Biomedical subjects

Robert J McDonald

Publications and source records attributed to Robert J McDonald.

At least 19 recordsLinked to original sources

PubMed2006

DNA bending by bHLH charge variants.

We wish to understand the role of electrostatics in DNA stiffness and bending. The DNA charge collapse model suggests that mutual electrostatic repulsions between neighboring phosphates significantly contribute to DNA stiffness. According to this model, placement of fixed charges near the negatively charged DNA surface should induce bending through asymmetric reduction or enhancement of these inter-phosphate repulsive forces. We have reported previously that charged variants of the elongated basic-leucine zipper (bZIP) domain of Gcn4p bend DNA in a manner consistent with this charge collapse model. To extend this result to a more globular protein, we present an investigation of the dimeric basic-helix-loop-helix (bHLH) domain of Pho4p. The 62 amino acid bHLH domain has been modified to position charged amino acid residues near one face of the DNA double helix. As observed for bZIP charge variants, DNA bending toward appended cations (away from the protein:DNA interface) is observed. However, unlike bZIP proteins, DNA is not bent away from bHLH anionic charges. This finding can be explained by the structure of the more globular bHLH domain which, in contrast to bZIP proteins, makes extensive DNA contacts along the binding face.

Basic Helix-Loop-Helix Proteins↗

PubMed2006

A double dissociation of dorsal and ventral hippocampal function on a learning and memory task mediated by the dorso-lateral striatum.

The objectives of this research were to further delineate the neural circuits subserving proposed memory-based behavioural subsystems in the hippocampal formation. These studies were guided by anatomical evidence showing a topographical organization of the hippocampal formation. Briefly, perpendicular to the medial/lateral entorhinal cortex division there is a second system of parallel circuits that separates the dorsal and ventral hippocampus. Recent work from this laboratory has provided evidence that the hippocampus incidentally encodes a context-specific inhibitory association during acquisition of a visual discrimination task. One question that emerges from this dataset is whether the dorsal or ventral hippocampus makes a unique contribution to this newly described function. Rats with neurotoxic lesions of the dorsal or ventral hippocampus were assessed on the acquisition of the visual discrimination task. Following asymptotic performance they were given reversal training in either the same or a different context from the original training. The results showed that the context-specific inhibition effect is mediated by a circuit that includes the ventral but not the dorsal hippocampus. Results from a control procedure showed that rats with either dorso-lateral striatum damage or dorsal hippocampal lesions were impaired on a tactile/spatial discrimination. Taken together, the results represent a double dissociation of learning and memory function between the ventral and dorsal hippocampus. The formation of an incidental inhibitory association was dependent on ventral but not dorsal hippocampal circuitry, and the opposite dependence was found for the spatial component of a tactile/spatial discrimination.

Animals↗

PubMed2005

Fornix, medial prefrontal cortex, nucleus accumbens, and mediodorsal thalamic nucleus: roles in a fear-based context discrimination task.

The goal of the present study was to evaluate the contributions of various brain structures anatomically and functionally linked to the hippocampus and amygdala in a fear-based context discrimination task. The brain areas of interest included the fornix, medial prefrontal cortex, mediodorsal (MD) thalamic nucleus, and nucleus accumbens. Damage to the MD thalamic nucleus and medial prefrontal cortex produced the largest impairment in context-specific fear responses. Damage to the fornix impaired some fear responses (freezing, ultrasonic vocalizations, defecation, and approach/avoidance) while leaving conditioned fear expression of heart rate and urination unaltered. Damage to the nucleus accumbens was also coupled with deficits in the discriminative expression of some (heart rate, urination, and ultrasonic vocalizations) but sparing of context-appropriate freezing, defecation, and approach/avoidance behaviors.

Analysis of Variance↗

PubMed2005

Post-training intra-amygdala amphetamine injections given during acquisition of a stimulus-response (S-R) habit task enhance the expression of stimulus-reward learning: further evidence for incidental amygdala learning.

