Delayed Nonmatching-to-sample Research Articles

Pharmacological elevation of anandamide impairs short-term memory by altering the neurophysiology in the hippocampus

In rodents, many exogenous cannabinoid agonists including Δ 9-THC and WIN55,212-2 (WIN-2) have been shown to impair short-term memory (STM) by inhibition of hippocampal neuronal assemblies. However, the mechanisms by which endocannabinoids such as anandamide and 2-arachidonyl glycerol (2-AG) modulate STM processes are not well understood. Here the effects of anandamide on performance of a Delayed-Non-Match-to-Sample (DNMS) task (i.e. STM task) and concomitant hippocampal ensemble activity were assessed following administration of either URB597 (0.3, 3.0 mg/kg), an inhibitor of the Fatty Acid Amide Hydrolase (FAAH), AM404 (1.5, 10.0 mg/kg), a putative anandamide uptake/FAAH inhibitor, or R-methanandamide (3.0, 10.0 mg/kg), a stable analog of anandamide. Principal cells from hippocampal CA3/CA1 were recorded extracellularly by multi-electrode arrays in Long-Evans rats during DNMS task (1–30 s delays) performance and tracked throughout drug administration and recovery. Both R-methanandamide and URB597 caused dose- and delay-dependent deficits in DNMS performance with suppression of hippocampal ensemble activity during the encoding (sample) phase. R-methanandamide-induced effects were not reversed by capsaicin excluding a contribution of TRPV-1 receptors. AM404 produced subtle deficits at longer delay intervals but did not alter hippocampal neuronal activity during task-specific events. Collectively, these data indicate that endocannabinoid levels affect performance in a STM task and their pharmacological elevation beyond normal concentrations is detrimental also for the underlying physiological responses. They also highlight a specific window of memory processing, i.e. encoding, which is sensitive to cannabinoid modulation.

Effects of memantine and donepezil on cortical and hippocampal acetylcholine levels and object recognition memory in rats

This preclinical study investigated the ability of memantine (MEM) to stimulate brain acetylcholine (ACh) release, potentially acting synergistically with donepezil (DON, an acetylcholinesterase inhibitor). Acute systemic administration of either MEM or DON to anesthetized rats caused dose-dependent increases of ACh levels in neocortex and hippocampus, and the combination of MEM (5 mg/kg) and DON (0.5 mg/kg) produced significantly greater increases than either drug alone. To determine whether ACh release correlated with cognitive improvement, rats with partial fimbria-fornix (FF) lesions were treated with acute or chronic MEM or DON. Acute MEM treatment significantly elevated baseline hippocampal ACh release but did not significantly improve task performance on a delayed non-match-to-sample (DNMS) task, whereas chronic MEM treatment significantly improved DNMS performance but only marginally elevated baseline ACh levels. Acute or chronic treatment with DON (in the presence of neostigmine to allow ACh collection) did not significantly improve DNMS performance or alter ACh release. In order to investigate the effect of adding MEM to ongoing DON therapy, lesioned rats pretreated with DON for 3 weeks were given a single intraperitoneal dose of MEM. MEM significantly elevated baseline hippocampal ACh levels, but did not significantly improve DNMS task scores compared to chronic DON-treated animals. These data indicate that MEM, in addition to acting as an NMDA receptor antagonist, can also augment ACh release; however, in this preclinical model, increased ACh levels did not directly correlate with improved cognitive performance.

