English articles, Neurotransmisores, Videos y enseñanza.

¿Qué sucede en nuestro cerebro cuando nos sentimos mal? Una colaboración con Ted-Ed.

El día de hoy compartimos una colaboración con Ted-Ed en donde hablamos de los cambios que sufre el cerebro cuando estamos enfermos, en breve se agregarán subtítulos en español.

“It starts with a tickle in your throat that becomes a cough. Your muscles begin to ache, you grow irritable, and you lose your appetite. It’s official: you’ve got the flu. It’s logical to assume that this miserable medley of symptoms is the result of the infection coursing through your body — but is that really the case? Marco A. Sotomayor explains what’s actually making you feel sick.

Lesson by Marco A. Sotomayor, animation by Henrik Malmgren.”

 

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English articles, Neurotransmisores, Videos y enseñanza.

GABA and your brain’s “off”button

Continuing with neurotransmitters now we review the main inhibitory neurotransmitter, gamma amino butiric acid a.k.a. GABA, we check out it’s physiology and pharmacology.

Want to know more about other neurotransmitters? Check this out: The King of Neurotransmitters: Glutamate

English articles, Noticias y artículos

New Frontiers in Depression

Depression is a terrible disease, according to the WHO approximately 350 million people from all ages has to live with it, it is the leading cause of disability worldwide and in severe cases it leads to suicide.

Despite the advances in the field and the availability of a range of antidepressants, still a number of patients have refractory depression, this can partly be explained due to our lack of a complete understanding of this disease, however new research into brain-immune communication could be the key we were missing.

We have all experienced the torment caused by an infection, we feel terrible, everything aches and hurts us, we are cranky, downhearted, we’re never hungry and we are really sleepy, but why do we feel like this? And what does it has to do with depression?

When something activates our immune system, like an infection, as a part of the response a group of glycoproteins called cytokines are released, these affect all of the cells around them in different ways, they can increase the activity of other immune cells to increase their capacity to phagocytize and destroy harmful agents, they can also prepare other cells to endure damage, secrete hormones and now we know they also change the way our brain works.

So to alter brain function cytokines must reach it first, but as we have reviewed in prior posts the blood-brain barrier is a problem for anything in the periphery that might need to do something in the brain, so to surpass this cytokines have 4 main routes to reach the brain:

  1. Citokines activate the vagus nerve, which sends the signal through the solitary tract nucleus in the medulla oblongata, modifying the activity of this area.
  2. The circumventricular organs (area postrema, subfornical organ, organum vasculosum laminae terminalis, choroid plexus) lack a traditional blood-brain barrier, allowing them to sense citokines and respond releasing cytokines to the brain.
  3. The blood-brain barrier has specialized transporters to some cytokines, which allows them to pass a certain quantity.
  4. A number of brain venules present a large number of macrophages and endothelial cells which upon cytokine activation secrete an other transmitter called prostaglandin E towards the brain.

This signals allow the brain to create an image of the immune’s system activity so it generates an adequate response, all of the manifestations that ensue are calles sickness behavior, that includes a heightened pain perception, fatigue, hypersomnia, lack of appetite, irritability and of great importance anhedonia, anxiety and depression.

When Smith in the 90s saw these manifestations, he proposed the “macrophage theory of depression”, he also found that depressed patients had an increased level of inflammatory markers (acute phase proteins) along with an increase in the hypothalamus-hypophysis-adrenal gland axis.

Other experiments supported this view, for example patients that received IL-2 or INF α, inflammatory mediators used in the treatment of hepatitis C and melanoma, developed major depressive disorder, the pretreatment with an antidepressant like paroxetine prevented the depressive effect of these mediators.

The mechanism through which inflammation generates the sickness behavior is still elusive, however a number of mechanisms seem to play a role. When macrophages in the periphery, or microglial cells in the brain are activated with cytokines they avidly take tryptophan and metabolize it to a compound named kynurenine, this process has 2 important outcomes, firstly there is a tryptophan depletion and since it is serotonin’s precursor this important neurotransmitter is also depleted, on the other hand kynurenine by itself can block the activity or release of other neurotransmitters like glutamate and dopamine.

