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PubMed2005

Reduced prepulse inhibition of startle in STAT6-deficient mice.

To determine the role of STAT6 transcription factors in brain function, we performed a battery of mouse behavioral analyses of STAT6-deficient mice. We recently showed that STAT6-deficient mice displayed increased locomotor activities and had reduced levels of dopamine transporter (DAT) expression in the striatum. To further examine the behavioral effects of STAT6 deficiency, we subjected STAT6-deficient mice to behavior task testing prepulse inhibition (PPI) of the auditory startle response. In acoustic prepulse conditions, STAT6-deficient mice displayed significantly lower levels of PPI in acoustic startle than did wild-type mice, indicating their sensorimotor gating deficits. Thus, STAT6 transcription factors may be crucially implicated in sensorimotor gating by modulating the expression of several genes, including DAT in brain neurons.

Acoustic Stimulation↗
PubMed2001

Vasopressin-deficient rats exhibit sensorimotor gating deficits that are reversed by subchronic haloperidol.

BACKGROUND: Brattleboro (BB) rats are Long Evans rats with a single base pair genetic mutation that impairs their ability to synthesize vasopressin, a neurotransmitter and neurohormone. Brattleboro rats are known to have deficits in memory, emotional reactivity, motivation, attention, and social recognition, abnormalities associated with schizophrenia. Prepulse inhibition (PPI) of the acoustic startle reflex (ASR) is a measure of sensorimotor gating. Prepulse inhibition is deficient in unmedicated schizophrenia patients, and PPI deficits in schizophrenia may be related to the cognitive and behavioral abnormalities associated with this disorder. In this study we tested the hypothesis that BB rats exhibit PPI deficits analogous to those exhibited by schizophrenia patients. METHODS: In one experiment, BB rats homozygous (BB-Ho) or heterozygous (BB-Hz) for the mutated vasopressin gene were compared with normal Long Evans (LE) rats from the same breeder source. In separate studies, BB-Ho and LE rats were treated with acute or subchronic (22 days) injections of haloperidol. RESULTS: Both BB-Ho and BB-Hz rats had significantly higher ASR and significantly lower PPI compared with LE rats, with BB-Ho rats exhibiting the lowest PPI among all three genotypes. Furthermore, a single subcutaneous (SC) injection of haloperidol (0.5 mg/kg) did not reverse the PPI deficits in BB rats. In contrast, daily SC administration of haloperidol for 22 days reversed PPI deficits in BB rats. CONCLUSIONS: These results suggest that PPI deficient BB rats may be an important genetic model of PPI deficits, which may help elucidate genetic, pharmacologic, and pathophysiologic mechanisms underlying PPI deficits and the effects of antipsychotic drugs on PPI.

Animals↗
PubMed2001

A neural network approach to the acoustic startle reflex and prepulse inhibition.

Prepulse inhibition (PPI) is the normal suppression of the startle reflex when an intense stimulus is preceded by a weak non-startling prestimulus. PPI is widely used as a model for sensorimotor gating processes and has been shown to be impaired in various neuropsychiatric disorders, including schizophrenia. We have reproduced startle-like behavior and basic PPI modifications with a neural network. The network design was constrained by the attempt (1) to use as few connections as possible and (2) to relate neuroanatomical structures to the simulated network. Performance of the network was evaluated by the behavior of the simulated motor neurons in response to prepulse and pulse stimuli presented with various lead intervals and prepulse intensities. A delayed inhibitory pathway via the pedunculopontine nucleus (PPTg) to the caudal pontine reticular nucleus was found to be a necessary but insufficient requirement to reproduce basic PPI output patterns. Additional requirements included (a) a low threshold at or below the caudal pontine reticular formation, (b) signal amplification in the inhibitory pathway and (c) prolongation of activity in the inhibitory pathway. On the grounds of the most appropriate output patterns of the simulations, we propose a mechanism of sustained activation in the PPTg due to recursive connections. Relations between stimuli, behavior (motor output) and the underlying architecture are discussed. Potentially, this modeling technique can be extended to investigate the impact of drugs and higher brain regions on PPI.

Animals↗
PubMed1998

Cellular and functional recovery of Parkinsonian rats after intrastriatal transplantation of carotid body cell aggregates.

