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J Rochford

Publications and source records attributed to J Rochford.

At least 19 recordsLinked to original sources
PubMed2005

Effect of apolipoprotein E deficiency on reactive sprouting in the dentate gyrus of the hippocampus following entorhinal cortex lesion: role of the astroglial response.

This study investigated the effect of apolipoporotein E (apoE) deficiency on hippocampal reactive sprouting responses of the septohippocampal cholinergic (SHC) and commissural/associational fibers (C/A) following an electrolytic lesion of the entorhinal cortex (ECL), using apoE knockout (apoEKO) and age-matched control wild-type mice. Based on recent evidence suggesting that apoE plays a role in the modulation of glial inflammation, we also tested the hypothesis that the pattern of the astroglial response to ECL might be related to the defective reinnervation previously reported in apoEKO mice. Consistent with our hypothesis, we report a differential pattern of astroglial response that concurred with impairments in the sprouting of the SHC and corresponding synaptic replacement in apoEKO mice at 14 and 30 days post-lesion (DPL), a time range covering the onset of axonal/terminal sprouting to synaptogenesis. We also report a limited sprouting of the C/A fiber system in apoEKO relative to control mice at 30 DPL, a period of active dendritic remodeling. The results of the present study confirm and extend previous findings that apoEKO mice display impaired regenerative capacity in response to ECL and argue that in addition to the effect of apoE on lipid trafficking, apoE may also influence the astroglial response to damage, and that both of these effects account for the defective reinnervation observed in apoEKO mice.

Animals↗
PubMed2003

The cholesterol-lowering drug probucol increases apolipoprotein E production in the hippocampus of aged rats: implications for Alzheimer's disease.

Several recent epidemiological studies have proposed that cholesterol-lowering drug Statin may provide protection against Alzheimer's disease (AD). Probucol is a non-Statin cholesterol-lowering drug and a potent inducer of apolipoprotein E (apoE) production in peripheral circulation. A recent clinical study using Probucol in elderly AD subjects revealed a concomitant stabilisation of cognitive symptoms and significant increases in apoE levels in the cerebral spinal fluid in these patients. To gain insight into the mechanisms underlying these effects, we treated a cohort of aged male rats (26-month-old) with oral dose of Probucol for 30 days. Specifically, we examined the effects of Probucol on apoE production and its receptors (low density lipoprotein receptor [LDLr] and low density lipoprotein receptor-related protein [LRP]), astroglial marker of cell damage (glial fibrillary acidic protein [GFAP]), markers of neuronal synaptic plasticity and integrity (synaptosomal associated protein of 25 kDa [SNAP-25] and synaptophysin) as well as cholesterol biosynthesis (3-hydroxy-3-methylglutaryl coenzyme A reductase [HMGCoAr]) in the hippocampus. We report that Probucol induces the production of apoE and one of its main receptors, LRP, increases HMGCoAr (rate-limiting enzyme in cholesterol synthesis), substantially attenuates age-related increases in glial activation, and induces production of synaptic marker SNAP-25, a molecule commonly associated with synaptogenesis and dendritic remodeling. These findings suggest that Probucol could promote neural and synaptic plasticity to counteract the synaptic deterioration associated with brain aging through an apoE/LRP-mediated system. Consistent with the beneficial effects of other cholesterol-lowering drugs such as the Statin, Probucol could also offers additional benefits based on apoE neurobiology.

Aging↗
PubMed2002

Apolipoprotein E knockout mice display procedural deficits in the Morris water maze: analysis of learning strategies in three versions of the task.