Other proposed mechanisms are the hypothalamus-hypophysis-adrenal hyperactivity with the consequent excess of CRH and glucocorticoids, which are known to cause depression and even psicosis.

Inflammation can also inactivate tetrahydrobipterin, an essential cofactor in the synthesis of serotonin, melatonin, dopamine, noradrenaline and nitric oxide.

The discoveries in this field of the neurosciences has important repercussions, for example in the treatment of depression that is refractory to current therapy, for example in patients with depression accompanied with high inflammatory markers in blood, the addition of aspirin or a COX 2 inhibitor like celecoxib can lead to an important recovery, the use of antibodies that block cytokines has also shown promise, drugs like etanercept can also help alleviate depression in a subset of patients.

The research in neuro-immune interactions has shown a lot of promise in a number of pathologies and depression could be next, offering hope to patients with severe refractory depression, and maybe later even diseases like anxiety, schizophrenia and autism, that we will cover in further articles.

 

OMS depresión: http://www.who.int/mediacentre/factsheets/fs369/en/

Dantzer, R., Connor, J. C. O., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2010). NIH Public Access, 9(1), 46–56. http://doi.org/10.1038/nrn2297.From

Smith RS. The macrophage theory of depression. Med Hypotheses 1991;35:298–306. [PubMed: 1943879]

Berk, M., Dean, O., Drexhage, H., McNeil, J. J., Moylan, S., O’Neil, A., … Maes, M. (2013). Aspirin: a review of its neurobiological properties and therapeutic potential for mental illness. BMC Medicine, 11(1), 74. http://doi.org/10.1186/1741-7015-11-74

Muller N, et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry 2006;11:680–684. [PubMed: 16491133]

Tyring S, et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet 2006;367:29–35. [PubMed: 16399150]

English articles

The origin of intelligence, is it acquired or is it inherited?

Academic

The origin of intelligence has been a historical debate, is it acquired or is it inherited? Let us just think about the Bohr family. Christian Bohr was a successful physician in Edinburgh, his son, Niehls Bohr, was a Nobel Laureate in Physics, and his grandson, Aage Bohr also won a Nobel Prize in Physics. So, here is the question: Was geniality printed in their genes or did they live in an enriching environment that facilitated their academic achievements?

Nowadays it is hard to deny that academic achievement has become a major goal in society; indeed, academic achievement has been associated to better health, life expectancy and career success. And, as with intelligence, academic achievement appears to depend, at least partially, on the subject’s genetics.

On the other hand, the role of a common environment (family, income, school, educational system, etc) is more difficult to explain. It is an everyday observation that children in the same school, even in the same classroom exhibit higher, or lower, performance that their peers.

An article addressing this question of genetic versus environmental influences on academic achievement has been recently published by a research group from King’s College London (United Kingdom). This large study investigated the academic outcomes of more than 12,000 twins that took their GCSE* (General certificate of Secondary Education – an important test performed at age 16) and analyzed if these outcomes were more related to inheritance or environment.

The results were interesting. The heritability had a correlation of around 54 to 65% with the GCSE outcomes, while environment only had one of 14 to 21%. Heritability had an even greater impact on intelligence, with a correlation of 56%. On the contrary, environment factors were only 5% correlated.

But here is a problem: twins are often raised in the same environment, so to eliminate this factor, the researchers also used a new technique called GCTA (Genome-Wide Complex Trait Analysis). The GCTA is a genetic tool that enables us to study the effect of genetic influence of unrelated individuals**. In this case in academic performance. After the exclusion of 1 out of every twin, a correlation between the genetic similarity of unrelated individuals and the academic performance was addressed again. The new results supported the previous findings in wins, even using the new GCTA technique, a genetic correlation was found in both intelligence and academic achievement in unrelated individuals.