We have tested the suitability of chromaffin-like carotid body glomus cells for dopamine cell replacement in Parkinsonian rats. Intrastriatal grafting of cell aggregates resulted in almost optimal abolishment of motor asymmetries and deficits of sensorimotor orientation. Recovery of transplanted animals was apparent 10 days after surgery and progressed throughout the 3 months of the study. The behavioral effects were correlated with the long survival of glomus cells in the host brain. In host tissue, glomus cells were organized into glomerulus-like structures and retained the ability to secrete dopamine. Several weeks after transplantation, dopaminergic fibers emerged from the graft, reinnervating the striatal gray matter. The special durability of grafted glomus cells in the conditions of brain parenchyma could be related to their sensitivity to hypoxia, which is known to induce cell growth, excitability, and dopamine synthesis. This work should stimulate research on the clinical applicability of carotid body autotransplants in Parkinson's disease.

Amphetamine↗
PubMed2005

Neural correlates of spatial judgement during object construction in parietal cortex.

We recorded the activity of parietal area 7a neurons in monkeys performing an object construction task. In each trial, a model object consisting of a variable arrangement of squares was presented, followed after a delay by a copy of the model object that was missing a single square. Monkeys replaced the missing square to reconstruct the model configuration. Activity of many 7a neurons varied systematically with the position of the missing square and predicted where monkeys were going to add parts to the object they were building. The location of the missing square was a computed spatial datum important to object construction which did not correlate with the retinal location of a visual stimulus or the direction of the required motor response. The population of cells coding this coordinate was generally inactive when the same spatial locations were made relevant by visual targets to which monkeys either planned saccades or directed attention in other behavioral contexts. The data suggest that some parietal neurons participate in neural representations of space that reflect spatial cognitive as opposed to sensorimotor processing, coding the results of spatial computations performed on visual stimuli to meet cognitive objectives.

Animals↗
PubMed1992

Contrast sensitivity is increased in a case of nonparkinsonian freezing gait.

We measured spatiotemporal contrast sensitivity and gait variables in a 60-year-old man who had spontaneous episodes of freezing gait without any sign of rigidity or tremor. One major factor triggering freezing was the characteristics of visual space, as freezing episodes occurred during spontaneous walking and passing through apertures and never during walking with eyes closed. Initiation and maintenance of locomotion were greatly facilitated when transverse stripes with optimal intervals were placed on the ground in front of the patient. On the other hand, contrast sensitivity to low-to-intermediate spatiotemporal frequencies was increased in this patient when compared with that of elderly controls. These data suggest that hypersensitivity to visual stimulation and to modifications of the visual environment, associated with abnormal ocular motor behavior, can be one factor leading to the freezing gait phenomenon, which could be called "hypersensitivity braking" and be considered as a sensorimotor disorder.

Aged↗
PubMed2005

Treatment with magnesium improves reference memory but not working memory while reducing GFAP expression following traumatic brain injury.

PURPOSE: Previous studies have shown that administration of MgCl2 in animal models of brain injury significantly improves functional recovery: however, few studies have examined cognitive recovery. The present study evaluated the effect of MgCl2 pharmacotherapy on recovery of function following medial frontal cortex contusion injury. METHODS: Groups of rats were assigned to either MgCl2 (1.0 mmol/kg) or saline treatment conditions and prepared with contusion injuries or shams. Drug treatment was administered 15 min and 24 hr following injury. Rats were examined on tests of sensorimotor performance (bilateral tactile adhesive removal) and cognitive ability (reference and working memory). RESULTS: Administration of MgCl2 following injury significantly reduced the behavioral impairments observed on the bilateral tactile removal test. The acquisition of reference memory was also significantly improved compared to saline-treated rats; however, treatment did not improve working memory performance. Lesion analysis revealed that administration of MgCl2 did not significantly reduce lesion size compared to saline-treatment. Examination of glial fibrillary acidic protein (GFAP) expression showed that MgCl2 did significantly reduce the number of GFAP+ cells. CONCLUSION: These results indicate that MgCl2 administration significantly improved behavioral outcome following injury in a task dependent manner and reduced GFAP expression.

Animals↗
PubMed1989

[Mechanism of the action of the delta sleep-inducing peptide against a background of L-DOPA administration].

A reciprocal nature of the shifts in activity of type A and B monoamine oxidases has been observed under the effect of DSIP against the background of L-DOPA administration (50 micrograms/kg) in the subfractions from the rabbit sensorimotor cortex. The results suggest that the activation of type A monoamine oxidase and serotoninergic system is the basis of the adaptive behavior of animals.

Acetylcholinesterase↗
PubMed1997

Orphanin FQ acts as an anxiolytic to attenuate behavioral responses to stress.

