptom. Estrogen is produced by the ovaries in a cyclic manner under stimulation by gonadotropic hormones arising from the pituitary gland. When this stimulation ceases, estrogen production drops off. This is an undesirable state of affairs for a number of reasons, among them osteopenia and osteoporosis, not to mention the inability to conceive.

So if HA is caused by nutritional deficit, we might guess that some of the hormonal signals that the body uses to communicate energy balance might also be used by the reproductive system for the same reason. It turns out that this is a very good guess. In the paper I am covering today, the authors took women suffering from HA and assigned them to receive either recombinant leptin or a placebo. After the treatment period elapsed, 7 out of 10 women had seen their menstruation return, compared to just 2 out of 9 for the placebo group. There was also an increase is estrogen and progesterone among leptin treated women. There was not, on the other hand, any chance in bone mineral density did not improve significantly over the treatment period, though perhaps the 36 week observation period was not long enough to detect these differences.

This treatment offers an interesting proof of concept for the use of metabolic hormones in the treatment of female reproductive dysfunction. Leptin treatment is not the perfect therapy. To begin with, it has to be injected (peptide hormones like leptin and insulin are destroyed by digestion, precluding oral administration). It also carries the risk of causing weight loss and loss of fat mass. It also doesn’t seem to help bone restoration, which is a notoriously tricky thing for any treatment to do (it’s enough, perhaps, to simply halt decay). Under normal conditions, leptin is interpreted by the brain as a signal of adequate fat stores, leading to a decrease in food intake. Applying exogenous leptin may also trigger these mechanisms, leading to unnecessary and potentially unhealthy weight loss (remember, women with HA are often underweight to begin with). Likely the optimal treatment for HA will comprise psychological interventions to deal with the stress related problems and maladaptive coping that may give rise to HA. Similarly, replacement of estrogen with oral contraceptives may also form a useful adjunct. But these more complicated therapies would likely require more sensitive and larger-scale study, and papers like this are a necessary prerequisite.

Chou SH, Chamberland JP, Liu X, Matarese G, Gao C, Stefanakis R, Brinkoetter MT, Gong H, Arampatzi K, & Mantzoros CS (2011). Leptin is an effective treatment for hypothalamic amenorrhea. Proceedings of the National Academy of Sciences of the United States of America, 108 (16), 6585-90 PMID: 21464293

I have missed you! I have missed the constant stream of awesome science! I have missed SFN and its craziness! A lot of missing is happening folks. Now that we are back, we are trying to digest the insurmountable amount of information that was dumped on us and trying to integrate some awesome ideas into our research. As I mentioned in our Daily Diaries’ that we attended quite a number of lectures, and from these lectures we have been oh so inspired! So for a couple of upcoming posts we will be using these lectures as a foundation of the blog posts.

Leptin. The hormone that was thought to be the answer to obesity when it was discovered via ob/ob mice in 1994 by Jeffrey Friedman’s lab. Characterized by studying a mouse model that had a recessive genetic obesity, called the ob/ob mice which were sterile mice which over 50% body fat (Google Image ob/ob mice, you know how we feel about being trouble for using someone else’s picture)Leptin has put researchers, clinicians and pharmaceutical companies through the ringer since its discovery. Initially touted as being the be all end all of controlling obesity, due to it decreasing body weight & increasing energy expenditure, it was soon realized that it was not as simple as that (more on leptin and obesity in another post).

Leptin, predominately synthesized by your adipose tissue (fat cells), is central to the regulation of energy intake, energy utilization, & metabolism (pretty much everything relates to it). When humans are in a neutral energy balance (basically that the number of calories consumed are just enough to satisfy their metabolic needs) the levels of leptin expression and secretion is representative the amount of body fat mass. Leptin levels are elevated in humans days after over eating, and are decreased in hours after fasting is initiated.

It’s important to note that leptin receptors are widely expressed not only in the periphery of the body but also the brain, making it difficult to study specific regions.

Dr. Martin Myers, from the University of Michigan, talk largely covered a paper, which he and his group have recently published in Cell Metabolism. I am gonna give you lovelies, a brief (very brief) snippet of the paper. Through a series of elegant experiments they haves specifically looked at leptin receptors expressed in the lateral hypothalamus which contain neurotensin (LepRbNts), a neuropeptide that interacts with the dopaminergic system. These neurons are activated by leptin and are part of network that is connected to a population of orexin (also known as hypocretin, are implicated in wakefulness, food intake and energy expenditure) neurons and the ventral tegmental area (VTA, we will look into the wonderful world of the VTA in another post). The researchers found that these neurons are regulating orexin expression and the activity of these neurons. This suggests that LepRbNts neurons may be involved in the physiologic leptin action of the orexin neurons.

