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D M Diamond

Publications and source records attributed to D M Diamond.

At least 19 recordsLinked to original sources
PubMed2003

Simultaneous induction of long-term potentiation in the hippocampus and the amygdala by entorhinal cortex activation: mechanistic and temporal profiles.

The medial temporal lobe, including the entorhinal cortex, the amygdala and the hippocampus, has an important role in learning and memory, and its circuits exhibit synaptic plasticity (long-term potentiation [LTP]). The entorhinal cortex is positioned to exert a potent influence on the amygdala and the hippocampus given its extensive monosynaptic projections to both areas. We therefore studied the effects of activation of the entorhinal cortex with simultaneous recording of LTP in the hippocampus and amygdala in the anesthetized rat. theta Burst stimulation of the lateral entorhinal cortex induced LTP simultaneously in the basal amygdaloid nucleus and in the dentate gyrus. However, the mechanisms involved in the induction of LTP in the two areas differed. The N-methyl-D-aspartate receptor antagonist 3-[(+/-)-2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid delivered 1 h before LTP induction (10 mg/kg, i.p.), blocked LTP in the dentate gyrus but not in the amygdala. In addition we found that the basal amygdala as well as the dentate gyrus sustained late-phase LTP (10 h) which may participate in memory encoding and/or modulation processes. Overall, the results suggest a coordinating role for the entorhinal cortex by simultaneously modulating activity and plasticity in these structures, albeit through different mechanisms. Interactive encoding of this sort is believed to endow memories with a different, more integrative, quality than when either pathway is activated alone.

Amygdala↗
PubMed2003

Short-term beta-amyloid vaccinations do not improve cognitive performance in cognitively impaired APP + PS1 mice.

Prior work demonstrated that beta-amyloid (A beta) immunotherapy for 8 months prevented cognitive impairment in 16-month-old APP + PS1 transgenic mice. In the present study, 4 immunizations administered biweekly to cognitively impaired 16-month-old transgenic mice could not reverse deficits in working memory or reference memory in the radial arm water maze or in visual platform recognition, possibly because of inadequate antibody exposure. Nontransgenic mice showed cognitive savings between the 16- and 18-month test periods, but the transgenic groups did not. These results suggest that a longer period of active immunotherapy, or passive immunization, may be required to provide sufficient antibody titers to improve cognition in older transgenic mice. A beta-based immunotherapy for Alzheimer's disease will likely be more successful prophylactically than therapeutically.

Amyloid beta-Peptides↗
PubMed2001

Chronic psychosocial stress impairs learning and memory and increases sensitivity to yohimbine in adult rats.

BACKGROUND: It is well known that intense and prolonged stress can produce cognitive impairments and hippocampal damage and increase noradrenergic activity in humans. This study investigated the hypothesis that chronic psychosocial stress would affect behavior, drug sensitivity, and hippocampal-dependent learning and memory in rats. The work provides a novel connection between animal and human studies by evaluating the effects of stress on a rat's response to yohimbine, an alpha(2) adrenergic receptor antagonist. METHODS: Rats were exposed to a cat for 5 weeks and randomly housed with a different group of cohorts each day (psychosocial stress). The effects of the stress manipulations were then assessed on open field behavior, spatial learning and memory in the radial arm water maze and the behavioral response to a low dose of yohimbine (1.5 mg/kg). RESULTS: Stressed rats displayed impaired habituation to a novel environment, heightened anxiety, and increased sensitivity to yohimbine. In addition, the stressed rats exhibited impaired learning and memory. CONCLUSIONS: There are commonalities between the current findings on stressed rats and from studies on traumatized people. Thus, psychosocial stress manipulations in rats may yield insight into the basis of cognitive and neuroendocrine disturbances that commonly occur in people with anxiety disorders.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed2001

Progressive, age-related behavioral impairments in transgenic mice carrying both mutant amyloid precursor protein and presenilin-1 transgenes.