Orphanin FQ (OFQ, Nociceptin) is a recently discovered 17-amino acid neuropeptide that is structurally related to the opioid peptides but does not bind opioid receptors. OFQ has been proposed to act as an anti-opioid peptide, but its widespread sites of action in the brain suggest that it may have more general functions. Here we show that OFQ plays an important role in higher brain functions because it can act as an anxiolytic to attenuate the behavioral inhibition of animals acutely exposed to stressful/anxiogenic environmental conditions. OFQ anxiolytic-like effects were consistent across several behavioral paradigms generating different types of anxiety states in animals (light-dark preference, elevated plus-maze, exploratory behavior of an unfamiliar environment, pharmacological anxiogenesis, operant conflict) and were observed at low nonsedating doses (0.1-3 nmol, intracerebroventricular). Like conventional anxiolytics, OFQ interfered with regular sensorimotor function at high doses (>3 nmol). Our results show that an important role of OFQ is to act as an endogenous regulator of acute anxiety responses. OFQ, probably in concert with other major neuropeptides, exerts a modulatory role on the central integration of stressful stimuli and, thereby, may modulate anxiety states generated by acute stress.

Animals↗
PubMed1990

Org2766 improves performance of rats with unilateral lesions in the fimbria fornix in a spatial learning task.

ACTH and related peptides are known for their effects on behavior and for their efficacy on peripheral nerve regeneration. More recently, evidence demonstrating neurotrophic effects of Org2766 on recovery after damage of the central nervous system has become available. Aging studies indicated that particularly the hippocampus appears susceptible to peptide treatment. Therefore, in this study the neurotrophic influence of Org2766 on recovery of hippocampal functioning was studied after transection of the fimbria fornix connection. Analogous to results obtained with recovery of sensorimotor function following peripheral nerve damage a chronic treatment with Org2766 facilitates recovery of the impaired function, i.e. spatial learning in a Morris maze. However, the lesion-induced impairment of avoidance behavior was not influenced by the peptide treatment.

Adrenocorticotropic Hormone↗
PubMed2001

Effects of chronic, post-injury Cyclosporin A administration on motor and sensorimotor function following severe, experimental traumatic brain injury.

PURPOSE: Cyclosporin A (CsA) is widely used in clinical situations to attenuate graft rejection following organ and central nervous system transplantation. Previous studies demonstrated that CsA administration is neuroprotective in models of traumatic brain injury (TBI). However, no studies, to date, have evaluated the influence of post-injury CsA administration on behavioral recovery after TBI. METHODS: Rats (n = 33) were anesthetized and subjected to severe, lateral fluid percussion brain injury. Fifteen minutes thereafter, animals were randomized to receive the first of 28 daily injections of either CsA (10 mg/kg, ip) or saline. Sham-operated animals (n = 14) were anesthetized and surgically prepared without injury and treated daily either with CsA or saline. Motor and sensorimotor functions were assessed at one day before and two days after injury, and weekly thereafter up to 4 wks post-injury. Cognition was assessed at 1 and 4 wks post-injury using a Morris Water Maze test. RESULTS: Injured animals showed significant impairments in motor, sensorimotor and cognitive function over the 4-week post-injury period. Injured animals treated with CsA showed a significant improvement in motor function assessed using a composite neuroscore (at day 28) and in sensorimotor function assessed using a sticky paper test (at days 2, 14, and 28) (p < 0.05, when compared to vehicle treated, injured animals). No beneficial effects on cognitive function were observed following CSA administration. CONCLUSION: These data suggest that daily post-injury treatment with CsA improves certain aspects of motor and sensorimotor function following experimental TBI.

Animals↗
PubMed1990

Distributed parallel processing in the vertical vestibulo-ocular reflex: learning networks compared to tensor theory.

The vestibulo-ocular reflex (VOR) is capable of producing compensatory eye movements in three dimensions. It utilizes the head rotational velocity signals from the semicircular canals to control the contractions of the extraocular muscles. Since canal and muscle coordinate frames are not orthogonal and differ from one another, a sensorimotor transformation must be produced by the VOR neural network. Tensor theory has been used to construct a linear transformation that can model the three-dimensional behavior of the VOR. But tensor theory does not take the distributed, redundant nature of the VOR neural network into account. It suggests that the neurons subserving the VOR, such as vestibular nucleus neurons, should have specific sensitivity-vectors. Actual data, however, are not in accord. Data from the cat show that the sensitivity-vectors of vestibular nucleus neurons, rather than aligning with any specific vectors, are dispersed widely. As an alternative to tensor theory, we modeled the vertical VOR as a three-layered neural network programmed using the back-propagation learning algorithm. Units in mature networks had divergent sensitivity-vectors which resembled those of actual vestibular nucleus neurons in the cat. This similarity suggests that the VOR sensorimotor transformation may be represented redundantly rather than uniquely. The results demonstrate how vestibular nucleus neurons can encode the VOR sensorimotor transformation in a distributed manner.