They generated a strain of mice that were without leptin receptors on the neurons that expressed neurotensin (Nts-LepRbKO) this resulted in the mice exhibiting early-onset obese phenotype, increased feeding and decreased locomotor activity. This strain revealed to have altered regulation of the orexin neurons and the mesolimbic dopamine system. Their overall take home message, is that there are important roles in which leptin action ‘s on LepRbNts neurons in relation to controlling energy balance and neurophysiology.

If you even have a remote interest in leptin, energy metabolism, interesting methods, or just really really pretty pictures, I highly recommend checking the paper out. It is published in Cell Metabolism, which may make it difficult to get, however hustle your librarians, supervisors, fellow bloggers, nerdy friends and if all else fails, shoot as an email and we will hook you up;)

coughsuperstarcough → Dr.Myers portfolio

Leinninger GM, Opland DM, Jo YH, Faouzi M, Christensen L, Cappellucci LA, Rhodes CJ, Gnegy ME, Becker JB, Pothos EN, Seasholtz AF, Thompson RC, & Myers MG Jr (2011). Leptin action via neurotensin neurons controls orexin, the mesolimbic dopamine system and energy balance. Cell metabolism, 14 (3), 313-23 PMID: 21907138

Epigenetics is a very interesting field, though for whatever reason, some find it unapproachable and intimidating. This could be due to the fact that the field is just so darn inclusive. If you dissect the etymology of the word, you see the prefix epi- which simply means “above” or “upon” and -genetics, which means, well genetics. So in the broadest sense, epigenetics concerns things that relate to genetics (in practice: how genes are expressed) that exist over and above the genetics themselves. Since the field is so broad, and constitutes yet another layer of molecular complexity on top of our already confusing genetic code, it may seem difficult to apprehend.

Your genes are, after all, fixed at conception. But clearly that is not the entire story, as gene expression is regulated in a tissue dependent fashion (your liver expresses liver genes, your brain expresses brain genes, etc., in spite of the fact that each of them possesses a nucleus containing the same DNA). Gene expression is also regulated by experiential factors. Environmental factors during development, or even in adult life can affect the expression of genes in a long-term fashion. What’s interesting, from the point of view of scientists studying these phenomena, is that the changes tend to last much longer than the initial stimulation (whatever it was). So the question we’re dealing with is the following: what types of molecular changes underlie these long-term effects, and how do they relate to illnesses we face?

Researchers from the Mt. Sinai School of Medicine in NY discussed this topic in a minisymposium. Mental illness is an important topic for epigenetic studies, since often times the most challenging illnesses persist for long periods, perhaps indefinitely. It is possible, then, that epigenetic factors are involved in this persistence. The series of studies here took an interesting approach by focusing on models of depression that only affected female animals (this is a topic that Rim is quite interested in, but I’m blogging about it, so too bad for her). This is a very sensible approach, since depression is actually more common in females (though I dislike making sweeping generalizations, this does seem to hold up). In this model, mice were subjected to various mild stressors given at various, unpredictable times during the day. This treatment induced behaviors reminiscent of depression and anxiety in female, but not male mice.

After this treatment they found that stressed females showed an upregulation of two proteins involved in “stamping in” epigenetic marks in DNA. These proteins (one is an enzyme, the other a DNA binding protein) are crucial in DNA methylation, a type of epigenetic mark that involves attaching methyl groups to the points on the DNA thereby reducing transcription of nearby genes. To further cement this case, the authors used various techniques to artificially upregulate these methylation related genes, thereby mimicking the effects they saw in the stressed animals. Indeed, this manipulation actually made males more like females in their response to stress. On the other hand, blocking these seemed to have anti-depressent effects in females. The implication of all this, I suppose, is that since methylation is presumably being increased, genes that are protective against stress induced depression are being silenced, leading to the depressed phenotype.

What’s interesting about this study is that it addresses the very important issue of sex differences in mental illness. Well actually sex differences exist in practically everything, and more should be made of it. But since mental illnesses are particularly sexually dimorphic, studies that bring sex into the picture should hopefully be getting more and more common.