This study provides a comprehensive behavioral characterization during aging of transgenic mice bearing both presenilin-1 (PS1) and amyloid precursor protein (APP(670,671)) mutations. Doubly transgenic mice and non-transgenic controls were evaluated at ages wherein beta-amyloid (Abeta) neuropathology in APP+PS1 mice is low (5-7 months) or very extensive (15-17 months). Progressive cognitive impairment was observed in transgenic mice for both water maze acquisition and radial arm water maze working memory. However, transgenicity did not affect Y-maze alternations, circular platform performance, standard water maze retention, or visible platform recognition at either age, nor did transgenicity affect anxiety levels in elevated plus-maze testing. In sensorimotor tasks, transgenic mice showed a progressive increase in open field activity, a progressive impairment in string agility, and an early-onset impairment in balance beam. None of these sensorimotor changes appeared to be contributory to any cognitive impairments observed, however. Non-transgenic mice showed no progressive behavioral change in any measure evaluated. Given the age-related cognitive impairments presently observed in APP+PS1 transgenic mice and their progressive Abeta deposition/neuroinflammation, Abeta neuropathology could be involved in these progressive cognitive impairments. As such, the APP+PS1 transgenic mouse offers unique opportunities to develop therapeutics to treat or prevent Alzheimer's Disease through modulation of Abeta deposition/neuroinflammation.

Aging↗
PubMed2001

Corticosterone-attenuating and anxiolytic properties of mecamylamine in the rat.

1. The available evidence suggests that stress induced release of acetylcholine (ACh) in the brain has a significant role in mediating neuroendocrine, emotional, and physiological responses to stress. Recent findings also suggest that stress indirectly (via acetylcholine) and nicotine directly stimulates the HPA axis through activation of nAChRs. 2. Our working hypothesis is that under stressful conditions, nicotinic receptor antagonists, such as mecamylamine, should act to attenuate the activation of the HPA axis and exhibit anxiolytic behavioral effects. The purpose of this study was to determine whether or not mecamylamine would: a) produce anxiolytic effects in rats on the elevated plus maze and b) blunt the plasma corticosterone response to predator stress in rats. 3. Results suggested that mecamylamine has anxiolytic properties under stressful conditions. In the EPM experiment, mecamylamine (0.3 mg/kg) produced increased time spent in the open arms. Similarly, in the predator stressor experiment, mecamylamine blunted the stress-induced plasma corticosterone response, with the lowest dose of mecamylamine (0.1 mg/kg). 4. These findings may have important therapeutic implications since clinical observations have shown that low doses of mecamylamine reduce tension and anxiety in patients with Tourette syndrome.

Animals↗
PubMed2001

Behavioral assessment of Alzheimer's transgenic mice following long-term Abeta vaccination: task specificity and correlations between Abeta deposition and spatial memory.

Long-term vaccinations with human beta-amyloid peptide 1-42 (Abeta1-42) have recently been shown to prevent or markedly reduce Abeta deposition in the PDAPP transgenic model of Alzheimer's disease (AD). Using a similar protocol to vaccinate 7.5-month-old APP (Tg2576) and APP+PS1 transgenic mice over an 8-month period, we previously reported modest reductions in brain Abeta deposition at 16 months. In these same mice, Abeta vaccinations had no deleterious behavioral effects and, in fact, benefited the mice by providing partial protection from age-related deficits in spatial working memory in the radial arm water maze task (RAWM) at 15.5 months. By contrast, control-vaccinated transgenic mice exhibited impaired performance throughout the entire RAWM test period at 15.5 months. The present study expands on our initial report by presenting additional behavioral results following long-term Abeta vaccination, as well as correlational analyses between cognitive performance and Abeta deposition in vaccinated animals. We report that 8 months of Abeta vaccinations did not reverse an early-onset balance beam impairment in transgenic mice. Additionally, in Y-maze testing at 16 months, all mice showed comparable spontaneous alternation irrespective of genotype or vaccination status. Strong correlations were nonetheless present between RAWM performance and extent of "compact" Abeta deposition in both the hippocampus and the frontal cortex of vaccinated APP+PS1 mice. Our results suggest that the behavioral protection of long-term Abeta vaccinations is task specific, with preservation of hippocampal-associated working memory tasks most likely to occur. In view of the early short-term memory deficits exhibited by AD patients, Abeta vaccination of presymptomatic AD patients could be an effective therapeutic to protect against such cognitive impairments.

