Biomedical subjects

T J Gould

Publications and source records attributed to T J Gould.

At least 19 recordsLinked to original sources

PubMed2002

Effects of hippocampal lesions on patterned motor learning in the rat.

Motor skill learning in rats has been linked to cerebellar function as well as to cortical and striatal influences. The present study evaluated the contribution of the hippocampus to motor learning. Adult male rats received electrolytic lesions designed to selectively destroy the hippocampus; a sham-lesioned group of animals served as a control. The animals with hippocampal lesions acquired a patterned motor learning task as well as sham controls. In contrast, rats with hippocampal lesions were impaired in spatial, but not cued, learning in the Morris water maze. In addition, lesioned rats showed profound impairment in the novel object recognition memory task, when a 1-h delay was used between training and testing. Taken together, these results suggest that the hippocampus is not necessary during acquisition of the motor learning task.

Animals↗

PubMed2002

MK-801 disrupts acquisition of contextual fear conditioning but enhances memory consolidation of cued fear conditioning.

The effects of pre-training or post-training subcutaneous injections of multiple doses of the non-competitive NMDA-receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) on cued and contextual fear conditioning were examined in F344 rats. Pre-training injections of MK-801 (0.3 and 1.0 mg/kg) disrupted contextual fear conditioning but not cued fear conditioning. Post-training injections of MK-801 did not disrupt cued or contextual fear conditioning. In fact, the 0.3 mg/kg dose of MK-801 enhanced cued fear conditioning. Finally, rats were tested for MK-801-induced alterations in sensitivity to pain using the formalin test for nociception. MK-801 did not reduce sensitivity to pain. These results suggest that NMDA receptors are involved in acquisition of contextual fear conditioning but not in memory consolidation of the learned response.

Animals↗

PubMed2001

Differential sensitivity to lithium's reversal of amphetamine-induced open-field activity in two inbred strains of mice.

To determine whether genetic differences could contribute to the pharmacological sensitivity of lithium chloride (LiCl) to reverse amphetamine-associated changes in behavior C57BL/6nCrlBR and C3H/HenCrlBR male mice were tested for the ability of an acute dose of LiCl to reverse the locomotor enhancing effects of an acute dose of amphetamine. A series of experiments were conducted that compared dose response of LiCl, chamber lighting conditions, and chamber shape on amphetamine-induced activity in two strains of mice with different genetic backgrounds. Acute amphetamine (3 mg/kg) increased locomotor activity in C57BL/6nCrlBR mice and LiCl (1-4 mEq/kg) blocked this effect. LiCl-induced changes in baseline activity seen at high doses of LiCl were not seen for the low doses. The dark condition reduced time resting but chamber shape did not appear to alter results. In C3H/HenCrlBR mice, amphetamine did not significantly increase levels of activity but did decrease rearing behavior which suggests that genetic difference between C57BL/6nCrlBR and C3H/HenCrlBR mice may contribute to sensitivity to amphetamine. In sum, the ability of LiCl to reverse amphetamine-induced changes in locomotor activity in C57BL/6nCrlBR mice may provide a useful model to study genetic and pharmacological aspects of psychiatric illnesses such as bipolar disorder.

Amphetamines↗

PubMed2001

Nicotine enhances latent inhibition and ameliorates ethanol-induced deficits in latent inhibition.

Alcohol and nicotine are drugs of abuse that are used frequently together. One possible explanation for this co-administration is that nicotine prevents or lessens alcohol-associated impairments. The present study examined the dose-dependent effects of acute administration of nicotine, alcohol, or alcohol plus nicotine on latent inhibition as measured by lick suppression in C57BL/6 mice. Alterations in a lick suppression ratio were measured by assessing the effects of 10 pre-exposures to an auditory conditioned stimulus (CS) on formation of subsequent CS-shock unconditioned stimulus (US) associations. Mice pre-exposed to the CS were expected to develop a weaker CS-US association. Nicotine administered prior to pre-exposure to the CS produced increased suppression ratios, ethanol given prior to pre-exposure to the CS decreased suppression ratios, and nicotine reversed the effects of ethanol when the two drugs were co-administered. These opposing actions of nicotine and ethanol may have relevance to the high incidence of smoking and drinking in humans.

Animals↗

PubMed2000

Behavior and mutagenesis screens: the importance of baseline analysis of inbred strains.

