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The review of own and literature data devoted to structural and neurochemical organization of the nucleus accumbens (Acc) as well as spatial organization of their projection fibers in comparison with nucleus caudatus (neostriatum) has been presented. The facts concerned with correlations revealed between both the cell clusters and histochemical compartments as well as the compartmental organization of afferent and efferent striatal connections were analyzed. The presented data propose the existence of sensorimotor and limbic parts of the dorsal and ventral striatum, which are involved in the parallelly functioning systems. The common and different signs of these two systems and its role in the regulation of the movement behaviour has been proposed. A lot of attention also was payed to the Acc and the neostriatum interaction. The many pathways by which Acc can influence neostriatum functions and therefore the motor activity controlled by the neostriatum are discussed. It was shown that the Acc can influence on the striatal synaptic DA release. The sign of this influence depended upon DA/glutamic acid interactions in the Acc. It was stressed that the influence of Acc on striatal DA-ergic system is very likely mediated via kainate/quisqualate (but not NMDA) inputs of the neostriatum. The balance of DA-ergic mechanisms of neostriatum and Acc as important basis of animals adequate behaviour in conditioning situation was proposed. The disbalance of these mechanisms could leads to pathology.
Psychotomimetic effects of NMDA antagonists in humans suggest that NMDA receptor hypofunction could contribute to the pathophysiology of schizophrenia. A mouse line that expresses low levels of the NMDA R1 subunit (NR1) of the NMDA receptor was generated to model endogenous NMDA hypofunction. These mutant mice show increased locomotor activity, increased acoustic startle reactivity and deficits in prepulse inhibition (PPI) of acoustic startle. The present study examined effects of a typical antipsychotic drug, haloperidol, and two atypical antipsychotic drugs (olanzapine and risperidone) on behavioral alterations in the NR1 hypomorphic (NR1-/-) mice. Haloperidol significantly reduced activity in the wild type controls at each dose tested (0.05, 0.1, and 0.2 mg/kg). The NR1-/- mice were less sensitive to the haloperidol-induced locomotor inhibition in comparison to the NR1+/+ mice. In contrast to haloperidol, olanzapine reduced the hyperactivity in the NR1-/- mice at a dose that produced minimal effects on locomotor activity in the wild type mice. These data suggest that non-dopaminergic blocking properties of olanzapine contribute to the drug's ability to reduce hyperactivity in the NR1 deficient mice. In the PPI paradigm, haloperidol (0.5 mg/kg) did not affect the increased startle reactivity in the NR1-/- mice, but did reduce startle amplitude in the NR1+/+ mice. Haloperidol increased PPI in both the mutant and wild type strains. Unlike haloperidol, risperidone (0.3 mg/kg) and olanzapine (3 mg/kg) reduced startle magnitude in both NR1+/+ and NR1-/- mice. Like haloperidol, risperidone and olanzapine increased PPI in both NR1+/+ and NR1-/- mice. The similar effects of these atypical antipsychotic drugs in wild type mice and mice with markedly reduced NR1 expression suggest that the drugs were not working by a NMDA receptor-dependent mechanism to increase PPI. Since both haloperidol and the atypical drugs increased PPI, it is likely that D2 dopamine receptor blockade is responsible for the drug effects on sensorimotor gating.
To determine the effects of the recessive retinal degeneration (rd) gene on behavioral performance, three Alzheimer's transgenic lines (APPsw, P301L, APPsw + P301L) and non-transgenic littermates were evaluated in a comprehensive behavioral battery between 5 and 8.5 months of age. For all four genotypes collectively, rd homozygosity resulted in profound impairment in spatial cognitive tasks requiring visual acuity (Morris maze, platform recognition, and radial arm water maze). Non-transgenic and P301L mutant tau mice contributed most to this rd effect since heterozygous and wild type mice performed well. By contrast, spatial cognitive performance of both APPsw-expressing lines was often impaired, irrespective of rd status. Sensorimotor performance was unaffected by rd homozygosity, while rd effects on anxiety were genotype-dependent (less anxiety in NT, APPsw; more anxiety in P301L, APPsw + P301L). Our results strongly encourage rd screening of genetically manipulated mouse lines produced from rd-carrying strain backgrounds to avoid serious potential confounds in the interpretation of spatially based cognitive performance.