Apolipoprotein E knockout (apoEKO) mice have been shown to be impaired in the spatial Morris water maze (MWM). However, several groups failed to replicate this finding. One reason for this inconsistency may stem from variations in the experimental protocols and environment between laboratories. In the present study, we have tested if age and variations in protocol implementation that specifically affect salience of the visual extramaze cues influence performance and navigational strategies in the MWM. We tested three- and 12-month-old apoEKO and wild type mice in three versions of the MWM differing on the availability of visual extramaze cues: (1) salient cues, (2) diffuse cues, and (3) absence of cues. Our results show that the presence of salient cues enhances acquisition performance of wild type, but not apoEKO mice in the MWM. This effect was restricted to the acquisition phase since apoEKO mice reached a level of performance that was comparable to that of controls toward the end of the task. No significant differences were detected between apoEKO and controls in either the diffuse cues or absence of cues paradigms. Thigmotaxic tendencies were observed in apoEKO mice and correlated high latency scores. Thigmotaxis may have interfered with the initial ability to engage in a proficient navigational strategy. These findings suggest that, in contrast to what has been proposed in the past, apoEKO mice appear not to be impaired in spatial memory per se but are deficient in a procedural component of the MWM. Furthermore, the procedural deficit and corresponding thigmotaxic tendencies of apoEKO mice appeared to increase with age. Taken together, these findings confirm our hypothesis that age and variations in experimental protocols can influence MWM performances.

Age Factors↗
PubMed2001

Dopaminergic activity in transgenic mice underexpressing glucocorticoid receptors: effect of antidepressants.

Transgenic mice bearing a transgene coding for a glucocorticoid receptor antisense mRNA, which partially blocks glucocorticoid receptor expression, were used to investigate the long-term effect of hypothalamic-pituitary-adrenal axis dysfunction on brain dopamine transmission. Compared to control mice, the transgenic animals showed increased amphetamine-induced locomotor activity and increased concentrations of striatal dopamine and its metabolites dihydroxyphenylacetic acid and homovanillic acid. Binding of [3H]SCH 23390 and [3H]spiperone to, respectively, D1 and D2 dopamine receptors was increased in transgenic mice. In contrast, autoradiography of striatal [3H]GBR 12935 binding to the dopamine transporter was decreased and the mRNA levels of this transporter, measured by in situ hybridization, remained unchanged in the substantia nigra pars compacta. The effect of chronic treatment for two weeks with amitriptyline or fluoxetine was compared in control and transgenic mice. No significant changes were observed in control mice following antidepressant treatment, whereas in transgenic mice both antidepressants reduced striatal [3H]SCH 23390 and [3H]raclopride specific binding to D1 and D2 receptors. Amitriptyline, but not fluoxetine, increased striatal [3H]GBR 12935 binding to the dopamine transporter, whereas its mRNA level in the substantia nigra pars compacta was decreased in fluoxetine, compared to vehicle- or amitriptyline-treated transgenic mice. From these results we suggest that hyperactive dopaminergic activity of the nigrostriatal pathway controls motor activity in the transgenic mice. Furthermore, antidepressant treatment corrected the increased striatal D1 and D2 receptors and decreased dopamine transporter levels in the transgenic mice.

Amitriptyline↗
PubMed2001

Central 5-hydroxytryptamine-2A receptor expression in transgenic mice bearing a glucocorticoid receptor antisense.

Transgenic mice bearing a transgene coding for a glucocorticoid receptor antisense mRNA that partially blocks glucocorticoid receptor expression were used to investigate the long-term effect of hypothalamic-pituitary-adrenal dysfunction on brain 5-hydroxytryptamine-2A (5-HT2A) receptor expression. The brain 5-HT2A receptor mRNA levels in transgenic mice were measured by in situ hybridization and compared to those in control mice. We also studied the effect of a 3-week treatment with fluoxetine on brain 5-HT2A receptor expression in the transgenic mice. No difference in 5-HT2A mRNA levels was observed between transgenic and control mice in cortical or striatal regions, and fluoxetine treatment was without effect. No difference in hypothalamic 5-HT2A mRNA levels was observed between transgenic and control mice, while fluoxetine treatment increased these levels in both transgenic as well as in the hypothalamic ventromedial and paraventricular nuclei of control mice. 5-HT2A receptor mRNA levels were similar in hippocampal CA1 and CA2 subregions of control and transgenic, but were lower in the CA3 and CA4 subregions of transgenic mice. Fluoxetine had no effect on 5-HT2A mRNA levels of transgenic mice but reduced control mouse 5-HT2A receptor mRNA levels in the CA3 subregion. These results suggest that impaired glucocorticoid receptor function can affect hippocampal 5-HT2A receptor expression in transgenic mice and that this is not corrected by fluoxetine treatment.

