Cannabis has a long history of use as medicine, with historical evidence dating back more than 4000 years. The potential therapeutic benefits of cannabinoid compounds are huge, but this substance can also have negative effects. A recent paper by Andrés Ozaita and colleagues at the Neurophar laboratory of Rafael Maldonado (CEXS-UPF) has given new insights into the molecular mechanisms that underlie cannabinoid-mediated effects.
Using mice as a model system, the authors had previously shown that blocking the mTOR pathway prevented the amnesic-like effects of THC (a synthetic form of cannabinoid). In the present study, published in the journal Neuropsychopharmacology, they have gone further, proving that the inhibition of the mTOR pathway by the rapamycin derivative temsirolimus, prevents both the anxiogenic- and the amnesic-like effects produced by acute THC, but has no effect on THC-induced anxiolysis, hypothermia, hypolocomotion, and antinociception (lack of pain perception).
Therefore, treatment with temsirolimus could segregate the potentially beneficial effects of cannabinoid agonists, such as the decrease of pain and anxiety, from the negative effects, such as amnesia and an increase of anxiety. As the authors say, these results could help targeting the endocannabinoid system in order to prevent possible side effects.
Puighermanal E, Busquets-Garcia A, Gomis-González M, Marsicano G, Maldonado R, Ozaita A. Dissociation of the Pharmacological Effects of THC by mTOR Blockade. Neuropsychopharmacology. 2013 Jan 28;
Attention-Deficit/Hyperactivity Disorder ADHD involves robust alterations in the cortical cerebral mantle, as shown in a recent article by Òscar Vilarroya and colleagues from the Neuroimaging Research Group at the IMIM-Hospital del Mar. These alterations are most prominent in brain regions involved in attention processing, and are more common in the childhood form of the disorder than in the adult one.
ADHD is a psychiatric and neurobehavioral disorder characterized by either significant difficulties of inattention or hyperactivity and impulsiveness or a combination of the two. Although it was initially regarded as a disorder exclusive to childhood – affecting about 3 to 5 percent of children globally -, nowadays its prevalence in adulthood is well established.
Previous research on children with ADHD has shown a general reduction of brain volume, but with a proportionally greater reduction in the volume of the left-sided prefrontal cortex. The researchers at the IMIM have now used anatomical brain MRI scans to analyse cortical thickness in 41 normal children and 43 children with ADHD, as well as three groups of adult individuals: 31 normal, 31 ADHD patients treated with stimulants and 24 medication-naïve ADHD patients.
The results, published in PLoS One, show several clusters of reduced laminar cortical thickness in ADHD patients in comparison to neurotypical individuals. These differences were primarily located in the dorsal attention network.
Hoekzema E, Carmona S, Ramos-Quiroga JA, Fernández VR, Picado M, Bosch R, Soliva JC, Rovira M, Vives Y, Bulbena A, Tobeña A, Casas M, Vilarroya O. Laminar thickness alterations in the fronto-parietal cortical mantle of patients with attention-deficit/hyperactivity disorder. PLoS One. 2012;7(12):e48286
Several studies have suggested that daily caffeine administration can protect against brain injury in some cases, for example in animal models of neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases, as well as in ischemic and traumatic brain injury, or allergic encephalitis. Olga Valverde’s group at the CEXS-UPF decided to check if it could also have a positive effect on MDMA-induced neuroinflammation.
The recreational drug MDMA, or ecstasy, induces astrocytic and microglial activation in mice striatum, which leads to inflammation and neurotoxicity. They injected caffeine (10, 20, or 30 mg/kg, i.p) for 21 consecutive days into mice, and then on day 22, mice pretreated with caffeine or saline (controls) received a neurotoxic regimen of MDMA (3 × 20 mg/kg, i.p., 2-h interval) or saline. Changes in body temperature were evaluated. Forty-eight hours after the last MDMA or saline injection, behavioral parameters such as locomotor activity, sensorimotor reflexes, and anxiety were investigated and microglia and astroglia activation to MDMA treatment was examined in the mouse striatum.
The results, published in the journal Psychopharmacology, show that consuming regularly low doses of caffeine (10 mg/kg) completely prevented MDMA-induced glial activation without inducing physiological or behavioral alterations in any of the assays performed. Therefore, caffeine can have anti-inflammatory effects on ecstasy-induced neuroinflammation in mice.
Ruiz-Medina J, Pinto-Xavier A, Rodríguez-Arias M, Miñarro J, Valverde O. Influence of chronic caffeine on MDMA-induced behavioral and neuroinflammatory response in mice. Psychopharmacology (Berl). 2012 Nov 29;
This interview was published in the PRBB monthly newspaper, Ellipse.
You can also read an earlier post about his talk here.
