ABSTRACT
Forced choice between alternative options of unpredictable outcome is a complex task that requires continual update of the value associated with each option. Prefrontal areas such as the orbitofrontal cortex (OFC) have been shown to play a major role in performance on ambiguous decision-making tasks with substantial risk component, broadly named as "gambling tasks." We have recently demonstrated that rats display complex decision-making behavior in a rodent gambling task based on serial choices between rewards of different value and probability. This rodent task retains many of the key characteristics of the human Iowa Gambling Task (IGT), and performance in this novel task is also disrupted by OFC or amygdalar lesioning. In the present study we addressed if rat models of chronic pain would have impaired performance in this gambling task, since it is already known that the IGT response patterns of human pain patients are comparable to individuals with OFC lesions. We found that animals with a monoarthritic inflammatory model of chronic pain systematically preferred the lever associated with larger but infrequent rewards. In addition, we measured the neurochemical content of the OFC, amygdala and nucleus accumbens using HPLC, and found that in prolonged chronic pain animals there was a decrease in the tonic levels of dopamine, DOPAC (3,4-hydroxyphenyl-acetic acid) and 5-HIAA (5-hydroxyindole-3-acetic acid) in the OFC. This is the first report of the effect of chronic pain in rat decision-making processes and supports the notion that pain may have profound effects on the functioning of the reward-aversion circuitry relevant to strategic planning.
Subject(s)
Cognition , Decision Making , Pain/psychology , Prefrontal Cortex/physiopathology , 3,4-Dihydroxyphenylacetic Acid/metabolism , Amygdala/metabolism , Animals , Chronic Disease , Disease Models, Animal , Dopamine/metabolism , Freund's Adjuvant , Gambling , Hydroxyindoleacetic Acid/metabolism , Male , Neuropsychological Tests , Nucleus Accumbens/metabolism , Pain/chemically induced , Prefrontal Cortex/metabolism , Rats , Rats, Sprague-Dawley , Reinforcement Schedule , Reward , Time FactorsABSTRACT
Fabry disease (OMIM 301500) is a rare X-linked recessive disorder caused by mutations in the alpha-galactosidase gene (GLA). Loss of alpha-galactosidase (alpha-Gal) activity leads to the abnormal accumulation of glycosphingolipids in lysosomes predominantly of vascular endothelial cells. Clinically the disorder presents with angiokeratomas, clouding of the cornea, and renal, cardiac, and cerebrovascular complications. In addition, there is an increased incidence of neuropathic pain in Fabry patients. In this study, we investigated the implications of loss of alpha-galactosidase A activity on sensorimotor function and peripheral nervous system. Similar to the described in Fabry disease patients, the sensorimotor assessment of Fabry mice revealed diminished locomotor activity and warm hypoalgesia as assessed in the hot-plate. Moreover Fabry mice displayed alterations both in balance and co-ordination. By histological analysis, the cyto-architecture of Fabry mice sciatic nerves showed an increase in mean cross-sectional area accompanied by a decrease in the density of non-myelinated fibers as well as a trend for a decreased number of small myelinated fibers, a well established feature of Fabry disease. A relative preservation of large myelinated fibers and nerve conduction velocity measurements was observed. Our findings demonstrate for the first time that Fabry knockout mice have Gb3 accumulation in the peripheral nervous system, alterations in sensorimotor function, hypoalgesia and no impairment of motor nerve conduction.
Subject(s)
Fabry Disease , Peripheral Nervous System/pathology , Peripheral Nervous System/physiopathology , alpha-Galactosidase/genetics , Animals , Ataxia/physiopathology , Disease Models, Animal , Fabry Disease/pathology , Fabry Disease/physiopathology , Fabry Disease/psychology , Female , Glycosphingolipids/metabolism , Hot Temperature , Hypesthesia/physiopathology , Male , Mice , Mice, Knockout , Motor Activity , Nerve Fibers/pathology , Nerve Fibers/physiology , Nerve Fibers/ultrastructure , Neural Conduction/physiology , Pain/physiopathology , Peripheral Nervous System/ultrastructure , Phenotype , Postural Balance , Sciatic Nerve/pathology , Sciatic Nerve/physiopathology , Sciatic Nerve/ultrastructure , Thermosensing , Trihexosylceramides/metabolism , alpha-Galactosidase/metabolismABSTRACT
Neurobiological mechanisms of decision-making have been shown to be modulated by a number of frontal brain regions. Among those areas, the orbitofrontal cortex (OFC) is thought to play an important role in the decision of behavioral actions when faced with alternative options of ambiguous outcome. Here we present a novel neurobehavioral task to study affective decision-making in the rat, based on evaluation of consecutive choices between two levers associated with rewards of different value and probability. Two groups of animals were studied; a sham control group (n=6) and an OFC-lesioned group (n=7). In the first 30 trials both groups had similar preference patterns but at the end of the 90 trials of the task both groups developed specific preferences. The control group systematically preferred the lever associated with smaller but more reliable rewards (low risk lever) while the OFC lesion group preferred the high risk lever (index of preference of 0.21+/-0.21 vs. -0.45+/-0.10; t-test, P<0.05). Analysis of choice persistence (i.e. choosing the same lever in consecutive trials) suggests that the OFC-lesioned group became less sensitive to risk, seeking large rewards irrespective of their success probability.