Alzheimer Disease↗
PubMed1999

Exposing rats to a predator blocks primed burst potentiation in the hippocampus in vitro.

This study evaluated the effects of acute psychological stress (cat exposure) in adult male rats on electrophysiological plasticity subsequently assessed in the hippocampus in vitro. Two physiological models of memory were studied in CA1 in each recording session: (1) primed burst potentiation (PBP), a low-threshold form of plasticity produced by a total of five physiologically patterned pulses; and (2) long-term potentiation (LTP), a suprathreshold form of plasticity produced by a train of 100 pulses. Three groups of rats were studied: (1) undisturbed rats in their home cage (home cage); (2) rats placed in a chamber for 75 min (chamber); and (3) rats placed in a chamber for 75 min in close proximity to a cat (chamber/stress). At the end of the chamber exposure period, blood samples were obtained, and the hippocampus was prepared for in vitro recordings. Only the chamber/stress group had elevated (stress) levels of corticosterone. The major finding was that PBP, but not LTP, was blocked in the chamber/stress group. Thus, the psychological stress experienced by the rats in response to cat exposure resulted in an inhibition of plasticity, which was localized to the intrinsic circuitry of the hippocampus. This work provides novel observations on the effects of an ethologically relevant stressor on PBP in vitro and of the relative insensitivity of LTP to being modulated by psychological stress. We discuss the relevance of these electrophysiological findings to our behavioral work showing that predator stress impairs spatial memory.

Action Potentials↗
PubMed1999

Exposing rats to a predator impairs spatial working memory in the radial arm water maze.

This series of studies investigated the effects of predator exposure on working memory in rats trained on the radial arm water maze (RAWM). The RAWM is a modified Morris water maze that contains four or six swim paths (arms) radiating out of an open central area, with a hidden platform located at the end of one of the arms. The hidden platform was located in the same arm on each trial within a day and was in a different arm across days. Each day rats learned the location of the hidden platform during acquisition trials, and then the rats were removed from the maze for a 30-min delay period. During the delay period, the rats were placed either in their home cage (nonstress condition) or in close proximity to a cat (stress condition). At the end of the delay period, the rats were run on a retention trial, which tested their ability to remember which arm contained the platform that day. The first experiment confirmed that the RAWM is a hippocampal-dependent task. Rats with hippocampal damage were impaired at learning the location of the hidden platform in the easiest RAWM under control (non-stress) conditions. The next three experiments showed that stress had no effect on memory in the easiest RAWM, but stress did impair memory in more difficult versions of the RAWM. These findings indicate that the capacity for stress to impair memory is influenced not only by the brain memory system involved in solving the task (hippocampal versus nonhippocampal), but also by the difficulty of the task. This work should help to resolve some of the confusion in the literature regarding the heterogeneous effects of stress on hippocampal-dependent learning and memory.

Analysis of Variance↗
PubMed1999

The enhancement of hippocampal primed burst potentiation by dehydroepiandrosterone sulfate (DHEAS) is blocked by psychological stress.

This series of studies investigated the effects of psychological stress and the neurosteroid dehydroepiandrosterone sulfate (DHEAS) on hippocampal primed burst (PB) and long-term (LTP) potentiation, two electrophysiological models of memory. The DHEAS and stress manipulations were performed on awake rats, and then PB and LTP were recorded while the rats were anesthetized. DHEAS enhanced PB potentiation when administered to rats under non-stress conditions, but had no effect when given to stressed rats. Further study showed that DHEAS enhanced PB potentiation only when it was administered before, but not after, the rats were stressed. The DHEAS and stress manipulations had no effect on LTP. This study provides three major findings regarding stress, neurosteroids and hippocampal plasticity. First, DHEAS enhanced a threshold form of plasticity (PB potentiation), but had no effect on a supra-threshold form of plasticity (LTP). Second, stress blocked the DHEAS-induced enhancement of PB potentiation. Third, stress and DHEAS effects on the hippocampus were so durable they could be performed on awake animals and then be studied while the animals were anesthetized. That DHEAS enhanced a subset of forms of hippocampal plasticity under restricted behavioral conditions may help to resolve conflicting observations of DHEAS effects on cognition and mood in people.

