Delayed Nonmatching-to-sample Research Articles

Enhanced expression of activity-regulated cytoskeleton-associated protein in the medial prefrontal cortex is involved in working memory performance.

Working memory (WM) is a cognitive function important for guiding the on-going or upcoming behavior. A memory-related protein Arc (activity-regulated cytoskeleton-associated protein) is implicated in long-term memory consolidation. Recent evidence further suggests the involvement of hippocampal Arc in spatial WM. The medial prefrontal cortex (mPFC) is a key brain region mediating WM. However, the role of mPFC Arc in WM is still uncertain. To investigate whether mPFC Arc protein is involved in WM performance, delayed non-match to sample (DNMS) T-maze task was performed in rats with or without blocking new synthesis of mPFC Arc. In DNMS task, a 10-s or 30-s delay between the sample run and the choice run was given to evaluate WM performance. To block new Arc protein synthesis during the DNMS task, Arc antisense oligodeoxynucleotides (ODNs) were injected to the bilateral mPFC. The results show that, in rats without surgery for cannula implantation and subsequent intracerebral injection of ODNs, WM was functioning well during the DNMS task with a delay of 10 s but not 30 s, which was accompanied with a significantly increased level of mPFC Arc protein, indicating a possible link between enhanced Arc protein expression and the performance of WM. After preventing the enhancement of mPFC Arc protein expression with Arc antisense ODNs, rat's WM performance was impaired. These findings support enhanced mPFC Arc protein expression playing a role during WM performance.

Effects of Stimulus Timing on the Acquisition of an Olfactory Working Memory Task in Head-Fixed Mice.

Acquisition of a behavioral task is influenced by many factors. The relative timing of stimuli is such a factor and is especially relevant for tasks relying on short-term memory, like working memory paradigms, because of the constant evolution and decay of neuronal activity evoked by stimuli. Here, we assess two aspects of stimulus timing on the acquisition of an olfactory delayed nonmatch-to-sample (DNMS) task. We demonstrate that head-fixed male mice learn to perform the task more quickly when the initial training uses a shorter sample-test odor delay without detectable loss of generalizability. Unexpectedly, we observed a slower task acquisition when the odor-reward interval was shorter. The effect of early reward timing was accompanied by a shortening of reaction times and more frequent sporadic licking. Analysis of this result using a drift-diffusion model indicated that a primary consequence of early reward delivery is a lowered threshold to act, or a lower decision bound. Because an accurate performance with a lower decision bound requires greater discriminability in the sensory representations, this may underlie the slower learning rate with early reward arrival. Together, our results reflect the possible effects of stimulus timing on stimulus encoding and its consequence on the acquisition of a complex task.SIGNIFICANCE STATEMENT This study describes how head-fixed mice acquire a working memory task (olfactory delayed nonmatch-to-sample task). We simplified and optimized the stimulus timing, allowing robust and efficient training of head-fixed mice. Unexpectedly, we found that early reward timing leads to slower learning. Analysis of this data using a computational model (drift-diffusion model) revealed that the reward timing affects the behavioral threshold, or how quickly animals respond to a stimulus. But, to still be accurate with early reaction times, the sensory representation needs to become even more refined. This may explain the slower learning rate with early reward timing.

Altered prefrontal-striatal theta-band oscillatory dynamics underlie working memory deficits in neuropathic pain rats.

Prelimbic medial prefrontal cortex (PL-mPFC) and nucleus accumbens core region (NAcc) play an important role in supporting several executive cognitive mechanisms, such as spatial working memory (WM). Recently, this circuit has been also associated with both sensory and affective components of pain. However, it is still unclear whether this circuit is endogenously engaged in neuropathic pain-related cognitive dysfunctions. To answer this question, we induced the expression of halorhodopsin in local PL-mPFC neurons projecting to NAcc, and then selectively inhibited the terminals of these neurons in the NAcc while recording neural activity during the performance of a delayed non-match to sample (DNMS) spatial WM task. Within-subject behavioural performance and PL-mPFC to NAcc circuit neural activity was assessed after the onset of a persistent rodent neuropathic pain model-spared nerve injury (SNI). Our results revealed that the induction of the neuropathy reduced WM performance, and altered the interplay between PL-mPFC and NAcc neurons namely in increasing the functional connectivity from NAcc to PL-mPFC, particularly in the theta-band spontaneous oscillations; in addition, these behavioural and functional perturbations were partially reversed by selective optogenetic inhibition of PL-mPFC neuron terminals into the NAcc during the DNMS task delay-period, without significant antinociceptive effects. Altogether, these results strongly suggest that the PL-mPFC excitatory output into the NAcc plays an important role in the deregulation of WM under pain conditions. Selective optogenetic inhibition of prefrontal-striatal microcircuit reverses pain-related working memory deficits but has no significant impact on pain responses. Neuropathic pain underlies an increase of functional connectivity between the nucleus accumbens core area and the prelimbic medial prefrontal cortex mediated by theta-band activity.

