Biomedical subjects

Robert E Clark

Publications and source records attributed to Robert E Clark.

16 recordsLinked to original sources

PubMed2005

Hippocampus and remote spatial memory in rats.

Damage to the hippocampus typically produces temporally graded retrograde amnesia, whereby memories acquired recently are impaired more than memories acquired remotely. This phenomenon has been demonstrated repeatedly in a variety of species and tasks. It has also figured prominently in theoretical treatments of memory and hippocampal function. Yet temporally graded retrograde amnesia has not been demonstrated following hippocampal damage in spatial tasks like the water maze. We have assessed recent and remote spatial memory following hippocampal lesions in three different tests of spatial memory: (1) the standard water maze; (2) the Oasis maze, a dry-land version of the water maze; and (3) the annular water maze, where training and testing occur within a circular corridor. Training protocols were developed for each task such that retention of spatial memory could be expressed after very long retention intervals. In addition, retention in each task was assessed with single probe trials so that the assessment of remote memory did not depend on the ability to relearn across multiple trials. The findings were consistent across the three tasks. In the standard water maze (Experiment 1), spatial memory was impaired after training-surgery intervals of 1 day, 8 weeks, or 14 weeks. Similarly, in the Oasis maze (Experiment 2), spatial memory was impaired after training-surgery intervals of 1 day and 9 weeks. Finally, in the annular water maze (Experiment 3), spatial memory was impaired after training-surgery intervals of 9 weeks and 14 weeks. Dorsal hippocampal lesions impaired performance to the same extent as complete lesions. The impairment in remote spatial memory could reflect disruption of previously acquired spatial information. Alternatively, it is possible that in these tasks hippocampal lesions might produce an impairment in performance that prevents the expression of an otherwise intact spatial memory.

Amnesia, Retrograde↗

PubMed2005

Impaired remote spatial memory after hippocampal lesions despite extensive training beginning early in life.

Damage to the hippocampus typically produces temporally graded retrograde amnesia, whereby memories acquired recently are impaired more than memories acquired remotely. This phenomenon has been demonstrated repeatedly in a variety of species and tasks, and it has figured prominently in theoretical treatments of memory and hippocampal function. A striking exception to the finding of temporally graded retrograde amnesia comes from studies with rodents using spatial tasks like the water maze. In these studies, recent and remote memory were similarly impaired following hippocampal lesions. In contrast to work with rodents, studies of patients with medial temporal lobe lesions, including complete hippocampal lesions, indicate that remote spatial memory can be intact. One difference between studies in humans and studies in rodents is that spatial memory in animal studies is acquired during a limited period of time when the animals are adults. In contrast, the spatial memory studied in humans was acquired beginning at an early age and learning continued for a considerable period of time. We initiated training in a standard water maze immediately after rats had been weaned at 21 days of age and continued training until the rats were young adults (90 days old). Large hippocampal lesions were made 100 days after the completion of training. After recovery from surgery, control rats exhibited good retention on the first retention probe trial, but rats with hippocampal lesions performed at chance. Thus, even after extended training beginning early in life, and with a prolonged training-surgery interval, hippocampal lesions impair performance in the water maze task. Possible reasons for these findings are discussed in the context of the specific performance requirements of the water maze task.

Aging↗

PubMed2005

Interrogating rodents regarding their object and spatial memory.

Today, neuroscientists have access to a host of advanced techniques -- ranging from targeted genetic interventions to brain imaging -- that are rapidly providing new insights. Ultimately, however, memory must be inferred from its behavioral read-out. Thus, to fully utilize the advanced technologies available today, we must select the most appropriate behavioral procedures from those currently available, or else devise novel behavioral techniques to meet a specific demand. If we merely use standard tests of memory in a non-optimal way, we risk collecting incomplete information and reaching erroneous conclusions. Relevant to these issues, there have been substantial developments in the methods used to evaluate two of the most frequently studied forms of memory in the rodent -- recognition memory and spatial memory.

Animals↗

PubMed2005

Acquisition of differential delay eyeblink classical conditioning is independent of awareness.

