Brain-stimulation reward thresholds raised by an antisense oligonucleotide for the M5 muscarinic receptor infused near dopamine cells.
(1/98)
Oligonucleotides targeting M5 muscarinic receptor mRNA were infused for 6 d into the ventral tegmental area of freely behaving rats trained to bar-press for lateral hypothalamic stimulation. The bar-pressing rate was determined at a range of frequencies each day to evaluate the effects of infusions on reward. M5 antisense oligonucleotide (oligo) infusions increased the frequency required for bar pressing by 48% over baseline levels, with the largest increases occurring after 4-6 d of infusion. Two control oligos had only slight effects (means of 5 and 11% for missense and sense oligos, respectively). After the infusion, the required frequency shifted back to baseline levels gradually over 1-5 d. Antisense oligo infusions decreased M5 receptors on the ipsilateral, but not the contralateral, side of the ventral tegmentum, as compared with a missense oligo. Therefore, M5 muscarinic receptors associated with mesolimbic dopamine neurons seem to be important in brain-stimulation reward. (+info)
Dynamics of hippocampal ensemble activity realignment: time versus space.
(2/98)
Whether hippocampal map realignment is coupled more strongly to position or time was studied in rats trained to shuttle on a linear track. The rats were required to run from a start box and to pause at a goal location at a fixed location relative to stable distal cues (room-aligned coordinate frame). The origin of each lap was varied by shifting the start box and track as a unit (box-aligned coordinate frame) along the direction of travel. As observed by Gothard et al. (1996a), on each lap the hippocampal activity realigned from a representation that was box-aligned to one that was room-aligned. We studied the dynamics of this transition using a measure of how well the moment-by-moment ensemble activity matched the expected activity given the location of the animal in each coordinate frame. The coherency ratio, defined as the ratio of the matches for the two coordinate systems, provides a quantitative measure of the ensemble activity alignment and was used to compare four possible descriptions of the realignment process. The elapsed time since leaving the box provided a better predictor of the occurrence of the transition than any of the three spatial parameters investigated, suggesting that the shift between coordinate systems is at least partially governed by a stochastic, time-dependent process. (+info)
Hippocampal place-cell firing during movement in three-dimensional space.
(3/98)
"Place" cells of the rat hippocampus are coupled to "head direction" cells of the thalamus and limbic cortex. Head direction cells are sensitive to head direction in the horizontal plane only, which leads to the question of whether place cells similarly encode locations in the horizontal plane only, ignoring the z axis, or whether they encode locations in three dimensions. This question was addressed by recording from ensembles of CA1 pyramidal cells while rats traversed a rectangular track that could be tilted and rotated to different three-dimensional orientations. Cells were analyzed to determine whether their firing was bound to the external, three-dimensional cues of the environment, to the two-dimensional rectangular surface, or to some combination of these cues. Tilting the track 45 degrees generally provoked a partial remapping of the rectangular surface in that some cells maintained their place fields, whereas other cells either gained new place fields, lost existing fields, or changed their firing locations arbitrarily. When the tilted track was rotated relative to the distal landmarks, most place fields remapped, but a number of cells maintained the same place field relative to the x-y coordinate frame of the laboratory, ignoring the z axis. No more cells were bound to the local reference frame of the recording apparatus than would be predicted by chance. The partial remapping demonstrated that the place cell system was sensitive to the three-dimensional manipulations of the recording apparatus. Nonetheless the results were not consistent with an explicit three-dimensional tuning of individual hippocampal neurons nor were they consistent with a model in which different sets of cells are tightly coupled to different sets of environmental cues. The results are most consistent with the statement that hippocampal neurons can change their "tuning functions" in arbitrary ways when features of the sensory input or behavioral context are altered. Understanding the rules that govern the remapping phenomenon holds promise for deciphering the neural circuitry underlying hippocampal function. (+info)
Independence of firing correlates of anatomically proximate hippocampal pyramidal cells.
(4/98)
In neocortex, neighboring neurons frequently exhibit correlated encoding properties. There is conflicting evidence whether a similar phenomenon occurs in hippocampus. To assess this quantitatively, a comparison was made of the spatial and temporal firing correlations within and between local groups of hippocampal cells, spaced 350-1400 microm apart. No evidence of clustering was found in a sample of >3000 neurons. Moreover, cells active in two environments were uniformly interspersed at a scale of <100 microm, as assessed by the activity-induced gene Arc. Independence of encoding characteristics implies uncorrelated inputs, which could enhance the capacity of the hippocampus to store arbitrary associations. (+info)
Relapse to cocaine-seeking after hippocampal theta burst stimulation.
(5/98)
Treatment efforts for cocaine addiction are hampered by high relapse rates. To map brain areas underlying relapse, we used electrical brain stimulation and intracranial injection of pharmacological compounds after extinction of cocaine self-administration behavior in rats. Electrical stimulation of the hippocampus containing glutamatergic fibers, but not the medial forebrain bundle containing dopaminergic fibers, elicited cocaine-seeking behavior dependent on glutamate in the ventral tegmental area. This suggests a role for glutamatergic neurotransmission in relapse to cocaine abuse. The medial forebrain bundle electrodes supported intense electrical self-stimulation. These findings suggest a dissociation of neural systems subserving positive reinforcement (self-stimulation) and incentive motivation (relapse). (+info)
Forced limb-use effects on the behavioral and neurochemical effects of 6-hydroxydopamine.