Random mutagenesis as a means of identifying the function of genes has been used extensively in a variety of model organisms. Until recently it has been used primarily in the identification of single-gene traits that cause visible and developmental mutations. However, this genetic approach also has the power to identify genes that control complex biological systems such as behavior. Mutagenesis screens for behavioral mutations require careful consideration of many factors, including choice of both assays and background strains for use in mutagenesis and subsequent mapping of the affected gene or genes. This paper describes behavioral assays for monitoring motor coordination on the accelerating rotarod, anxiety-related behaviors in the elevated zero maze and sensorimotor reactivity, gating, and habituation of acoustic startle. These five physiological or neurological behaviors can represent potential endophenotypes for a variety of neurological and psychiatric disorders. The significant degree of strain- and sex-specific differences in the performance of four inbred strains of mice (C57BL/6J, C3HeB/FeJ, DBA/2J, and 129/SvlmJ) in these behavioral assays illustrates the importance of performing baseline analysis prior to behavioral mutagenesis screens and genetic mapping of selected mutations.

Animals↗

PubMed1999

Nicotine enhancement of contextual fear conditioning.

Nicotine has been suggested to have cognitive enhancing effects. The present study examined the effects of nicotine and the nicotinic antagonist mecamylamine on contextual fear conditioning in C57BL/6 mice. The fear conditioning task was chosen because the task examines two types of learning: contextual learning, and conditioned stimulus (CS)-unconditioned stimulus (US) learning. Multiple doses of nicotine were tested and 0.5 mg/kg nicotine, given on both training and testing days, improved contextual learning but had no effect on formation of an auditory CS-US association. No effect was found at lower doses or when nicotine was given on training day only, or testing day only. The nicotinic receptor antagonist mecamylamine (1 and 2 mg/kg) did not alter contextual fear conditioning but mecamylamine did prevent the nicotine-associated increase in contextual learning. A higher dose of nicotine (1 mg/kg, training day only) interfered with contextual conditioning when the context was paired with both the CS and US, but had no effect on the auditory CS-US association. This effect of 1 mg/kg nicotine on contextual learning disappeared when mice were trained without the CS. The present results indicate that nicotine enhancement of contextual fear conditioning is dose-dependent, but the presence of nicotine is required both during training and testing.

Animals↗

PubMed1999

Genetic influences on latent inhibition.

The present study examined the development of latent inhibition in a number of inbred strains of mice. C57BL/6J, DBA/2J, C3H/Ibg, BALB/cByJ, A/J, CBA/J, 129/SvevTac, 129/SvJ, and AKR/J mice were screened for the development of latent inhibition. The latent inhibition paradigm involved 1 day of either 40 preexposures to the conditioned stimulus (CS) or no preexposure. On the following training day, the CS was twice paired with a shock unconditioned stimulus (US). On a subsequent test day, the strength of the CS-US association was measured. Mice preexposed to the CS should show a weaker CS-US association, which would reflect development of latent inhibition. Significant between-strain differences existed. The 129/Svev, C57BL/6, BALB/cByJ, AKR, and DBA/2 mice developed latent inhibition, but 129/SvJ, CBA, A, and C3H mice did not. Thus, genetic variance contributes to variability in the development of latent inhibition.

Animals↗

PubMed1998

Antioxidant protection of cerebellar beta-adrenergic receptor function in aged F344 rats.

We examined whether a 2-week treatment with the spin-trapping agent MDL 101.002 (MDL) or a diet supplemented with vitamin E (Vit E) would alleviate age-related deficits in cerebellar noradrenergic function of male 18-20 month old F344 rats compared to age-matched controls. Cerebellar beta-adrenergic receptor function was assessed using extracellular recordings of Purkinje cells during iontophoresis of GABA and isoproterenol (ISO). Noradrenergic receptor function of MDL and Vit E-treated rats was similar to young rats whereas for non-treated rats it was typical of that previously recorded in aged rats. Thus, treatment with MDL or Vit E reverses age-related deficits in cerebellar noradrenergic receptor function.

Age Factors↗

PubMed1998

Beta-adrenergic involvement in acquisition vs. extinction of a classically conditioned eye blink response in rabbits.

Beta-adrenergic involvement in classical conditioning and extinction was investigated. Five groups of rabbits (saline, 1, 3, 5 or 10 mg kg(-1) of the beta-adrenergic antagonist propranolol) were trained with a tone conditioned stimulus (CS) paired with a corneal air puff unconditioned stimulus (US). Both 5 mg kg(-1) and 10 mg kg(-1) propranolol delayed acquisition of conditioned responses but all groups were able to learn the task to criterion. Consistent changes were not seen during extinction.

Adrenergic beta-Antagonists↗

PubMed1997

Beta-adrenergic modulation of GABAergic inhibition in the deep cerebellar nuclei of F344 rats.