So, it might appear as if all is lost and that our genes will always write our destiny, but do not despair. The researchers explain that the negligible effect of environment may be due to the highly standardized curriculum in the United Kingdom, a country with a strongly centralized educational system. In other studies the effect of environment, health, family, educational system, etc. have proven to be more important when compared with the present study.

Sinapsis MX

* The GCSE evaluates different academic subjects such as mathematics, science, English, art, humanities and second language learning.
** GCTA search for thousands of single nucleotide polymorphisms (SNPs) to calculate the phenotypic variance.

Reference:
Rimfeld K, Kovas Y, Dale PS, Plomin R. Pleiotropy across academic subjects at the end of compulsory education. Sci Rep. 2015 Jul 23;5:11713. doi: 10.1038/srep11713.

English articles

Different synaptic properties of GABAergic neurons integrated into the Olfactory Bulb during adulthood.

olfac
Neuronal regeneration occurs naturally in a few restricted mammalian brain regions, but its functional significance remains debated. The vast majority of adult-generated interneurons in the Olfactory Bulb become granule cells. Interestingly, there are several physiological differences between immature granular cells and those that have matured and are stably integrated within the circuit. In fact, previous work has shown that the recruitment of synaptic inputs onto new granular cells occurs soon after they arrive in the Olfactory Bulb. However, little is known about the functional differences between granular cells born at different periods in the animal’s life.
In this study, the synaptic properties of adult-born granule cell interneurons integrated in the mouse olfactory bulb were assessed by optogenetically targeting newborn granule cells at different stages of its maturation. The authors found that the dendrodendritic interactions that adult-born interneurons establish whit resident mitral cells lack metabotropic GABAergic modulation. This is in contrast with the well-established presynaptic GABAB-mediated depression of GABA release observed in the dendrodendritic communication between mitral neurons and granule cells born just after birth. The lack of metabotropic GABAergic modulation of dendrodendritic interactions between mitral neurons and adult-born granule cells, correlates with the extrasynaptic localization of GABAB receptors in adult-born granule cells. These results indicate that adult neurogenesis produces a population of functionally unique GABAergic synapses in the olfactory bulb, suggesting that these newcomers may perform different computations to those similar neurons already residing in the circuit.
José María Cornejo Montes de Oca
Reference:
Valley M, Henderson L, Inverso S, Lledo, P. (2013). Adult neurogenesis produces neurons with unique GABAergic synapses in the olfactory bulb. The Journal of Neuroscience, 33(37):14660–14665.
English articles

Understanding sensory-motor circuits, the hierarchical level of the cerebral cortex.

cort

In a recent study, Suter and Sheperd identify many shared features in the circuits of primary motor (M1) and secondary somatosensory (S2) cortices and show that these areas communicate via mutual projections that give each area monosynaptic access to the other one. These interareally corticoespinal (CSPs) neuron circuits may enable M1 and S2 to operate in a coordinated manner for sensorimotor integration.

M1 and S2 cortices, although anatomically and functionally distinct, share an intriguing cellular component: corticospinal neurons in layer 5B. Their functions are diverse and complex, with M1 generally involved in movement-related functions and S2 in higher-order somatosensory processing. But how these areas fit into the corticocortical hierarchy? One intriguing possibility is that, whereas M2–>M1 and S1–>M1 projections follow feedback (“top-down”) and feed forward (“bottom-up”) patterns, respectively, the bidirectional connections between M1 and S2 may be reciprocally organized, implying a shared hierarchical level.

The authors explored these issues by adapting photostimulation-based tools combined with retrograde and anterograde tracers to characterize the reciprocal interareal excitatory inputs to CSPs in mouse M1 and S2. They focused on the lateral agranular region of M1containing the forelimb representation area, and the corresponding forelimb area within S2. These methods allowed them to analyze monosynaptic inputs from long-range axonal projections at cellular and subcellular (dendritic) resolution.  They found that the mutual connections S2–>M1-CSP and M1–>S2-CSP closely resemble one another, albeit with several area-specific differences. Thus, the circuits of M1 and S2 are not only organized in parallel but are synaptically linked through interareal connections that directly innervate CSPs in each area.