Animals↗
PubMed1998

Amphotericin B colloidal dispersion combined with flucytosine with or without fluconazole for treatment of murine cryptococcal meningitis.

Studies with animals and in vitro studies have demonstrated that flucytosine plus amphotericin B or fluconazole has significantly improved mycologic activity against meningitis caused by Cryptococcus neoformans compared to the activity of amphotericin B or fluconazole used alone. However, few doses have been tested in combination. This study evaluated the antifungal efficacy of amphotericin B colloidal dispersion (ABCD) combined with flucytosine with and without fluconazole in a murine model of cryptococcal meningitis. The following dosages were tested: ABCD at 0 to 12.5 mg/kg of body weight given intravenously 3 days/week, flucytosine at 0 to 110 mg/kg/day, and fluconazole at 0 to 50 mg/kg/day. Meningitis was established in male BALB/c mice by intracerebral injection of C. neoformans. Treatment with flucytosine with or without fluconazole dissolved in the sole source of drinking water was started on day 2; animals were sacrificed at 16 days, and the numbers of fungal colonies in the brain were quantified. A survival rate of 100% was achieved with ABCD plus flucytosine without fluconazole; however, the addition of fluconazole was required to prevent weight loss (P < 0.00001) and to achieve the maximum antifungal effect (P < 0.00001). The only region of dose combinations for which the 99% confidence intervals were less than 100 CFU/g of brain was defined by ABCD at 5.0 to 7.5 mg/kg combined with flucytosine at 20 to 60 mg/kg/day and fluconazole at 30 to 40 mg/kg/day. The triple combination of ABCD plus flucytosine and fluconazole was necessary to achieve the greatest antifungal activity.

Amphotericin B↗
PubMed1997

Effect of severity of meningitis on fungicidal activity of flucytosine combined with fluconazole in a murine model of cryptococcal meningitis.

We studied the effect of the severity of meningitis on the response to therapy with fluconazole and flucytosine in a murine model of cryptococcal meningitis. Meningitis was established by intracerebral injection of Cryptococcus neoformans. The severity of meningitis was varied by delaying the onset of treatment from 3 to 7 days. Animals were sacrificed after 14 days of treatment, and the numbers of C. neoformans per gram of brain tissue were quantified. The range of effective dose combinations of fluconazole and flucytosine became progressively reduced as the severity of meningitis increased. The magnitude of treatment effect, as measured by the numbers of CFU/gram of brain tissue, was also reduced with increasing severity of meningitis. In this model, as the severity of meningitis increases, higher doses of fluconazole are required to achieve equivalent levels of activity. The combination of fluconazole and flucytosine appears to have the most-potent antifungal effects. This is most readily observed in animals with more-severe meningitis.

Animals↗
PubMed1996

The neurosteroid dehydroepiandrosterone sulfate (DHEAS) enhances hippocampal primed burst, but not long-term, potentiation.

Dehydroepiandrosterone sulfate (DHEAS), which is synthesized in the brain and in the periphery, is known to affect the excitability of hippocampal neurons. However, its influence on electrophysiological plasticity has not been addressed. We have studied the effects of DHEAS on primed burst (PB) and long-term (LTP) potentiation, two electrophysiological models of memory. PB potentiation is a lasting increase in the amplitude of the CA1 population spike produced by minimal (threshold) electrical stimulation; LTP is produced by more extensive (supra-threshold) stimulation. Whereas intermediate doses (24 and 48 mg/kg, s.c.) of DHEAS given to rats enhanced PB potentiation, low (6 mg/kg) and high (96 mg/kg) doses were ineffective. LTP was not affected by any dose of DHEAS. The inverted-U relationship between DHEAS and PB potentiation is consistent with previous work demonstrating an inverted-U dose-dependent enhancement of memory by DHEAS. The present findings suggest that DHEAS could enhance memory by facilitating the induction of neural plasticity.