Figuring out how the brain works is the obsession of Rodrigo Quian, professor at the University of Leicester (UK). This challenge led him to apply his physics training and a PhD in maths to neuroscience. With the discovery of the “Jennifer Aniston neurone”, or concept cells, it seems we have taken a step towards the understanding of memory.
How can we “see” neurones?
We work on patients with epilepsy requiring hippocampus surgery. As part of this they have electrodes attached to the brain for several hours. This allows us to talk to them and detect how the neurones respond to stimuli we present them with.
Why the Jennifer Aniston neurone?
We did experiments where we showed patients people close to them like relatives and celebrities. The first neurone I found responded to pictures of Jennifer Aniston. It was a shock to discover that somewhere in the brain are neurones that respond in such a specific way to abstract concepts.
Did it only respond to photos?
It responded to various photos of Aniston, images as different in colour and format as we were able to find. The same with her name when written or spoken. Specifically, to the ‘concept’ of Jennifer Aniston. We found neurones that responded to different famous people depending on the person. The only neurones that did not respond were in an autistic patient.
One neurone per concept?
If I could find one neurone that responded to Jennifer Aniston, there must be more because if it was the only one, the probability of me finding it among the thousands of neurones in that area is practically zero. There has to be a network of neurones that encode a concept. These concept cells can quickly generate associations, so there are neurones that respond to two concepts, but they are always related to one another. This is a key mechanism for generating memories. I think they are the building blocks of memory and the link between perception and memory. This is a radically different idea to what was believed until now, that the basis of memory was distributed networks of millions of neurones.
Can you locate complex thoughts like phobias?
Often a complex thought is an association of simple thoughts. My old mentor at Caltech, Christof Koch, said it was necessary to break down the difficult problem of consciousness into related problems that are simpler and easier to attack. The consciousness of self is a very complex thing. One must first understand how the flow of consciousness works. That is, that one thing makes me think about another thing and that about another and so on. This can be studied in the neurones generating associations between two concepts and, from the moment we have made this association, we can see if the neurone also responds to the association and encodes it. In a few tests we have found that these concept cells begin to respond to the association we have created.
What other experiments are you working on?
We want to know if neurone response changes according to the presentation of the stimulus, for example the exposure time to the photos. The results demonstrate that neural response is closely related to the conscious perception of the patient. That is, if the patient believes that he has seen something, then the neurone is activated. In fact, it is even possible to predict beforehand when neurones will be activated and know what image a patient is looking at only from the neurone records.
Coming from the Rockefeller University in NY, Matthieu Louis leads the Sensory Systems and Behaviour group at the CRG, the only lab in Barcelona, and one of the few in Spain, investigating Drosophila neuroscience. His team comprises eight people with backgrounds in molecular biology, engineering and physics. Their aim is to correlate neural circuit function with behaviour using fruit fly larvae. “The Drosophila larva has a repertoire of complex behaviours and key cognitive functions. Yet its nervous system has 10 million neurones fewer than humans”, explains the physicist.
The group tries to understand how odours are encoded by the olfactory system. Features such as quality, “Does this smell like banana?”, and intensity, “Is this a morsel of banana or a bunch?”, are efficiently represented by only 21 olfactory sensory neurones, so that the larva can distinguish between hundreds of food-related odours. The researcher says that there must be a combinatorial code, yet it does not seem to be as trivial as the activation of different combinations of neurones by distinct odours. “We have evidence that the nature and the intensity of an odour is represented not only by the identity of the sensory neurones it activates, but also the way each one is activated”, he explains.
From information processing to chemotaxis
Once a smell has been encoded, it has to be processed. To find the higher-order neurones involved in the integration of olfactory information, the group is undertaking a large behavioural screen. They test thousands of fly lines in which subsets of neurones are inhibited or over-activated. They then characterise how these perturbations affect chemotaxis, the orientation behaviour observed in response to an odour gradient. To decide whether to go straight ahead or turn, the larva monitors information about odour concentration changes. When a wild-type animal detects an intensity increase of an attractive odour, it keeps going forwards, but, as the group has recently described, if the odour intensity decreases the larva reorients through an active-sampling mechanism: much like rats and dogs, the larva sweeps its head laterally to check intensity levels on either side.
With their screen, the researchers are looking for mutants showing reorientation defects. To that end, they have developed their own computer-vision software. “We needed an algorithm to quantify subtle movements of the head and body posture with a high space-time accuracy. As no tool like this existed, we spent a year developing one”, says the head of the group.
“If we understand the neural logic of larval chemotaxis well enough, we should be able to synthetically produce predictable behavioural sequences”. Such a model could be useful for robotics. “Currently, dogs are trained to find mines. We could design robots that navigate spatially, searching for the chemical compounds present in explosives”.