There has been debate about whether differential delay eyeblink conditioning can be acquired without awareness of the stimulus contingencies. In 4 experiments, the authors reexamined this question. Older participants were tested with a tone and white noise (Experiment 1) or with 2 tones (Experiment 2). In addition, younger participants were tested with 2 tones (Experiment 3) or with 2 tones plus the parameters from an earlier study that had reported a relationship between conditioning and awareness (Experiment 4). Participants who were designated aware of the stimulus contingencies and participants who were designated unaware exhibited equivalent levels of differential eyeblink conditioning. Awareness of stimulus contingencies is not required for differential delay eyeblink conditioning when simple conditioned stimuli are used.

Adult↗

PubMed2004

Spatial memory, recognition memory, and the hippocampus.

There is wide agreement that spatial memory is dependent on the integrity of the hippocampus, but the importance of the hippocampus for nonspatial tasks, including tasks of object recognition memory is not as clear. We examined the relationship between hippocampal lesion size and both spatial memory and object recognition memory in rats. Spatial memory was impaired after bilateral dorsal hippocampal lesions that encompassed 30-50% total volume, and as lesion size increased from 50% to approximately 100% of total hippocampal volume, performance was similarly impaired. In contrast, object recognition was intact after dorsal hippocampal lesions that damaged 50-75% of total hippocampal volume and was impaired only after larger lesions that encompassed 75-100% of hippocampal volume. Last, ventral hippocampal lesions that encompassed approximately 50% of total hippocampal volume impaired spatial memory but did not affect object recognition memory. These findings show that the hippocampus is important for both spatial memory and recognition memory. However, spatial memory performance requires more hippocampal tissue than does recognition memory.

Animals↗

PubMed2004

The importance of awareness for eyeblink conditioning is conditional: theoretical comment on Bellebaum and Daum (2004).

Eyeblink conditioning entails a variety of paradigms that differ in terms of the brain systems that support conditioning and the importance of awareness. In this issue, C. Bellebaum and I. Daum (2004) that reports that conditional discrimination learning depends on awareness. Their findings, along with other recent work, suggest a framework whereby the temporal features of the conditioning paradigm are critical in determining the ability of the cerebellum to support conditioning and, as a result, the role of awareness in conditioning.

Awareness↗

PubMed2004

The medial temporal lobe.

The medial temporal lobe includes a system of anatomically related structures that are essential for declarative memory (conscious memory for facts and events). The system consists of the hippocampal region (CA fields, dentate gyrus, and subicular complex) and the adjacent perirhinal, entorhinal, and parahippocampal cortices. Here, we review findings from humans, monkeys, and rodents that illuminate the function of these structures. Our analysis draws on studies of human memory impairment and animal models of memory impairment, as well as neurophysiological and neuroimaging data, to show that this system (a) is principally concerned with memory, (b) operates with neocortex to establish and maintain long-term memory, and (c) ultimately, through a process of consolidation, becomes independent of long-term memory, though questions remain about the role of perirhinal and parahippocampal cortices in this process and about spatial memory in rodents. Data from neurophysiology, neuroimaging, and neuroanatomy point to a division of labor within the medial temporal lobe. However, the available data do not support simple dichotomies between the functions of the hippocampus and the adjacent medial temporal cortex, such as associative versus nonassociative memory, episodic versus semantic memory, and recollection versus familiarity.

Animals↗

PubMed2003

Cyclin dependent kinase inhibitor p27(Kip1) is upregulated by hypoxia via an ARNT dependent pathway.

