Relationship between BDNF expression in major striatal afferents, striatum morphology and motor behavior in the R6/2 mouse model of Huntington's disease.

Patients with Huntington's disease (HD) and transgenic mouse models of HD show neuronal loss in the striatum as a major feature, which contributes to cognitive and motor manifestations. Reduced expression of the neurotrophin brain-derived neurotrophic factor (BDNF) in striatal afferents may play a role in neuronal loss. How progressive loss of BDNF expression in different cortical or subcortical afferents contributes to striatal atrophy and behavioral dysfunction in HD is not known, and may best be determined in animal models. We compared age-dependent alterations of BDNF mRNA expression in major striatal afferents from the cerebral cortex, thalamus and midbrain in the R6/2 transgenic mouse model of HD. Corresponding changes in striatal morphology were quantified using unbiased stereology. Changes in motor behavior were measured using an open field, grip strength monitor, limb clasping and a rotarod apparatus. BDNF expression in cortical limbic and midbrain striatal afferents is reduced by age 4 weeks, prior to onset of motor abnormalities. BDNF expression in motor cortex and thalamic afferents is reduced by 6 weeks, coinciding with early motor dysfunction and reduced striatum volume. BDNF loss in afferents progresses until death at 13-15 weeks, correlating with progressive striatal neuronal loss and motor abnormalities. Mutant huntingtin protein expression in R6/2 mice results in progressive loss of BDNF in both cortical and subcortical striatal afferents. BDNF loss in limbic and dopaminergic striatal inputs may contribute to cognitive/psychiatric dysfunction in HD. Subsequent BDNF loss in cortical motor and thalamic afferents may accelerate striatal degeneration, resulting in progressive involuntary movements.

Critical roles for the netrin receptor deleted in colorectal cancer in dopaminergic neuronal precursor migration, axon guidance, and axon arborization.

DCC (deleted in colorectal cancer), a receptor for the axon guidance cue netrin-1, is highly expressed by mesencephalic dopaminergic (DA) neurons during development; however, the contribution of DCC to DA development remains largely uncharacterized. DA neurons in ventral mesencephalic nuclei also express UNC5 homologue netrin receptors from late embryogenesis to adulthood, raising the possibility that DA axons could be attracted or repelled by netrins. Examining newborn dcc null mice, we report that loss of DCC function results in profound alterations of DA circuitry, including DA progenitor cell migration defects, reduced numbers of DA cells in midbrain nuclei, an anomalous DA ventral commissure, malformed DA innervation of the ventral striatum, and reduced DA innervation of the cerebral cortex. Caspase-3 activation was detected in inappropriately localized DA cells, consistent with apoptosis contributing to reduced cell numbers. Dcc heterozygous mice express reduced levels of DCC protein. Although less severely disrupted than dcc nulls, newborn and adult dcc heterozygotes also have fewer DA neurons in ventral mesenscephalic nuclei. Despite the reduced numbers of DA neurons, newborn dcc heterozygotes and nulls exhibit similar DA innervation density as wild-type littermates in the nucleus accumbens core, and adult dcc heterozygotes exhibit increased DA innervation in medial prefrontal cortex. A trend towards increased innervation of medial prefrontal cortex was detected in newborn dcc heterozygotes, but did not reach statistical significance, suggesting that the increase in adult heterozygotes results from enhanced DA arborization during postnatal development. Consistent with the hypothesis that DCC regulates DA axonal projections, disrupting DCC function in culture inhibits netrin-1 induced DA axon extension and axon branching. Furthermore, disrupting DCC function in isolated DA neurons grown as micro-island cultures reduces the number of autaptic synapses per cell. We conclude that DCC regulates appropriate precursor cell migration, axon guidance, and terminal arborization by DA neurons.

[Our experience with 2220 stereotaxic operations]. / Nash opyt 2220 stereotaksicheskikh operatsii.

The article deals with the results of 2,220 stereotaxic operations carried out on 1,812 patients with various diseases of the central nervous system: 1,286 operations in parkinsonism, 439 in cerebral infantile paralysis, 150 in torsion dystonia (dystonia musculorum deformans), etc. The best results were produced in parkinsonism and dystonia musculorum deformans.

[Stereotaxic operations in the treatment of patients with infantile cerebral palsy]. / Stereotaksicheskie operatsii v lechenii bol'nykh detskim tserebral'nym paralichom.

The main neurosurgical forms of infantile cerebral palsy (ICP) are singled out: athetosis-torsional-dystonic, athetosis-spastic, athetosis-torsional-choreatic. Results of 273 stereotaxic operations in 163 ICP patients are analyzed. The best results were observed in with athetosis-choreatic and athetosis-torsional-dystonic forms that were associated with rigidity-spasticity.

[Stereotaxic surgery in infantile cerebral palsy]. / Stereotaksicheskie operatsii pri detskom tserebal'nom paraliche.

The article analyses the results of 439 stereotaxic operations performed on 326 patients with the spastic-hyperkinetic form of infantile cerebral paralysis (ICP). Differentiated destructions of the brain structures were conducted. Extended thalamotomy, sagittal thalamotomy, and combined (cross) thalamodentatotomy were the most frequent complexes of destructions. Essential diminution of hyperkineses and hypertonia was noted in 86 and 81% of patients, respectively, in the immediate postoperative periods; the condition of 70% of patients improved in the late-term periods as compared to that in the preoperative period. Combined (cross) thalamodentatomy was found to be the most effective operative intervention.