The therapeutic potential of glial cell line-derived neurotrophic factor (GDNF) for Parkinson's disease is likely to depend on sustained delivery of the appropriate amount to the target areas. Recombinant adeno-associated viral vectors (rAAVs) expressing GDNF may be a suitable delivery system for this purpose. The aim of this study was to define a sustained level of GDNF that does not affect the function of the normal dopamine (DA) neurons but does provide anatomical and behavioral protection against an intrastriatal 6-hydroxydopamine (6-OHDA) lesion in the common marmoset. We found that unilateral intrastriatal injection of rAAV resulting in the expression of high levels of GDNF (14 ng/mg of tissue) in the striatum induced a substantial bilateral increase in tyrosine hydroxylase protein levels and activity as well as in DA turnover. Expression of low levels of GDNF (0.04 ng/mg of tissue), on the other hand, produced only minimal effects on DA synthesis and only on the injected side. In addition, the low level of GDNF provided approximately 85% protection of the nigral DA neurons and their projections to the striatum in the 6-OHDA-lesioned hemisphere. Furthermore, the anatomical protection was accompanied by a complete attenuation of sensorimotor neglect, head position bias, and amphetamine-induced rotation. We conclude that when delivered continuously, a low level of GDNF in the striatum (approximately threefold above baseline) is sufficient to provide optimal functional outcome.
We used multislice functional magnetic resonance imaging (fMRI) to investigate the association between behavioral and neurophysiological measures of working memory task performance in 20 right-handed male healthy volunteers. Images were acquired over a 5-min period at 1.5 Tesla. We used a periodic design, alternating 30-s blocks of the "n-back" working memory task with 30-s blocks of a sensorimotor control task to activate verbal working memory systems. The power of functional response to the task was estimated by sinusoidal regression at each voxel. The relationship between power of fMRI response and mean reaction time over all 11 working memory trials was explored by multiple regression, with age and mean reaction time to the control task as covariates, at voxel and regional levels of analysis. All subjects were able to perform the n-back task accurately. A spatially distributed network was activated, including dorsolateral prefrontal cortex, inferior frontal gyrus, lateral premotor cortex, and supplementary motor area (SMA) in the frontal lobes. More posteriorly, there were major foci of activation in parietal and occipitoparietal cortex, precuneus, lingual, and fusiform gyri of the ventral occipital lobe, inferior temporal gyrus, and cerebellum. The power of functional response was positively correlated with reaction time in bilateral posterior parietal cortex (Talairach coordinates in x, y, z (mm) 35, -44, 37 and -32, -56, 42), indicating that subjects who found the task difficult, and responded with a slower reaction time, tended to activate these regions more powerfully. One interpretation of this regionally specific relationship between prolonged reaction time and increased power of posterior parietal activation is consistent with prior studies identifying similar areas of parietal cortex as the site of the phonological storage function in verbal working memory.
The maps of visual and auditory space within the superior colliculus are in approximate register both with each other and with the underlying motor maps associated with orienting responses. The fact that eyes and ears can move independently poses a problem for the sensorimotor organization of these two modalities. By monitoring eye and pinna positions in alert, head-fixed cats, we showed that the accuracy of saccadic eye movements to auditory targets was little affected by eye eccentricity (range +/- 15 deg) at the onset of the sound. A possible neural basis for this behavioral compensation was suggested by recordings from superior colliculus neurons. The preferred sound directions of some neurons in the deep layers of this midbrain nucleus exhibited a shift with the direction of gaze, while in others the response throughout the auditory receptive field was either increased or decreased, suggesting that changes in eye position alter the gain of the auditory response.
Unilateral lesions of the forelimb area of the sensorimotor cortex in adult rats resulted in time-dependent increases in the number of synapses per neuron and the volume and membrane surface area of dendritic processes per neuron within layer V of the contralateral motor cortex in comparison to sham-operated rats. Based on previous findings of a behavioral relationship with increased dendritic arborization, these changes may be related to lesion-induced compensatory changes in the use of the non-impaired (ipsilateral to the lesion) forelimb.
