We remember, right down to the tiniest detail, a car accident that happened over two years ago, when we feared for our lives; and yet, who among us can still remember a very good meal enjoyed just last year, even if it was really very, very good? Today, there is ever-increasing understanding of the biological bases behind this “adaptive” capacity to remember a stressful. However, until now, we knew very little about the state of post-traumatic stress disorder (PTSD). This pathological state is triggered in some individuals after exposure to a highly stressful event. In this state, patients are gripped by fear even when faced with elements that have no objective danger. Is PTSD specific to the human race, influenced by its history and culture? Or is it a state that is found in various species, resulting in common biological changes? These are the questions that Pier-Vincenzo Piazza, Director of the Neurocentre Magendie in Bordeaux (Inserm/ Université Victor Segalen), and his collaborators, have attempted to answer. Details of their results are provided in the Science review (advance publication on-line on Science Express website on 23 February).

It is easier to memorize a stressful event than an agreeable one. Almost all species capable of behaviour are able to recall negative events, proof that this is likely to be a capacity selected during evolution: it ensures survival in a hostile environment.

However, for some individuals, exposure to very stressful events may trigger a pathological state: post-traumatic stress disorder (PTSD) being the most emblematic. In the United States, estimates suggest that this syndrome afflicts 6.8% of the general population and that 30% of veterans from the Vietnam war and 12% of the Gulf war suffer from it (source National Centre for PTSD).

In this state of stress, the memory of the patient is impaired: it is no longer capable of adapting its reaction of fear to the “right” context and to the “right” predictive elements. Sufferers experience fear in situations where there are no threats. These fears become all-consuming, eventually preventing a normal life. “If you are attacked by a lion in the savannah as a flock of birds flew overhead, it would be normal to feel fear if you were to make a return trip to the savannah” explains Pier-Vincenzo Piazza. “However, you should not be gripped by fear if, when strolling around another natural open space, for example a golf green, you hear a bird cry or catch sight of birds on the horizon,” thethe Inserm research director goes on. If this is the case, you may have developed post-traumatic stress disorder as a consequence to the lion attack.

The teams, led by Pier-Vincenzo Piazza and Aline Desmedt, have demonstrated that such memory impairment associated with PTSD is not specific to humans and is also found in mice. To this end, the researchers conditioned mice to a) anticipate a threat (an electric shock of varying intensity) by using the same specific context (an indicating environment) and b) to distinguish this specific context from stimuli, which although present during the conditioning process, did not predict the threat (a sound).

In normal conditions, the mice showed a reaction of fear when exposed to the specific context (the indicator environment) of the threat, but did not react to the sound (not predictive of threat).

Following this conditioning session, the researchers then administered increasing concentrations of glucocorticoid hormones, the main biological response to stress in mammals. When administration of the glucocorticoids followed an intense threat, as is the case with individuals suffering from post-traumatic stress, the mice were no longer able to restrict their fear reaction to the “right” context and to the correct indicators pronouncing a possible threat. The animals began to show fear: they froze in response to indicators, which although present during the stressful situation, were not predictive of the threat in any way. These results show that PTSD is probably due to a simultaneous overproduction of glucocorticoids in some subjects as the traumatic event occurs.

Memory impairment induced by glucocorticoids is accompanied by activity reorganisation in the brain, and, more specifically, the hippocampus-amygdale circuit, which is essential for coding memories associated with fear. In normal conditions, when an individual associates a threat with a context, strong activity is observed in the hippocampus, the structure in the brain required for all knowledge acquisition associating a specific context, area, etc. with an event. However, activity in the amygdale is low. The amygdale is an area of the brain that is also involved in emotional memory, but it memorizes specific indicators, such as sounds, which predict the threat.

When the mice were subject to an increase in glucocorticoids and memory impairment characterising PTSD was observed, activity in the hippocampus was reduced, whereas activity in the amygdale increased. In states of post traumatic stress, the researchers noted an inversion of normal activity in the brain. Normal activity in the amygdale may explain the fact that the subject begins to “over-respond” to presumed indicators, present during the traumatising event, but which are not, themselves, predictive of any danger. Low activity in the hippocampus may explain why subjects no longer recognize the right context: they are therefore incapable of containing their fear to appropriate situations.

“PTSD is not only an overbearing memory of the traumatizing situation, but also a memory impairment that prevents patients from containing their reaction of fear to the context that predicts the threat”, explain the researchers. In the case of post-traumatic stress disorder, a vivid memory of the traumatising event is associated with amnesia in terms of the surrounding context of the event. Some contextual elements present during the traumatising event are wrongly considered to be predictive of the event.

To conclude, the authors explain that PTSD-related memory problems seem to be caused by a biological response to abnormal stress suffered by some patients: for these patients, excessive glucocorticoid production at the same time as exposure to intense stress triggers an inversion of normal activity in brain structures that code fear-related memories.

“We have demonstrated that PTSD can occur in species other than humans and that there are shared biological origins. The mice model of this pathology now paves the way for better understanding of the molecular bases of this pathology, which could lead to the development of a treatment,” conclude the Inserm researchers.

A team coordinated by Mathias Pessiglione, Inserm researcher at the “Centre de recherche en neurosciences de la Pitié Salpêtrière” (Inserm/UPMC-Université Pierre and Marie Curie/CNRS) have identified the part of the brain driving motivation during actions that combine physical and mental effort: the ventral striatum. The results of their study were published in PLoS Biology on 21 February 2012.

