Pharmacological evidence for the implication of noradrenaline in effort.

The trade-off between effort and reward is one of the main determinants of behavior, and its alteration is at the heart of major disorders such as depression or Parkinson's disease. Monoaminergic neuromodulators are thought to play a key role in this trade-off, but their relative contribution remains unclear. Rhesus monkeys (Macaca mulatta) performed a choice task requiring a trade-off between the volume of fluid reward and the amount of force to be exerted on a grip. In line with a causal role of noradrenaline in effort, decreasing noradrenaline levels with systemic clonidine injections (0.01 mg/kg) decreased exerted force and enhanced the weight of upcoming force on choices, without any effect on reward sensitivity. Using computational modeling, we showed that a single variable ("effort") could capture the amount of resources necessary for action and control both choices (as a variable for decision) and force production (as a driving force). Critically, the multiple effects of noradrenaline manipulation on behavior could be captured by a specific modulation of this single variable. Thus, our data strongly support noradrenaline's implication in effort processing

Dual contributions of noradrenaline to behavioural flexibility and motivation

International audienceINTRODUCTION: While several theories have highlighted the importance of the noradrenergic system for behavioral flexibility, a number of recent studies have also shown a role for noradrenaline in motivation, particularly in effort processing. Here, we designed a novel sequential cost/benefit decision task to test the causal influence of noradrenaline on these two functions in rhesus monkeys.METHODS: We manipulated noradrenaline using clonidine, an alpha-2 noradrenergic receptor agonist, which reduces central noradrenaline levels and examined how this manipulation influenced performance on the task.RESULTS: Clonidine had two specific and distinct effects: first, it decreased choice variability, without affecting the cost/benefit trade-off; and second, it reduced force production, without modulating the willingness to work.CONCLUSIONS: Together, these results support an overarching role for noradrenaline in facing challenging situations in two complementary ways: by modulating behavioral volatility, which would facilitate adaptation depending on the lability of the environment, and by modulating the mobilization of resources to face immediate challenges

Percentage of normalized reaction time for different combinations of successive modalities.

<p>Auditory (A) N trials are plotted in the left part of the figures, visual (V) in the center and auditory-visual (AV) in the right part. N trials are sorted by N-1 trials’ modality, with auditory on the left in blue, visual in the center in green and auditory-visual on the right in red. Once sorted, N-1 reaction times are divided by the median reaction time of all N trials for the corresponding modality. For example, for the three leftmost bars, the data was normalized by dividing by the median reaction time of all auditory trials. Bars and error bars represent respectively median and 95% confidence interval of the median. Significance is reported using asterisks depending on the P value: * for p<0.05, ** for p<0.01 and *** for p<0.001.</p

Reaction time data for monkey 1 (A), for monkey 2 (B) and for humans (C).

<p>Blue box plots correspond to auditory (A), green to visual (V) and red to auditory—visual (AV) stimuli. The box and horizontal bar within represent the interquartile range and the median of RT, respectively. The whiskers extend to the most extreme data point, which is no more than 1.5 times the interquartile range from the box. The notch approximates a 95% confidence interval for the median. Significance is reported using asterisks depending on the P value: * for p<0.05, ** for p<0.01 and *** for p<0.001.</p

Formula of physical parameters of sounds and images.

<p>Formula of physical parameters of sounds and images.</p

Ratescale values of sounds as a function of time for the four groups of stimuli.

<p>Group 1: positive gain and violation of race model, group 2: positive gain and race model satisfied, group 3: positive gain and inverse violation of race model and group 4: negative gain and inverse violation of race model. Groups are described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0172480#pone.0172480.g003" target="_blank">Fig 3</a>. Note that there are differences between group 4 versus all other groups of stimuli for humans, which is not found for monkeys.</p

Multisensory gain for each stimulus, ranked by gain, for the 3 subject species.

<p>Group 1 (orange) corresponds to stimuli which induce positive gain and race model violation, group 2 (yellow) to stimuli which induce positive gain and satisfy race model, group 3 (light grey) to stimuli which induce positive gain and violate the race model inversely and group 4 (dark grey) to stimuli with negative gain and violate the race model inversely.</p

Effect of congruence (upper part) and salience (lower part) on multisensory gains.

<p>Same convention as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0172480#pone.0172480.g001" target="_blank">Fig 1</a> for the box plots. Significance is reported using asterisks depending on the P value: * for p<0.05, ** for p<0.01 and *** for p<0.001.</p

Failed remyelination of the nonhuman primate optic nerve leads to axon degeneration, retinal damages, and visual dysfunction

International audienceWhite matter disorders of the central nervous system (CNS), such as multiple sclerosis (MS), lead to failure of nerve conduction and long-lasting neurological disabilities affecting a variety of sensory and motor systems, including vision. While most disease-modifying therapies target the immune and inflammatory response, the promotion of remyelination has become a new therapeutic avenue to prevent neuronal degeneration and promote recovery. Most of these strategies have been developed in short-lived rodent models of demyelination, which spontaneously repair and do not reflect the size, organization, and biology of the human CNS. Thus, well-defined nonhuman primate models are required to efficiently advance therapeutic approaches for patients. Here, we followed the consequence of long-term toxin-induced demyelination of the macaque optic nerve on remyelination and axon preservation, as well as its impact on visual functions. Findings from oculomotor behavior, ophthalmic examination, electrophysiology, and retinal imaging indicate visual impairment involving the optic nerve and retina. These visual dysfunctions fully correlated at the anatomical level, with sustained optic nerve demyelination, axonal degeneration, and alterations of the inner retinal layers. This nonhuman primate model of chronic optic nerve demyelination associated with axonal degeneration and visual dysfunction, recapitulates several key features of MS lesions and should be instrumental in providing the missing link to translate emerging repair promyelinating/neuroprotective therapies to the clinic for myelin disorders, such as MS