A comparison of striatal-dependent behaviors in wild-type and hemizygous Drd1a and Drd2 BAC transgenic mice

Studies of striatal physiology and motor control have increasingly relied on the use of bacterial artificial chromosome (BAC) transgenic mice expressing fluorophores or other genes under the control of genetic regulatory elements for the dopamine D1 receptor (D1R) or dopamine D2 receptor (D2R). Three recent studies have compared wild-type, D1R, and D2R BAC transgenic mice, and found significant differences in physiology and behavior, calling into question the use of these mice in studies of normal circuit function. We repeated the behavioral portions of these studies in wild-type C57BL/6 mice and hemizygous Drd1a-td Tomato (D1-Tmt), Drd1a-eGFP (D1-GFP), and Drd2-eGFP (D2-GFP) mice backcrossed into the C57BL/6 background. Our three laboratories independently found that open-field locomotion, acute locomotor responses to cocaine (20 mg/kg), locomotor sensitization to 5 d of daily injections of cocaine (15 mg/kg) or amphetamine (3 mg/kg), cocaine (20 mg/kg) conditioned place preference, and active avoidance learning to paired light and footshock were indistinguishable in these four mouse lines. These results suggest that while it is crucial to screen new transgenic mouse lines for abnormal behavior and physiology, these BAC transgenic mouse lines remain extremely valuable tools for evaluating the cellular, synaptic, and circuit basis of striatal motor control and associative learning.     

Central resetting of neuromuscular steady states may underlie rhythmical arm movements

Changing the steady-state configuration of the body or its segments may be an important function of central pattern generators for locomotion and other rhythmical movements. Thereby, muscle activation, forces, and movement may emerge following a natural tendency of the neuromuscular system to achieve the current steady-state configuration. To verify that transitions between different steady states occur during rhythmical movements, we asked standing subjects to swing one or both arms synchronously or reciprocally at approximately 0.8 Hz from the shoulder joints. In randomly selected cycles, one arm was transiently arrested by an electromagnetic device. Swinging resumed after some delay and phase resetting. During bilateral swinging, the nonperturbed arm often stopped before resuming swinging at a position that was close to either the extreme forward or the extreme backward arm position observed before the perturbation. Oscillations usually resumed when both arms arrived at similar extreme positions when a synchronous bilateral pattern was initially produced or at the opposite positions if the initial pattern was reciprocal. Results suggest that a central generator controls both arms as a coherent unit by producing transitions between its steady state (equilibrium) positions. By controlling these positions, the system may define the spatial boundaries of movement. At these positions, the system may halt the oscillations, resume them at a new phase (as observed in the present study), or initiate a new motor action. Our findings are relevant to locomotion and suggest that walking may also be generated by transitions between several equilibrium configurations of the body, possibly accomplished by modulation and gating of proprioceptive reflexes.     

Role of the pituitary–adrenal axis in granulocyte-colony stimulating factor-induced neuroprotection against hypoxia–ischemia in neonatal rats