Animals↗
PubMed2000

Antidepressants preferentially enhance habituation to novelty in the olfactory bulbectomized rat.

RATIONALE: The mechanisms whereby antidepressant drugs exert their therapeutic effects remain unknown. Responses to stressful stimuli are currently thought to contribute to the onset and course of affective disorders. It has been postulated that antidepressants might act by ameliorating response patterns to challenging life events, such as processes of reactivity and/or habituation. OBJECTIVE: Using the olfactory bulbectomy (OBX) rat model, this study examined the effects of various antidepressants on measures of reactivity and habituation in behavioral tests assessing responses to novel stimuli. METHODS: Sham-operated and OBX rats received 21 daily injections of fluoxetine (10 mg/kg), amitriptyline (10 mg/kg), desipramine (10 mg/kg), buspirone (3 mg/kg), or vehicle. Forty-eight hours after the last injection, animals were tested in the open field, elevated plus maze, and startle apparatus. For each test, time series data were collected and fit with exponential random effects models, in which estimated parameters assessed behavioral reactivity and habituation. RESULTS: Relative to sham controls, OBX rats displayed increased total locomotor activity in the open field and exhibited increased open arm behavior in the elevated plus maze. Through comparison with zinc sulfate-treated anosmic controls, these OBX-induced increases were attributed to both an augmentation of initial reactivity due to anosmia and an attenuation of the average rate of habituation. Chronic antidepressant treatment did not reduce the anosmia-related initial reactivity levels of OBX rats to that of sham controls. Rather, the antidepressants evoked their restorative effects by increasing the rate of habituation. CONCLUSIONS: These findings suggest that antidepressants restore normal responding by permitting more effective adaptation to novel stimuli.

Animals↗
PubMed2000

Selective mu and delta, but not kappa, opiate receptor antagonists inhibit the habituation of novelty-induced hypoalgesia in the rat.

RATIONALE: There is now extensive evidence demonstrating that exposure to novel stimuli induces hypoalgesia and that this effect habituates over repeated exposure to the stimuli. Moreover, it has been shown that administration of the nonselective opiate receptor antagonist naloxone can attenuate the rate of habituation of novelty-induced hypoalgesia. OBJECTIVES: The present experiments were conducted to determine the relative influence of different opiate receptor subtypes in the attenuation of the habituation of novelty-induced hypoalgesia. METHODS: In experiments 1-3, different groups of male, Wistar rats (275-300 g) were administered vehicle, 0. 5, 1.0 or 2.0-nmol doses of the mu-selective antagonist Cys(2)-Tyr(3)-Orn(5)-Pen(7)-amide (CTOP), the delta-receptor selective antagonist naltrindole, or the kappa-selective antagonist nor-binaltorphimine (nor-BNI). In experiment 4, animals were administered vehicle, 5, 25 or 75-nmol doses of nor-BNI. All injections were delivered to the right lateral ventricle 30 min prior to exposure to a novel hot-plate apparatus (48.5 degrees C), once a day for eight consecutive days. RESULTS: Paw-lick latencies in vehicle-treated animals were long during the initial exposures and declined over repeated tests, suggesting the habituation of novelty-induced hypoalgesia. The rate of habituation was significantly attenuated by administration of 1.0-nmol and 2.0-nmol doses of CTOP, by a 2.0-nmol dose of naltrindole, but was unaffected by all doses of nor-BNI. CONCLUSIONS: These results support the involvement of the mu and delta, but not the kappa, opiate receptor subtypes in the habituation of novelty-induced hypoalgesia.

Animals↗
PubMed1999

Cholinergic systems and long-term potentiation in memory-impaired apolipoprotein E-deficient mice.

