Odor Span Research Articles

This or not that: select and reject control of relational responding in rats using a blank comparison procedure with odor stimuli

The blank comparison (BLC) task was developed to assess stimulus relations in discrimination learning; that is, are subjects learning to “select” the correct stimulus (S+) or “reject” the incorrect stimulus (S-) or both? This task has been used to study exclusion learning, mostly in humans and monkeys, and the present study extends the procedure to rats. The BLC task uses an ambiguous stimulus (BLC+/-) that replaces S+ (in the presence of S-) and replaces S- (in the presence of S+). In the current experiment, four rats were trained to remove session-novel scented lids from sand-filled cups in a two-choice, simultaneous presentation procedure called the Odor Span Task (OST) before being trained on the BLC procedure using odors as the discriminative stimuli. The BLC training procedure utilized simple discrimination training (S+ and S-) and added select (S+ and BLC-) and reject (BLC+ and S-) trial types. All rats demonstrated accurate performance in sessions with both select and reject type trials. Next, BLC probe trials were interspersed in standard OST sessions to assess the form of stimulus control in the OST. Rats performed accurately on select type probe trials (similar to baseline OST performance) and also showed above chance accuracy on reject type trials. Thus, we demonstrated that rats could acquire an odor-based version of the BLC task and that both select and exclusion-based (reject) relations were active in the OST. The finding of exclusion in rats under the rigorous BLC task conditions confirms that exclusion-based responding is not limited to humans and non-human primates.

Evidence for novelty reward cross-cueing in the odor span task in rats: implications for odor-based reward-motivated tasks.

The odor span task (OST) infers working memory capacity (WMC) by requiring rodents to discriminate between previously presented and session-novel odors to obtain a hidden food reward. Here, rats' responses to session-novel odors and food rewards were assessed to determine whether rats use mitigating strategies in the OST. Rats accurately responded to session-novel odors but also reliably responded to the food reward alone and performed at chance when both a session-novel odor and food reward were presented in separate locations. The inclusion of unscented sand in the cups holding the food reward significantly reduced the rats' responses to the food reward alone. Collectively, these results demonstrate the need for rigorous tests of potential mitigating strategies and hold wide implications for rodent odor discrimination-based behavioral tasks.

Nucleus accumbens core dopamine D2 receptors are required for performance of the odor span task in male rats.

The nucleus accumbens (NAc) core gates motivationally relevant behavioral action sequences through afferents from cortical and subcortical brain regions. While the role of the NAc core in reward and effort-based decision making is well established, its role in working memory (WM) processes is incompletely understood. The odor span task (OST) has been proposed as a measure of non-spatial working memory capacity (WMC) as it requires rodents to select a novel odor from an increasing number of familiar odors to obtain a food reward. To assess the role of the NAc core in the OST using (1) reversible chemical inactivation and (2) selective blockade of dopamine D1 and D2 receptors in the area. Well-trained male rats were tested on the OST following intra-NAc core infusions of muscimol/baclofen, the D1 receptorantagonist SCH-23390 (1 μg/hemisphere) and the D2 receptorantagonist eticlopride (1 μg/hemisphere). Behavioral measurements included the average odor span, maximum odor span, choice latency, searching vigor, and patterns of responding during foraging that may relate to impulsivity. Chemical inactivation of the NAc core significantly decreased odor span relative to sham and vehicle conditions. Selective antagonism of D2, but not D1, receptors in the NAc core also produced deficits in odor span. We found that secondary behavioral measures of choice latency, searching vigor, and responding to the first odor stimulus encountered were largely unaffected by treatment. These findings suggest that D2 receptors in the NAc core are required for OST performance.

Male and female impairments in odor span are observed in a rat model of PTSD.

Posttraumatic stress disorder (PTSD) is associated with neural and behavioral alterations in response to trauma exposure, including working memory impairments. Rodent models of PTSD have not fully investigated chronic or reactive working memory deficits, despite clinical relevance. The present study uses footshock to induce a posttraumatic stress state in male and female rats and evaluates the effect of footshock and trauma-paired odor cues on working memory performance in the odor span task. Results demonstrate the emergence of chronic deficits in working memory among animals exposed to footshock by 3 wk after traumatic stress. The presentation of a trauma-paired odor cue was associated with further decrement in working memory performance for male animals. Furthermore, anxiety-like behaviors associated with the PTSD-like phenotype could predict the degree of working memory impairment in response to the trauma-paired odor cue. This study enhances validation of an existing rodent model of PTSD through replication of the clinical observations of working memory deficits associated with PTSD and provides novel insight into effects in female rodents. This will facilitate work to probe underlying mechanistic dysregulation of working memory following footshock trauma exposure and future development of novel treatment strategies.