Animals↗
PubMed2006

Exaggerated behavioral phenotypes in Fmr1/Fxr2 double knockout mice reveal a functional genetic interaction between Fragile X-related proteins.

Individuals affected by Fragile X syndrome (FXS) experience cognitive impairment, hyperactivity, attention deficits, social anxiety and autistic-like behaviors. FXS results from the loss of expression of the Fragile X mental retardation (FMR1) gene, whose protein product FMRP is thought to play an important role in neuronal function and synaptic plasticity. Two paralogs of FMRP, FXR1P and FXR2P, have been identified, forming the Fragile X-related (FXR) family of proteins. Although the functions of FXR1P and FXR2P are not well understood, there are similarities among all three FXR proteins in gene structure, amino acid sequence, expression pattern and cellular functions. Mouse models have been described for loss of Fmrp, Fxr1p and Fxr2p, the mouse homologs of FMRP, FXR1P and FXR2P. In earlier studies, we found that Fmr1 knockout (KO) mice, which do not express Fmrp, and Fxr2 KO mice, which do not express Fxr2p, show similarities in some behavioral responses such as hyperactivity. To better understand the functional relationship between FMRP and FXR2P, we generated Fmr1 KO, Fxr2 KO, Fmr1/Fxr2 double KO and wild-type control mice as littermates on the same genetic background and examined them in several behavioral assays. Results show that Fmr1/Fxr2 double KO mice have exaggerated behavioral phenotypes in open-field activity, prepulse inhibition of acoustic startle response and contextual fear conditioning when compared with Fmr1 KO mice, Fxr2 KO mice or wild-type littermates. Our findings suggest that Fmr1 and Fxr2 genes contribute in a cooperative manner to pathways controlling locomotor activity, sensorimotor gating and cognitive processes.

Acoustic Stimulation↗
PubMed1995

Disorders of regulation of cognitive activity in autistic children.

Infantile autism is a pervasive developmental disorder characterized by disturbances concerning not only the areas of socialization and communication ("aloneness") but also the ability to modify and change behavior ("need for sameness"). In most recent studies, various abnormal and deviant cognitive activities, such as the ability to regulate one's behavior, were considered as accounting for these signs. In this report, we examined the regulation of cognitive activity, from a developmental perspective in comparing autistic with mentally retarded children matched in a pairwise manner by global, verbal, and nonverbal developmental ages. All children were tested with tasks adapted from the Object Permanence Test which corresponds to Piaget's sensorimotor development Stages IV to VI. Results showed that autistic children had a pervasive difficulty in maintenance set, made more perseverative errors when the abstraction degree of task was higher, and were more variable in their behavioral strategies. Discussion is focused on the interests and limits of these tasks for the examination of regulation activity from diagnostic and developmental perspectives. Finally, interpretations about recent neuropsychological and neurophysiological works, and additional interdisciplinary studies are suggested.

Attention↗
PubMed1999

Social behavior of juvenile rats after in utero exposure to morphine: dose-time-effect relationship.

In the present study, the effects of morphine exposure in utero on social behavior in juvenile male rats was investigated. Pinning, a measure for play behavior, and social grooming of the offspring were measured at postnatal day 21. The subjects were offspring of Wistar rat dams given sc. injections of 1 or 10 mg/kg body weight morphine HCl daily from gestational days 8 (GD8)-GD 21 and control dams injected daily with saline. Pinning and social grooming of the morphine-treated offspring were significantly elevated compared to saline controls. The doses of morphine used neither affected the gestation of pregnant mother rats nor sensorimotor development of the juvenile rats. Prenatal exposure to morphine of 10 mg/kg daily increased both pinning and social grooming, prenatal exposure to a lower dose of 1 mg/kg increased pinning behavior but not social grooming in the offspring. To study the importance of the gestational period, offspring of dams given 10 mg/kg body weight morphine HCl from GD8-GD15 and saline from GD16-parturition or morphine from GD16-parturition and saline from GD8-GD15 was tested. Pinning was only increased when morphine exposure occurred during the third week of gestation, social grooming was increased when morphine exposure had been in the second week of gestation. Subcutaneous administration of 1 mg/kg naltrexone 1 h before the test significantly decreased play behavior in control rats, but not in animals prenatally exposed to morphine. From these experiments we conclude that the long term effect of in utero exposure to morphine on play behavior is established by affecting the endogenous opioid system.

Age Factors↗
PubMed2006

Interregional long-range and short-range synchrony: a basis for complex sensorimotor processing.

