Rodent Tasks Research Articles

Tetrahydrocannabinolic acid reduces nausea‐induced conditioned gaping in rats and vomiting in Suncus murinus

We evaluated the anti-emetic and anti-nausea properties of the acid precursor of Δ(9) -tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), and determined its mechanism of action in these animal models. We investigated the effect of THCA on lithium chloride- (LiCl) induced conditioned gaping (nausea-induced behaviour) to a flavour, and context (a model of anticipatory nausea) in rats, and on LiCl-induced vomiting in Suncus murinus. Furthermore, we investigated THCA's ability to induce hypothermia and suppress locomotion [rodent tasks to assess cannabinoid1 (CB1 ) receptor agonist-like activity], and measured plasma and brain THCA and THC levels. We also determined whether THCA's effect could be blocked by pretreatment with SR141716 (SR, a CB1 receptor antagonist). In rats, THCA (0.05 and/or 0.5 mg·kg(-1) ) suppressed LiCl-induced conditioned gaping to a flavour and context; the latter effect blocked by the CB1 receptor antagonist, SR, but not by the 5-hydroxytryptamine-1A receptor antagonist, WAY100635. In S. murinus, THCA (0.05 and 0.5 mg·kg(-1) ) reduced LiCl-induced vomiting, an effect that was reversed with SR. A comparatively low dose of THC (0.05 mg·kg(-1) ) did not suppress conditioned gaping to a LiCl-paired flavour or context. THCA did not induce hypothermia or reduce locomotion, indicating non-CB1 agonist-like effects. THCA, but not THC was detected in plasma samples. THCA potently reduced conditioned gaping in rats and vomiting in S. murinus, effects that were blocked by SR. These data suggest that THCA may be a more potent alternative to THC in the treatment of nausea and vomiting.

Development of a paradigm to investigate mechanisms of divided and selective attention impairment in the rodent models of Alzheimer’s disease

In Alzheimer’s disease impaired attention can be detected almost immediately after the first signs of memory loss and is considered to be a major cause of difficulties in the patients everyday life in the early stages of Alzheimer’s disease. Several types of attention are recognized such as divided, selective and sustained attention. Selective and divided attention are impaired most in the Alzheimer’s disease patients while sustained attention remains relatively intact. However, most attention tests in animal models of Alzheimer’s disease such as the five-choice serial reaction time task evaluates sustained but not other attention types. We decided to profit from a recent finding that Alzheimer’s patients have an impaired ability to detect objects approaching on a collision course in tests for selective and divided visual attention [1,2]. Collision detection is conserved across species and is performed by specialized collision-sensitive neurons in the superior colliculus of both in humans and rodents facilitating extension to humans of the results obtained in animals. However, so far little is known about collision-sensitive neurons in rats and mice and such a visual stimulus has not been used in attention tasks in rodents. To establish a paradigm for selective and divided visual attention tests in rodents, we recorded collision sensitive neurons in the rat superior colliculus by employing tetrode extracellular recordings in male, >1 month old rats. Collision sensitive neurons in the superficial layers of the superior colliculus were identified by their ability to respond to stimuli imitating collision but not to the ones veering slightly off. Collision sensitive neurons responded well to both dark (a black image on a white background) and bright (a bright image on a dark background) stimuli. Most putative collision-sensitive neurons could be assigned to eta class. Importantly, responses of collision-sensitive neurons were highly dependent on contrast, a parameter to be used to evaluate divided attention by presenting two different collision stimuli of different contrast. We will use these tests to investigate the effects of a 2-week intracerebroventricular infusion of beta-amyloid-(1-42), a rat model of Alzheimer’s disease [3], on divided and selective attention. This work was supported by a Lithuanian Research Council grant Nr. VP1-3.1-SMM-08-K-01-022.

Spatial memory tasks in rodents: what do they model?