Expression of cyclin dependent kinase (Cdk) inhibitor p27(Kip1), which blocks cell cycle progression from G(1) to S phase, can be regulated via multiple mechanisms including transcription, protein degradation, and translation. Recently, it was shown that p27(Kip1) plays an important role in the cellular response to hypoxia. However, the mechanisms involved in the hypoxia-induced regulation of p27(Kip1) expression are still not clear. In this study, we compare the expression of p27(Kip1) in two related murine hepatoma cell lines, Hepa-1 and c4. Hepa-1 produces functional aryl hydrocarbon receptor nuclear translocator (ARNT). c4 cells are derived from Hepa-1, but are ARNT deficient. Interestingly, we observed cell line-dependent effects of hypoxia on the expression of p27(Kip1). The level of p27(Kip1) protein in Hepa-1 cells is enhanced by hypoxia, but is reduced by hypoxia in c4 cells. Further investigation demonstrated that hypoxia-induced, ARNT-mediated, transactivation of the p27(Kip1) gene in Hepa-1 cells is responsible for the increase in p27(Kip1) protein. Once c4 cells were stably transfected with the wild type ARNT gene, a hypoxia-induced increase in p27(Kip1) mRNA was observed and reduction of p27(Kip1) protein caused by hypoxia was blocked. Hence, our data indicate that ARNT is involved in transcriptional upregulation of the p27(Kip1) gene under hypoxic conditions.

Animals↗

PubMed2003

Selective neurotoxic amygdala lesions in monkeys disrupt reactivity to food and object stimuli and have limited effects on memory.

Monkeys with bilateral neurotoxic amygdala lesions and normal monkeys were administered tests of emotional reactivity, recognition memory, and reward association memory. There were 3 main findings. First, monkeys with amygdala lesions performed differently than normal monkeys on initial administrations of the emotional reactivity tests and on retests that were given 21-23 months after surgery. Second, they performed like normal monkeys on tests of recognition memory. Third, they were initially impaired on a test of reward association memory, but they were not impaired on a retest that was given 16 months after surgery. These findings underscore the role of the amygdala in aspects of emotional reactivity and reward association memory, but not in recognition memory. In addition, at least some of the behavioral effects of amygdala damage can be long lasting.

Amygdala↗

PubMed2003

Botulinum toxin type B (MYOBLOC) versus botulinum toxin type A (BOTOX) frontalis study: rate of onset and radius of diffusion.

BACKGROUND: Botulinum toxin types A and B can improve the appearance of facial wrinkles. Differences in the time until onset and the degree of diffusion have been observed anecdotally, but no direct comparative studies have been done. OBJECTIVE: To compare the rate of onset and the radius of diffusion of botulinum toxin types A and B in the rhytides of the forehead. METHODS: Adults with symmetrical moderate to severe forehead wrinkles at full contracture received botulinum toxin type A (BOTOX; 5 U) on one side of the forehead and type B (MYOBLOC; 500 U) on the other side. Photographs taken at rest and full frontalis contracture were analyzed by computer, and a time-lapse motion picture was created. Radius of diffusion and time until full effect were measured. RESULTS: Botulinum toxin type B had a slightly faster onset of action than type A. All patients responded to type B quickly, whereas some had a delayed response to type A. A greater radius of diffusion was consistently observed with botulinum toxin type B, as measured by the greater area of wrinkle reduction at the doses used. CONCLUSIONS: In this comparative study of patients with symmetrical forehead wrinkles, botulinum toxin type B produced a greater area of diffusion and a more rapid onset of action than type A.

Adult↗

PubMed2003

Botulinum A toxin (BOTOX) in the lower eyelid: dose-finding study.