A cortical neural prosthesis for restoring and enhancing memory

A primary objective in developing a neural prosthesis is to replace neural circuitry in the brain that no longer functions appropriately. Such a goal requires artificial reconstruction of neuron-to-neuron connections in a way that can be recognized by the remaining normal circuitry, and that promotes appropriate interaction. In this study, the application of a specially designed neural prosthesis using a multi-input/multi-output (MIMO) nonlinear model is demonstrated by using trains of electrical stimulation pulses to substitute for MIMO model derived ensemble firing patterns. Ensembles of CA3 and CA1 hippocampal neurons, recorded from rats performing a delayed-nonmatch-to-sample (DNMS) memory task, exhibited successful encoding of trial-specific sample lever information in the form of different spatiotemporal firing patterns. MIMO patterns, identified online and in real-time, were employed within a closed-loop behavioral paradigm. Results showed that the model was able to predict successful performance on the same trial. Also, MIMO model-derived patterns, delivered as electrical stimulation to the same electrodes, improved performance under normal testing conditions and, more importantly, were capable of recovering performance when delivered to animals with ensemble hippocampal activity compromised by pharmacologic blockade of synaptic transmission. These integrated experimental-modeling studies show for the first time that, with sufficient information about the neural coding of memories, a neural prosthesis capable of real-time diagnosis and manipulation of the encoding process can restore and even enhance cognitive, mnemonic processes.

Stimulus similarity and encoding time influence incidental recognition memory in adult monkeys with selective hippocampal lesions

Recognition memory impairment after selective hippocampal lesions in monkeys is more profound when measured with visual paired-comparison (VPC) than with delayed nonmatching-to-sample (DNMS). To clarify this issue, we assessed the impact of stimuli similarity and encoding duration on the VPC performance in monkeys with hippocampal lesions and sham-operated controls. The novelty preference was compared for pictures of dissimilar vs. similar objects and for encoding duration of 30, 10, 5, and 1 sec. The novelty preference was spared after hippocampal lesions with dissimilar (colored or black and white [BW]) stimuli and an encoding time ≥10 sec, but declined with similar stimuli or a short encoding time of 1 or 5 sec. Therefore, the severe VPC impairment reported earlier after hippocampal damage cannot be attributed to the long encoding time used (30 sec) relative to DNMS (1-5 sec). However, it may result, at least in part, from the poorer distinctiveness of the stimuli typically used for VPC (BW slides of pictures of equal size and brightness of objects differing in shape) relative to the actual objects used for DNMS, differing in shape, color, size, brightness, and texture. This conclusion fits well with current models that view the hippocampus as a comparator capable of individualizing the representations of highly overlapping inputs.

Cannabinoid and cholinergic systems interact during performance of a short-term memory task in the rat

It is now well established that cannabinoid agonists such as Δ(9)-tetrahydrocannabinol (THC), anandamide, and WIN 55,212-2 (WIN-2) produce potent and specific deficits in working memory (WM)/short-term memory (STM) tasks in rodents. Although mediated through activation of CB1 receptors located in memory-related brain regions such as the hippocampus and prefrontal cortex, these may, in part, be due to a reduction in acetylcholine release (i.e., cholinergic hypofunction). To determine the interaction between cannabinoid and cholinergic systems, we exposed rats treated with WIN-2 or cholinergic drugs to a hippocampal-dependent delayed nonmatch to sample (DNMS) task to study STM, and recorded hippocampal single-unit activity in vivo. WIN-2 induced significant deficits in DNMS performance and reduced the average firing and bursting rates of hippocampal principal cells through a CB1 receptor-mediated mechanism. Rivastigmine, an acetylcholinesterase inhibitor, reversed these STM deficits and normalized hippocampal discharge rates. Effects were specific to 1 mg/kg WIN-2 as rivastigmine failed to reverse the behavioral and physiological deficits that were observed in the presence of MK-801, an NMDA receptor antagonist. This supports the notion that cannabinoid-modulated cholinergic activity is a mechanism underlying the performance deficits in DNMS. Whether deficits are due to reduced nicotinic or muscarinic receptor activation, or both, awaits further analysis.

Recruitment of hippocampal neurons to encode behavioral events in the rat: alterations in cognitive demand and cannabinoid exposure.