The analysis of spatial learning and memory in rodents is commonly used to investigate the mechanisms underlying certain forms of human cognition and to model their dysfunction in neuropsychiatric and neurodegenerative diseases. Proper interpretation of rodent behavior in terms of spatial memory and as a model of human cognitive functions is only possible if various navigation strategies and factors controlling the performance of the animal in a spatial task are taken into consideration. The aim of this review is to describe the experimental approaches that are being used for the study of spatial memory in rats and mice and the way that they can be interpreted in terms of general memory functions. After an introduction to the classification of memory into various categories and respective underlying neuroanatomical substrates, I explain the concept of spatial memory and its measurement in rats and mice by analysis of their navigation strategies. Subsequently, I describe the most common paradigms for spatial memory assessment with specific focus on methodological issues relevant for the correct interpretation of the results in terms of cognitive function. Finally, I present recent advances in the use of spatial memory tasks to investigate episodic-like memory in mice.

NMDA receptor antagonists distort visual grouping in rats performing a modified two-choice visual discrimination task

Visual perception is impaired during pathological psychosis, which can be mimicked by NMDA receptor antagonists. However, the underlying mechanisms are poorly understood, partly due to limits of current rodent models for visual integration. The objectives of the study are (1) to develop a rodent task that can differentiate between effects on perception and nonspecific effects on task performance and (2) to test whether NMDA receptor antagonists affect visual perception in rats. We used an adaptation of Glass patterns to assess visual grouping in rats using a two-choice visual discrimination task in an infrared touch screen conditioning chamber. After rats learned to discriminate between a radial and a concentric bipole pattern, the ability to discriminate between these patterns was tested at various levels of distortion and a psychometric function was fit to obtain the maximum task performance and signal level needed for half-maximum performance. NMDA receptor antagonists ketamine and phencyclidine at low doses increased the signal quality needed to discriminate between the visual patterns, without affecting the ability to discriminate between undistorted images. At higher doses, the ability to perform the task even with undistorted images was impaired, which was associated with stereotypic behaviour and increased impulsivity. The Glass pattern-based visual grouping task is able to differentiate the effect of psychotomimetic NMDA receptor antagonists on visual perception from the effects on motor and memory functions. The half-maximum performance signal level allows quantification of cognitive psychosis in rodents, which can be translated to human psychometric functions and can be used in the development of more effective treatments.

Cognitive improvement by acute growth hormone is mediated by NMDA and AMPA receptors and MEK pathway

It has been reported that Growth hormone (GH) has an immediate effect enhancing excitatory postsynaptic potentials mediated by AMPA and NMDA receptors in hippocampal area CA1. As GH plays a role in adult memory processing, this work aims to study the acute effects of GH on working memory tasks in rodents and the possible involvement of NMDA and AMPA receptors and also the MEK/ERK signalling pathway. To evaluate memory processes, two different tests were used, the spatial working memory 8-arm radial maze, and the novel object recognition as a form of non-spatial working memory test. Acute GH treatment (1mg/kg i.p., 1h) improved spatial learning in the radial maze respect to the control group either in young rats (reduction of 46% in the performance trial time and 61% in the number of errors), old rats (reduction of 38% in trial time and 48% in the number of errors), and adult mice (reduction of 32% in the performance time and 34% in the number of errors). GH treatment also increased the time spent exploring the novel object respect to the familiar object compared to the control group in young rats (from 63% to 79%), old rats (from 53% to 70%), and adult mice (from 61 to 68%). The improving effects of GH on working memory tests were blocked by the NMDA antagonist MK801 dizocilpine (0.025 mg/kg i.p.) injected 10 min before the administration of GH, in both young and old rats. In addition, the AMPA antagonist DNQX (1mg/kg i.p.) injected 10 min before the administration of GH to young rats, blocked the positive effect of GH. Moreover, in mice, the MEK inhibitor SL 327 (20mg/kg i.p.) injected 30 min before the administration of GH, blocked the positive effect of GH on radial maze and the novel object recognition. In conclusion, GH improved working memory processes through both glutamatergic receptors NMDA and AMPA and it required the activation of extracellular MEK/ERK signalling pathway. These effects could be related to the enhancement of excitatory synaptic transmission in the hippocampus reported by GH.