The presence of norepinephrine (NE) and NE activated cells, in the deep cerebellar nuclei (DCN) of male F344 rats, was investigated using immunohistochemistry and electrophysiology, during iontophoresis of the beta-adrenergic agonist isoproterenol (ISO). During extracellular electrophysiology, GABA was iontophoretically applied to the cell and ISO was then co-applied in an attempt to modulate the GABAergic inhibition of cell firing in the DCN. Immunohistochemistry was used to detect tyrosine hydroxylase (TH) positive fibers in the DCN. Isoproterenol modulated GABAergic inhibition in 51% of the DCN cells recorded from. In addition, TH-positive fibers that appeared to make contact with DCN cells were found. Therefore, this study demonstrated that functional NE receptors exist in the DCN and NE appears to be present in fibers therein.

Adrenergic Fibers↗

PubMed1997

Age-related deficits in the cerebellar beta adrenergic signal transduction cascade in Fischer 344 rats.

Localization of age-related deficits in the cerebellar beta adrenergic signal transduction cascade were investigated electrophysiologically using forskolin (FORSK) and adenosine-3',5'-cyclic monophosphothioate Sp-isomer (Sp-cAMPS) applied via pressure ejection from extracellular multibarreled glass electrodes to activate the transduction cascade. In young rats, 100 microM FORSK activated AC, and 100 microM Sp-cAMPS activated protein kinase A; thus, both increased GABAergic inhibition of Purkinje cell firing. In aged rats, however, 100 microM FORSK was unable to increase GABAergic inhibition of Purkinje cell firing. In addition, 1 mM 7 beta-decacetyl-7 beta-(gamma-N-methylpiperazino)butyryl-forskolin, an analog of FORSK, was also unable to increase GABAergic inhibition in aged rats. In contrast, Sp-cAMPS was able to increase GABAergic inhibition in aged rats, but higher doses were required than in young rats, Isoproterenol (ISO), a beta adrenergic agonist, was ineffective in increasing GABAergic inhibition of Purkinje firing in aged rats when tested alone, but ISO was effective in increasing Purkinje cell inhibition when ISO was tested with Sp-cAMPS. The results of this experiment indicate that one age-related deficit in the cerebellar beta adrenergic system occurs at the level of protein kinase A activation.

Aging↗

PubMed1996

The effects of aging on cerebellar beta-adrenergic receptor activation and motor learning in female F344 rats.

Female Fischer 344 (F344) rats were tested for age-related differences in both cerebellar beta-adrenergic receptor activation and motor learning. Three and 20 month old rats were tested on a motor learning paradigm that required the rats to adjust their gait to navigate a runway of unevenly spaced pegs. Rates of acquisition were compared between age groups. After behavioral testing, cerebellar beta-adrenergic receptor function was assessed using extracellular recordings of Purkinje cells during iontophoresis of GABA and isoproterenol (ISO). Aged female rats showed deficits in motor learning and in beta-adrenergic receptor activation. In young rats, ISO modulated GABAergic inhibition of Purkinje cell firing in more cells compared with aged rats. Thus, aging produces deficits in both motor learning and in beta-adrenergic receptor activation in aged female F344 rats.

Action Potentials↗

PubMed1996

Changes in rabbit cerebellar cortical and interpositus nucleus activity during acquisition, extinction, and backward classical eyelid conditioning.

Multiple- and single-unit neuronal activities were recorded from cerebellar cortex (Larsell's lobule HVI and adjacent ansiform cortex) and the cerebellar interpositus nucleus during forward (CS-US), backward (US-CS), and explicitly unpaired classical eyeblink conditioning in several rabbits. Whereas learning-related activity was observed in the interpositus nucleus only during forward pairing of the conditioning stimuli, a variety of patterns of learning-related neuronal firings were observed in cerebellar cortex during forward, backward, and even unpaired presentations of the conditioning stimuli. These data suggest that the cerebellar cortex and the deep cerebellar nuclei play different roles during classical eyeblink conditioning.

Animals↗

PubMed1996

Acquisition of a runway motor learning task is impaired by a beta adrenergic antagonist in F344 rats.