Successful performance by rats of a delayed-nonmatch-to-sample (DNMS) task is hippocampal dependent. We have shown that neurons in hippocampus differentially encode task-relevant events. These responses are critical for correct DNMS performance and are diminished by exogenous cannabinoids. We therefore reasoned that hippocampal neural correlates of behavior are likely shaped during learning; however, to date, no work has examined these correlates during DNMS acquisition training. Consequently, the present study assessed the emergence of hippocampal neural encoding when (i) cognitive task demands were increased through prolongation of delay intervals between sample and nonmatch phase and (ii) when animals are under cannabinoid treatment and performance is compromised. Adult, male Long-Evans rats were trained to perform the DNMS task without delay and then implanted with multielectrode recording arrays directed to CA3 and CA1 subfields of the hippocampus. Following recovery, single units were isolated and animals divided into two treatment groups: vehicle or WIN 55,212-2 (WIN-2, 0.35 mg/kg). Ensemble firing was monitored during retraining in DNMS task at 0 s, and subsequently delay intervals were progressively increased to 1-10 s, 11-20 s, and 21-30 s when animals met criterion (80% correct) at each respective interval. Hippocampal CA3 and CA1 principal cells were isolated and recorded throughout treatment. Extension of the delay led to an increase in the number of task-correlated neurons in controls. This recruitment of novel cells was reduced/prevented in the presence of WIN-2 and was paralleled by impairment in acquisition learning at longer delay intervals. Moreover, WIN-2 suppressed hippocampal ensemble firing during the sample (encoding) but not nonmatch phase of the DNMS task across all delays. These cannabinoid-induced alterations in hippocampal neuronal activity may explain the observed deficits in DNMS performance.

The monkey pulvinar neurons differentially respond to emotional expressions of human faces

Recent psychological studies suggest that the amygdala is not essential for early stages of emotional facial processing, and that the colliculo-pulvinar pathway might play this role. Nevertheless, the actual role of pulvinar nucleus on the recognition of emotional faces remains obscure. In the present study, we recorded single-unit activity of pulvinar neurons in 2 monkeys during recognition of emotional faces in a delayed non-match-to-sample (DNMS) task, using human face stimuli with differing emotional expressions (sad, angry, happy, surprised and neutral) and simple geometric pattern control figures. A total of 184 single neurons from lateral and medial pulvinar have been sampled. From this total, 41 (22.2%) were found to be “visually responsive”, that is, responded to one or more of the visual stimuli. Among the visually responsive neurons, 23 responded non-differentially to all stimuli (facial stimuli and control). Another 18 responded differentially to facial identity and/or emotional expression. Response latencies of the pulvinar neurons to these facial stimuli ranged very widely; firing onsets for 16 (39.0%, 16/41) neurons were shorter than 100 ms, while for 13 (31.7%, 13/41) it was greater than 300 ms. The results thus indicate that 43.9% of the visually responsive pulvinar neurons differentially responded to the emotional expressions of the human faces. Furthermore, wide distribution of the response latencies of the pulvinar neurons suggests that pulvinar neurons might mediate intracortical connections as well as the fast subcortical pathway to the amygdala. These results highlight a role of the pulvinar in the processing of emotional facial stimuli.

Selective changes in thin spine density and morphology in monkey prefrontal cortex correlate with aging-related cognitive impairment.

Age-associated memory impairment (AAMI) occurs in many mammalian species, including humans. In contrast to Alzheimer's disease (AD), in which circuit disruption occurs through neuron death, AAMI is due to circuit and synapse disruption in the absence of significant neuron loss and thus may be more amenable to prevention or treatment. We have investigated the effects of aging on pyramidal neurons and synapse density in layer III of area 46 in dorsolateral prefrontal cortex of young and aged, male and female rhesus monkeys (Macaca mulatta) that were tested for cognitive status through the delayed non-matching-to-sample (DNMS) and delayed response tasks. Cognitive tests revealed an age-related decrement in both acquisition and performance on DNMS. Our morphometric analyses revealed both an age-related loss of spines (33%, p < 0.05) on pyramidal cells and decreased density of axospinous synapses (32%, p < 0.01) in layer III of area 46. In addition, there was an age-related shift in the distribution of spine types reflecting a selective vulnerability of small, thin spines, thought to be particularly plastic and linked to learning. While both synapse density and the overall spine size average of an animal were predictive of number of trials required for acquisition of DNMS (i.e., learning the task), the strongest correlate of behavior was found to be the head volume of thin spines, with no correlation between behavior and mushroom spine size or density. No synaptic index correlated with memory performance once the task was learned.