Incrementing non-matching- but not matching-to-sample is rapidly learned in an automated version of the odor span task.

The odor span task (OST) is frequently used to assess memory capacity in rodents. Odor stimuli are presented in a large arena and choices of session-novel odors produce food reward. The procedure can be described as an incrementing non-matching-to-sample contingency because on each trial one new stimulus is presented along with one or more previously presented (non-reinforced) comparison odors. An automated version of this task has recently been developed in which odors are presented with an olfactometer in an operant chamber using a successive conditional discrimination procedure. The present study compared the acquisition of matching- vs. non-matching-to-sample versions of the task with six rats tested under each procedure. All six rats trained on the non-matching variation showed rapid acquisition of the discrimination with high rates of responding to odor stimuli when they were session-novel and low rates of responding to subsequent presentations of those odors. However, only three of the six rats trained on the matching variation met acquisition criteria, and two of the three that did acquire the task required extensive training to do so. These results support findings from the OST that rats can differentiate between stimuli that are session-novel and those previously encountered, but alsothat a matching contingency is more difficult to learn than a non-matching arrangement. These findings parallel differences observed between acquisition of simple matching- and non-matching-to-sample tasks, but accounts such as novelty preference or the oddity preference effect may not be sufficient to explain the present results.

Successive incrementing non-matching-to-samples in rats: An automated version of the odor span task.

The odor span task is a procedure frequently used to study remembering of multiple stimuli in rodents. A large arena is used and odor stimuli are presented using scented cups. Selection of each odor is reinforced when first presented, but not on subsequent presentations; correct selections depend on remembering which stimuli were previously presented. The use of an arena setting with manual stimulus presentation makes the odor span task labor-intensive and limits experimental control; thus, an automated version of the task would be of value. The present study used an operant chamber equipped with an olfactometer and trained rats using successive conditional discrimination procedures under an incrementing non-matching-to-samples contingency. High rates of responding developed to odor stimuli when they were session-novel with low rates of responding to subsequent presentations of that odor. Additional experiments assessed variations of the procedure to determine the role of the frequency of odor presentation and the retention interval separating sample and comparison. Discrimination was impaired with long retention intervals suggesting the importance of this variable. These findings confirmed that rats differentiate between stimuli that are session-novel and those previously encountered and support the use of an automated procedure as an alternative to the odor span task.

Odor span task in dogs (Canis familiaris).

Working memory is essential for organisms to solve problems related to their survival and to adapt to changes in their environment. Researchers sought to create a non-human model of working memory that could be used to better understand its predictive value and underlying brain function. Several of these studies were conducted using the odor span task (OST) with rodents, and here, we present the first OST with domestic dogs (n = 6). The OST is an incrementing non-match-to-sample task in which dogs were presented with both a session novel (S +) and a previously encountered (S -) odor on each trial. A response to the session novel odor was always reinforced. Upon meeting training criterion on sessions with 24 trials or odors to remember, the dogs were tested on the OST with up to 72 odors to remember in the session. All dogs learned the OST and displayed accurate performance (≥ 79%) for the largest set size of 72 odors. In an analysis focused on the effect of intervening odors (i.e., the number of trials since the S - was last encountered), dogs demonstrated above-chance performance for up to eight intervening odors. The implications of these findings are discussed in the context of dog working memory for odors.

Roles of the medial prefrontal cortex, mediodorsal thalamus, and their combined circuit for performance of the odor span task in rats: analysis of memory capacity and foraging behavior.