BACKGROUND: Botulinum toxin type A (BTX-A, BOTOX) is an excellent therapeutic option for hyperkinetic facial lines. It improves wrinkles by relaxing the muscles of facial expression, which underlie the rhytids. Periocular wrinkles such as lateral orbital rhytids respond well to treatment. BOTOX can be used in the lower eyelid to improve wrinkles and widen the eye. OBJECTIVE: To determine whether there is additional benefit in using more than 2 U of BTX-A to improve infraorbital wrinkles and widen the eye. METHODS: Nineteen women had BTX-A injected into the orbicularis oculi muscle. Eleven women had 4 U injected into the lower eyelid bilaterally, 3 mm below the ciliary margin, and 12 U of BTX-A injected into one lateral orbital (crow's feet) area. Eight patients had 8 U injected bilaterally into the lower eyelid and 12 U placed unilaterally into the crow's feet. Physicians and patients independently evaluated the degree of improvement (grade 3=dramatic improvement, grade 2=moderate improvement, grade 1=mild improvement, and grade 0=no improvement). Single investigator analysis was used to measure, in actual millimeters, the amount of increase in palpebral aperture. Side effects were noted. RESULTS: Improvement was noted in lower eyelid wrinkles by both physicians and patients at both dose groups. When only the lower lid was injected, patients reported an improvement of 1.18 with 4 U and a grade of 1.63 with 8 U. When both the lower eyelid the lateral orbital area were treated, an improvement of 1.73 was reported with 4 U and a grade of 2.25 reported with 8 U in the lower eyelid. Physician evaluations had grades of 1.85 for 4 U alone and 1.85 with 8 U alone. Grades of 2.35 and 2.25 were obtained for 4 U plus 12 U and 8 U plus 12 U, respectively. An increase in palpebral aperture (IPA) occurred in all subjects. Subjects who received 4 U in the lower eyelid alone had a 1.8-mm IPA at rest and a 2.6-mm increase at full smile. Subjects who received 8 U of BTX-A alone in the lower lid had an IPA of 2.2 mm at rest and 2.9 mm at full smile. Eyes treated with 12 U in the bilateral orbital area plus 4 U in the lower eyelid had an IPA of 2.2 at rest and 4.5 mm at full smile. Those treated with 8 U in the lower lid plus the crow's feet had an IPA of 1.5 at rest and 4.0 at full smile. Side effects increased with dosage, with eight of eight subjects in the 8-U dose groups reporting bothersome side effects such as lower eyelid edema and incomplete sphincter function. CONCLUSION: A dose-response curve is seen with increasing doses of BTX-A used in the lower eyelid. Treatment of the lateral orbital area in combination with the lower lid produces a synergistic response at lower doses, but at higher doses, a plateau effect is suggested. Although increasing doses of BTX-A increases eye widening, unattractive results and side effects are seen at higher doses. The authors recommend that lower 2- or 4-U doses of BTX-A be used in the lower eyelid and specifically discuss techniques.

Adolescent↗

PubMed2002

Anterograde amnesia and temporally graded retrograde amnesia for a nonspatial memory task after lesions of hippocampus and subiculum.

We studied the importance of the hippocampus and subiculum for anterograde and retrograde memory in the rat using social transmission of food preference, a nonspatial memory task. Experiment 1 asked how long an acquired food preference could be remembered. In experiment 2, we determined the anterograde amnesic effects of large lesions of the hippocampus that included the subiculum. In experiment 3, large lesions of the hippocampus that included the subiculum were made 1, 10, or 30 d after learning to determine the nature and extent of retrograde amnesia. Normal rats exhibited memory of the acquired food preference for at least 3 months after learning. Hippocampal lesions that included the subiculum produced marked anterograde amnesia and a 1-30 d temporally graded retrograde amnesia. The results show the importance of the hippocampus and related structures for nonspatial memory and also demonstrate the temporary role of these structures in long-term memory.

Amnesia, Anterograde↗

PubMed2002

Cyclic AMP inducibility of the myelin basic protein gene promoter requires the NF1 site.

In the central nervous system oligodendrocyte differentiation is accompanied by the activation of a specific transcriptional program responsible for the synthesis of myelin genes. One of the signals leading to the expression of myelin components, such as the myelin basic protein (MBP) gene is cyclic AMP (cAMP). Previous work using a cell line in which the endogenous MBP gene can be induced by increased cAMP levels (D6P2T) showed that the region of the MBP gene that was required for induction of the gene by cAMP lay between -248 and -105 in the 5' flanking region. This region contains numerous transcription factor binding sites, including sites for NF1, Sp1, and MEBA. In order to determine if the NF1 site itself was specifically responsible for the cAMP responsiveness of the MBP promoter, stably transfected cells carrying MBP promoter deletion constructs were used. Deletion of just the NF1 site caused loss of responsiveness to cAMP levels. Furthermore, site-specific mutations in the NF1 site that interfere with NF1 protein binding, in the context of the full length promoter, abolished cAMP responsiveness and caused derepression of the promoter. Analysis of protein binding to the NF1 site showed that the mutation resulted in loss of binding to the site and that the proteins binding at the site are modified in the presence of cAMP elevating agents. These results demonstrate that the NF1 site is indispensable for cAMP responsiveness of the MBP promoter and, together with other DNA elements, plays a role in controlling MBP gene expression.