The effect of post-training intra-amygdala amphetamine injections was examined on the acquisition and expression of a visual discrimination task. Rats were trained to enter four lit arms for food (stimulus-response) and avoid unlit arms on an eight-arm radial maze visual discrimination task. Post-training intra-amygdala amphetamine injections (10 microg) were given for 4 consecutive days during the mid-point of training (days 20-23). The number of lit arm entries was used as a measure of stimulus-response habit learning 24 h after each injection. Twenty-four hours after the last injection, a transfer test was run to assess the effect of the same post-training manipulation. This transfer test assessed the amount of time spent in the lit arms and was used as a measure of stimulus-reward learning. Compared to saline-injected rats, rats that received post-training amphetamine spent more time in lit as opposed to dark arms during the transfer test. This occurred in the absence of an increase in the number of correct arm entries during visual discrimination training. This suggests that post-training amphetamine strengthened a stimulus-reward association that did not immediately affect behavioral output. This association may reflect a mnemonic representation stored in an ensemble of amygdala neurons.

Amphetamine↗

PubMed2005

Defective place cell activity in nociceptin receptor knockout mice with elevated NMDA receptor-dependent long-term potentiation.

There is growing evidence that NMDA receptor-dependent long-term potentiation (LTP) in the hippocampus mediates the synaptic plasticity that underlies spatial learning and memory. LTP deficiencies correlate well with spatial memory deficits and LTP enhancements may improve spatial memory. In addition, LTP deficiencies are associated with abnormal place cells as expected from the spatial mapping hypothesis of hippocampal function. In contrast, nothing is known on how enhanced NMDA receptor-dependent LTP affects place cells. To address this question we recorded place cells from mice lacking the nociceptin receptor (NOP1/ORL1/OP4) that have enhanced hippocampal LTP. We found that the enhanced LTP was mediated by NMDA receptors, did not require L-type calcium channels, and occurred only when high frequency tetanizing stimulus trains were used. Place cells in nociceptin receptor knockout mice were abnormal in several ways: they were less stable, had noisier positional firing patterns, larger firing fields and higher discharge rates inside and outside the firing fields. Our results suggest that excessive LTP can cause subnormal hippocampal place cell function. The effects of LTP enhancement on place cell function may therefore also depend on molecular details of synaptic plasticity, including the relationship between stimulus frequency and synaptic strength, and not merely on the magnitude of synaptic strength increases. The data have important clinical implications on development of strategies to improve cognitive function.

Action Potentials↗

PubMed2005

Impairment in long-term retention but not short-term performance on a water maze reversal task following hippocampal or mediodorsal striatal N-methyl-D-aspartate receptor blockade.

Male Long-Evans rats were injected with 32 ng/mul of the N-methyl-D-aspartate (NMDA) receptor antagonist 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP) or vehicle and trained to locate a hidden platform in a different location (reversal training) than used on the initial 4 days of training. Rats treated with vehicle or CPP into the dorsal hippocampus, basolateral amygdala, or mediodorsal striatum had similar latencies to locate the platform on the reversal day. Rats infused with CPP into the dorsal hippocampus or mediodorsal striatum failed to search preferentially in the novel location during a 24-hr, drug-free retention test, whereas all other groups searched preferentially in this location. Therefore, blocking dorsal hippocampal or mediodorsal striatal NMDA receptors selectively blocked long-term spatial retention without producing short-term performance deficits.

Analysis of Variance↗

PubMed2005

NMDA-receptor blockade by CPP impairs post-training consolidation of a rapidly acquired spatial representation in rat hippocampus.