Many questions remain to be answered before this becomes reality. How does the larva integrate a series of stimuli (touch, light, heat, smell) that are received simultaneously before deciding what to do next? And how is sensory input converted into motor output? “There are many challenges ahead. But it is thrilling to witness the genesis of a decision in a minibrain, from elementary spikes in sensory neurones down to the coordinated contraction of dozen of muscles. Flies have much to teach us about the function of our own brain”, concludes the Belgian researcher.
This article was published in the El·lipse publication of the PRBB.
Drug abuse and emotional disorders, such as anxiety and depression, are generating a serious social problem. This is why Rafael Maldonado’s neuropharmacology group at the CEXS-UPF studies the common biological mechanisms involved in these two phenomena. They focus particularly in nicotine, cannabis, cocaine and ecstasy, and in the possible mechanisms underlying the abusive consume of these substances.
Maldonado explains there are three factors to understand why some people become addictive and others don’t: drug consume (the quantity, the frequency, the mode); social and environmental factors; and individual vulnerability, which includes genetic factors. A classical example of the effect of the environment is how the American marines that were heroin addicts in Vietnam quitted easily once back at home.
In order to understand addiction and emotional disorders, the group, formed by 29 people, uses different techniques: classical pharmacological strategies, using compounds that act on the nervous system receptors; ‘knock-out’ mice in which a specific gene has been deleted in order to understand its function; and animal models for behaviour studies which, according to Maldonado, are very complex but once they are established they allow a good prediction of what can happen in humans.
Maldonado highlights the discovery that specific components of the endogenous opioid system are a common substrate for different addictive behaviours as a major contribution of his group. His dream: that this knowledge gives rise to effective treatments for the addicts, who are people with a chronic disease, emphasizes the researcher.
This article was published in the El·lipse publication of the PRBB.
The New Cajal Era
More than 100 years have passed after the first contributions made by Santiago Ramón y Cajal to the neural network theory. Nowadays neuroscientists take advantage of innovative tools to study neural circuits in order to understand complex behaviours.
This image by David D’Amico, from the group on neurobehavioral phenotyping of mouse models of disease at the CRG, shows the hippocampus of a transgenic mouse expressing yellow fluorescent protein (YFP) in specific subsets of central neurons. This type of tansgenic mice help scientists to understand neural networks in both physiological and pathological conditions.
An interview published in Ellipse, the monthly magazine of the PRBB.
Philippe Grandjean, Adjunct Professor of Environmental Health at Harvard University, delivered a lecture in Barcelona invited by Jordi Sunyer, from the CREAL, a ‘model institution’ according to Grandjean. Sunyer introduced the talk about what the Danish-born scientist calls a ‘silent pandemic’: the effect of chemical pollutants on neurodevelopment.
To what extent do in utero conditions affect adult health?
There are several studies that show that exposing pregnant women to mercury can affect the development of their children, even if they are not affected themselves. Minamata disease, a neurological syndrome caused in children whose mothers suffer severe mercury exposure, was discovered in Japan in the 1950s, and was a shock to the world. Since then many other studies have demonstrated the effect of mercury exposure on foetal development. However, it wasn’t until 2009 that an international agreement was reached to control mercury emissions into the environment!
How many pollutants can be neurotoxic during early development?
There are about 100,000 chemicals in the world. About 200 have been documented as being neurotoxic to adult humans, and only five to foetuses: lead, mercury, PCBs (polychlorinated biphenyls), arsenic and toluene. However, the foetal brain is much more sensitive than the adult one! So I think we are only seeing the tip of the iceberg. For example, many pesticides can be neurotoxic to humans, as the nervous system of the insects that the pesticides attack is very similar to ours. For example, we did a study in Ecuador on pregnant women working in flower plantations, who were exposed to pesticides. Their children at school age presented a delay of up to two years in their brain development.
Are these effects irreversible?
The brain has great plasticity, so one might think that with enough effort we could get kids with lower cognitive abilities to catch up with the rest. But the problem is for this plasticity to occur your neurones must be in the right place. You cannot develop your full potential if you don’t have the correct anatomical foundation and if your nerve cells and connections are abnormal.
And does mercury exposure cause anatomical problems in the brain?
Normally we have no way of checking, but with Minamata disease, quite a few of the children died, and when they were examined at autopsy it was seen that their brain cells appeared in a disrupted pattern, as if their migration during brain development had been affected. So yes, we think so.
If they are so dangerous, why are these pollutants not banned?
The problem is that chemicals are not banned unless it’s proven that they are dangerous. But then it’s too late! I think we need to move towards the opposite strategy: a chemical should be banned unless it is proven not to be dangerous to brain development. Prevention should come before science. After all, we have only once chance to develop a brain.