Impairments in cholinergic neurotransmitter systems of the basal forebrain are a hallmark of Alzheimer's disease pathophysiology. The presence of the epsilon4 allele of apolipoprotein E was recently implicated as a major risk factor in both familial and sporadic Alzheimer's disease. The present study examined the integrity of cholinergic and non-cholinergic systems in apolipoprotein E-deficient, memory-impaired mice. Choline acetyltransferase activity, hippocampal acetylcholine release, nicotinic and muscarinic (M1 and M2) receptor binding sites and acetylcholinesterase cell or terminal density showed no signs of alteration in either three-month or 9.5-month-old apolipoprotein E-deficient mice compared to controls. In contrast, long-term potentiation was found to be markedly reduced in these mice, but increases in the strength of stimulation induced the same level of long-term potentiation as that observed in controls. These alterations did not appear to be the consequence of modifications in the binding properties of glutamatergic receptors (N-methyl-D-aspartate and [RS]-alpha-amino-3-hydroxy-5-methylisoxazole propionic acid) but from defective regulation of the (RS)-alpha-amino-3-hydroxy-5-methylisoxazole propionic acid receptor by phospholipase A2 activity. These results support the notion that apolipoprotein E plays a fundamental role in neuronal plasticity, which could in turn affect cognitive performance through imbalances in extra- and intracellular lipid homeostasis.

Acetylcholine↗
PubMed1999

Lactation-induced reduction in rats' acoustic startle is associated with changes in noradrenergic neurotransmission.

The acoustic startle response (ASR) with or without fear conditioning was compared between cycling (CYC) and lactating (LACT) female rats. ASR sensitivity to changes in endogenous noradrenergic (NA) release was examined using the alpha-2 NA receptor drugs yohimbine and clonidine. Groups of CYC and LACT females were also tested in the open field. ASR was reduced in all LACT, compared with that in CYC females. Both groups exhibited a robust response to fear conditioning and unpotentiated ASR subsequent to conditioning was increased in LACT females. The lowest dose of yohimbine significantly increased ASR in LACT females, but not in CYC females. Clonidine reduced ASR in both groups of females, with a greater potency in CYC females. In the open field, LACT females displayed a shorter latency to emerge, less freezing behavior, and more entries into the field than did CYC females. The authors concluded that (a) LACT females are less anxious in a novel environment and that decreased anxiety can be efficiently counteracted by fear conditioning, and (b) changes in NA neurotransmission contribute to lactation-induced modifications in ASR.

Acoustic Stimulation↗
PubMed1998

NCAM-180 knockout mice display increased lateral ventricle size and reduced prepulse inhibition of startle.

NCAM-180 knockout mice, which have documented deficits in neural migration, were used to determine whether developmental abnormalities could lead to morphological changes and alterations in sensory motor gating mechanisms. Measurement of the lateral ventricle showed that NCAM-180-/- mice had marked increases in both the left and right anterior horns of the lateral ventricle. Furthermore, these mice also displayed a reduction of prepulse inhibition that was differentially affected by the dopamine agonist apomorphine. These results are discussed in light of the known increase in lateral ventricle size and reduction in prepulse inhibition that are seen in schizophrenia.

Acoustic Stimulation↗
PubMed1998

Reactivity to novelty in cognitively-impaired and cognitively-unimpaired aged rats and young rats.

Two distinct populations of aged, Long-Evans rats can be identified on the basis of performance in the Morris water maze task. Aged (24 month) unimpaired rats perform similarly to young (six month) animals. Aged, impaired rats display latencies to find the submerged platform greater than two standard deviations from the mean of the young animals. A hallmark of efficient cognitive processing is the ability to cope with environmental change. Consequently, the present studies were conducted to assess if aged, impaired animals display differential reactivity to repeated exposure to novel stimuli. Reactivity was assessed by examining the degree of (i) consumption of a novel gustatory/olfactory stimulus (sweetened milk), (ii) pain inhibition induced by exposure to a novel hot-plate (48.5 degrees C) apparatus and (iii) exploratory behaviour in an elevated plus maze and a novel open field. Aged, impaired rats exhibited lower milk consumption on day one and protracted reactivity (lower consumption over days two to eight) in comparison to aged, unimpaired and young animals. Aged, impaired rats were more reactive to novelty on the hot plate test (as indicated by longer paw lick latencies); this novelty-induced pain inhibition did not habituate in aged, impaired rats following repeated plate exposures. The degree of exploratory behaviour in both the plus maze and the open field was reduced in aged, impaired rats. This effect was not entirely a consequence of deficient affective mechanisms, as measures of anxiety (e.g., time in open arms, time in inner squares) were not different among aged impaired, aged unimpaired and young animals. These results are the first to demonstrate that behavioural deficits observed in aged, impaired animals extend beyond the impairments observed in the water maze. This behavioural profile is attributed, in part, to heightened anxiety. In addition, the impairments observed in aged, impaired animals may also reflect a reduced sensitivity to the positive incentive properties of novel stimuli.