These results may be relevant to the concept of a “sensorimotor interface” in cortical networks involved in sensory perception, decision-making, and motor control which suggests that the ability to make decisions occurs at the sensory-motor interface. Sensory responses are often observed in M1 neurons and may depend on S2 in particular. Indeed, in a recent study in the rat, the S2–>M1 projection was proposed to subdivide M1 into sensory-input and motor-output areas. The converse possibility, that M1–>S2 projections endow S2 with “motor” properties, has not been functionally assessed but would be consistent with the M1–>S2 projections reported by Suter and Shepherd.

Rafael Olivares Moreno

Reference:
Benjamin A. Suter and Gordon M.G. Shepherd. Reciprocal Interareal Connections to Corticospinal Neurons in Mouse M1 and S2.X The Journal of Neuroscience. 2015  doi: 10.1523/JNEUROSCI.4287-14.2015

English articles

The cancer therapeutic implications of the Warburg effect.

TumorMetabolome

Whereas normal human cells use a process named mitochondrial oxidative phosphorylation (MOP) to generate energy from glucose, some unicellular organisms (eg: microbes) use a different process called anaerobic glycolysis to reproduce as quickly as possible when nutrients are available.

The Nobel laureate, Otto Warburg, noticed in 1924 that cancer cells metabolize glucose in a different way to cells in normal tissues. Cancer cells tend to ferment glucose into lactate (even in the presence of sufficient oxygen to support MOP) using aerobic glycolysis as their principal metabolism pathway, a process similar to the one used by microbes; today we know this type of metabolism as Warburg effect.
In fact, nowadays, we know that a generalized property of primary and metastatic cancers is upregulation from glycolysis, resulting in increased glucose consumption (even 200 fold higher than a normal cell).

Why do cancer cells use aerobic glycolysis to produce energy? Some researchers explain that this type of metabolism is used because the tumor environment lacks sufficient oxygen to support the uncontrolled proliferation and high-metabolism rate of malignant cells; others hypothesize that cancer cells develop a defect in mitochondria that leads to impaired aerobic respiration. However, recent investigations showed that mitochondria are not impaired in most cancer cells and that even in presence of oxygen, the Warburg’s effect takes place. A third hypothesis is that proliferating cells prefer aerobic glycolysis because this process generates critical molecules to support cell growth and division (eg: carbon and nitrogen).

The metabolic dependencies of cancer-cells can be used for the development of cancer treatments that target the Warburg effect. Recently a research article, published in Cancer Cell, showed that a newly-developed drug can stop cancer-cell growth in animal models and human cancer-cells in vitro. The new drug, named SR9243, suppresses abnormal glucose consumption (Warburg effect) and cuts off energy supply driven by lipogenesis. SR9243 acts by disrupting the function of the liver-X-receptor (a master protein that regulates the expression of glycolytic and lipogenic genes).

This is not the first drug developed against the Warburg’s effect, but the previous ones had poor toxicity-profile with a broad collection of side-effects. SR9243 selectively induces destruction of cancer cells and spares non-malignant tissues. It also offers a better safety profile without over-toxicity effects. All of this makes SR9243 a significant promise to be used in human clinical trials in the future.

Alfredo Manzano


References:
i) Gatenby RA, Gilles RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004; 4(11):891-9.
ii) Vander-Helen MG, et al. Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation. Science. 2009; 324(5930): 1029-1033.
Free article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849637/
iii) Flaveny CA, et al. Broad Anti-tumor Activity of a Small Molecule that Selectively Targets the Warburg Effect and Lipogenesis. Cancer Cell. 2015.

English articles

Low carb diets. Useful as autoimmune disease treatment?