Effect of voluntary physical exercise and post-training epinephrine on acquisition of a spatial task in the barnes maze

A number of experiments have shown that physical exercise improves acquisition and retention for a variety of learning tasks in rodents. Most of these works have been conducted with tasks associated with a considerable level of stress, physical effort and/or food deprivation that might interact with exercise, thus hindering the interpretation of the results. On the other hand, it is well established that post-training epinephrine is able to facilitate memory consolidation, but only a few works have studied its effect on the process of acquisition. The present work was aimed at studying whether 17 days of voluntary physical exercise (running wheels) and/or post-training epinephrine (0.01 or 0.05mg/kg) could improve the acquisition of a spatial task in the Barnes maze, and whether the combination of the two treatments have additive effects. Our results showed that exercise improved acquisition, and 0.01mg/kg of epinephrine tended to enhance it, by reducing the distance needed to find the escape hole. The combination of both treatments failed to further improve the acquisition level. We concluded that both treatments exerted their effect on acquisition by enhancing the process of learning itself, and that exercise is able to improve acquisition even using tasks with a low level of stress and physical effort.

Environmental Enrichment Enhances Episodic-Like Memory in Association with a Modified Neuronal Activation Profile in Adult Mice

Although environmental enrichment is well known to improve learning and memory in rodents, the underlying neuronal networks' plasticity remains poorly described. Modifications of the brain activation pattern by enriched condition (EC), especially in the frontal cortex and the baso-lateral amygdala, have been reported during an aversive memory task in rodents. The aims of our study were to examine 1) whether EC modulates episodic-like memory in an object recognition task and 2) whether EC modulates the task-induced neuronal networks. To this end, adult male mice were housed either in standard condition (SC) or in EC for three weeks before behavioral experiments (n = 12/group). Memory performances were examined in an object recognition task performed in a Y-maze with a 2-hour or 24-hour delay between presentation and test (inter-session intervals, ISI). To characterize the mechanisms underlying the promnesiant effect of EC, the brain activation profile was assessed after either the presentation or the test sessions using immunohistochemical techniques with c-Fos as a neuronal activation marker. EC did not modulate memory performances after a 2 h-ISI, but extended object recognition memory to a 24 h-ISI. In contrast, SC mice did not discriminate the novel object at this ISI. Compared to SC mice, no activation related to the presentation session was found in selected brain regions of EC mice (in particular, no effect was found in the hippocampus and the perirhinal cortex and a reduced activation was found in the baso-lateral amygdala). On the other hand, an activation of the hippocampus and the infralimbic cortex was observed after the test session for EC, but not SC mice. These results suggest that the persistence of object recognition memory in EC could be related to a reorganization of neuronal networks occurring as early as the memory encoding.

Representation of three‐dimensional objects by the rat perirhinal cortex

The perirhinal cortex (PRC) is known to play an important role in object recognition. Little is known, however, regarding the activity of PRC neurons during the presentation of stimuli that are commonly used for recognition memory tasks in rodents, that is, three-dimensional objects. Rats in the present study were exposed to three-dimensional objects while they traversed a circular track for food reward. Under some behavioral conditions, the track contained novel objects, familiar objects, or no objects. Approximately 38% of PRC neurons demonstrated "object fields" (a selective increase in firing at the location of one or more objects). Although the rats spent more time exploring the objects when they were novel compared to familiar, indicating successful recognition memory, the proportion of object fields and the firing rates of PRC neurons were not affected by the rats' previous experience with the objects. Together, these data indicate that the activity of PRC cells is powerfully affected by the presence of objects while animals navigate through an environment; but under these conditions, the firing patterns are not altered by the relative novelty of objects during successful object recognition.

Rodent Model of the Effect of beta-Adrenergic Agents on Creative Problem Solving (IN4-1.008)