Aging↗
PubMed1998

Responses to stress and novelty in adult rats born vaginally, by cesarean section or by cesarean section with acute anoxia.

The aim of this study was to test the hypothesis that alterations in birth conditions, specifically vaginal birth vs. birth by Cesarean section (C-section) vs. birth by C-section with an added period of acute global anoxia, produces long-term differences in behavioral responses to stress or novelty in the rat at adulthood. In comparison to animals born by rapid C-section alone, animals born by C-section with 10 or 15 min of added anoxia were significantly more immobile during forced swim stress administered for 6 trials over several weeks. In a step-down passive avoidance task, there were no group differences in acquisition or retention of the avoidance response. However, when initially placed in the passive avoidance apparatus before delivery of shock, animals born by C-section with 15 min of anoxia required significantly more pretrials to step down from the wooden platform, than did vaginally born or C-sectioned animals. No group differences were observed on measures of exploratory behavior in an elevated plus-maze or of approach behavior either to food or to a novel object in an open field. These findings suggest that birth conditions which include a degree of perinatal hypoxia can contribute to variability in selective responses to stress and novelty in the adult rat.

Acute Disease↗
PubMed1997

Spatial memory in transgenic mice with impaired glucocorticoid receptor function.

Spatial learning and memory function of transgenic mice with impaired glucocorticoid receptor function was assessed in the Morris water maze and the radial arm maze. Transgenic mice took longer to find a submerged and a visual platform in the water maze task than did mice from the parent strain (B6C/3F1), although performance was improved in the visible platform condition relative to the submerged platform task. In the radial arm maze, transgenic mice made significantly more errors than B6C/3F1 mice. In both tasks, the behavioural strategies adopted by transgenic mice were non-optimal for correct performance. It is suggested that the impaired performance displayed by transgenic mice in both tests is largely attributable to these altered behavioural strategies.

Animals↗
PubMed1997

Behavioral reactivity to aversive stimuli in a transgenic mouse model of impaired glucocorticoid (type II) receptor function: effects of diazepam and FG-7142.

Transgenic mice with impaired type II-glucocorticoid receptor mediated feedback inhibition of hypthalamic-pituitary-adrenal activity were assessed in three different tests assessing behavioral reactivity to aversive stimuli, the elevated plus maze, the Thatcher-Britton novelty-conflict paradigm, and the startle paradigm. Transgenic mice more frequently entered and spent more time in the open arms of the elevated plus in comparison to B6C/3F1 mice. Transgenic mice took significantly longer to begin eating in the Thatcher-Britton novelty conflict paradigm, and displayed increased reactivity in the startle paradigm. Administration of 1 or 2 mg/kg diazepam reversed the behavioral effects observed in all three tests. Administration of the benzodiazepine receptor inverse agonist N-methyl-beta-carboline-3 carboxamide (FG-7142, 10 mg/kg) reduced the ratio of open to total arm entries and the time spent in the open arms of the plus maze in transgenic, but not B6C/3F1, mice. This dose of FG-7142 did not influence performance of either strain in the Thatcher-Britton or startle paradigms. These results are discussed in terms of the hypothesis that the transgenic mice are more sensitive to the aversive properties of novel stimuli, and that they may have difficulty discriminating between signals of relative safety and danger.

Animals↗
PubMed1996

The effect of quisqualic acid-induced lesions of the nucleus basalis magnocellularis on latent inhibition.