The acoustic startle reflex was modified by presenting gaps (0-30 ms) in a continuous noise (70 dB) before the startle eliciting stimulus. The effects of midazolam (0.4-1.8 mg/kg, IP), DMCM (0.1-0.4 mg/kg, IP), buspirone (5-20 mg/kg, PO), 8-OH-DPAT (0.5-8 mg/kg, IP), and clonidine (0.009-0.08 mg/kg, IP) on startle amplitudes (reflecting sensorimotor reactivity) on the one hand, and on gap inhibition of the startle reflex (a measure of temporal acuity) on the other hand, were investigated. The results showed that midazolam and clonidine attenuated sensorimotor reactivity dose-dependently. DMCM had no systematic effect on sensorimotor reactivity. Buspirone and 8-OH-DPAT increased sensorimotor reactivity dose dependently. Furthermore, midazolam and clonidine did not affect the neuronal systems underlying inhibition of the startle reflex. In contrast, DMCM and buspirone increased inhibition dose-dependently, and 8-OH-DPAT first increased and then decreased inhibition of the startle reflex. The possibility that drug-induced behavior affected the startle reflex was discussed.
A myriad of neurological symptoms including muscle and joint pain, ataxia, chronic fatigue, headache, and difficulty in concentration have been reported by Persian Gulf War (PGW) veterans. A large number of these veterans were prophylactically treated with pyridostigmine bromide (PB) and possibly exposed to sarin. In the present study we investigated the effects of PB and sarin, alone and in combination, on sensorimotor performance and the central cholinergic system of rats. Male Sprague-Dawley rats were treated with PB (1.3 mg/kg, 15 daily doses, oral) and sarin (50, 75, 90, and 100 microg/kg, single im dose on day 15), alone and in combination. The animals were evaluated for postural reflexes, limb placing, orienting to vibrissae touch, incline plane performance, beam-walk time, and forepaw grip time 7 and 15 days following treatment with sarin. Treatment with either PB or sarin alone resulted in significant sensorimotor impairments. Coexposure to sarin and PB resulted in significant sensorimotor deficits that worsened over time. By 15 days following sarin treatment, plasma butyrylcholinesterase (BChE) activity returned to normal levels in the animals treated with sarin alone, whereas in the animals exposed to PB or PB plus sarin, there was an increase in the enzyme activity. Cortical acetylcholinesterase (AChE) activity remained inhibited in the animals treated with sarin alone and in combination with PB. Muscarinic acetylcholine receptor (m2 mAChR) ligand binding with [(3)H]AFDX-384 in cortex and brain stem showed significant increases (approximately 120-130% of control) following coexposure to PB and sarin at higher doses. To evaluate the potential of PB for augmentation or inhibition of the toxicity induced by acute sarin exposure, the animals were exposed to either 10 or 100 microg/kg sarin (single im injection) with or without pretreatment with PB, and sacrificed 3 h after treatment with sarin. Pretreatment with PB offered slight protection in the plasma as well as brain regional enzyme activities. Pretreatment with PB did not have any effect on sarin-inhibited brain regional AChE activity following treatment with 100 microg/kg sarin. These results show that prophylactic treatment with PB offers some degree of protection in peripheral cholinesterase. Furthermore, these results show that treatment with either sarin or PB alone resulted in sensorimotor impairments, while coexposure to high doses of sarin with PB caused an exacerbated deficit.
The primate striatum is composed of limbic, cognitive, and sensorimotor functional domains. Although the effects of cocaine have generally been associated with the ventral striatum, or limbic domain, recent evidence in rodents suggests the involvement of the dorsal striatum (cognitive and sensorimotor domains) in cocaine self-administration. The goals of the present studies were to map the topography of the functional response to cocaine throughout the entire extent of the striatum of monkeys self-administering cocaine and determine whether this response is modified by chronic exposure to cocaine. Rhesus monkeys were trained to self-administer 0.3 mg/kg per injection cocaine for 5 d (initial stages; n = 4) or 100 d (chronic stages; n = 4) and compared with monkeys trained to respond under an identical schedule of food reinforcement (n = 6). Monkeys received 30 reinforcers per session, and metabolic mapping was conducted at the end of the 5th or 100th self-administration session. In the initial phases of cocaine exposure, self-administration significantly decreased functional activity in the ventral striatum, but only in very restricted portions of the dorsal striatum. With chronic cocaine self-administration, however, the effects of cocaine intensified and spread dorsally to include most aspects of both caudate and putamen. Early experiences with cocaine, then, involve mainly the limbic domain, an area that mediates motivational and affective functions. In contrast, as exposure to cocaine continues, the impact of cocaine impinges progressively on the processing of sensorimotor and cognitive information, as well as the affective and motivational information processed in the ventral striatum.
