Markers of serotonergic function in the orbitofrontal cortex and dorsal raphé nucleus predict individual variation in spatial-discrimination serial reversal learning.

Dysfunction of the orbitofrontal cortex (OFC) impairs the ability of individuals to flexibly adapt behavior to changing stimulus-reward (S-R) contingencies. Impaired flexibility also results from interventions that alter serotonin (5-HT) and dopamine (DA) transmission in the OFC and dorsomedial striatum (DMS). However, it is unclear whether similar mechanisms underpin naturally occurring variations in behavioral flexibility. In the present study, we used a spatial-discrimination serial reversal procedure to investigate interindividual variability in behavioral flexibility in rats. We show that flexibility on this task is improved following systemic administration of the 5-HT reuptake inhibitor citalopram and by low doses of the DA reuptake inhibitor GBR12909. Rats in the upper quintile of the distribution of perseverative responses during repeated S-R reversals showed significantly reduced levels of the 5-HT metabolite, 5-hydroxy-indoleacetic acid, in the OFC. Additionally, 5-HT2A receptor binding in the OFC of mid- and high-quintile rats was significantly reduced compared with rats in the low-quintile group. These perturbations were accompanied by an increase in the expression of monoamine oxidase-A (MAO-A) and MAO-B in the lateral OFC and by a decrease in the expression of MAO-A, MAO-B, and tryptophan hydroxylase in the dorsal raphé nucleus of highly perseverative rats. We found no evidence of significant differences in markers of DA and 5-HT function in the DMS or MAO expression in the ventral tegmental area of low- vs high-perseverative rats. These findings indicate that diminished serotonergic tone in the OFC may be an endophenotype that predisposes to behavioral inflexibility and other forms of compulsive behavior.This work was supported by Medical Research Council Grants (G0701500; G0802729), a 503 Wellcome Trust Programme Grant (grant number 089589/Z/09/Z), and by a Core Award 504 from the Medical Research Council and the Wellcome Trust to the Behavioural and Clinical 505 21 Neuroscience Institute (MRC Ref G1000183; WT Ref 093875/Z/10/Z). RLB was supported 506 by a studentship from the Medical Research Council. JA was supported by a Fellowship from 507 the Swedish Research Council (350-2012-230). BJ was supported by Fellowships from the 508 AXA Research Fund and the National Health and Medical Research Council of Australia. 509 Financial support from the Fredrik and Ingrid Thuring Foundation is also acknowledged.This is the accepted manuscript. The final version is available from Nature Publishing at http://www.nature.com/npp/journal/vaop/ncurrent/full/npp2014335a.html

Force Control Deficits in Individuals with Parkinson’s Disease, Multiple Systems Atrophy, and Progressive Supranuclear Palsy

OBJECTIVE: This study examined grip force and cognition in Parkinson’s disease (PD), Parkinsonian variant of multiple system atrophy (MSAp), progressive supranuclear palsy (PSP), and healthy controls. PD is characterized by a slower rate of force increase and decrease and the production of abnormally large grip forces. Early-stage PD has difficulty with the rapid contraction and relaxation of hand muscles required for precision gripping. The first goal was to determine which features of grip force are abnormal in MSAp and PSP. The second goal was to determine whether a single variable or a combination of motor and cognitive measures would distinguish patient groups. Since PSP is more cognitively impaired relative to PD and MSAp, we expected that combining motor and cognitive measures would further distinguish PSP from PD and MSAp. METHODS: We studied 44 participants: 12 PD, 12 MSAp, 8 PSP, and 12 controls. Patients were diagnosed by a movement disorders neurologist and were tested off anti-Parkinsonian medication. Participants completed a visually guided grip force task wherein force pulses were produced for 2 s, followed by 1 s of rest. We also conducted four cognitive tests. RESULTS: PD, MSAp, and PSP were slower at contracting and relaxing force and produced longer pulse durations compared to controls. PSP produced additional force pulses during the task and were more cognitively impaired relative to other groups. A receiver operator characteristic analysis revealed that the combination of number of pulses and Brief Test of Attention (BTA) discriminated PSP from PD, MSAp, and controls with a high degree of sensitivity and specificity. CONCLUSIONS: Slowness in contracting and relaxing force represent general features of PD, MSAp, and PSP, whereas producing additional force pulses was specific to PSP. Combining motor and cognitive measures provides a robust method for characterizing behavioral features of PSP compared to MSAp and PD