A Go/No-go delayed nonmatching-to-sample procedure to measure object-recognition memory in rats

The novel-object preference (NOP) test is widely used to assess object-recognition memory in rats. When interpreting behaviour on the test, a common assumption is that the magnitude of a rat’s novel-object preference reflects the persistence or accuracy of its memory for the previously encountered object. However, some concerns have been raised regarding the latter interpretation, and hence, the internal validity of the NOP test as a gauge of object-recognition abilities. Given the concerns, we developed a new Go/No-go delayed nonmatching-to-sample (DNMS) procedure to measure object-recognition memory, which circumvents the interpretational problems associated with the NOP test. Rats were trained to displace an unfamiliar object (sample) from over a food well to obtain a food reward. Then on a choice phase, rats were presented with novel objects (“Go” trial) or copies of the sample object (“No-go” trial). On Go trials rats received a reward for displacing the novel object and on No-go trials no reward was provided for displacing the sample object. Rats required an average 54 sessions to reach a performance criterion of at least 80 % correct choices on five consecutive sessions (16 correct choices out of 20). Afterwards, rats were tested on the NOP test, and we found that scores on both tasks were not significantly correlated, indicating performance on the Go/No-go DNMS task did not predict novelty preference scores. The findings from this experiment reveal the benefits of an alternative approach to assess object-recognition memory in rats.

Medial prefrontal lesions impair performance in an operant delayed nonmatch to sample working memory task.

Cognitive functions, such as working memory, are disrupted in most psychiatric disorders. Many of these processes are believed to depend on the medial prefrontal cortex (mPFC). Traditionally, maze-based behavioral tasks, which have a strong exploratory component, have been used to study the role of the mPFC in working memory in mice. In maze tasks, mice navigate through the environment and require a significant amount of time to complete each trial, thereby limiting the number of trials that can be run per day. Here, we show that an operant-based delayed nonmatch to sample (DNMS) working memory task, with shorter trial lengths and a smaller exploratory component, is also mPFC-dependent. We created excitotoxic lesions in the mPFC of mice and found impairments in both the acquisition of the task, with no delay, and in the performance with delays introduced. Importantly, we saw no differences in trial length, reward collection, or lever-press latencies, indicating that the difference in performance was not due to a change in motivation or mobility. Using this operant DNMS task will facilitate the analysis of working memory and improve our understanding of the physiology and circuit mechanisms underlying this cognitive process. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Resting State Networks in the TgF344-AD Rat Model of Alzheimer's Disease Are Altered From Early Stages.

A better and non-invasive characterization of the preclinical phases of Alzheimer’s disease (AD) is important to advance its diagnosis and obtain more effective benefits from potential treatments. The TgF344-AD rat model has been well characterized and shows molecular, behavioral and brain connectivity alterations that resemble the silent period of the pathology. Our aim was to longitudinally investigate functional brain connectivity in established resting-state networks (RSNs) obtained by independent component analysis (ICA) in a cohort of TgF344-AD and control rats every 3 months, from 5 to 18 months of age, to cover different stages of the disease. Before each acquisition, working memory performance was evaluated by the delayed non match-to-sample (DNMS) task. Differences in the temporal evolution were observed between groups in the amplitude and shape of the somatosensorial and sensorimotor networks but not in the whole default mode network (DMN). Subsequent high dimensional ICA analysis showed early alterations in the anterior DMN subnetwork activity of TgF344-AD rats compared to controls. Performance of DNMS task was positively correlated with somatosensorial network at 5 months of age in the wild-type (WT) animals but not in the Tg-F344 rats. At different time points, DMN showed negative correlation with cognitive performance in the control group while in the transgenic group the correlation was positive. In addition, behavioral differences observed at 5 months of age correlated with alterations in the posterior DMN subnetwork. We have demonstrated that functional connectivity using ICA represents a useful biomarker also in animal models of AD such as the TgF344AD rats, as it allows the identification of alterations associated with the progression of the disease, detecting differences in specific networks even at very early stages.