Recent evidence suggests that N-methyl-D-aspartate (NMDA)-receptor mediated plasticity in hippocampus has a more subtle role in memory-based behaviours than originally thought. One idea is that NMDA-based plasticity is essential for the consolidation of post-training memory but not for the initial encoding or for short-term memory. To further test this idea we used a three-phase variant of the hidden goal water maze task. In the first phase, rats were pre-trained to an initial location. Next, intense, massed training was done in a 2-h interval to teach the rats to go to a new location after either an injection of the NMDA receptor antagonist (6)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) or of vehicle. Finally, under drug-free conditions 24 h after new location training, a competition test was done between the original and new locations. We find that N-methyl-D-aspartate (NMDA)-receptor blockade has little or no effect on new location training. In contrast, when tested 24 h later, the strength of the trace for the new location learned during NMDA-receptor blockade was much weaker compared with the trace for the new location learned after saline injection. Further experiments showed similar effects when NMDA-receptors were blocked immediately after the new location training, suggesting that this is a memory consolidation effect. Our results therefore reinforce the notion that hippocampal NMDA-receptors participate in post-training memory consolidation but are not essential for the processes necessary to learn or retain navigational information in the short term.

Animals↗

PubMed2004

Blunted cortisol rhythm is associated with learning impairment in aged hamsters.

In mammals, the cognitive decline that accompanies unsuccessful aging is associated with circadian rhythm dysfunction and increased levels of circulating glucocorticoids. The possible causal relations among these factors are not known. To test for primary effects of circadian clock dysfunction versus increased glucocorticoid levels as contributors to age-related learning impairment, we measured cortisol and wheel-running rhythms along with context learning in aged hamsters (15-18 months). At this age, locomotor rhythms of learners and nonlearners were found to be indistinguishable. However, plasma cortisol levels were lower, and the amplitude of the cortisol rhythm was reduced in the impaired animals. These data suggest that age-related cognitive decline may be related more to a loss of hormone rhythmicity than to a loss of behavioral rhythmicity or an increase in hormone level.

Aging↗

PubMed2004

Incidental information acquired by the amygdala during acquisition of a stimulus-response habit task.

In the present paper we tested the hypothesis that the amygdala incidentally acquires information during the acquisition of a task sensitive to damage to the dorso-lateral striatum. Two groups of rats were trained on a stimulus-response (S-R) habit task on the eight-arm radial maze. Prior to initial acquisition, one group received NMDA lesions of the amygdala and the other received sham surgeries. After reaching a strict learning criterion, both groups underwent reversal training in either the same or different context from original training. Consistent with our previous work, the sham group showed enhanced reversal learning in a context different from original training. The rats with amygdala damage showed a deficit in reversal learning in both contexts, although the deficit was more apparent in the different context. Both groups of rats that underwent reversal training in the context different from original training showed a normal competition effect for this task (chance performance) when they were returned to the initial training context. This data supports the idea that the second S-R association, acquired during reversal training, and the context-specific inhibitory association, acquired during original training, were unaffected by the amygdala damage. Taken together, this pattern of data suggests that the amygdala incidentally acquired information during the acquisition of the S-R habit task. The nature of the association acquired in this learning paradigm, and the implications of this finding for theories dealing with the organization and functions of mammalian learning and memory are discussed.

Amygdala↗

PubMed2004

The challenges of understanding mammalian cognition and memory-based behaviours: an interactive learning and memory systems approach.

Various research problems are presented to illustrate the utility of using the interactive multiple learning and memory systems view to better understand normal and abnormal manifestations of mammalian behaviour. Evidence for incidental learning and memory processes is presented and various implications of this work are discussed. Empirical and theoretical work directed at understanding the cognitive and non-cognitive processes associated with place learning in the water task and context conditioning during aversive events is also presented.

Amnesia, Retrograde↗

PubMed2004

Multiple memory systems: the power of interactions.

Two relatively simple theories of brain function will be used to demonstrate the explanatory power of multiple memory systems in your brain interacting cooperatively or competitively to directly or indirectly influence cognition and behaviour. The view put forth in this mini-review is that interactions between memory systems produce normal and abnormal manifestations of behaviour, and by logical extension, an understanding of these complex interactions holds the key to understanding debilitating brain and psychiatric disorders.

Amygdala↗

PubMed2003

Hsp90 inhibition depletes Chk1 and sensitizes tumor cells to replication stress.