A novel delayed non-match to sample object recognition task that allows simultaneous in vivo microdialysis

We present a modification of the widely used delayed non-match to sample (DNMS) paradigm for assessment of object recognition memory that can be combined with simultaneous in vivo microdialysis. The present study provides evidence that hippocampal ACh release increases from baseline during active exploration of the test environment and an empty test board, but a specific further increase is seen during the recognition memory task performance. This novel experimental model offers a good tool to study the impact of selective lesions or pharmacological manipulation simultaneously on neurotransmitter levels and memory task performance.

Information in small neuronal ensemble activity in the hippocampal CA1 during delayed non-matching to sample performance in rats

BackgroundThe matrix-like organization of the hippocampus, with its several inputs and outputs, has given rise to several theories related to hippocampal information processing. Single-cell electrophysiological studies and studies of lesions or genetically altered animals using recognition memory tasks such as delayed non-matching-to-sample (DNMS) tasks support the theories. However, a complete understanding of hippocampal function necessitates knowledge of the encoding of information by multiple neurons in a single trial. The role of neuronal ensembles in the hippocampal CA1 for a DNMS task was assessed quantitatively in this study using multi-neuronal recordings and an artificial neural network classifier as a decoder.ResultsThe activity of small neuronal ensembles (6-18 cells) over brief time intervals (2-50 ms) contains accurate information specifically related to the matching/non-matching of continuously presented stimuli (stimulus comparison). The accuracy of the combination of neurons pooled over all the ensembles was markedly lower than those of the ensembles over all examined time intervals.ConclusionThe results show that the spatiotemporal patterns of spiking activity among cells in the small neuronal ensemble contain much information that is specifically useful for the stimulus comparison. Small neuronal networks in the hippocampal CA1 might therefore act as a comparator during recognition memory tasks.

Effects of testosterone on cognition in young adult male rhesus monkeys

The relationships between testosterone (T) and cognitive function remain unclear. In men, associations between endogenous T levels and cognitive performance have not consistently been found and the effects of T treatment on cognition remain ambiguous: several studies have reported beneficial effects of T administration on cognitive function, but recent data indicate no effect or even detrimental effects of T. Studies in nonhuman primates may help resolve these discrepancies. We conducted the first study examining the activational effects of T on cognition in adult male nonhuman primates. Six young adult male rhesus monkeys (5–6 years old) were tested for 16 weeks on a battery of 4 memory tasks (1) when intact at baseline (winter); (2) when hypogonadal with add-back of T or placebo in a double blind cross-over design and (3) when intact following wash-out (summer phase). The cognitive tasks consisted of the Delayed Non-Matching-To-Sample (DNMS) with mixed delays, the spatial-Delayed Recognition Span Test (spatial-DRST) and the Delayed Response (DR) task. Following a 4-week baseline period, monkeys were treated with a gonadotropin releasing hormone (GnRH) agonist (Depot Lupron, 200 μg/kg) before being randomly assigned to one of 2 treatment groups: Lupron + testosterone enanthate (TE, 20 mg/kg) or Lupron + oil vehicle. In each treatment group, monkeys received Lupron + TE, or Lupron + oil, for 4 weeks before crossing over to the alternate treatment for an additional 4 weeks. After a 2 months wash-out period, monkeys were retested on the battery of tasks for an additional 4 weeks. T levels did not vary significantly between the winter and summer months of testing, indicating a lack of seasonal effect in these monkeys housed indoors. TE treatment yielded supraphysiological T levels decreasing progressively over 4 weeks. This treatment was associated with impaired recognition memory at the 600 s delay of the DNMS, suggesting compromised medial temporal lobe function, but had no effect on DR or spatial-DRST. Further studies are needed to determine whether T may enhance memory in aged male monkeys.