Day 5 of the epic SFN 11. Harry took a well deserved day to actually “see” Washington beyond 7th Street and Independence Ave. He hit up the Aquarium and the Natural History Museum. I on the other had could not bring my self to miss two talks that I just had to go to.

The first one was The Molecular Dissection of Leptin by Dr. Martin Myers. Oft. There are just so many things that were right about this talk I don’t know where to begin or how to do it justice. The best I can do is actually right up an overview post of leptin and review some of his papers. Such a clean, crisp, story teller of a presenter.

The second lecture I attended was the Neurobiology of Mood by Huda Akil. This combined what I love (mental disorders) with something I dislike (genetics:P). Her presentation style was straightforward and clear. I felt like I was getting alot of information but in such a systematic way that it all made sense.

Walking away from the Walter E Convention Center with the sky pouring rain, I felt both a sense of relief and sadness. We will update you guys about our experience, about attending the conference for the first time, getting to blog/tweet about it, and experiencing D.C.

Will update you as soon as we get back home.
Stay nerdfabulous,
Rim

I hope you guys finished up day 4 of SFN feeling gooooooood! I spent the morning presenting my research on the poster floor:) after knocking down one of the presentation boards and giggling uncontrollably for half an hour:P

During my poster presentation I met some amazing people, people who I read their work and want to marry their brains. One of them was Caroline Escobar. Yes THAT Caroline Escobar. She was NOTHING like I would have expected! Petite, gorgeous, gracious, funny and kind. Legit. She gave me tips on how to improve the study from everything in methodology to how to present my graphs:) It was Awesome:) I was in love:p

After the poster presentation I had rush to women’s luncheon, which was nice:) it’s inspiring to hear the stories, triumphs and tribulations of these insanely talented ladies!

I headed back to check out the posters, and hustled some exhibitors (I’m looking at you JOVE:p)

I finally had the opportunity to check out National Geographic!

How was your day 4?

As always, stay nerd fabulous lovers,
Rim

One of the big questions here concerns what the downstream effects of this procedure might be? In a talk I saw today, Min and company presented a new model to study this treatment. To do this, they implanted electrodes in the pig subthalamic nucleus, and scanned their brains using a specialized functional MRI machine. They found that electrical stimulation resulted in increases in activity in the motor and premotor cortical areas, as well as the basal ganglia and cerebellum. The idea here, I think, is that while this form of stimulation is of therapeutic value, how it works is somewhat mysterious. By working with this pig based model, we can hopefully determine how it works in humans.

In other SfN related news, I spent some time jumping on the various structures outside the conference centre. I think Rim posted a video on the youtube.

1) In the morning I made my way to the Special Lecture Rapid Synaptic Actions of Estrogens by Dr. Catherine Wooley. This was one of my favourite talks so far. Terrific research of course, and she’s such a cool chill person. I wish she was there at the Perils of Sex differences symposium;)

2) In the late morning I attended the Special Lecture, Protein Synthesis and Degradation at Synapses by Dr. Erin Schuman. Again, great talk but it made me feel that I need to brush up on my protein education

3) In the afternoon, I attended the Symposium Genetically Driven Manipulation of Hypothalamic Circuitry Controlling Behavior. The panel included, Anderson, Sternson, Elmquist, Saper, & Elias. I missed the first talk but out of the ones that I did see, I really really enjoyed the talk by Elmquist and the one by Saper.

After taking some time to eat, get caffeinated I headed over with Harry to #sfnBANTER, a meet up for the neuroscientists that are tweeting and blogging. It was organized by the lovely @doc_becca . It was so surreal to meet people, who we both read,dissect and aspire to be:) It was such a relief to discover how nice they were! As relatively new bloggers and blogging for SFN, we both understand that there are expectations for us to reach within the blogging community. However, we found that the people we met were nothing short of welcoming and sweet. We did spot some bloggers/tweeters that we knew who they were, but neither one of us had the guts to approach them and say hello..

What?
We are both total chickens.
Don’t judge.

But, we did meet some superstars, so a shout out to our now blog homies

Our gorgeous host Doc_Becca http://scientopia.org/blogs/drbecca/
The incomparable & hilarous Scicurious http://scientopia.org/blogs/scicurious/
The beautiful social butterfly Braininteresting http://www.brainteresting.org
The charming gentleman ThatBS http://www.thatsbasicscience.blogspot.com/

It was such a pleasure meeting them! GROUP HUG!