Inflammation is an immune physiological process that usually helps to control infections as well as in the subsequent repair of the affected tissue. Inflammasomes are multiproteic complexes expressed by the innate immune system cells whose activation induces the release of proinflammatory substances as interleukin-1.

These multiproteic complexes are clinically-important because some autoimmune diseases express an increase in the activity of the inflammasomes. Therefore, the downregulation of inflammasomes could be of help in the treatment of such diseases.

It has been recently published in Nature Medicine that a subtype of inflammasome named NL3P is inhibited by a ketone: hydroxybutyrate. But, when is this ketone produced in physiological conditions? In a healthy adult these ketones are produced in some states of energy deficit such as intense aerobic exercise, fasting, with caloric restriction diets and with low carb diets (for example, the popular: Atkins diet®). In an interesting series of experiments (in vitro and in vivo), the research team in the USA showed  that fasting and low carb diets produce a reduction of inflammation in various animal models of autoimmune diseases.

Maybe the title of this article was a little ambitious, but in fact the ketogenic diets will probably be part of the treatment for autoimmune diseases in the near future. Besides, it has also been recently shown that these are the best diets for losing weight (JAMA, 2015).

Alfredo Manzano MD.


References:
Youm YH, Nguyen KY, et al. The ketone metabolite β-hydroxybutyrate blocks NLP3 inflammasome-mediated inflammatory disease. Nat Med. 2015; 21(3):263-9.

Johnston BC, Kanters S. Comparison of weight loss among named diet programs in overweight and obese adults: a meta-analysis. JAMA. 2014;312(9): 923-33.

Dolor, English articles

Can bacteria cause pain?

What is the cause of the pain produced during an infection? Until now it was thought that it is originated by the inflammatory response triggered by immune-derived substances such as cytokines, prostaglandins and growth factors. However, in a recent study published in Nature, researchers from Harvard University found that some peptides in bacteria can directly activate nociceptors therefore producing pain, without requiring the activation of the immune system. Furthermore, they found that neuropeptides released by nociceptors produce a direct immunomodulatory response.

In a first set of experiments the authors caused an infection on the hindpaws of mice (by local inoculation of the bacteria S.aureus) and then assessed the mechanically and thermally-induced pain. They found that the pain intensity is directly correlated to the bacterial load, but not with swelling or the quantity of immune cells and cytokines present in the site of infection. Using genetically-modified mice, this group also found that the pain caused by the bacterial load was not produced through the activation of the immune system by S. aureus.

In order to elucidate which bacterial elements were causing pain, the activity of nociceptive cells of the dorsal root ganglion (DRG) was measured using an electrophysiology technique (patch-clamp) and calcium imaging. The research team found that two bacterial products (N-formylated peptides and pore-forming toxin) produce higher levels of electrical activity and an increase in calcium influx in DRG nociceptive neurons.

Finally this group studied the role of nociceptors in modulating the immune response. They used genetically-modified mice that have a total lack of nociceptors. After S.aureus infection these mice displayed increased tissue swelling and a greater local infiltration of neutrophils relative to control littermates; which suggests that the nociceptor ablation leads to an increased local inflammatory response.

In summary this research team postulates that the direct activation of nociceptors by bacterial products could be the principal mechanism leading to pain; such finding is relevant since could improve the current treatments for painful infections. Moreover, the discovery of the down regulation in the local inflammatory response mediated by nociceptor activation is remarkable since this mechanism could be used by some pain-producing bacteria to increase their virulence.

Reference:
Bacteria activate sensory neurons that modulate pain and inflammation.
Chiu IM, Heesters BA, Ghasemlou N, Von Hehn CA, Zhao F, Tran J, Waigner B, Strominger A, Muralidharan S, Horswill AR, Bubeck Wardenburg J, Hwang SW, Carroll MC, Woolf CJ.
Nature. 2013 Sep 5; 501(7465):52-7. doi:10.1038/nature12479. Epub 2013 Aug 21.