Objective: Our purpose is to develop a rodent model of creative problem solving and examine the effect of propranolol on performance. Background Previous research revealed benefit from β adrenergic antagonists in creative problem solving. However, animal model pharmacological studies have exclusively explored constrained problem solving (set shifting) tasks, where α-1 adrenergic and dopaminergic, but not β adrenergic effects have been found. To address this gap, we developed a novel unconstrained problem solving task in rodents, analogous to tasks recently utilized to examine creative problem solving in larger mammals, and examined the effect of propranolol. Design/Methods: Rats were food restricted, and then trained to dig for food in the three reward pots. They were then trained in odor discrimination and medium discrimination. Then, after administration of 1mg/kg propranolol or placebo, the rats were tested on simple discrimination, compound discrimination, reversal learning, and set shifting, using the 2 side reward pots. During these tasks, the digging chamber in the middle was blocked off. Then, the digging chamber was filled with sawdust, the entrance to the digging chamber was unblocked, and the reward was moved from the side pots to the pot at the end of the digging chamber, such that the rats were required to generate the novel solution to this problem by digging through the sawdust to access the reward pot. Results: Preliminary data revealed no effect of propranolol on any of the reversal learning or set shifting tasks. However, performance on propranolol was found to be better as compared to placebo for the novel digging task as assessed by time to completion (maximum 20 minutes allowed). Conclusions: This is, to our knowledge, the first rodent model of creative problem solving, allowing for the possibility of examination of the mechanism of action of this process in a way not possible with most other organisms. Supported by: Funded by Department of Radiology Mission Enhancement, University of Missouri School of Medicine (Beversdorf) and National Science Foundation Research Experiences for Undergraduates in Neuroscience grant DBI-1062667 (University of Missouri). Disclosure: Dr. Beversdorf has nothing to disclose. Dr. Hecht has nothing to disclose. Dr. Hampton has nothing to disclose. Dr. Schachtman has nothing to disclose. Dr. Will has nothing to disclose.

Corticostriatal plasticity is necessary for learning intentional neuroprosthetic skills

The ability to learn new skills and perfect them with practice applies not only to physical skills but also to abstract skills, like motor planning or neuroprosthetic actions. Although plasticity in corticostriatal circuits has been implicated in learning physical skills, it remains unclear if similar circuits or processes are required for abstract skill learning. Here we use a novel behavioural task in rodents to investigate the role of corticostriatal plasticity in abstract skill learning. Rodents learned to control the pitch of an auditory cursor to reach one of two targets by modulating activity in primary motor cortex irrespective of physical movement. Degradation of the relation between action and outcome, as well as sensory-specific devaluation and omission tests, demonstrate that these learned neuroprosthetic actions are intentional and goal-directed, rather than habitual. Striatal neurons change their activity with learning, with more neurons modulating their activity in relation to target-reaching as learning progresses. Concomitantly, strong relations between the activity of neurons in motor cortex and the striatum emerge. Specific deletion of striatal NMDA receptors impairs the development of this corticostriatal plasticity, and disrupts the ability to learn neuroprosthetic skills. These results suggest that corticostriatal plasticity is necessary for abstract skill learning, and that neuroprosthetic movements capitalize on the neural circuitry involved in natural motor learning.

Remaking memories: Reconsolidation updates positively motivated spatial memory in rats

There is strong evidence that reactivation of a memory returns it to a labile state, initiating a restabilization process termed reconsolidation, which allows for updating of the memory. In this study we investigated reactivation-dependent updating using a new positively motivated spatial task in rodents that was designed specifically to model a human list-learning paradigm. On Day 1, rats were trained to run to three feeders (List 1) for rewards. On Day 2, rats were trained to run to three different feeders (List 2) in either the same (Reminder condition) or a different (No Reminder condition) experimental context than on Day 1. On Day 3, rats were cued to recall List 1. Rats in the Reminder condition made significantly more visits to List 2 feeders (intrusions) during List 1 recall than rats in the No Reminder condition, indicating that the reminder triggered reactivation and allowed integration of List 2 items into List 1. This reminder effect was selective for the reactivated List 1 memory, as no intrusions occurred when List 2 was recalled on Day 3. No intrusions occurred when retrieval took place in a different context from the one used at encoding, indicating that the expression of the updated memory is dependent upon the retrieval context. Finally, the level of intrusions was highest when retrieval took place immediately after List 2 learning, and generally declined when retrieval occurred 1-4 h later, indicating that the List 2 memory competed with short-term retrieval of List 1. These results demonstrate the dynamic nature of memory over time and the impact of environmental context at different stages of memory processing.