Basal ganglia and memory retrieval during delayed match-to-sample and non-match-to-sample tasks

Top-down guidance of visual search requires the ability tobias the processing of visual features towards the charac-teristics of the desired object. Whatever form they maytake, these characteristics (that we will call here a templateof the object) have to be transferred from memory to thevisual cortical areas, either from long-term memory orworking memory. High visual areas like the inferotempo-ral cortex, or visuo-mnemonic areas in the medial tempo-ral lobe have been shown to exhibit sustained activitiesduring delayed matching-to-sample (DMS) or delayednon-matching-to-sample (DNMS) tasks, showing theirinvolvement in working memory (WM) processes [1].Particularly, perirhinal cortex (PRh) is involved in objectrecognition, novelty detection and categorization, and itsimpairment leads to severe deficits in DMS and DNMStasks [2].We designed in [3] a computational model of PRh thatwas able to perform multimodal categorization despitepartial object presentation. Its main feature was the incor-poration of dopaminergic modulation of synaptic cur-rents, which allowed the model to exhibit sustainedactivities in clusters of cells representing a given objectunder an optimal level of tonic dopamine (DA) firing. Wealso observed propagation of activity within a cluster,which leads to the interesting property that the visualinformation contained in a cluster can be retrieved troughthe stimulation of a very limited number of cells by tha-lamic afferents. We therefore formulated the hypothesisthat PRh is potential site where visual memory can beretrieved through partial thalamic stimulation in order tobias processing in the ventral stream through feedbackmodulation.Given the fact that PRh receives connections from parts ofthe thalamus that are tonically inhibited by basal ganglia(BG) structures [4], we here suggest that BG can act as con-troller for memory retrieval in PRh, but without any visualdetails about the object to be retrieved. We tested thishypothesis by building a computational model involvingPRh, BG structures, thalamus and a prefrontal cortex(PFC) area that performs static working memory in amanner functionally similar to [5]. We applied this modelto interlaced DMS and DNMS tasks, where one of twoobjects (A or B) is first presented to the system, followedby a task cue indicating whether the system should per-form DMS or DNMS, then both A and B objects. If the sys-tem selects the correct object in PRh, it receives aprobabilistic reward that elicits a phasic DA burst.The model is composed of competing mean firing-rateneurons that interacts through connections havingweights evolve through an homeostatic Hebbian learningrule. Both PRh and PFC areas project on the input struc-ture of BG, the nucleus accumbens (NAcc), which in turnproject to the globus pallidus (GPi) that tonically inhibitsthe thalamus. Selective inhibition of a GPi cell allows itsefferent thalamic cells to exhibit activity and thereforestimulate the corresponding cluster in PRh. The DA cellsslowly learn to predict reward associated to NAcc patterns

Severe Scene Learning Impairment, but Intact Recognition Memory, after Cholinergic Depletion of Inferotemporal Cortex Followed by Fornix Transection

To examine the generality of cholinergic involvement in visual memory in primates, we trained macaque monkeys either on an object-in-place scene learning task or in delayed nonmatching-to-sample (DNMS). Each monkey received either selective cholinergic depletion of inferotemporal cortex (including the entorhinal cortex and perirhinal cortex) with injections of the immunotoxin ME20.4-saporin or saline injections as a control and was postoperatively retested. Cholinergic depletion of inferotemporal cortex was without effect on either task. Each monkey then received fornix transection because previous studies have shown that multiple disconnections of temporal cortex can produce synergistic impairments in memory. Fornix transection mildly impaired scene learning in monkeys that had received saline injections but severely impaired scene learning in monkeys that had received cholinergic lesions of inferotemporal cortex. This synergistic effect was not seen in monkeys performing DNMS. These findings confirm a synergistic interaction in a macaque monkey model of episodic memory between connections carried by the fornix and cholinergic input to the inferotemporal cortex. They support the notion that the mnemonic functions tapped by scene learning and DNMS have dissociable neural substrates. Finally, cholinergic depletion of inferotemporal cortex, in this study, appears insufficient to impair memory functions dependent on an intact inferotemporal cortex.