Working memory (WM), the capacity for short-term storage of small quantities of information for immediate use, is thought to depend on activity within the prefrontal cortex. Recent evidence indicates that the prefrontal neuronal activity supporting WM is driven by thalamocortical connections arising in mediodorsal thalamus (mdThal). However, the role of these connections has not been studied using olfactory stimuli leaving open the question of whether this circuit extends to all sensory modalities. Additionally, manipulations of the mdThal in olfactory memory tasks have yielded mixed results. In the present experiment, we investigated the role of connections between the rat medial prefrontal cortex (mPFC) and mdThal in the odor span task (OST) using a pharmacological contralateral disconnection technique. Inactivation of either the mPFC or mdThal alone both significantly impaired memory performance in the OST, replicating previous findings with the mPFC and confirming that the mdThal plays an essential role in intact OST performance. Contralateral disconnection of the two structures impaired OST performance in support of the idea that the OST relies on mPFC-mdThal connections, but ipsilateral control infusions also impaired performance, complicating this interpretation. We also performed a detailed analysis of rats’ errors and foraging behavior and found a dissociation between mPFC and mdThal inactivation conditions. Inactivation of the mdThal and mPFC caused a significant reduction in the number of approaches rats made per odor, whereas only mdThal inactivation or mPFC-mdThal disconnection caused significant increases in choice latency. Our results confirm that the mdThal is necessary for performance of the OST and that it may critically interact with the mPFC to mediate OST performance. Additionally, we have provided evidence that the mPFC and mdThal play dissociable roles in mediating foraging behavior.

Effects of NMDA antagonist dizocilpine (MK-801) are modulated by the number of distractor stimuli in the rodent odor span task of working memory.

The rodent odor span task (OST) uses an incrementing non-matching to sample procedure in which a series of odors is presented and selection of the session-novel odor is reinforced. An OST is frequently used to test the effects of neurobiological variables on memory capacity as the number of odors to remember increases during the course of the session. In this regard, one important finding has been that NMDA receptor antagonists selectively impair OST performance at doses that spare accuracy on control tasks. However, in many versions of the odor span task the number of stimuli to remember is confounded with the number of distractor odors presented to the rat on each trial. The present study compared the effects of the NMDA antagonist dizocilpine when the number of choices was held constant at two (one novel odor-S+ and one previously presented distractor odor-S-) and when the number of choice stimuli was permitted to increase up to 10 (one S+ and 9 S-). Dizocilpine impaired OST accuracy at doses that had no effect on a reference memory control task in both 2-choice and 10-choice conditions; however, the dose-response function was shifted to the left in the 10-choice tests. The impairments produced by dizocilpine were exacerbated as the memory load increased in both 2- and 10-choice conditions. These findings support the hypothesis that NMDA antagonism reduces the number of stimuli that rats can remember accurately, but the interaction between the effective DZP dose and the number of distractors shows that drug effects on OST performances may involve attentional factors in addition to memory capacity. The findings also demonstrate that variations in number of OST distractors can be used to alter sensitivity of the task.

The Rat Medial Prefrontal Cortex Exhibits Flexible Neural Activity States during the Performance of an Odor Span Task.

Medial prefrontal cortex (mPFC) activity is fundamental for working memory (WM), attention, and behavioral inhibition; however, a comprehensive understanding of the neural computations underlying these processes is still forthcoming. Toward this goal, neural recordings were obtained from the mPFC of awake, behaving rats performing an odor span task of WM capacity. Neural populations were observed to encode distinct task epochs and the transitions between epochs were accompanied by abrupt shifts in neural activity patterns. Putative pyramidal neuron activity increased earlier in the delay for sessions where rats achieved higher spans. Furthermore, increased putative interneuron activity was only observed at the termination of the delay thus indicating that local processing in inhibitory networks was a unique feature to initiate foraging. During foraging, changes in neural activity patterns associated with the approach to a novel odor, but not familiar odors, were robust. Collectively, these data suggest that distinct mPFC activity states underlie the delay, foraging, and reward epochs of the odor span task. Transitions between these states likely enables adaptive behavior in dynamic environments that place strong demands on the substrates of working memory.

Effects of N-Methyl-D-aspartate (NMDA) antagonists ketamine, methoxetamine, and phencyclidine on the odor span test of working memory in rats.