Several reports indicate that the activity of the hypothalamic–pituitary–adrenal axis (HPA) is increased after a brain insult and that its down-regulation can improve detrimental outcomes associated with ischemic brain injuries.Granulocyte-colony stimulating factor (G-CSF) is a neuroprotective drug shown in the na?ve rat to regulate hormones of the HPA axis. In this study we investigate whether G-CSF confers its neuroprotective properties by influencing the HPA response after neonatal hypoxia–ischemia (HI). Following the Rice–Vannucci model, seven day old rats (P7)were subjected to unilateral carotid ligation followed by 2.5 h of hypoxia. To test our hypothesis,metyrapone was administered to inhibit the release of rodent specific glucocorticoid, corticosterone, at the adrenal level. Dexamethasone, a synthetic glucocorticoid, was administered to agonize the effects of corticosterone.Our results show that both G-CSF and metyrapone significantly reduced infarct volume while dexamethasone treatment did not reduce infarct size even when combined with G-CSF. The protective effects of G-CSF do not include blood brain barrier preservation as suggested by the brain edema results. G-CSF did not affect the pituitary released adrenocorticotropic hormone (ACTH) levels in the blood plasma at 4 h, but suppressed the increase of corticosterone in the blood. The administration of G-CSF and metyrapone increased weight gain, and significantly reduced the Bax/Bcl-2 ratio in the brain while dexamethasone reversed the effects of G-CSF. The combination of G-CSF and metyrapone significantly decreased caspase-3 protein levels in the brain, and the effect was antagonized by dexamethasone.We report that G-CSF is neuroprotective in neonatal HI by reducing infarct volume, by suppressing the HI-induced increase of the Bax/Bcl-2 ratio, and by decreasing corticosterone in the blood. Metyrapone was able to confer similar neuroprotection as G-CSF while dexamethasone reversed the effects of G-CSF. In conclusion, we show that decreasing HPA axis activity is neuroprotective after neonatal HI, which can be conferred by administering G-CSF.     

Threshold position control signifies a common spatial frame of reference for motor action and kinesthesia

Abundance of muscle spindles is most likely related to gradual recruitment and functional specialization of motor units, as well as to their fundamental role in reflex intermuscular interaction and cooperation with other sensory systems. Spindle afferents per se usually convey ambiguous kinesthetic information to the brain. Experimental data indicate that the nervous system cannot use efferent copies, i.e., pre-programmed imitations of motor commands to muscles to overcome this ambiguity and form adequate position sense. Instead, position sense becomes adequate when proprioceptive signals are interpreted in reference to the threshold limb position set by the brain. By resetting the threshold position, the nervous system not only appropriately adjusts kinesthetic sense but also causes motor action. This brief analysis illustrates not only that action and perception are coupled [J.J. Gibson, The Senses Considered as Perceptual Systems. George Allen and Unwin Ltd., London, 1968; W.H. Warren, The dynamics of perception and action. Psychol. Rev. 113 (2006) 358-89] but also that they are accomplished in the same spatial frame of reference selected and manipulated by the brain.     

Functionalized magnetonanoparticles for MRI diagnosis and localization in epilepsy

Purpose: The development of nonradioactive and targeted magnetonanoparticles (MNP) capable of crossing the blood–brain barrier (BBB) and of concentrating in the epileptogenic tissues of acute and chronic animal models of temporal lobe epilepsy to render these tissues visible on magnetic resonance imaging (MRI).
Methods: Nonradioactive alpha methyl tryptophan (AMT) was covalently attached to MNP composed of iron oxide and dextran. A rodent model of temporal lobe epilepsy was prepared by injecting kainic acid into the right hippocampus. AMT-MNP or plain MNP was injected in the tail-vein of two animals during the acute stage 3 days after status epilepticus, and AMT-MNP in five animals during the chronic stage. MRIs were obtained before and after particle injection in all animals. Intracranial EEGs were obtained in all chronic animals after completion of MRI studies.
Results: AMT-MNP crossed the BBB and intraparenchymal uptake was visible on MRI. In the acute condition, AMT-MNP appeared to localize to both hippocampi, whereas plain MNP only identified unilateral, presumably inflammatory, changes. In the chronic condition, AMT-MNP uptake correlated with the occurrence of spontaneous seizures, and the location of uptake appeared to agree with bilateral or unilateral epileptogenicity confirmed by subsequent intracranial EEG.
Discussion: Nonradioactive AMT-MNP can cross the BBB and may accurately localize epileptogenic cerebral regions. The MNP-MRI approach is potentially applicable to the use of any bioactive molecules as ligands for imaging normal and abnormal localized cerebral functions, accurately, safely, and inexpensively.     

Untersuchungen über den Leukocytensturz nach Intracutaninjektion bei Dermatosen

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