Fronto‐temporal dysregulation in remitted bipolar patients: an fMRI delayed‐non‐match‐to‐sample (DNMS) study

Bipolar disorder is associated with working memory (WM) impairments that persist during periods of symptomatic remission. However, the neural underpinnings of these deficits are not well understood. Fifteen clinically remitted bipolar patients and 15 demographically matched healthy controls underwent functional magnetic resonance imaging while performing a novel delayed-non-match-to-sample (DNMS) task. This nonverbal DNMS task involves two conditions, one requiring the organization of existing memory traces ('familiarity'), and one involving the formation of new memory traces ('novelty'). These processes are thought to differentially engage the prefrontal cortex and medial temporal lobe, respectively. Although behavioral performance did not differ between groups, bipolar patients and controls exhibited significantly different patterns of neural activity during task performance. Patients showed relative hyperactivation in the right prefrontal gyrus and relative hypoactivation in visual processing regions compared to healthy subjects across both task conditions. During the novelty condition, patients showed a pattern of hypoactivation relative to controls in medial temporal regions, with relative hyperactivation in the anterior cingulate. These findings suggest that disruption in fronto-temporal neural circuitry may underlie memory difficulties frequently observed in patients with bipolar disorder.

A computational model of basal ganglia involved in the cognitive control of visual perception

Event Abstract Back to Event A computational model of basal ganglia involved in the cognitive control of visual perception Fred H. Hamker1* and Julien Vitay2 1 Technichal University Chemnitz, Computer Science Department, Germany 2 Westfalischen Wilhelms Universitat, Psychologisches Institut II, Germany Goal-directed visual perception requires to maintain and manipulate a template of the desired target in visual working memory (WM) that allows to bias processing in the posterior lobe. It is still unclear how such goal-directed perception is implemented in the brain. We propose that such interaction between visual WM and attentional processing involves a network of brain areas consisting of inferotemporal cortex (IT) for the retrieval of visual information associated to the target, dorsolateral-prefrontal cortex (dlPFC) for the manipulation and maintenance of the target template in face of distractors, medial temporal lobe (MTL) regions for rapid encoding and novelty detection, as well as basal ganglia (BG) for the switching and activation of WM representations in dlPFC.We designed a novel computational model of BG, while it interacts with a model of perirhinal cortex (PRh, part of the medial temporal lobe) and a simple model of dlPFC for memorizing objects, to explore how the BG might be involved in the cognitive control of visual perception. The BG model is composed of the striatum receiving connections from PRh and dlPFC. The striatum inhibits SNr which in turn tonically inhibits a thalamic nucleus interacting with PRh. Homeostatic Hebbian learning takes place simultaneously in the connections from cortical areas to the striatum (representing the context of of the task) and in the connections from striatum to SNr as well as within SNr (learning to retrieve the correct representation). Moreover, a dopaminergic cell learns to compute the difference between the reward actually received and the expectation of reward based on striatal representations and modulates learning in the other areas.We applied this model to simultaneously learn delayed matching-to-sample (DMS) and delayed nonmatching-to-sample (DNMS) tasks. Whether DMS or DNMS should be performed is defined by a contextual information presented after the sample and before the search array composed of two targets. Reward is given to the system when it selects the correct target through thalamic stimulation of PRh. The model has to represent efficiently the context in the striatum to solve the tasks and is able to learn them concurrently after 400 trials, independently of the number of cells in SNr, what denotes a parallel search of the correct representation. If at the beginning of learning, several cells in SNr can become selective for the same striatal pattern, the learned competition between them progressively selects the only one that disinhibits the correct target. The reward-predictive value of striatal representations also takes into account the probability of reward associated to an object.Similarly to the PVLV model of O'Reilly and Frank, our model reproduces the reward-related firing pattern of dopaminergic cells in conditioning. However, our model highlights the role of BG processing in visual WM processes, not only in its cognitive component but also in the retrieval of target information. It explains how vision can be guided by the goals of the task at hand. Conference: Bernstein Conference on Computational Neuroscience, Frankfurt am Main, Germany, 30 Sep - 2 Oct, 2009. Presentation Type: Poster Presentation Topic: Decision, control and reward Citation: Hamker FH and Vitay J (2009). A computational model of basal ganglia involved in the cognitive control of visual perception. Front. Comput. Neurosci. Conference Abstract: Bernstein Conference on Computational Neuroscience. doi: 10.3389/conf.neuro.10.2009.14.006 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 25 Aug 2009; Published Online: 25 Aug 2009. * Correspondence: Fred H Hamker, Technichal University Chemnitz, Computer Science Department, Chemnitz, Germany, fred.hamker@informatik.tu-chemnitz.de Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Fred H Hamker Julien Vitay Google Fred H Hamker Julien Vitay Google Scholar Fred H Hamker Julien Vitay PubMed Fred H Hamker Julien Vitay Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Ketamine analgesia for inflammatory pain in neonatal rats: a factorial randomized trial examining long-term effects