No, we don’t mean to say that Rachel from “Friends” has only one nerve cell… This was the title of the talk Rodrigo Quian Quiroga, from the University of Leicester, gave at the PRBB a couple of weeks ago. This physicist did a PhD in maths and then turned to neuroscience, something that fascinates him. “I can see you. Isn’t this amazing?”, he said to start the talk. As the Chilean researcher said, we can all remember and have emotions. How do neurons do that? This is what Quian Quiroga has been trying to understand for the last 10 years, and he was invited by the Pasqual Maragall Foundation (FPM) to the PRBB to tell us about his latest research into a particular type of neurons at the hippocampus, which he calls ‘concept cells’.
He discovered them by doing single cell recordings in epilepsy patients who were subject to surgery to remove a specific area of the hippocampus. During 1 or 2h, the researcher had time to do some tests, with the patient awake. He showed them hundreds of unrelated pictures, and checked if the sight of these images was activating some neurons. In a specific patient, he found a neuron that fired every time the patient saw an image of Jennifer Aniston. Also, it wasn’t a specific image of Jennifer Aniston, but any picture of her. Or the sound of her voice, or her name written or spoken. Basically, this neuron responded to the ‘concept’ of Jennifer Aniston!
But the American actress isn’t the only one who has a neuron just for herself. In different patients, Quiroga found neurons responding to different concepts, always concepts that were familiar to the patient: mostly he discovered other celebrities, such as Maradona or Hally Berry, but he even found a patient with ‘concept neurons’ firing at pictures of himself. He found only one person who didn’t seem to have these neurons, and the patient turned out to be autistic – someone who cannot think abstract.
He then discovered that these neurons don’t fire to a single concept, but are able to make associations and fire to related concepts. Thus, the Jennifer Aniston neuron could also fire, although less strongly, to images of her friend Phoebe in the popular TV series.
How durable is the ‘memory’ of these cells? Will a neuron that fires for Brad Pitt today still do so in 10 years? The scientist thinks this depends on how familiar the person is with the concept and his relation to it. In any case, these cells are, he thinks, the building blocks for explicit memory functions, and the neural substrate to make associations. We probably all have thousands of these cells in the hippocampus, and the most familiar a concept is, the more neurons we will have encoding for it. If one of these neurons fires to 3 or 4 different concepts, and another one fires to one of those plus 5 new ones, the neurons might activate each other and create networks of related concepts, which would build our memory.
A fascinating story that will surely bring more surprises. Stay tuned for Quian Quiroga’s research!
A publication in Amino Acids by researchers from UPF, CRG and other centers provides the first in vivo evidence of the involvement of the CHRNA5/A3/B4 gene cluster in nicotine addiction. It happens through modifying the activity of brain regions responsible for the balance between the rewarding and the aversive properties of this drug. CHRNA5/A3/B4 codes for the nicotinic acetylcholine receptor subunits A5, A3 and B4. Together they form the ligand-gated pentameric ion channels that modulate key physiological processes ranging from neurotransmission to cancer signaling. These receptors are activated by the neurotransmitter, acetylcholine, and the tobacco alkaloid, nicotine. Recently, the gene cluster received interest after a succession of linkage analyses and association studies identified multiple single-nucleotide polymorphisms in these genes that are associated with an increased risk for nicotine dependence and lung cancer.
To see the in vivo effects of the cluster, a transgenic mouse overexpressing the human CHRNA5/A3/B4 cluster was generated using a bacterial artificial chromosome. Transgenic mice showed increased functional receptors in brain regions where these subunits are highly expressed under normal physiological conditions. Moreover, they exhibited increased sensitivity to the pharmacological effects of nicotine. Transgenic mice also showed increased acquisition of nicotine self-administration.
Gallego X, Molas S, Amador-Arjona A, Marks MJ, Robles N, Murtra P, Armengol L, Fernández-Montes RD, Gratacòs M, Pumarola M, Cabrera R, Maldonado R, Sabrià J, Estivill X, Dierssen M. Overexpression of the CHRNA5/A3/B4 genomic cluster in mice increases the sensitivity to nicotine and modifies its reinforcing effects. Amino Acids. 2011 Nov 19
© 2010 Oncogene: Structure of the Nicotinic acetylcholine receptor (nAChR). (a) Schematic representation illustrating the pentameric arrangement of subunits in an assembled nAChR. (b) Conserved domains of a nAChR subunit including the amino (N) and carboxy (C) terminals, transmembrane segments (M1–M4) and the intracellular loop. (c) Assembly of heteromeric and homomeric nAChR subtypes. Individual nAChR subunits are represented as colored circles, with diamonds representing ligand-binding sites. Pentagons in the center of each pentamer represent the pore region.