Bidirectional optogenetic modulation of prefrontal-hippocampal connectivity in pain-related working memory deficits

Dysfunction of the prefrontal-hippocampal circuit has been identified as a leading cause to pain-related working-memory (WM) deficits. However, the underlying mechanisms remain poorly determined. To address this issue, we implanted multichannel arrays of electrodes in the prelimbic cortex (PL-mPFC), and in the dorsal hippocampal CA1 field (dCA1) to record the neural activity during the performance of a delayed non-match to sample (DNMS) task. The prefrontal-hippocampal connectivity was selectively modulated by bidirectional optogenetic inhibition or stimulation of local PL-mPFC glutamatergic calcium/calmodulin-dependent protein kinase-II alpha (CaMKIIα) expressing neurons during the DNMS task delay-period. The within-subject behavioral performance was assessed using a persistent neuropathic pain model – spared nerve injury (SNI). Our results showed that the induction of the neuropathic pain condition affects the interplay between PL-mPFC and dCA1 regions in a frequency-dependent manner, and that occurs particularly across theta oscillations while rats performed the task. In SNI-treated rats, this disruption was reversed by the selective optogenetic inhibition of PL-mPFC CaMKIIα-expressing neurons during the last portion of the delay-period, but without any significant effect on pain responses. Finally, we found that prefrontal-hippocampal theta connectivity is strictly associated with higher performance levels. Together, our findings suggest that PL-mPFC CaMKIIα-expressing neurons could be modulated by painful conditions and their activity may be critical for prefrontal-hippocampal connectivity during WM processing.

Behavioral Impact of Long-Term Chronic Implantation of Neural Recording Devices in the Rhesus Macaque

Ensemble recording methods are pervasive in basic and clinical neuroscience research. Invasive neural implants are used in patients with drug resistant epilepsy to localize seizure origin, in neuropsychiatric or Parkinson's patients to alleviate symptoms via deep brain stimulation, and with animal models to conduct basic research. Studies addressing the brain's physiological response to chronic electrode implants demonstrate that the mechanical trauma of insertion is followed by an acute inflammatory response as well as a chronic foreign body response. Despite use of invasive recording methods with animal models and humans, little is known of their effect on behavior in healthy populations. To quantify the effect of chronic electrode implantation targeting the hippocampus on recognition memory performance. Four healthy female rhesus macaques were tested in a delayed nonmatching-to-sample (DNMS) recognition memory task before and after hippocampal implantation with a tetrode array device. Trials to criterion and recognition memory performance were not significantly different before vs. after chronic electrode implantation. Our results suggest that chronic implants did not produce significant impairments on DNMS performance.

Cognitive impairment in an animal model of multiple sclerosis and its amelioration by glatiramer acetate

The severe motor impairment in the MS animal model experimental autoimmune encephalomyelitis (EAE) obstructs the assessment of cognitive functions. We developed an experimental system that evaluates memory faculties in EAE-affected mice, irrespective of their motor performance, enabling the assessment of cognitive impairments along the disease duration, the associated brain damage, and the consequences of glatiramer acetate (GA) treatment on these manifestations. The delayed-non-matching to sample (DNMS) T-maze task, testing working and long term memory was adapted and utilized. Following the appearance of clinical manifestations task performances of the EAE-untreated mice drastically declined. Cognitive impairments were associated with disease severity, as indicated by a significant correlation between the T-maze performance and the clinical symptoms in EAE-untreated mice. GA-treatment conserved cognitive functions, so that despite their exhibited mild motor impairments, the treated mice performed similarly to naïve controls. The cognitive deficit of EAE-mice coincided with inflammatory and neurodegenerative damage to the frontal cortex and the hippocampus; these damages were alleviated by GA-treatment. These combined findings indicate that in addition to motor impairment, EAE leads to substantial impairment of cognitive functions, starting at the early stages and increasing with disease aggravation. GA-treatment, conserves cognitive capacities and prevents its disease related deterioration.

Systemic Blockade of the CB1 Receptor Augments Hippocampal Gene Expression Involved in Synaptic Plasticity but Perturbs Hippocampus-Dependent Learning Task.