BackgroundNeonatal rats exposed to repetitive inflammatory pain have altered behaviors in young adulthood, partly ameliorated by Ketamine analgesia. We examined the relationships between protein expression, neuronal survival and plasticity in the neonatal rat brain, and correlated these changes with adult cognitive behavior.MethodsUsing Western immunoblot techniques, homogenates of cortical tissue were analyzed from neonatal rats 18–20 hours following repeated exposure to 4% formalin injections (F, N = 9), Ketamine (K, 2.5 mg/kg × 2, N = 9), Ketamine prior to formalin (KF, N = 9), or undisturbed controls (C, N = 9). Brain tissues from another cohort of rat pups (F = 11, K = 12, KF = 10, C = 15) were used for cellular staining with Fos immunohistochemistry or FluoroJade-B (FJB), followed by cell counting in eleven cortical and three hippocampal areas. Long-term cognitive testing using a delayed non-match to sample (DNMS) paradigm in the 8-arm radial maze was performed in adult rats receiving the same treatments (F = 20, K = 24, KF = 21, C = 27) in the neonatal period.ResultsGreater cell death occurred in F vs. C, K, KF in parietal and retrosplenial areas, vs. K, KF in piriform, temporal, and occipital areas, vs. C, K in frontal and hindlimb areas. In retrosplenial cortex, less Fos expression occurred in F vs. C, KF. Cell death correlated inversely with Fos expression in piriform, retrosplenial, and occipital areas, but only in F. Cortical expression of glial fibrillary acidic protein (GFAP) was elevated in F, K and KF vs. C. No significant differences occurred in Caspase-3, Bax, and Bcl-2 expression between groups, but cellular changes in cortical areas were significantly correlated with protein expression patterns. Cluster analysis of the frequencies and durations of behaviors grouped them as exploratory, learning, preparatory, consumptive, and foraging behaviors. Neonatal inflammatory pain exposure reduced exploratory behaviors in adult males, learning and preparatory behaviors in females, whereas Ketamine ameliorated these long-term effects.ConclusionNeuroprotective effects of Ketamine attenuate the impaired cognitive behaviors resulting from pain-induced cell death in the cortical and hippocampal fields of neonatal rats. This cell death was not dependent on the apoptosis associated proteins, but was correlated with glial activation.

A novel spatial Delayed Non-Match to Sample (DNMS) task in the Göttingen minipig

The pig (Sus scrofus) is a valuable animal for modeling human brain diseases. When evaluating animal models of many human brain disorders cognitive testing is crucial, but the pig's ability to learn the typical types of tasks used in neuropsychological testing of other species is largely unknown. The present study is the first study to evaluate the pig's ability to learn the Delayed Non-Match to Sample (DNMS) task.The pigs were trained in a maze on a spatial version of the DNMS task. Initially, the pigs were trained with a 60s delay interval between sample and test phases, and we found that the pigs required an average of 144 trials to reach criterion for learning the task, which is similar to macaque monkeys. We also found that pigs, in contrast to rats, do not have a natural tendency to alternate in their choices in the task. To evaluate the sensitivity to reduced memory function longer delay intervals (300s and 900s) and a scopolamine challenge were introduced.In our test condition we found a significant effect of longer delay intervals (F2,21=34.43, P<0.0001) and of scopolamine (F1,14=14.28, P=0.002) on the number of correct choices in the task.We conclude that the Göttingen minipig can solve the spatial DNMS task and that the task is sensitive to both increasing delay intervals and to scopolamine.