The glutamate hypothesis proposes that N-Methyl-D-aspartate (NMDA) receptor hypofunction underlies cognitive and perhaps other schizophrenic symptoms. The present study used the odor span task to assess the effects of NMDA antagonists on remembering multiple stimuli in rodents. This task uses an incrementing nonmatching-to-sample procedure in which responses to a new olfactory stimulus are reinforced on each trial, whereas responses to previously presented stimuli are not. NMDA antagonists have been associated with memory impairments in a variety of animal models; however, there are inconsistencies across different NMDA antagonists and tasks used. The current study compared the acute effects of phencyclidine (PCP), ketamine (KET), and the novel NMDA antagonist methoxetamine (MXE) on responding in the odor span task and a simple discrimination control task. PCP and MXE impaired odor span accuracy at doses that did not impair simple discrimination in most rats; however, the effects of KET were less selective. Within-session analyses indicated that the effects of PCP and MXE depended on the number of stimuli to remember, that is, impairment only occurred when the memory load was relatively high. These effects of PCP and MXE were consistent with the hypothesis that NMDA antagonists may interfere with working memory, but the basis for less selective results with KET are unclear. (PsycINFO Database Record

Performance of the odour span task is not impaired following inactivations of parietal cortex in rats

Working memory (WM) is the ability to temporarily store information for use and manipulation. Working memory is thought to depend on a distributed set of higher cortical areas including the prefrontal and parietal cortex in primates while relatively little research has been conducted in rodents to elucidate the exact role of the parietal cortex (PC) in WM, particularly in relation to the construct of WM capacity. Previous work in our lab demonstrates that performance of the odour span task (OST), an olfactory incremental delayed nonmatching-to-sample task, relies on the medial prefrontal cortex (mPFC). However, the effects of inactivating the PC on the OST have not been studied. Therefore, the present experiment assessed the effects of inactivating the PC with the GABA receptor agonists muscimol/baclofen on performance of the OST. Infusions of muscimol/baclofen did not disrupt working memory performance, assessed by the mean number of odours each rat could remember before making an error on each day of testing. In contrast, performance of a positive control task, spontaneous cross-modal object recognition, was impaired by inactivating the PC. These results suggest that performance of the OST does not depend on the PC in rats. Our results are notable given past research demonstrating the importance of the parietal cortex for attentional processes and working memory in other tasks.

Interactions between medial prefrontal cortex and dorsomedial striatum are necessary for odor span capacity in rats: role of GluN2B-containing NMDA receptors.

Working memory is involved in the maintenance and manipulation of information essential for complex cognition. While the neural substrates underlying working memory capacity have been studied in humans, considerably less is known about the circuitry mediating working memory capacity in rodents. Therefore, the present experiments tested the involvement of medial prefrontal cortex (mPFC) and dorsal striatum (STR) in the odor span task (OST), a task proposed to assay working memory capacity in rodents. Initially, Long Evans rats were trained to dig in scented sand for food following a serial delayed nonmatching-to-sample rule. Temporary inactivation of dorsomedial (dm) STR significantly reduced span in well trained rats. Inactivation of mPFC or contralateral disconnection of the mPFC and dmSTR also reduced span. Infusing the GluN2B-containing NMDA receptor antagonist Ro 25-6981 into mPFC did not affect span; however, span was significantly reduced following bilateral Ro 25-6981 infusions into dmSTR or contralateral disconnection of mPFC (inactivation) and dmSTR (Ro 25-6981). These results suggest that span capacity in rats depends on GluN2B-containing NMDA receptor-dependent interactions between the mPFC and the dmSTR. Therefore, interventions targeting this circuit may improve the working memory capacity impairments in patients with schizophrenia, Alzheimer's disease, and Parkinson's disease.

Amnestic drugs in the odor span task: Effects of flunitrazepam, zolpidem and scopolamine

The odor span task is an incrementing non-matching–to-sample procedure designed to provide an analysis of working memory capacity in rodents. The procedure takes place in an arena apparatus and rats are exposed to a series of odor stimuli in the form of scented lids with the selection of new stimuli reinforced. This procedure makes it possible to study drug effects as a function of the number of stimuli to remember. In the present study, the non-selective positive allosteric GABAA receptor modulator flunitrazepam impaired odor span performance at doses that did not affect a control odor discrimination. In contrast, the alpha-1 selective positive GABAA receptor modulator zolpidem and the cholinergic receptor antagonist scopolamine only impaired odor span at doses that produced more global impairment, including decreased accuracy in the control discrimination and increased response omissions in the both the odor span and control discrimination procedures. Even though the effects of flunitrazepam were selective to odor span performance, they did not depend on the number of stimuli to remember—the same degree of impairment occurred regardless of the memory load. These findings suggest that flunitrazepam interfered selectively with conditional discrimination performance rather than working memory and tentatively suggest that flunitrazepam’s selective effects in the odor span task relative to the control odor discrimination are mediated by one or more non-alpha1 GABAA receptor subtypes.