DNA damage and replication stress activate the Chk1 signaling pathway, which blocks S phase progression, stabilizes stalled replication forks, and participates in G2 arrest. In this study, we show that Chk1 interacts with Hsp90, a molecular chaperone that participates in the folding, assembly, maturation, and stabilization of specific proteins known as clients. Consistent with Chk1 being an Hsp90 client, we also found that Chk1 but not Chk2 is destabilized in cells treated with the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). 17-AAG-mediated Chk1 loss blocked the ability of Chk1 to target Cdc25A for proteolytic destruction, demonstrating that the Chk1 signaling pathway was disrupted in the 17-AAG-treated cells. Finally, 17-AAG-mediated disruption of Chk1 activation dramatically sensitized various tumor cells to gemcitabine, an S phase-active chemotherapeutic agent. Collectively, our studies identify Chk1 as a novel Hsp90 client and suggest that pharmacologic inhibition of Hsp90 may sensitize tumor cells to chemotherapeutic agents by disrupting Chk1 function during replication stress.

Antimetabolites, Antineoplastic↗

PubMed2003

Both dorsal and ventral hippocampus contribute to spatial learning in Long-Evans rats.

The hippocampus (HPC) may be functionally heterogeneous in supporting spatial learning in rats. Thus, dorsal but not ventral HPC lesions have been reported to impair acquisition in the Morris water task which consists of finding a submerged platform in a pool filled with opaque water. To further investigate the functional differences between dorsal and ventral HPC regions, we used a one-trial matching to position water task in which the submerged platform occupied a different position during each session. This task is very sensitive to HPC damage. The results show that either dorsal or ventral HPC NMDA lesions disrupt the rapid acquisition of new place information. The acquisition deficit diminishes with training in both lesion groups. The data thus suggest that the entire HPC axis is involved in acquisition of spatial information.

Animals↗

PubMed2003

Partial reinforcement across trials impairs escape performance but spares place learning in the water maze.

We studied the effects of partial reinforcement on escape performance and place learning in the water maze. Rats given 50% reinforcement across trials (i.e. the escape platform was present only on odd trials) were compared to controls given 100% reinforcement (platform present on all trials). Control groups either received 8 or 4 trials per day, which was equal to either the total number of trials (100%-8) or reinforced escapes (100%-4) of the 50% group. Analysis of escape performance (latency) revealed that the 50% group was impaired relative to the 100%-8 group, but not the 100%-4 group, during the first 5 days of acquisition. The 50% group was impaired relative to both control groups on days 6-10 of overtraining. However, analyses of within-trial behavior (target annulus preference and thigmotaxis) on nonreinforced trials suggest that the 50% group did learn the location of the hidden platform (place information), in addition to a wall-based thigmotactic response. By dividing the 60s nonreinforced trials into three 20-s time bins, we were able to detect a significant preference for the target annulus early in the trial (bin 1 of trial 40 and bins 1-2 of trial 80). Further, there was a significant increase in time spent in the periphery of the pool, near the wall, in the last time bin of trial 40. Because the platform was in the middle zone, this behavior competed with a place response. We conclude that across-trial partial reinforcement procedures may promote response competition and mask evidence of place learning in addition to weakening escape performance late in training.

Animals↗

PubMed2003

Aging effects on spatial tuning of hippocampal place cells in mice.

One reason the electrophysiological correlates of hippocampal neurons are of interest is the possibility that they reflect their representational properties, presumably spatial/relational ones. Stable spatial representations, based on activity of ensembles of hippocampal place cells, initially develop through a series of short-episodic spatial tunings. Hence these short-episodic spatial tunings are important for understanding the establishment of stable place fields. Studies of age-related changes in place cell activities traditionally focus on place fields. In the present study, we characterized the short-episodic spatial tunings (1-min bins) of hippocampal CA1 place cells of freely moving mice in a familiar cylinder arena, and compared these functions in young and old mice. Spatial tuning was expressed by spatial selectivity, which we found fluctuated across a 16-min recording session in both young and old mice. High spatial selectivity, which is mainly due to the low firing of a place cell out of the place field in young mice, was significantly higher in old mice. The high firing rate out of the place field was the main factor contributing to significantly lower spatial selectivity in old mice. In addition, young mice showed a broad peak in the spatial selectivity between 4 and 10 min. In contrast old mice showed no peak in the spatial selectivity during this time period. The stability of place fields after a 24-h interval was also lower in old mice than in young mice. The low spatial tuning and unstable place fields suggest that a hippocampal-based spatial representation was impaired in the old mice. Furthermore, we speculate that the age-related impairment in hippocampal inhibition system may be involved in the impaired spatial representation of hippocampal CA1 place cells in old mice.