A modified adjusting delay task to assess impulsive choice between isocaloric reinforcers in non-deprived male rats: effects of 5-HT2A/C and 5-HT1A receptor agonists

Existing animal models of impulsivity frequently use food restriction to increase subjects' motivation. In addition, behavioral tasks that assess impulsive choice typically involve the use of reinforcers with dissimilar caloric content. These factors represent energy-homeostasis limitations, which may confound the interpretation of results and limit the applicability of these models. This study was aimed at validating face and convergent validities of a modified adjusting delay task, which assesses impulsive choice between isocaloric reinforcers in ad libitum fed rats. Male Wistar rats (n = 18) were used to assess the preferredness and reinforcing efficacy of a "supersaccharin" solution (1.5% glucose/0.4% saccharin) over a 1.5% glucose solution. A separate group of rats (n = 24) was trained in a modified adjusting delay task, which involved repeated choice between the glucose solution delivered immediately and the supersaccharin solution delivered after a variable delay. To pharmacologically validate the task, the effects of the 5-HT(2A/C) receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(±)-DOI] and the 5-HT(1A) receptor agonist (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide [(±)-8-OH-DPAT] on impulsive choice were then evaluated. Supersaccharin was highly reinforcing and uniformly preferred over the glucose solution by all subjects. Rats quickly learned the task, and impulsivity was a very stable and consistent trait. DOI and 8-OH-DPAT significantly and dose dependently increased impulsive choice in this modified adjusting delay task. We validated a rodent task of impulsive choice, which eliminates typical energy-homeostasis limitations and, therefore, opens new avenues in the study of impulsivity in preclinical feeding and obesity research.

Effects of Chlorpyrifos and Chlorpyrifos-Oxon on the Dynamics and Movement of Mitochondria in Rat Cortical Neurons

Organophosphate (OP)-based pesticides have been used extensively for decades, and as a result, they have become almost ubiquitous in our environment. There is clinical and animal evidence to suggest that chronic exposures to OPs can lead to cognitive dysfunction and other neurological abnormalities, although the mechanism for these effects is unknown. We previously reported that repeated, subthreshold exposures (defined as doses not associated with signs of acute toxicity) to the commonly used OP chlorpyrifos (CPF) resulted in protracted impairments in the performance of attention and memory-related tasks in rodents as well as deficits in axonal transport ex vivo (in the sciatic nerve). Here, we investigated the effects of CPF and its active metabolite CPF oxon (CPO) on the dynamics and movement of mitochondria in rat primary cortical neurons using time-lapse imaging techniques. Exposure to CPF (1.0-20.0 μM) or CPO (5.0 nM-20.0 μM) for 1 or 24 h resulted in a concentration-dependent increase in mitochondrial length, a decrease in mitochondrial number (indicative of increased fusion events), and a decrease in their movement in axons. The changes occurred at concentrations of CPF and CPO that did not inhibit acetylcholinesterase activity (the commonly cited mechanism of acute OP toxicity), and they were not blocked by cholinergic receptor antagonists. Furthermore, the changes did not seem to be associated with direct (OP-related) effects on mitochondrial viability or function (i.e., mitochondrial membrane potential or ATP production). The results suggest that an underlying mechanism of organophosphate-based deficits in cognitive function might involve alterations in mitochondrial dynamics and/or their transport in axons.

Novel, highly translational learning assessment in a mouse model of Alzheimer's disease

The ability to apply previously learned information to novel problems and situations has been referred to as reconfiguration of stimuli or ‘transfer learning’. Deficits in this type of learning, in humans, correlate with mild hippocampal atrophy in non-demented elderly and appear to aid in the prediction of the progression into Alzheimer's disease (AD). To date, theories and models regarding this facet of hippocampal function have not been applied to animal models of pathological aging associated with hippocampal/medial temporal lobe deficits despite the fact that such learning offers direct translational advantages compared to conventional human and rodent assessments. In the current study, a mouse task was developed to determine if “transfer learning” assessment was sensitive to pathological changes in a mouse model of AD (APPswe, PSEN1dE9)85Dbo/o; APP+PS1 mice) and if this type of learning was hippocampal dependent. In the rodent task, mice learned a series of concurrent discriminations in one dimension (pairs of odors/digging media) in the presence of a feature-irrelevant stimulus in the other dimension not predictive of reward (learning phase). This irrelevant stimulus was then changed and discrimination performance evaluated (transfer phase). Three month old APP+PS1 mice were not impaired in initial discrimination learning or on the ability to transfer this learned information to the altered context. In contrast, at 12 months of age, APP+PS1 mice learned the initial concurrent discriminations on par with NTgs, but were impaired when required to “transfer” this learning into a new configuration/context. There were no differences in spatial learning in the Morris water maze (a hippocampal dependent task) between the APP+PS1 and NTgs at 12 months of age. Furthermore, ibotenic acid was used to produce bilateral neurotoxic hippocampal lesions in a cohort of C57Bl/6J mice. Lesioned mice were not impaired in the initial discrimination learning, but were impaired when required to transfer this learned information to the new context. Also, lesioned mice were impaired in the spatial version of the Morris water maze. These data describe a novel and sensitive hippocampal-dependent paradigm (“transfer learning”) that is analogous in humans and mice, appears to be sensitive to AD-like pathology and is well-suited to within-subject experimental design.

