Neuroscience
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Differential gene expression in the rat hippocampus during learning of an operant conditioning task.
Changes in transcription levels of brain-derived neurotrophic factor (BDNF), cyclic adenosine monophosphate (cAMP) response element binding (CREB), Synapsin I, Ca(2+)/calmodulin-dependent protein kinase II (CamKII), activity-regulated cytoskeleton-associated protein (Arc), c-jun and c-fos have been associated to several learning paradigms in different brain areas. In this study, we measured mRNA expression in the hippocampus by real time (RT)-PCR mRNA levels of BDNF, CREB, Synapsin I, CamKII, Arc, c-jun and c-fos, during learning and operant conditioning task. Experimental groups were as follows: control (C, the animals never left the bioterium), when the animals reached 50-65% of the expected response (Incompletely Trained, IT), when animals reached 100% of the expected response with a latency time lower than 5 s (Trained, Tr), Box Control of Incompletely Trained (BCIT), animals spent the same time as the IT in the operant conditioning box and Box Control of Trained (BCTr) animals spent the same time as the Tr in the operant conditioning box. ⋯ We found increments of mRNA levels of most genes (BDNF, CREB, Synapsin I, Arc, c-jun and c-fos) in IT and Tr groups compared to their box controls, but increments in Tr were smaller compared with IT. These results describe a differential gene expression in the rat hippocampus when the animals are learning and when animals have already learned. Taking together the results presented herein with the known functions of these genes, we propose a link between changes in gene expression in the hippocampus and different degrees of cellular activation and plasticity during learning of an operant conditioning task.
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In many everyday settings, the relationship between our choices and their potentially rewarding outcomes is probabilistic and dynamic. In addition, the difficulty of the choices can vary widely. Although a large body of theoretical and empirical evidence suggests that dopamine mediates rewarded learning, the influence of dopamine in probabilistic and dynamic rewarded learning remains unclear. ⋯ The patients also exhibited compromised adaptability to the reversal. A computational model of the subjects' trial-by-trial choices demonstrated that the adaptability was sensitive to the gain with which patients weighted pre-reversal feedback. Collectively, the results implicate the nigral dopaminergic system in learning to make choices in environments with probabilistic and dynamic reward contingencies.
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The embryonic mid-hindbrain organizer, which is composed of a transient cell population in the brainstem, controls the development of dopaminergic and serotonergic neurons. Different genes determining the position and activity of this embryonic structure have been implicated in dopamine- and serotonin-associated disorders. Mouse mutants with a caudally shifted mid-hindbrain organizer, are hyperactive, show increased numbers of dopaminergic neurons and a reduction in serotonergic cells. ⋯ Transmitter measurements, dopamine and serotonin transporter binding assays and autoradiography, indicated a subtle increase in striatal dopaminergic innervation and a marked general decrease of serotonergic innervation in mutants. Taken together, our data suggest that mice with an aberrantly positioned mid-hindbrain organizer show altered sensitivity to psychostimulants and that an increase of serotonergic neurotransmission reverses their hyperactivity. We conclude that the mid-hindbrain organizer, by orchestrating the formation of dopaminergic and serotonergic neurons, is an essential developmental parameter of locomotor activity and psychostimulant response.
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Anxiety disorders, depression and animal models of vulnerability to a depression-like syndrome have been associated with dysregulation of brain serotonergic systems. These effects could result from genetic influences, adverse early life experiences (ELE), or acute stressful life events, all of which can alter serotonergic neurotransmission and have been implicated in determining vulnerability to neuropsychiatric disorders. To evaluate the effects of ELE, adverse experiences during adulthood, and potential interactions between these factors on neuronal tryptophan hydroxylase 2 (tph2) mRNA expression, we investigated in rats the effects of maternal separation (MS)(separation from the dam for 180 min/day from postnatal day 2-14; MS180, a model of vulnerability to a depression-like syndrome), neonatal handling (separation from the dam for 15 min/day from postnatal day 2-14; MS15, a model of decreased stress sensitivity), or normal animal facility rearing (AFR) control conditions, with or without subsequent exposure to adult social defeat, on tph2 mRNA expression in the dorsal raphe nucleus (DR). ⋯ Social defeat increased tph2 mRNA expression, but only in MS180 rats and only in the "lateral wings" of the DR, a subdivision of the DR that is part of a sympathomotor command center. Overall, these data demonstrate that ELE and stressful experience during adulthood interact to determine tph2 mRNA expression. These changes in tph2 mRNA expression represent a potential mechanism through which adverse ELEs and stressful life experiences during adulthood may interact to increase vulnerability to stress-related psychiatric disease.