Stay neruolicious loves,
Rim

Title :
Lithium Ameliorates Neurodegeneration, Suppresses Neuroinflammation and Improved Behavioral Performance in a Mouse Model of Tramatic Brain Injury

Authors:
Fengshan Yu, Flaubert Tchantchou, Chi-tso Chiu, Yumin Zhang, De-Maw Chaung

The poster highlighted Traumatic Brain Injury (TBI) was amongst the leading causes of mortality in developing countries, with no FDA approved pharmaceutical treatment that is currently available. The researchers were investigating the neuroprotective effects of lithium on mouse models of TBI.

NOTE: Tramatic Brain Injuries are those that result from the head suddenly making impact with a heavy object, or when the head is hit with something that causes the skull to collapse inwards.

After inducing TBI via Controlled Cortical Impact (CCI) in their mouse model, the researcher then administered doses of Lithium 15 minutes after the TBI and continued to administer a daily injection for two weeks.

NOTE: Lithium is a drug that is used to treat bi-polar disorder, it has been shown to have robust neuroprotective effects in animal models. It is hypothesized that it works through glycogen synthase kinase- 3 (GSK-3)

The authors found that Lithium treatment significantly reduced tissue damage and hippocampal (dentate gyrus specifically) neurodegeneration after TBI.
Lithium was found to also suppress neuroinflammation and improved functional outcomes (via beam walk performance task). Finally, neuroprotective effects of lithium are likely mediated through GSK-3 inhibition.

This poster has defiantly inspired future blog posts outlining TBI’s, Lithium treatments and the methods used:)

Hope that those who are at SFN are loving it as much as we are, and those who are at home, I hope our blog posts are making you feel as if you are here with us!!

Stay nerdfabulous.
Rim

The first set of talks I attended was The Promise and Peril of Research of Sex Differences, the panel included Lise Eliot,Larry Cahill,Melissa Hines, Janet Hyde, and Maryjane Warga. One word that I would use to summarize it would be interesting. The speakers came from diverse fields, some were not members of SFN. While the presentations seemed overall emphasize the lack of a gender gap, save for Dr. Cahill’s talk, I found something was lacking. Individually all the members were naturally very well versed in their area of expertise. However as a researcher who is studying sex differences I found that I was disagreeing with a lot of what was being said. Needless to say during the question period things got a bit heated up with regards to whether or not sex differences were “relevant” enough to study. Overall it was a fascinating experience.

Right after that I hit up the poster sessions, saw some pretty cool stuff at the optiogenetics section, and met Michael Lehman who I will blog about after SFN:)

I discovered that I have no patience or time to go through the exhibitors for information or swag.. I did get a squishy brain though and an I love brains tote from the lovely people at protientech

Day 3 has already been crazy. Stay tuned for more updates!

Talk to y’all soon,
Rim

Today I found a really cool poster called “Medial Temporal Lobe Atrophy in People with Type 2 Diabetes: A Possible Early Biomarkers for Alzheimer’s Disease”. I stopped by a little late and must have missed the presenting author. But it was a great poster all the same. So it seems that what they did was gather age-matched participants who were either from a population of healthy controls, or individuals diagnosed with Type 2 Diabetes (T2DM). Using structural MRI, they were able to show that individuals with T2DM had reductions in the size of their hippocampus and entorhinal cortex (on the right side of their brain only), and reduced perirhinal cortex on both sides. I’m not sure what to make of the asymmetry, though looking at their data, it’s probably just a matter of statistical power, since both left and right sides look quite low compared to their respective controls. Interestingly, they also found a negative correlation between glycated hemoglobin (a marker of persistent hyperglycemia) and hippocampal volume on both sides of the brain.

Because I’m a metabolic person, I found this a really interesting study. There’s good reason to think, based on these findings, that something about T2DM and the metabolic syndrome negatively affects brain morphology. It could be that the syndrome itself does not affect the brain volume, perhaps the lifestyle variables that lead to diabetes are themselves causing the problems. As the authors suggest, a larger and more comprehensive study is needed to further explore these findings. This also brings up the issue of early intervention. It’s possible that these reductions in size could be the first signs of impending Alzheimer’s Disease (or some other type of neurodegenerative disorder, for that matter), so if they are indeed caused by diabetes early intervention would be essential.

In other conference related news: the exhibitors and vendors opened up today. I experienced transcranial magnetic stimulation (in a very mild form – they got my finger to twitch and I saw some visual artifacts), failed miserably at putting a golf ball, and secured enough free pens to last an entire year, even with my horrible track record for losing them.