Performance of rats on a motor learning paradigm that has been demonstrated to be dependent upon cerebellar norepinephrine (NE) was studied in male F344 rats treated with an alpha 1 antagonist (prazosin), an alpha 2 antagonist (yohimbine) or a beta noradrenergic antagonist (propranolol). The ability of propranolol-treated rats (10 mg/kg i.p. 30 min prior to daily testing) to acquire proficiency on the novel motor task was impaired while prazosin-treated rats' (0.5 mg/kg i.p. 30 min prior to daily testing) and yohimbine-treated rats' (1 mg/kg i.p. 30 min prior to daily testing) rates of acquisition of the novel motor task were not different from controls. In an attempt to distinguish between alterations in motor coordination and motor learning, additional tests of psychomotor performance were assessed for all groups of rats. These examinations included a walking test on 2.5 and 5 cm rods and speed of running on the motor task. The data indicate that drug-treated rats show no difference from controls on the above parameters. Some differences, however, were observed between propranolol and controls in the time spent in the goal box. Overall, the data are consistent with our hypothesis that the beta noradrenergic receptor is involved in the ability to acquire novel motor tasks.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed1996

Effect of levodopa and carbidopa on recovery of visual function in patients with nonarteritic anterior ischemic optic neuropathy of longer than six months' duration.

PURPOSE: We conducted a pilot clinical trial to determine the efficacy of levodopa in promoting visual recovery in eyes with nonarteritic anterior ischemic optic neuropathy of greater than six months' duration. METHODS: This prospective, randomized, double-masked, placebo-controlled clinical trial involved 20 subjects with nonarteritic anterior ischemic optic neuropathy of 30 months' mean duration. Subjects were randomly assigned to receive either low-dose levodopa and carbidopa or a placebo for three weeks. At 12 weeks after the baseline visit, the levodopa group then was provided a higher, conventional dose of levodopa and carbidopa for three more weeks. Change in visual function was monitored at four, 12, 16, and 24 weeks after the baseline visit. RESULTS: At 12 weeks after the baseline visit, the levodopa group experienced a significant (P = .016) mean difference in improvement of visual acuity of 5.9 letters from the placebo group. At 24 weeks after the baseline visit, a significant treatment effect (P = .036) for visual acuity was still evident; the levodopa group had a mean gain in improvement of 7.5 letters difference from baseline from the placebo group. Three subjects in the levodopa group experienced a doubling of the visual angle as denoted by a gain of at least 15 letters. Significant improvement was not observed for color vision (P = .82) or mean deviation of visual field loss (P = .82). CONCLUSION: The study found significant improvement of visual acuity among subjects receiving levodopa and carbidopa despite long-standing visual loss from nonarteritic anterior ischemic neuropathy. Confirmation of our results is awaited from larger population studies and with a longer follow-up time interval regarding the efficacy of levodopa in reversing visual loss in this disease.

Aged↗

PubMed1996

Intrasellar vascular malformation mimicking a pituitary macroadenoma.

We report the case of a 61-year-old man with an unusual intrasellar vascular malformation, who presented with symptoms of hypopituitarism and whose neuroradiologic evaluation mimicked a pituitary macroadenoma. The histopathologic and radiologic findings are discussed. This rare lesion should be considered in the diagnosis of a sellar mass lesion.

Adenoma↗

PubMed1995

Effects of dietary restriction on motor learning and cerebellar noradrenergic dysfunction in aged F344 rats.

Fisher 344 rats were fed either ad libitum or with a diet containing a 40% reduction of calories beginning at 4 months of age. At 14 months and 22 months male rats were tested for their ability to learn a complex motor skill. At both ages the diet restricted rats reached criterion of performing 10 successful crosses in 10 min at an earlier time than ad libitum fed controls. At 22 months of age the diet restricted rats showed improved acquisition of running times for the task. Male rats at 14 and 22 months and female rats at 24 months were examined electrophysiologically for the ability of isoproterenol to augment the action of GABA in the cerebellum when both substances were applied iontophoretically from an extracellular multibarreled glass electrode. In all 3 age and sex groups there was an improvement in the beta-adrenergic receptor modulation of GABA responses in the dietary restricted vs. ad libitum rats. However, no difference was observed between dietary restricted and ad libitum rats when the number and affinity of cerebellar beta-adrenergic receptors was assessed with 125I-iodopindolol binding. Overall, there was a significant improvement in cerebellar noradrenergic function in the dietary restricted rats and this was accompanied by an improvement in motor learning.

Age Factors↗

PubMed1994

The effects of chronic treatment with N-tert-butyl-alpha-phenylnitrone on cerebellar noradrenergic receptor function in aged F344 rats.

We examined if a 2 week treatment with the spin trapping agent N-tert-butyl-alpha-phenylnitrone (PBN) would alleviate age-related deficits in cerebellar noradrenergic function of male 21-22 month old F344 rats compared to age-matched controls. Noradrenergic receptor function of PBN-treated rats was similar to young rats whereas for non-treated rats it was typical of that previously recorded in aged rats. Thus, treatment with PBN may reverse age-related deficits in cerebellar noradrenergic receptor function.

Aging↗