Animals↗

PubMed2002

Phosphatidylinositol-3 kinase p85 enhances expression from the myelin basic protein promoter in oligodendrocytes.

Phosphatidylinositol-3 kinase (PI3K) is a family of enzymes that phosphorylates the D3 position of phosphoinositides in membranes which can then act as a second messenger and affect many essential cellular processes such as survival, proliferation and differentiation. Class IA PI3K is composed of two subunits: a regulatory subunit, p85, and a catalytic subunit, p110. The p85 subunit is composed of several adapter domains which, upon interaction with the appropriate molecules, transmit the signal to activate p110. We have used the spontaneously immortalized oligodendrocyte cell line, CG4, to examine the role of PI3K in maturation of the oligodendrocyte. We show that overexpression of the p85 subunit enhances expression of myelin basic protein (MBP) upon differentiation of CG4 cells and primary oligodendrocytes. In experiments in CG4 cells, neither cotransfection with the tumor suppressor PTEN, which dephosphorylates the D3 position of phosphoinositides, nor inhibition of PI3K activity with wortmannin mimics this effect. Further, we have shown that this effect is dependent on the coexpression of the two SH2 domains within p85. Thus, the p85-mediated enhancement of MBP promoter activity in oligodendrocytes appears to be independent of PI3K activity and dependent on the adapter functions of the p85 subunit's SH2 domains.

Animals↗

PubMed2002

Closure of lacerations and incisions with octylcyanoacrylate: a multicenter randomized controlled trial.

BACKGROUND: Most lacerations and surgical incisions are closed with sutures or staples. Octylcyanoacrylate tissue adhesive (OCA) was recently approved for use in the United States. We compared the cosmetic appearance of lacerations and incisions repaired with OCA versus standard wound closure methods (SWC). METHODS: A multicenter randomized clinical trial including patients with simple lacerations or surgical incisions was conducted at 10 clinical sites. Patients were randomly assigned to treatment with OCA or SWC. Follow-up was performed at 1 week and at 3 months to determine infection rates and cosmetic outcome. RESULTS: Eight hundred fourteen patients with 924 wounds (383 traumatic lacerations, 235 excisions of skin lesions or scar revisions, 208 minimally invasive surgeries, and 98 general surgical procedures) were enrolled. Groups were similar in baseline characteristics. Wound closure with OCA was faster than with SWC (2.9 vs 5.2 minutes, P <.001). At 1 week infection rates were similar (OCA, 2.1% vs SWC, 0.7%; P =.09) and fewer OCA wounds were erythematous (18% vs 36%, P <.001). There were no differences in wound dehiscence rates (OCA, 1.6% vs SWC, 0.9%; P =.35). At 3 months there was no difference in the percent of wounds with optimal appearance (OCA, 82% vs SWC, 83%; P =.67). CONCLUSIONS: Repair of traumatic lacerations and surgical incisions with OCA is faster than with SWC, and cosmetic outcome is similar at 3 months.

Adolescent↗

PubMed2002

Standard delay eyeblink classical conditioning is independent of awareness.

P. F. Lovibond and D. R. Shanks (2002) suggested that all forms of classical conditioning depend on awareness of the stimulus contingencies. This article considers the available data for eyeblink classical conditioning, including data from 2 studies (R. E. Clark, J. R. Manns, & L. R. Squire, 2001; J. R. Manns, R. E. Clark, & L. R. Squire, 2001) that were completed too recently to have been considered in their review. In addition, in response to questions raised by P. F. Lovibond and D. R. Shanks, 2 new analyses of data are presented from studies published previously. The available data from humans and experimental animals provide strong evidence that delay eyeblink classical conditioning (but not trace eyeblink classical conditioning) can be acquired and retained independently of the forebrain and independently of awareness. This conclusion applies to standard conditioning paradigms; for example, to single-cue delay conditioning when a tone is used as the conditioned stimulus (CS) and to differential delay conditioning when the positive and negative conditioned stimuli (CS+ and CS-) are a tone and white noise.

Aged↗