Action Potentials↗

PubMed2002

Attenuation of context-specific inhibition on reversal learning of a stimulus-response task in rats with neurotoxic hippocampal damage.

Rats with hippocampal or sham lesions were trained on a stimulus-response task developed for the 8-arm radial maze. After reaching a stringent learning criterion, different context manipulations were performed. In Experiment I, the different groups were transferred to an identical radial maze in a different room to determine the context specificity of the discrimination learning. Experiment I revealed that although rats with hippocampal lesions did not show a normal context detection effect, the expression of the discrimination was not context dependent for either the lesion or sham groups. In Experiment II, animals were trained to criterion on the discrimination task and then both groups were divided into sub-groups based on whether they would experience reversal training in the same or different context from original training. Experiment II indicated that animals with hippocampal lesions and shams reversed in a different context were significantly enhanced in reaching the learning criterion compared to either counterparts that were reversed in the same context. Reversal learning in rats with hippocampal lesions was faster than sham animals in the same context suggesting that the context-specific inhibition effect was hippocampal-based. After learning the reversal task, the groups of animals trained and reversed in different contexts were brought back into the original training context to test for competitive effects. Animals with hippocampal lesions that were reversed in the different context, did not show a competition between the most recently acquired discrimination and a context-specific association acquired during original training whereas sham animals in the same condition did. Taken together these results suggest that rats with hippocampal lesions do not acquire normal context-specific inhibition during discrimination learning.

Animals↗

PubMed2002

The significance of circadian phase for performance on a reward-based learning task in hamsters.

In humans and animal models, circadian modulation of learning has been demonstrated on numerous tests. However, it is unclear which aspects of the cognitive process are rhythmically regulated. In these experiments, we used a conditioned place preference task in hamsters to ask whether memory acquisition (hypothesis 1) or memory recall and performance (hypothesis 2) were subject to circadian modulation. In golden hamsters, access to a running wheel has been used as a reward to condition a place preference, but when given unrestricted access to a wheel, animals perform most of their spontaneous running within a few hours each day or circadian cycle. This suggested that either the perceived reward value of the wheel changes through the day or that the response to this reward is temporally restricted. Contrary to the hypotheses, we found that learning was not tied to the time of training nor to the time of testing, but rather animals showed a preference for a reward-paired context only at the circadian time that training had taken place. Timing is not an explicit discriminative cue in these experiments. Hence, the learning mechanism must be predisposed to register circadian time as an attribute during context learning.

Animals↗

PubMed2002

Differential involvement of amygdala and hippocampus in responding to novel objects and contexts.

Different medial temporal lobe structures are involved in memory for different types of novel cues and novel relationships among familiar cues. We measured the behavior of rats with amygdala or hippocampal damage, when confronted with novelty in an incidental learning paradigm. We examined both direct and indirect measures of memory. Following habituation to an environment, proximal objects or distal cues were manipulated in several ways. We found that rats with hippocampal damage exhibited a deficit on direct measures of memory, but performed normally on all indirect measures. Rats with amygdala damage exhibited a deficit on a direct measure, and performed normally on an indirect measure, of memory for proximal object identity. Thus, the hippocampus may be necessary for success on direct measures of memory for distal cues and proximal objects and the relationships among them. Likewise, the amygdala may be necessary for success on some direct measures of memory, such as memory for aspects of proximal object identity. Neither the amygdala nor the hippocampus functions as a generalized novelty detection system. To the extent that we tap implicit and explicit knowledge using this paradigm, we suggest that in the rat, the amygdala and hippocampal systems are necessary for at least some types of explicit knowledge.

Amygdala↗