Estrogen receptor ligands counteract cognitive deficits caused by androgen deprivation in male rats

Androgen deprivation causes impairment of cognitive tasks in rodents and humans, and this deficit can be reverted by androgen replacement therapy. Part of the effects of androgens in the male may be mediated by their local metabolism to estradiol or 3-alpha androstanediol within the brain and the consequent activation of estrogen receptors. In this study we have assessed whether the administration of estradiol benzoate, the estrogen receptor β selective agonist diarylpropionitrile or the estrogen receptor α selective agonist propyl pyrazole triol affect performance of androgen-deprived male Wistar rats in the cross-maze test. In addition, we tested the effect of raloxifene and tamoxifen, two selective estrogen receptor modulators used in clinical practice. The behavior of the rats was assessed 2 weeks after orchidectomy or sham surgery. Orchidectomy impaired acquisition in the cross-maze test. Estradiol benzoate and the selective estrogen receptor β agonist significantly improved acquisition in the cross-maze test compared to orchidectomized animals injected with vehicle. Raloxifene and tamoxifen at a dose of 1 mg/kg, but not at doses of 0.5 or 2 mg/kg, also improved acquisition of orchidectomized animals. Our findings suggest that estrogenic compounds with affinity for estrogen receptor β and selective estrogen receptor modulators, such as raloxifene and tamoxifen, may represent good candidates to promote cognitive performance in androgen-deprived males.

Sub-optimal performance in the 5-choice serial reaction time task in rats was sensitive to methylphenidate, atomoxetine and d-amphetamine, but unaffected by the COMT inhibitor tolcapone

Prefrontal cortical dopamine (DA) and norepinephrine (NE) are implicated in multiple aspects of cognitive function assessed via the 5-choice serial reaction time task (5-CSRTT) in rodents. The present studies assessed the effects of the NE reuptake inhibitor atomoxetine (0.5–2.0 mg/kg), the mixed DA/NE reuptake inhibitor methylphenidate (0.1–2.0 mg/kg), the catecholamine releaser d-amphetamine (0.1–1.0 mg/kg) and the catecholamine-o-methyl-transferase (COMT) inhibitor tolcapone (3.0–30.0 mg/kg) in rats that exhibited sub-optimal performance (reduced accuracy: <70% correct) in the 5-CSRTT. Increased ITI durations were associated with increased premature responding. Decreased ITI durations resulted in increased percent omissions, increased perseverative responses and increased response latencies, but had no effects on magazine latencies or percent correct. Atomoxetine decreased premature responding at prolonged ITI durations and methylphenidate decreased percent omissions at low doses (0.1 and 0.5 mg/kg). By contrast, d-amphetamine increased premature and perseverative responding in a dose-dependent manner (0.3–1.0 mg/kg). Finally, tolcapone had no effects on sub-optimal performance in the variable ITI 5-CSRTT. These results suggest minimal potential of tolcapone as a therapeutic agent for ADHD and implicate cortical NE, not DA, in impulsive action.

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.