Validation of the human odor span task: effects of nicotine.

Amongst non-smokers, nicotine generally enhances performance on tasks of attention, with limited effect on working memory. In contrast, nicotine has been shown to produce robust enhancements of working memory in non-humans. To address this gap, the present study investigated the effects of nicotine on the performance of non-smokers on a cognitive battery which included a working memory task reverse-translated from use with rodents (the odor span task, OST). Nicotine has been reported to enhance OST performance in rats and the present study assessed whether this effect generalizes to human performance. Thirty non-smokers were tested on three occasions after consuming either placebo, 2mg, or 4mg nicotine gum. On each occasion, participants completed a battery of clinical and experimental tasks of working memory and attention. Nicotine was associated with dose-dependent enhancements in sustained attention, as evidenced by increased hit accuracy on the rapid visual information processing (RVIP) task. However, nicotine failed to produce main effects on OST performance or on alternative measures of working memory (digit span, spatial span, letter-number sequencing, 2-back) or attention (digits forward, 0-back). Interestingly, enhancement of RVIP performance occurred concomitant to significant reductions in self-reported attention/concentration. Human OST performance was significantly related to N-back performance, and as in rodents, OST accuracy declined with increasing memory load. Given the similarity of human and rodent OST performance under baseline conditions and the strong association between OST and visual 0-back accuracy, the OST may be particular useful in the study of conditions characterized by inattention.

Maternal immune activation during pregnancy in rats impairs working memory capacity of the offspring

Maternal immune activation during pregnancy is an environmental risk factor for psychiatric illnesses such as schizophrenia in the offspring. Patients with schizophrenia display an array of cognitive symptoms, including impaired working memory capacity. Rodent models have been developed to understand the relationship between maternal immune activation and the cognitive symptoms of schizophrenia. The present experiment was designed to test whether maternal immune activation with the viral mimetic polyinosinic:polycytidylic acid (polyI:C) during pregnancy affects working memory capacity of the offspring. Pregnant Long Evans rats were treated with either saline or polyI:C (4mg/kg; i.v.) on gestational day 15. Male offspring of the litters (2–3months of age) were subsequently trained on a nonmatching-to-sample task with odors. After a criterion was met, the rats were tested on the odor span task, which requires rats to remember an increasing span of different odors to receive food reward. Rats were tested using delays of approximately 40s during the acquisition of the task. Importantly, polyI:C- and saline-treated offspring did not differ in performance of the nonmatching-to-sample task suggesting that both groups could perform a relatively simple working memory task. In contrast, polyI:C-treated offspring had reduced span capacity in the middle and late phases of odor span task acquisition. After task acquisition, the rats were tested using the 40s delay and a 10min delay. Both groups showed a delay-dependent decrease in span, although the polyI:C-treated offspring had significantly lower spans regardless of delay. Our results support the validity of the maternal immune activation model for studying the cognitive symptoms of neurodevelopmental disorders such as schizophrenia.

Olfactory Stimulus Control and the Behavioral Pharmacology of Remembering.

Behavior analytic approaches and techniques have much to offer to the study of remembering. There is currently great interest in the development of animal models of human memory processes in order to enhance understanding of the neurobiology of memory and treatment of dementia and related disorders. Because rodent models are so important in contemporary neuroscience and genetics, development of procedures to study various forms of memory in rodents is a point of emphasis. The sense of smell plays an important role in rodent behavior and use of olfactory stimuli has permitted demonstrations of complex forms of stimulus control that have also served as baselines for studying drug effects on remembering. This article focuses on the effects of drugs on behavior maintained by two related procedures: delayed matching-to-sample with odors and the Odor Span Task. These types of procedures provide an opportunity to explore drug effects on behavior maintained by multiple stimuli and across a range of delay intervals with potential to advance analysis of the behavioral pharmacology of remembering.