OBJECTIVE: To determine if neurologic impairment is related to progressive autoimmune disease in 3 murine models of systemic lupus erythematosus (SLE): MRL/lpr, NZB, and NZB/WF1. METHODS: Sensorimotor function, learning, and memory were tested within strains at specific ages, before and after the appearance of SLE. These parameters were also compared between strains for young and older lupus mice and their congenic controls with reduced autoimmune disease (MRL/lpr versus MRL/+; NZB versus NZB/xid). RESULTS: Abnormal neurologic features were present at a much higher frequency in MRL/lpr mice than in age-matched MRL/+ control mice, and sensorimotor function deficits were also seen in NZB/WF1 mice. Strains that develop lupus showed deficits on a water-escape, distal cue discrimination task and on a food-rewarded, proximal cue discrimination task, but the cognitive impairments were not global. CONCLUSION: MRL/lpr, NZB, and NZB/WF1 mice differed in terms of which behaviors were impaired as well as when those impairments appeared.
The science of Tourette Syndrome (TS) is advancing at multiple levels of analysis and will be enhanced through the use of animal models. Particular challenges in the development of TS animal models reflect complex features of this disorder, including its waxing and waning course and its "invisible" sensory and psychic symptoms. Animal models can achieve face, predictive, or construct validity based on their particular features. Predictive validity, of most direct relevance to drug development for TS, is achieved to some degree by a several animal models, although the reliance of most of these models on measures of motor suppression may ultimately limit their utility. Other models achieve construct validity with proposed pathophysiological mechanisms related to the immune and neural circuit etiologies of TS. One model-deficient sensorimotor gating of the startle reflex-is discussed in terms of its present and future applications towards advancing our understanding of the pathophysiology and treatment of TS. In addition to models that will advance the pharmacotherapy of TS, other animal models may enhance the utility of nonpharmacologic TS treatments, ranging from behavior therapy to deep brain stimulation (DBS).
Mechanisms underlying the learned vocal behavior of songbirds were studied by examining expression of the protein product of the immediate early gene c-fos (Fos) in zebra finches. Auditory stimuli including the bird's own song did not induce Fos in the song system. In contrast, the motor act of singing induced Fos in two song sensorimotor nuclei, HVc and RA. This induction was independent of auditory feedback, since it occurred in deafened birds that sang. Double-labeling studies demonstrated that only one of the two sets of projection neurons in HVc expressed singing-related Fos. The motor-driven induction of Fos identifies functionally distinct cell populations in a network for singing and may point to sites of cellular plasticity necessary for song maintenance.
In studying brain activity during the behavior of living animals, it is not possible simultaneously to analyze all levels of control from molecular events to motor responses. To provide insights into how levels of control interact, we have carried out synthetic neural modeling using a brain-based real-world device. We describe here the design and performance of such a device, designated Darwin VII, which is guided by computer-simulated analogues of cortical and subcortical structures. All levels of Darwin VII's neural architecture can be examined simultaneously as the device behaves in a real environment. Analysis of its neural activity during perceptual categorization and conditioned behavior suggests neural mechanisms for invariant object recognition, experience-dependent perceptual categorization, first-order and second-order conditioning, and the effects of different learning rates on responses to appetitive and aversive events. While individual Darwin VII exemplars developed similar categorical responses that depended on exploration of the environment and sensorimotor adaptation, each showed highly individual patterns of changes in synaptic strengths. By allowing exhaustive analysis and manipulation of neuroanatomy and large-scale neural dynamics, such brain-based devices provide valuable heuristics for understanding cortical interactions. These devices also provide the groundwork for the development of intelligent machines that follow neurobiological rather than computational principles in their construction.