Animals↗
PubMed1996

Psychological stress impairs spatial working memory: relevance to electrophysiological studies of hippocampal function.

Stress blocks hippocampal primed-burst potentiation, a low threshold form of long-term potentiation, thereby suggesting that stress should also impair hippocampal-dependent memory. Therefore, the effects of stress on working (hippocampal-dependent) and reference (hippocampal-independent) memory were evaluated. Rats foraged for food in seven arms of a 14-arm radial maze. After they ate the food in four of the seven baited arms, they were placed in an unfamiliar environment (stress) for a 4-hr delay. At the end of the delay they were returned to the maze to locate the food in the 3 remaining baited arms. Stress impaired only working memory. Stress interfered with the retrieval of previously stored information (retrograde amnesia), but did not produce anterograde amnesia. Stress appears to induce a transient disruption of hippocampal function, which is revealed behaviorally as retrograde amnesia and physiologically as a blockade of synaptic plasticity.

Amnesia, Retrograde↗
PubMed1996

Effect of fluconazole on fungicidal activity of flucytosine in murine cryptococcal meningitis.

Both animal and in vitro studies have demonstrated that combinations of flucytosine with amphotericin B and with fluconazole have significantly improved activity against cryptococcal meningitis compared with the activity of each drug used alone. However, very few dose levels of these agents have been tested in combination. This study evaluated the efficacy of fluconazole plus flucytosine in a murine model of cryptococcal meningitis over a broad range of dose combinations (fluconazole, 0 to 40 micrograms/g of body weight per day; flucytosine, 0 to 200 micrograms/g/day). Both drugs were dissolved in drinking water, with treatment on days 2 to 11. In this highly reproducible model, fluconazole had a dramatic effect on the fungicidal activity of flucytosine. Flucytosine at dose levels of as much as 200 micrograms/g/day alone or in combination with low doses of fluconazole had minimal fungicidal activity, whereas in combination with fluconazole at 24 to 40 micrograms/g/day, flucytosine showed fungicidal activity in the range of 45 to 65% of the animals treated at doses of 40 to 100 micrograms/g/day. This striking effect of fluconazole is consistent with the results of both in vitro and clinical studies. In the clinic, the use of flucytosine is often limited by severe toxicity, while toxicity is rarely observed with fluconazole. These results suggest that when flucytosine is given with higher doses of fluconazole, the maximum therapeutic effect of the former in the clinic may be observed at dose levels that are far less than the doses commonly employed (150 micrograms/g daily).

Animals↗
PubMed1995

Enduring effects of chronic corticosterone treatment on spatial learning, synaptic plasticity, and hippocampal neuropathology in young and mid-aged rats.

Prolonged treatment with stress levels of corticosterone has been reported to produce changes in the hippocampus. In the experiments reported here, we examined for functional and morphological consequences of this treatment. First, young adult or mid-aged male Long-Evans rats were treated for either 1 or 3 months with corticosterone, at a dose sufficient to mimic the elevated hormone levels observed following exposure to mild stress. Two weeks following the termination of treatment, the animals were tested in the Morris water maze to assess spatial learning. No behavioral deficits were observed after 1 month of treatment. A 3 month treatment period also had no effect in young rats, but produced a learning impairment in the mid-aged rats. We then examined whether the effect of elevated corticosterone in mid-aged animals could be produced by a physiological stressor. Mid-aged rats were maintained for 6 months under conditions of low or high social stress. Six months of exposure to high social stress produced significant spatial learning impairments in the Morris water maze. These effects were absent in high social stress animals that had been previously adrenalectomized (with low-level corticosterone replacement), suggesting that elevated glucocorticoid levels mediate the effects of stress on spatial memory in older animals. In a final experiment, mid-aged rats were treated with corticosterone at levels that mimicked those naturally occurring at the diurnal peak (medium-B: 12-17 micrograms/dl) or in response to stress (high-B: 25-32 micrograms/dl). Only rats exposed to high levels of corticosterone demonstrated impaired performance in the Morris water maze.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