(6/98)
Rats with unilateral depletion of striatal dopamine (DA) show marked preferential use of the ipsilateral forelimb. Previous studies have shown that implementation of motor therapy after stroke improves functional outcome (Taub et al., 1999). Thus, we have examined the impact of forced use of the impaired forelimb during or soon after unilateral exposure to the DA neurotoxin 6-hydroxydopamine (6-OHDA). In one group of animals, the nonimpaired forelimb was immobilized using a cast, which forced exclusive use of the impaired limb for the first 7 d after infusion. The animals that received a cast displayed no detectable impairment or asymmetry of limb use, could use the contralateral (impaired) forelimb independently for vertical and lateral weight shifting, and showed no contralateral turning to apomorphine. The behavioral effects were maintained throughout the 60 d of observation. In addition to the behavioral sparing, these animals showed remarkable sparing of striatal DA, its metabolites, and the expression of the vesicular monoamine transporter, suggesting a decrease in the extent of DA neuron degeneration. Behavioral and neurochemical sparing appeared to be complete when the 7 d period of immobilization was initiated immediately after 6-OHDA infusion, only partial sparing was evident when immobilization was initiated 3 d postoperatively, and no sparing was detected when immobilization was initiated 7 d after 6-OHDA treatment. These results suggest that physical therapy may be beneficial in Parkinson's disease. (+info)
Restorative plasticity of dopamine neuronal transplants depends on the degree of hemispheric dominance.
(7/98)
The ability of dopaminergic (DA) transplants to restore complex sensorimotor behaviors in experimental Parkinson's disease is dependent on graft survival and reinnervation and is likely to be further modified by complex functional graft-host interactions. Here, we examined the impact of hemispheric dominance and extensive testing regimes on the functional capabilities of DA transplants to restore skilled forelimb movements in rats with unilateral 6-hydroxydopamine lesions. Interestingly, a near complete recovery was observed in DA-grafted animals that did not exhibit a strong hemispheric lateralization for paw use before lesion and implantation surgery, whereas animals with a clear lateralization of paw use and grafted into the contralateral hemisphere exhibited only moderate recovery. Finally, animals grafted ipsilateral to the preferred paw were most resistant to functional improvements in skilled forelimb use. However, the influence of hemispheric dominance on the degree of functional DA graft-induced restoration was specific for skilled forelimb use, whereas no such differences were observed in other tests for motor and sensory functions related to the DA system. Furthermore, functional recovery of DA-grafted animals in skilled forelimb use was significantly promoted by extensive behavioral testing regimes indicative of a "learning how to use" the transplant effect. These findings indicate the importance of the underlying functional architecture of complex sensorimotor behaviors, such as skilled forelimb use, and the DA neurotransmitter system for the plasticity of DA transplants to promoting a more complete behavioral recovery in experimental, and potentially, also in clinical forms of Parkinson's disease. (+info)
Preferential increases in nucleus accumbens dopamine after systemic cocaine administration are caused by unique characteristics of dopamine neurotransmission.
(8/98)
In vivo voltammetry was used to investigate the preferential increase of extracellular dopamine in the nucleus accumbens relative to the caudate-putamen after systemic cocaine administration. In the first part of this study, cocaine (40 mg/kg, i.p.) was compared with two other blockers of dopamine uptake, nomifensine (10 mg/kg, i.p.) and 3beta-(p-chlorophenyl)tropan-2beta-carboxylic acid p-isothiocyanatophenylmethyl ester hydrochloride (RTI-76; 100 nmol, i.c.v.), to assess whether the inhibitory mechanism of cocaine differed in the two regions. All three drugs robustly increased electrically evoked levels of dopamine, and cocaine elevated dopamine signals to a greater extent in the nucleus accumbens. However, kinetic analysis of the evoked dopamine signals indicated that cocaine and nomifensine increased the K(m) for dopamine uptake whereas the dominant effect of RTI-76 was a decrease in V(max). Under the present in vivo conditions, therefore, cocaine is a competitive inhibitor of dopamine uptake in both the nucleus accumbens and caudate-putamen. Whether the preferential effect of cocaine was mediated by regional differences in the presynaptic control of extracellular DA that are described by rates for DA uptake and release was examined next by a correlation analysis. The lower rates for dopamine release and uptake measured in the nucleus accumbens were found to underlie the preferential increase in extracellular dopamine after cocaine. This relationship explains the paradox that cocaine more effectively increases accumbal dopamine despite identical effects on the dopamine transporter in the two regions. The mechanism proposed for the preferential actions of cocaine may also mediate the differential effects of psychostimulant in extrastriatal regions and other uptake inhibitors in the striatum. (+info)