Behavioral pharmacology of the odor span task: Effects of flunitrazepam, ketamine, methamphetamine and methylphenidate.

The Odor Span Task is an incrementing non-matching-to-sample procedure that permits the study of behavior under the control of multiple stimuli. Rats are exposed to a series of odor stimuli and selection of new stimuli is reinforced. Successful performance thus requires remembering which stimuli have previously been presented during a given session. This procedure has been frequently used in neurobiological studies as a rodent model of working memory; however, only a few studies have examined the effects of drugs on performance in this task. The present experiments explored the behavioral pharmacology of a modified version of the Odor Span Task by determining the effects of stimulant drugs methylphenidate and methamphetamine, NMDA antagonist ketamine, and positive GABAA modulator flunitrazepam. All four drugs produced dose-dependent impairment of performances on the Odor Span Task, but for methylphenidate and methamphetamine, these occurred only at doses that had similar effects on performance of a simple odor discrimination. Generally, these disruptions were based on omission of responding at the effective doses. The effects of ketamine and flunitrazepam were more selective in some rats. That is, some rats tested under flunitrazepam and ketamine showed decreases in accuracy on the Odor Span Task at doses that did not affect simple discrimination performance. These selective effects indicate disruption of within-session stimulus control. Overall, these findings support the potential of the Odor Span Task as a baseline for the behavioral pharmacological analysis of remembering.

Influence of pharmacological manipulations of NMDA and cholinergic receptors on working versus reference memory in a dual component odor span task

Developed as a tool to assess working memory capacity in rodents, the odor span task (OST) has significant potential to advance drug discovery in animal models of psychiatric disorders. Prior investigations indicate OST performance is impaired by systemic administration of N-methyl-d-aspartate receptor (NMDA-r) antagonists and is sensitive to cholinergic manipulations. The present study sought to determine whether an impairment in OST performance can be produced by systemic administration of the competitive NMDA-r antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP; 3, 10, 17 mg/kg i.p.) in a unique dual-component variant of the OST, and whether this impairment is ameliorated by nicotine (0.75 mg/kg i.p.). Male Sprague-Dawley rats were trained to asymptotic level of performance on a 24-trial two-comparison incrementing nonmatching to sample OST. In addition, rats were administered a two-comparison olfactory reference memory (RM) task, which was integrated into the OST. The RM task provided an assessment of the effects of drug administration on global behavioral measures, long-term memory and motivation. Several measures of working memory (span, longest run, and accuracy) were dose dependently impaired by CPP without adversely affecting RM. Analysis of drug effects across trial blocks demonstrated a significant impairment of performance even at low memory loads, suggesting a CPP-induced deficit of olfactory short-term memory that is not load-dependent. Although nicotine did not ameliorate CPP-induced impairments in span or accuracy, it did block the impairment in longest run produced by the 10 mg/kg dose of CPP. Overall, our results indicate that performance in our 24 odor two-comparison OST is capacity dependent and that CPP impaired OST working, but not reference, memory.

Effects of MDMA on olfactory memory and reversal learning in rats

The effects of acute and sub-chronic MDMA were assessed using a procedure designed to test rodent working memory capacity: the odor span task (OST). Rats were trained to select an odor that they had not previously encountered within the current session, and the number of odors to remember was incremented up to 24 during the course of each session. In order to separate drug effects on the OST from more general performance impairment, a simple olfactory discrimination was also assessed in each session. In Experiment 1, acute doses of MDMA were administered prior to select sessions. MDMA impaired memory span in a dose-dependent fashion, but impairment was seen only at doses (1.8 and 3.0mg/kg) that also increased response omissions on both the simple discrimination and the OST. In Experiment 2, a sub-chronic regimen of MDMA (10.0mg/kg, twice daily over four days) was administered after OST training. There was no evidence of reduced memory span following sub-chronic MDMA, but a temporary increase in omission errors on the OST was observed. In addition, rats exposed to sub-chronic MDMA showed delayed learning when the simple discrimination was reversed. Overall, the disruptive effects of both acute and sub-chronic MDMA appeared to be due to non-mnemonic processes, rather than effects on specific memory functions.