The results of an activity (physical or mental) partly depend on the efforts devoted to it, which may be incentive-motivated. For example, a sportsperson is likely to train with “increased intensity” if the result will bring social prestige or financial gain. The same can be said for students who study for their exams with the objective of succeeding in their professional career. What happens when physical and mental efforts are required to reach an objective?

Mathias Pessiglione and his team from Inserm unit 975 “Centre de recherche en neurosciences de la Pitié-Salpêtrière” examined whether mental and physical efforts are driven by a motivation ‘centre’ or whether they are conducted by different parts of the brain. The researchers studied the neural mechanisms resulting from activities that combine both action and cognition.

To this end, a series of 360 tests, combining mental and physical effort, were performed whilst being monitored by a scanner. The 20 voluntary participants were placed in the supine position, with their heads in a functional MRI scanner. They then had to complete a series of tasks through which they could accumulate winnings. However, in each series the winnings were limited to the first incorrect response. The tasks combined cognitive and motor actions. The participants had to find the highest number from among different-sized numbers and then select it by squeezing a handle located by their left or right hand (depending on the number’s location). At the end of the test, a winnings summary was displayed to motivate the participant.

Using images obtained from the MRI scans taken during the test, Mathias Pessiglione and his team identified a general motivational system in the depths of the brain, i.e. a structure capable of activating any effort type, both mental (concentrating on the task in hand) or physical (lifting a load). The researchers observed that the ventral striatum was activated in proportion to the amount of money involved: the higher the degree of motivation, the higher the activation level. Furthermore, the ventral striatum is connected to the median part of the striatum (the caudate nucleus) when the task to be performed is cognitively difficult (when the physical size and the numerical value of the numbers did not correspond). This ventral region solicits the lateral part of the striatum (the putamen) when the difficulty is motor-related (when the handle had to be squeezed very tightly).

The researchers suggest that the expectation of a reward is encoded in the ventral striatum, which can then drive either the motor or cognitive part of the striatum, depending on the task, in order to boost performance. “The ventral striatum may commute connections in accordance with the request, i.e. enhance the neuronal activity in the caudate nucleus for a cognitive operation and in the putamen for a physical action” explains Mathias Pessiglione.

Research scientists from Inserm, CNRS, UPMC and AP-HP working for the Centre de Recherche de l’Institut du Cerveau et de la Moelle (CRICM) of la Pitié-Salpêtrière, have just discovered mutations that could be the cause of congenital mirror movement disorders. Persons suffering from this disorder are unable to perform different movements with different hands. Genome sequencing in several members of a French family showed the culprit to be the RAD51 gene. Further work carried out on mice suggests that this gene plays a part in motor network cross-over. Cross-over is a key factor in the transmission of brain signals, because it allows the right side of the brain to control the left side of the body and vice versa. This research has been published in The American Journal of Human Genetics.

Congenital mirror movement is a rare disease transmitted from one generation to another by dominant inheritance. The affected persons lose the ability to carry out different movements with separate hands: when one hand moves in a certain way, the other hand is “forced” to copy the same movement, even if the person does not wish to do so. So people suffering from this disease are totally incapable of bimanual motor activities, such as piano playing for example. This phenomenon has been observed in children, but generally cleared up spontaneously before the age of 10, no doubt due to maturing of the motoneuron networks. However, in people who are affected by the disorder, the illness starts in early childhood and remains unchanged throughout life.

In 2010, research scientists from Quebec analyzed the genome from the members of a large Canadian family and discovered a gene responsible for the disease. Mutations had been detected in the DCC (Deleted in Colorectal Carcinoma) gene. Following this discovery, the team of researchers and doctors coordinated by Emmanuel Flamand-Roze began to search for mutations in this gene in several members of a French family who were also suffering from congenital mirror movements disease, but without success. “The DCC gene was intact”, explained Emmanuel Flamand-Roze. “We thought we were nearly there and instead we had to start searching for mutation in a different gene”, he adds.

Using an approach that combines conventional genetic analysis and “whole exome” analysis (a new-generation genetic analysis technique that involves entirely sequencing the important part of the genome), scientists demonstrated that the RAD51 gene was responsible for congenital mirror movement disease in a large French family and went on to corroborate this result using the same techniques on a German family suffering from the same disorder.

“The RAD51 gene was already known to the scientific community as a potential catalyst for certain types of cancer and in problems of resistance to chemotherapy”, explains Emmanuel Flamand-Roze. “So we wondered whether it had yet another function that could explain the motor symptoms of CMM disease”.

In humans, the motor system is a cross-control system, which means that the left side of the brain controls the motor functions of the right side of the body and vice versa, with the cross-over taking place at the brainstem. While studying the expression of the RAD51 protein during development of the motor system in mice, the research scientists discovered that this gene could be implanted into the cross-over of the motor network that links the brain to the spinal fluid at the brainstem.

This discovery opens up a whole new field of investigation into the development of the motor system and to achieving better understanding of the cerebral mechanisms that control bimanual motricity. It could also shed light on other motricity disorders related to fine movement organization, such as dystonia or certain genetic neurodevelopmental diseases.

Sorry, this press release is only available in French.