Abnormalities in brain structure and behavior in GSK-3alpha mutant mice.

BACKGROUND: Glycogen synthase kinase-3 (GSK-3) is a widely expressed and highly conserved serine/threonine protein kinase encoded by two genes that generate two related proteins: GSK-3alpha and GSK-3beta. Mice lacking a functional GSK-3alpha gene were engineered in our laboratory; they are viable and display insulin sensitivity. In this study, we have characterized brain functions of GSK-3alpha KO mice by using a well-established battery of behavioral tests together with neurochemical and neuroanatomical analysis. RESULTS: Similar to the previously described behaviours of GSK-3beta(+/-) mice, GSK-3alpha mutants display decreased exploratory activity, decreased immobility time and reduced aggressive behavior. However, genetic inactivation of the GSK-3alpha gene was associated with: decreased locomotion and impaired motor coordination, increased grooming activity, loss of social motivation and novelty; enhanced sensorimotor gating and impaired associated memory and coordination. GSK-3alpha KO mice exhibited a deficit in fear conditioning, however memory formation as assessed by a passive avoidance test was normal, suggesting that the animals are sensitized for active avoidance of a highly aversive stimulus in the fear-conditioning paradigm. Changes in cerebellar structure and function were observed in mutant mice along with a significant decrease of the number and size of Purkinje cells. CONCLUSION: Taken together, these data support a role for the GSK-3alpha gene in CNS functioning and possible involvement in the development of psychiatric disorders.

Effects of 5-HT depletion in the frontal cortex or nucleus accumbens on response inhibition measured in the 5-choice serial reaction time test and on a DRL schedule.

Previous work has shown that global depletion of brain serotonin (5-HT) using the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) increases impulsive like behaviour measured as premature responding on the 5-choice serial reaction time (5-CSRT) test, and inefficient responding on a DRL20 schedule of food reinforcement. The present experiments examined whether these effects could be attributed to loss of 5-HT inputs to either the frontal cortex (FC) or the nucleus accumbens. Infusing 5,7-DHT into the FC depleted 5-HT by more than 80%. This did not alter premature responding on the 5-CSRT test, although the number of trials on which responses were omitted was reduced by this manipulation. Depletion of 5-HT in the FC did not alter responding on the DRL20 schedule, nor when the schedule value was increased to 40s. Infusing 5,7-DHT into the nucleus accumbens depleted 5-HT by greater than 80%, and modestly reduced 5-HT in the FC also. Depletion of 5-HT in the nucleus accumbens did not affect premature responding on the 5-CSRT test in rats trained on this test prior to the lesion. Acquisition of responding on this test was also not affected by this lesion. On the DRL20 schedule response rate was increased and the mean inter-response interval was significantly reduced in lesioned animals. Loss of 5-HT inputs to the FC does not appear to alter response inhibition, whereas loss of 5-HT innervation to the nucleus accumbens only affected inhibitory control on the DRL schedule. The behavioural profile of global 5-HT depletion cannot be accounted for by selective loss of 5-HT innervation to either the FC or the nucleus accumbens.

The challenge of leadership in technology and education.

The leadership qualities necessary today in technology, education, and other modern organizations include the ability to recognize rapid changes in organizational environments and ensure continuous transformation and adaptability to that change. The important skills of such leaders include understanding their own business, articulating vision, creating a positive culture, communicating effectively, and measuring results. Rapidly emerging technology is prone to misunderstanding by those who mistake the surface features of how technology works with the functional opportunities it provides. Organizations that transform processes in parallel by adopting new technologies can expect much larger productivity gains than can those who merely insert technology. The problems of memory, speed, and cost have been addressed; the new challenge of technology is making it universal. Education in America is in danger. The infrastructure is outdated and it is not oriented toward change. Jobs will follow competence. Although the challenges of leadership today, especially in technology and education, are great, so is the opportunity for impact and the excitement of bringing diverse skills to bear.

Neonatal ablation of the nigrostriatal dopamine pathway does not influence limb development in rats.

Hemiparkinson-hemiatrophy syndrome (HP-HA) is associated with skeletal hemiatrophy and the later development of parkinsonism. It is generally assumed that this phenotype is due to the combination of dysfunction of the basal ganglia (e.g., substantia nigra compacta and/or other related structures), causing parkinsonism, and of other areas (e.g., cerebral cortex), causing hemiatrophy. The occurrence of asymmetry of limb size in a patient with very asymmetric involvement of dopa-responsive dystonia encouraged Greene et al. (2000, Mov. Disord. 15: 537-541) to propose that lifelong deficits in nigrostriatal dopamine could account for limb asymmetry in HP-HA. The purpose of this study was to determine whether skeletal hemiatrophy could be produced in rats by unilateral, neonatal ablation of the nigrostriatal dopamine pathway. Infusion of 6-hydroxydopamine into the striatum of rat neonates resulted in loss of dopamine neurons in the ipsilateral substantia nigra, reduced striatal dopamine levels, and stimulant-induced motor asymmetry. Saline infusions neither altered the number of dopamine neurons nor produced behavioral changes. Both groups incurred discrete lesions of the ipsilateral motor cortex surrounding the infusion site and atrophy of the corresponding cerebral peduncle. Cortical, but not nigrostriatal, lesions were associated with significant atrophy of ipsilateral femora, humeri, and innominate bones, as assessed radiographically. Skeletal hemiatrophy was not observed in naive animals or in experimental animals that did not exhibit corticospinal abnormalities. The results of this study indicate that early skeletal development in rats is not affected by loss of nigrostriatal dopamine per se, but is markedly attenuated by corticospinal lesions sustained during the neonatal period.