Check or Go? Impact of Doubt on the Hierarchical Organization of the Mediofrontal Area.

BACKGROUND: Based on numerous imaging and electrophysiological studies, the presupplementary motor area (pre-SMA) and the rostral cingulate motor area are cortical regions considered to be essential to voluntary movement initiation and behavioral control. However, their respective roles and functional interactions remain a long-standing and still debated question. METHODS: Here, we trained 2 rhesus monkeys (Macaca mulatta) in a complex cognitive task to compare the neuronal activity of these 2 regions on the medial wall during both perceptual and internally guided decisions. RESULTS: We confirmed the implication of both areas throughout the decision process. Critically, we demonstrate that instead of a stable invariant role, the pre-SMA and rostral cingulate motor area manifested a versatile hierarchical relationship depending on the mode of movement initiation. Whereas pre-SMA neurons were primarily engaged in decisions based on perceptual information, rostral cingulate motor area neurons preempted the decision process in case of an internally doubt-driven checking behavior, withholding pre-SMA recruitment during the time spent inhibiting the habitual action. CONCLUSIONS: We identified a versatile hierarchical organization of the mediofrontal area that may substantially affect normal and pathological decision processes because adaptive behaviors, such as doubt-checking and its compulsive counterpart, rely on this subtle equilibrium in controlling action initiation.

Lack of limbic-predominant age-related TDP-43 encephalopathy (LATE) neuropathological changes in aged macaques with memory impairment.

The neuropathological changes of limbic-predominant age-related TDP-43 encephalopathy (LATE) are frequent in the aged population and are now recognized as a cause of memory impairment. However, it remains unknown if this proteinopathy is also present in other primate species. We thus investigated the presence and distribution of TDP-43 pathology in the hippocampus and amygdala of 7 aged memory-impaired rhesus macaques (Macaca mulatta, 18-32 years old) from 2 different cohorts. While present in an FTLD-TDP case used as a positive control for immunostaining, we found no TDP-43 or phosphorylated TDP-43 immunoreactive neuronal cytoplasmic inclusion in the amygdala or the hippocampus of these aged animals (as well as in young and mature macaques used as negative controls). We concluded that LATE is probably a human-specific condition, such as many other proteinopathies, and does not participate in age-related memory impairment in non-human primates.

A Subset of Purposeless Oral Movements Triggered by Dopaminergic Agonists Is Modulated by 5-HT2C Receptors in Rats: Implication of the Subthalamic Nucleus.

Dopaminergic medication for Parkinson's disease is associated with troubling dystonia and dyskinesia and, in rodents, dopaminergic agonists likewise induce a variety of orofacial motor responses, certain of which are mimicked by serotonin2C (5-HT2C) receptor agonists. However, the neural substrates underlying these communalities and their interrelationship remain unclear. In Sprague-Dawley rats, the dopaminergic agonist, apomorphine (0.03-0.3 mg/kg) and the preferential D2/3 receptor agonist quinpirole (0.2-0.5 mg/kg), induced purposeless oral movements (chewing, jaw tremor, tongue darting). The 5-HT2C receptor antagonist 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxyl]-5-pyridyl]carbamoyl]-6-trifluoromethylindone (SB 243213) (1 mg/kg) reduced the oral responses elicited by specific doses of both agonists (0.1 mg/kg apomorphine; 0.5 mg/kg quinpirole). After having confirmed that the oral bouts induced by quinpirole 0.5 mg/kg were blocked by another 5-HT2C antagonist (6-chloro-5-methyl-1-[6-(2-methylpiridin-3-yloxy)pyridine-3-yl carbamoyl] indoline (SB 242084), 1 mg/kg), we mapped the changes in neuronal activity in numerous sub-territories of the basal ganglia using c-Fos expression. We found a marked increase of c-Fos expression in the subthalamic nucleus (STN) in combining quinpirole (0.5 mg/kg) with either SB 243213 or SB 242084. In a parallel set of electrophysiological experiments, the same combination of SB 243213/quinpirole produced an irregular pattern of discharge and an increase in the firing rate of STN neurons. Finally, it was shown that upon the electrical stimulation of the anterior cingulate cortex, quinpirole (0.5 mg/kg) increased the response of substantia nigra pars reticulata neurons corresponding to activation of the "hyperdirect" (cortico-subthalamonigral) pathway. This effect of quinpirole was abolished by the two 5-HT2C antagonists. Collectively, these results suggest that induction of orofacial motor responses by D2/3 receptor stimulation involves 5-HT2C receptor-mediated activation of the STN by recruitment of the hyperdirect (cortico-subthalamonigral) pathway.

Checking behavior in rhesus monkeys is related to anxiety and frontal activity.

When facing doubt, humans can go back over a performed action in order to optimize subsequent performance. The present study aimed to establish and characterize physiological doubt and checking behavior in non-human primates (NHP). We trained two rhesus monkeys (Macaca mulatta) in a newly designed "Check-or-Go" task that allows the animal to repeatedly check and change the availability of a reward before making the final decision towards obtaining that reward. By manipulating the ambiguity of a visual cue in which the reward status is embedded, we successfully modulated animal certainty and created doubt that led the animals to check. This voluntary checking behavior was further characterized by making EEG recordings and measuring correlated changes in salivary cortisol. Our data show that monkeys have the metacognitive ability to express voluntary checking behavior similar to that observed in humans, which depends on uncertainty monitoring, relates to anxiety and involves brain frontal areas.

Serotonin2C Receptors and the Motor Control of Oral Activity.

Data from many experiments has shown that serotonin2C (5-HT2C) receptor plays a role in the control of orofacial activity in rodents. Purposeless oral movements can be elicited either by agonists or inverse agonists implying a tight control exerted by the receptor upon oral activity. The effects of agonists has been related to an action of these drugs in the subthalamic nucleus and the striatum, the two input structures for cortical efferents to the basal ganglia, a group of subcortical structures involved in the control of motor behaviors. The oral effects of agonists are dramatically enhanced in case of chronic blockade of central dopaminergic transmission induced by neuroleptics or massive destruction of dopamine neurons. The mechanisms involved in the hypersensitized oral responses to 5-HT2C agonists are not clear and deserve additional studies. Indeed, while the oral behavior triggered by 5-HT2C drugs would barely correspond to the dyskinesia observed in humans, the clinical data have consistently postulated that 5-HT2C receptors could be involved in these aberrant motor manifestations.