Endocannabinoids modulate encoding of sequential memory in the rat hippocampus

This report investigated the role of endocannabinoids in the encoding of task-relevant information by ensembles of hippocampal neurons under conditions in which the CB1 receptor antagonist, rimonabant, was administered during performance of a short-term memory delayed non-match to sample (DNMS) task in rats. The influence of endocannabinoids on the encoding of task relevant information was determined via examination of the firing patterns of ensembles of CA1/CA3 hippocampal neurons during individual trials while rats performed a DNMS task. Multivariate discriminant analysis of the firing patterns of ensembles of hippocampal neurons was used to extract trial-specific codes for task-relevant information under different types of trial sequences. It was discovered that rimonabant blocked an inherent hippocampal memory encoding bias used by all animals. This bias was characterized as the preferential encoding of sample information on individual trials based on the similarity (i.e., same or different) and duration of the delay in the preceding trial. The results indicate that endocannabinoids are a major influence on the strategic encoding biases of hippocampal ensembles and that pharmacological blockade of CB1 receptors facilitated performance by eliminating such influences.

Working Memory for Emotional Facial Expressions: Role of Estrogen in Humans and Non-Human Primates

In recent years, numerous studies focusing on the role of sex steroid hormones on neuropsychological functions have been reported. The influence of estrogens on cognition can be explained by the widespread presence of estrogen receptors (ERs) in limbic and cortical areas, and the modulator role of estrogens on numerous neurotransmitter systems. There is a great deal of evidence suggesting that estrogen can enhance memory processes and improve performance in working memory (WM) tasks, including face-tasks, delayed matching-to-sample (DMTS) and delayed non-matching-to-sample (DNMTS). The modulator effects exerted by estrogens are complex and may vary according to task, gender, and phase of the menstrual cycle. For many years, physiological hormonal fluctuations during the menstrual cycle, postpartum, and menopause have been said to influence mood, cognition, and affective disorders. In addition, it has been hypothesised that estrogens have a protective role in schizophrenia and Alzheimer's disease (AD). Taking into account that women's performance in memory tasks can also fluctuate with circulating hormone levels across the menstrual cycle, data related to the cognitive performance in a WM task for emotional facial expressions were reported. The findings described in this review can contribute to clarifying the role of the steroid hormone estrogen in the modulation of cognitive functions, particularly memory, and indicate the possible usefulness of applying a new paradigm, employing a DNMTS task with emotional facial expressions, in studies focused on emotional WM in relevant models of nonhuman primates. Such data could also represent a useful tool in individualizing effective therapy for the treatment of disturbances linked to menstrual cycle phases and menopause in women.

Short-term memory is modulated by the spontaneous release of endocannabinoids: evidence from hippocampal population codes

Population codes derived from ensembles of hippocampal neurons were assessed to determine whether endocannabinoids were active when rats performed a delayed-nonmatch-to-sample (DNMS) short-term memory task. Multivariate discriminant analyses of the firing patterns of ensembles of CA1 and CA3 hippocampal neurons extracted representations of information encoded at the time of the sample response (SmR codes) during individual DNMS trials. The 'strength' or distinctiveness of trial-specific SmR codes in normal sessions was compared with sessions in which either rimonabant, the well-characterized cannabinoid CB1 receptor antagonist, or WIN 55212-2 (WIN-2), a cannabinoid CB1 receptor agonist, were administered. Results show that performance on trials with delay intervals longer than 10 s was facilitated by rimonabant (2.0 mg/kg) owing to a significantly increased frequency of trials with stronger SmR codes. In contrast, WIN-2 (0.35 mg/kg) suppressed the strength of SmR codes necessary to perform trials with delays greater than 10 s. The positive influence of rimonabant on performance indicated that the action of endocannabinoids was to reduce SmR code strength, resulting in trials that were at risk for errors if the delay exceeded 10 s. Thus endocannabinoids, like exogenously administered cannabinoids, reduced hippocampal encoding necessary to perform long-delay trials. The findings therefore indicate a direct relationship between the actions of endocannabinoids on hippocampal processes and the ability to encode information into short-term memory.