Communication of distant brain areas provides the basis for integration of complex information in order to adapt to changes in the environment, to process this information, and to generate appropriate behavioral responses necessary for successful behavior in daily life. How is interregional communication realized in the brain? Perceptions and actions are likely to be represented in the brain by large numbers of distributed neurons firing in synchrony. This synchronous activity of distributed neuronal networks can be noninvasively evaluated by multichannel surface electroencephalography (EEG) and the event-related analysis of synchronous EEG signals in the frequency domain. In this chapter we will discuss the role of interregional synchronous activity and its relevance as a mechanism for implementation of successful human complex behavior exemplified within studies of complex finger movements, context-dependent control of complex motor behavior, bimanual motor tasks, visuo-tactile integration, and recovery of motor functions after stroke. These studies provide evidence that synchronous interregional neuronal activity, determined by event-related synchronization (ERS) and desynchronization (ERD), task-related power increases (TRPI) and decreases (TRPD), and event- and task-related coherence (ERCoh, TRCoh) analysis, is one important mechanism for cortical implementation of successful human complex behavior and adaptation to changes in daily life. These results are discussed in the light of recent findings in animal models, substantiating the view of the relevance of interregional synchronous activity for information coding and control of behavior.

Animals↗
PubMed1998

Behavioral studies of hallucinogenic drugs in animals: implications for schizophrenia research.

Schizophrenic and schizotypal patients exhibit deficits in the habituation and prepulse inhibition (PPI) of startle responses, providing operational measures of the sensorimotor gating or filtering deficits suggested to contribute to cognitive disorganization in these patients. In rats, hallucinogens, entactogens, and NMDA antagonists share the ability to both retard startle habituation and disrupt PPI. Extensive pharmacological studies in rats have indicated that the effects of hallucinogens on habituation are mediated by direct agonist actions at 5-HT2 receptors. The effects of the entactogens on both habituation and PPI reflect indirect agonist actions due to the stimulation of presynaptic serotonin release. These observations in rats have supported the development of 5-HT2A antagonists for the treatment of schizophrenia. Animal studies have shown that PPI is modulated by multiple interacting neurotransmitters, including dopaminergic, serotonergic, cholinergic, GABAergic, and glutamatergic systems within cortical, limbic, striatal, and brainstem structures. The effects of PCP and other NMDA antagonists on PPI are insensitive to either dopaminergic or serotonergic antagonists, but are reduced by atypical antipsychotics such as clozapine, olanzapine, and Seroquel. Thus, the PCP model of schizophrenia-like deficits in sensorimotor gating offers promise for the identification and neurobiological investigation of atypical antipsychotics. The cross-species study of homologous gating functions, such as habituation and PPI, in animal models and psychiatric patients provides novel opportunities for the exploration of neurobiological substrates relevant to the group of schizophrenias.

Animals↗
PubMed2001

Behavioral effects induced by acute exposure to benzo(a)pyrene in F-344 rats.

Polycyclic aromatic hydrocarbons (PAHs) are highly persistent environmental pollutants which pose potential adverse effects on human health. Benzo(a)-pyrene (B(a)P) is the prototypical representative of these widely dispersed lipophylic contaminants. (B(a)P) exposure in experimental animals results in an array of tissue- and organ-specific responses including carcinogenicity, teratogenicity, reproductive and immunotoxicity. However, no previous studies have examined the potential neurobehavioral toxicity of B(a)P in vivo. The present study was conducted to investigate the behavioral effects induced by single oral doses of (B(a)P) in 8-week-old male and female F-344 rats. Rats were exposed to 0, 12.5, 25, 50, 100 and 200 mg/kg of B(a)P by oral gavage. Motor activity measurements and the functional observational battery (FOB) were used to assess behavioral changes induced by B(a)P at 2, 4, 6, 8, 10, 12, 24, 48, 72 and 96 h post treatment. Statistical analyses revealed significant (p <0.001) dose, sex and time interactions. (B(a)P) doses ranging from 25 to 200 mg/kg produced a significant suppression (up to 60%) in four motor activity parameters: horizontal activity, total distance, stereotype and vertical activity in both sexes within 2 and 4h of dosing. B(a)P treated male and female animals also showed significant (p <0.001) changes in neuromuscular, autonomic, sensorimotor and physiological functions within 2 and 4h post B(a)P administration except in the 12.5 mg/kg treatment group. The 12.5 mg/kg dose did not produce significant (p > 0.05) behavioral toxicity in either males or females. All treated animals (25-200 mg/kg) recovered from the toxic effects of B(a)P by 72 h. Significant (p < 0.05) gender differences were noted in FOB test measures with males displaying greater sensitivity to B(a)P. These data suggest that motor activity and FOB measurements can be used as indices to detect B(a)P neurotoxicity.

Journal Article↗