Unilateral damage to the forelimb region of the sensorimotor cortex (FLsmc) results in time-dependent changes in neuronal activity, structure and connectivity in the contralateral motor cortex of adult rats. These changes have been linked to facilitation of motor skill learning in the less-affected/ipsilesional forelimb, which is likely to promote its use in the development of behavioral compensation. The goal of this study was to determine whether an early post-lesion-sensitive time period exists for this enhanced learning and whether it is linked to synaptogenesis in the contralesional motor cortex. Rats were trained for 21 days on a skilled reaching task with the ipsilesional forelimb beginning 4 or 25 days after unilateral ischemic (endothelin-1-induced) FLsmc lesions or sham operations. As found previously, reaching performance was significantly enhanced in rats trained early post-lesion compared with sham-operates. In rats trained later post-lesion, performance was neither significantly different from time-matched sham-operates nor strikingly different from animals trained earlier post-lesion. In layer V of the contralesional motor cortex, stereological methods for light and electron microscopy revealed significantly more total, multisynaptic bouton and perforated synapses per neuron compared with sham-operates, but there were no significant differences between early- and late-trained lesion groups. Thus, there appears to be a sensitive time window for the maximal expression of the enhanced learning capacity of the less-affected forelimb but this window is broadly, rather than sharply, defined. These results indicate that relatively long-lasting lesion-induced neuronal changes are likely to underlie the facilitation of learning with the less-affected forelimb.
OBJECTIVE: To develop a highly reproducible rat model and behavioral tests for acute subdural hematoma (ASDH) and to investigate the role of intravascular coagulation and thrombin in the pathogenesis of brain injury in this model. METHODS: A new method was implemented to inject 200 microl of autologous blood subdurally in rats. Immunohistochemistry was used to investigate intravascular fibrin deposition and thrombin levels in the cortex underlying the ASDH. Effectiveness of systemic heparin, argatroban, or ginkgolide B treatment was determined by histological lesion volume, number of occluded microvessels, and neurological deficits. Neurological deficits were monitored for 7 days after ASDH by use of forelimb placing, forelimb use asymmetry, and corner turn tests. RESULTS: Consistent brain damage and sensorimotor deficits were observed in all animals with ASDH. Histological analysis demonstrated occluded microvessels and enlarged perivascular spaces in the underlying cortex starting 1 hour after hematoma induction. Fibrin and thrombin immunoreactivity were increased in the lesioned cortical parenchyma at 4 and 24 hours. However, no intravascular fibrin deposition was detected. Heparin induced hemorrhagic transformation in the cortical lesion and did not attenuate microvessel occlusion. Argatroban and ginkgolide B did not induce hemorrhage but failed to improve microvessel occlusion, lesion volume, and neurological deficits. CONCLUSION: Intravascular coagulation and thrombin are not the major mediators of brain damage after ASDH. The model and behavioral tests presented in this study can be used to investigate other putative mechanisms of injury and to test future therapeutic interventions in ASDH.
In this experiment, we report a novel drug-free behavioural test of lateralised neglect which is sensitive to unilateral dopamine-denervating lesions and subsequent graft-derived striatal dopamine replacement. For the task, white plastic lids containing sugar pellets were placed along the left and right sides of the floor of a long narrow corridor at regular intervals. Hungry female Sprague-Dawley rats were placed individually into the corridor where they were allowed to make up to 20 pellet retrievals. The number of retrievals each rat made from its left and right sides was counted. Complete mesencephalic or partial nigrostriatal lesions were induced by injection of 6-hydroxydopamine into the medial forebrain bundle or striatum, respectively. Both lesions induced a pronounced ipsilateral retrieval bias in the task. Five weeks after lesion surgery, half of the rats from each lesion group were given E14 ventral mesencephalic cell suspension transplants into the denervated striatum, and were then re-tested in the Corridor Task 5 and 10 weeks later. There was no amelioration of the side bias in rats with medial forebrain bundle lesions. In contrast, in nigrostriatal-lesioned rats, the graft significantly reduced the lesion-induced ipsilateral bias. We conclude that the Corridor Task is a sensitive test of lateralised sensorimotor response selection, and is suitable for assessing deficits and recovery associated with lesions and grafts within the nigrostriatal system.