Latent inhibition (LI) is a reduction in the rate of acquisition of a Pavlovian conditioned response that results from prior nonreinforced preexposure to a conditioned stimulus (CS). LI has been suggested to reflect the operation of mechanisms involved in stimulus selection for subsequent cognitive processing. The present experiment was conducted to assess the effect of bilateral lesions of the nucleus basalis magnocellularis (NBM) on LI employing a conditioned emotional response paradigm. Bilateral lesions of the NBM were produced by administration of 0.12 M quisqualic acid and resulted in decreased cortical acetylcholinesterase staining, as well as a 40% reduction in cortical choline acetyltransferase activity. Following lever press training, preexposed animals received 40 presentations of a 60-s tone CS. Nonpreexposed animals received no tone presentations. Acquisition of conditioned suppression was then assessed over the course of 4 tone-shock (0.6 mA, 0.5 s) pairings. Control, preexposed animals displayed a retarded rate of acquisition in comparison to nonpreexposed controls, thereby demonstrating that the parameters used in the present experiment produced LI. In contrast, lesioned animals preexposed to the CS acquired conditioned suppression as readily as nonpreexposed lesioned animals. However, the acquisition of conditioned suppression in both lesioned groups was found to be similar to that displayed in the preexposed control group. This pattern of results was interpreted as being attributable to a lesion-induced impairment in the ability to maintain stimulus processing, rather than a deficit in the ability to filter a stimulus.

Acetylcholinesterase↗
PubMed1996

Effect of nicotine and nicotinic receptor agonists on latent inhibition in the rat.

The present experiments assessed the influence of nicotinic cholinergic receptors on latent inhibition (LI), which is the decrement in Pavlovian conditioning resulting from extensive preexposure to a conditioned stimulus (CS). LI was assessed within a conditioned emotional response paradigm involving three phases: preexposure [either 0 (nonpreexposed) or 60 (preexposed) presentations of a 60 sec tone], conditioning (two-tone, 0.6 mA; 0.5-sec footshock pairings) and test (assessment of CS-induced suppression of lever press responding). LI was obtained in that untreated preexposed-animals displayed less conditioned suppression compared to nonpreexposed controls. Administration of nicotine (0.4 mg/kg i.p.) augmented LI when administered during conditioning. In addition, nicotine enhanced LI when administered during preexposure, suggesting that nicotine can enhance the ability of an animal to filter irrelevant stimuli. The nicotinic agonists cytisine (5 mg/kg) and lobeline (10 mg/kg) also augmented LI. Nicotine did not influence the behavior of nonpreexposed animals, suggesting that nicotine's effect was specific to mechanisms mediating LI. The nicotinic antagonists hexamethonium (10 mg/kg) and mecamylamine (5 mg/kg) reversed nicotine's enhancement of LI. Finally, nicotine's effect on LI was found to depend upon CS preexposure parameters; nicotine attenuated, rather than enhanced, the LI observed after 40 presentations of a 5-sec CS. These results suggest that stimulation of nicotine receptors can either amplify or curtail the efficacy of mechanisms involved in filtering irrelevant stimuli from further cognitive processing and that the direction of this modulation depends on the CS preexposure parameters.

Alkaloids↗
PubMed1995

Transplants to the cerebral cortex of nucleus basalis magnocellularis-lesioned rats: effects on deficits in latent inhibition.

Bilateral quisqualic acid-induced lesions of the nucleus basalis magnocellularis (nbm) in rats disrupted the expression of latent inhibition, a phenomenon thought to be dependent upon selective attention processes. Since grafts of adrenal chromaffin cells to the cerebral cortex of nbm-lesioned rats have been shown to ameliorate other lesion-induced cognitive deficits, we tested here whether expression of latent inhibition could be reinstated by graft placement. Interestingly, grafts of either chromaffin cells or cells from kidney or liver that have been used previously as control grafts, were able to restore latent inhibition in lesioned animals. These results suggest that it may be a host response to graft placement rather than a factor supplied by the grafted tissue itself that is responsible for the amelioration of lesion-induced deficits of latent inhibition.

Adrenal Medulla↗