SLV330, a cannabinoid CB 1 receptor antagonist, ameliorates deficits in the T-maze, object recognition and Social Recognition Tasks in rodents

Cannabinoid CB 1 receptor (CB 1R) signaling has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the CB 1R antagonist SLV330 (doses ranging from 0.3 to 10 mg/kg, given orally, p.o.) could ameliorate impairments in distinct aspects of cognition using different disruption models in both mice and rats. Effects of SLV330 were tested on working memory deficits in the T-maze Continuous Alternation Task (T-CAT) in mice; episodic memory deficits in the Object Recognition Task (ORT) and Social Recognition Task (SRT) in rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept®, approved for symptomatic treatment of Alzheimer’s disease) and nicotine were used as reference compounds. SLV330 markedly improved aging and scopolamine-induced memory deficits in the T-CAT in mice with a lowest effective dose (LED) of 1 mg/kg p.o., while reversing the cognitive dysfunction induced by the N-methyl- d-aspartate (NMDA) antagonist dizocilpine (MK-801) only at the middle dose of 3 mg/kg. In the ORT, we have found that combined administration of subthreshold doses of SLV330 (1 mg/kg, p.o.) and the AChEI donepezil (0.1 mg/kg, p.o.), that had no discernable effects on performance when given alone, enhanced memory performance in Wistar rats with deficits induced by the muscarinic antagonist scopolamine, suggestive of additive synergistic effects of SLV330 and donepezil on cognitive impairment. Finally, SLV330 was found to have cognition enhancing properties in a time delay paradigm in the SRT at a LED dose of 3 mg/kg (p.o.). In conclusion, the CB 1R antagonist SLV330 was found to clearly improve memory in several preclinical models for cognitive impairment.

Subtype-selective nicotinic agonists enhance olfactory working memory in normal rats: A novel use of the odour span task

Nicotinic agonists have been shown to enhance performance in cognitive tasks based on attention and memory. The aim of this study was to use a test of olfactory working memory; the odour span task (OST) in rodents, to investigate the effects of subtype-specific nicotinic agonists on working memory in normal rats. Rats were trained in a non-matching to sample (NMTS) rule and then the full OST, which involved identifying a novel odour from an increasing number of presented odours. Male hooded Lister rats were treated with nicotine, selective nicotinic agonists or vehicle (saline). In order to validate the task, muscarinic and nicotinic receptor antagonists were also examined. Nicotine at both 0.05 and 0.1mg/kg significantly increased mean span length in the OST. The selective alpha 4 beta 2 nicotinic receptor agonist metanicotine (0.1mg/kg s.c.) and the selective alpha 7 nicotinic receptor agonist (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide) (compound A, 10mg/kg i.p.) also improved performance. In contrast, mecamylamine and scopolamine significantly decreased mean span length. These findings suggest a role for the activation of both alpha 4 beta 2 and alpha 7 subtypes of neuronal nicotinic receptor in mediating enhancements of olfactory working memory capacity in normal, non-compromised rats. These nicotinic receptor subtypes may therefore prove to be useful targets for the development of novel treatments for neuropsychiatric disorders that involve cognitive dysfunction.

Voluntary exercise improves both learning and consolidation of cued conditioned fear in C57 mice

Exercise is associated with improved cognitive function in humans as well as improved learning across a range of tasks in rodents. Although these studies provide a strong link between exercise and learning, to date studies have largely focused on tasks that principally involve the hippocampus. However, exercise has been shown to produce alterations in other brain areas suggesting that the cognitive enhancing effects of exercise may be more general. Therefore we set out to examine the effects of voluntary exercise on cued Pavlovian fear conditioning, a form of learning that is critically dependent on the amygdala. In Experiment 1 we showed that mice given 2 weeks of access to a running wheel prior to tone and foot shock fear conditioning showed enhanced conditioned fear as measured by fear-potentiated startle. This effect was not the result of altered shock reactivity nor was it to due to reduced baseline startle amplitude in exercising mice. In subsequent experiments we sought to examine whether the enhanced cued conditioned fear was the result of an improvement in learning, consolidation or retrieval of conditioned fear. In separate groups of mice, two weeks of access to a running wheel was begun either prior to fear conditioning, immediately after fear conditioning (consolidation period) or 2 weeks after fear conditioning. Compared to sedentary mice, mice that exercised either prior to fear conditioning, or immediately after fear conditioning, showed enhanced cued conditioned fear. Fear conditioning was not enhanced in mice that began exercising 2 weeks after fear conditioning. Taken together these results suggest that voluntary exercise improves the learning and consolidation of cued conditioned fear but does not improve the retrieval or performance of conditioned fear. Because a great deal is known about the neural circuit for cued conditioned fear, it is now possible to examine the cellular, molecular and pharmacological changes associated with exercise in this well-understood neural circuit.