Chronic and acute agonism as well as acute antagonism of CB1 receptors reveal modulation of learning and memory during stable performance of a delayed-nonmatch-to-sample (DNMS) memory task. However, it remains unclear how chronic blockade of the CB1 receptor alters acquisition of the behavioral task. We examined the effects of chronic rimonabant exposure during DNMS task acquisition to determine if blockade of the CB1 receptor with the antagonist rimonabant enhanced acquisition of operant task. Long-Evans rats, trained in the DNMS task before imposition of the trial delay, were surgically implanted with osmotic mini pumps to administer rimonabant (1.0 mg/kg/day) or vehicle (dimethyl sulfoxide/Tween-80/Saline). Following surgical recovery, DNMS training was resumed with the imposition of gradually longer delays (1-30 sec). The number of days required to achieve stable performance with either increasing length of delay or reversal of task contingency was compared between vehicle and rimonabant-treated rats. Following the completion of DNMS training, animals were euthanized, and both hippocampi were harvested for gene expression assay analysis. Rimonabant treatment animals required more time to achieve stable DNMS performance than vehicle-treated controls. Quantitative real-time polymerase chain reaction analysis revealed that the expressions of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit, brain-derived neurotrophic factor, and synapsin 1 (Syn1) were significantly increased. These results are consistent with rimonabant increasing mRNAs for proteins associated with hippocampal synapse remodeling, but that those alterations did not necessarily accelerate the acquisition of an operant behavioral task that required learning new contingencies.

Selective optogenetic inhibition of medial prefrontal glutamatergic neurons reverses working memory deficits induced by neuropathic pain.

Stability of local medial prefrontal cortex (mPFC) network activity is believed to be critical for sustaining cognitive processes such as working memory (WM) and decision making. Dysfunction of the mPFC has been identified as a leading cause to WM deficits in several chronic pain conditions; however, the underlying mechanisms remain largely undetermined. Here, to address this issue, we implanted multichannel arrays of electrodes in the prelimbic region of the mPFC and recorded the neuronal activity during a food-reinforced delayed nonmatch to sample (DNMS) task of spatial WM. In addition, we used an optogenetic technique to selectively suppress the activity of excitatory pyramidal neurons that are considered the neuronal substrate for memory retention during the delay period of the behavioral task. Within-subject behavioral performance and pattern of neuronal activity were assessed after the onset of persistent pain using the spared nerve injury model of peripheral neuropathy. Our results show that the nerve lesion caused a disruption in WM and prelimbic spike activity and that this disruption was reversed by the selective inhibition of prelimbic glutamatergic pyramidal neurons during the delay period of the WM task. In spared nerve injury animals, photoinhibition of excitatory neurons improved the performance level and restored neural activity to a similar profile observed in the control animals. In addition, we found that selective inhibition of excitatory neurons does not produce antinociceptive effects. Together, our findings suggest that disruption of balance in local prelimbic networks may be crucial for the neurological and cognitive deficits observed during painful syndromes.

Assessing object-recognition memory in rats: Pitfalls of the existent tasks and the advantages of a new test.

Studies of object-recognition memory in lab rats began in the late 1980s, using variants of the trial-unique delayed nonmatching-to-sample (DNMS) task. By the end of the 20th century, most investigators who wanted to study object-recognition in rodents had abandoned the DNMS task in favor of the novel-object-preference (NOP) test, mainly because the latter test is relatively easy to employ, whereas conventional DNMS tasks are not. Some concerns have been raised, however, about the internal validity of the NOP test as a method of measuring object-recognition abilities. We describe two experiments using a new DNMS procedure which requires considerably less training than the DNMS tasks of the 1980s and 1990s, and which cannot be subject to the same criticisms that have been leveled at the NOP test. In Experiment 1, rats were trained on the new modified-DNMS (mDNMS) task using short delays. Rats successfully learned the nonmatching rule in fewer than 25 trials, and they made accurate choices with retention intervals of up to 10 min. Experiment 2 examined a different group of rats' performance on the mDNMS task following long retention intervals (72 h, 3 weeks, and ~45 weeks). Rats made accurate choices on all retention intervals, even the longest retention interval of ~45 weeks. Overall, the findings demonstrate some benefits of an alternative approach to assess object-recognition memory in rats.

High-Throughput Automatic Training System for Odor-Based Learned Behaviors in Head-Fixed Mice.

Understanding neuronal mechanisms of learned behaviors requires efficient behavioral assays. We designed a high-throughput automatic training system (HATS) for olfactory behaviors in head-fixed mice. The hardware and software were constructed to enable automatic training with minimal human intervention. The integrated system was composed of customized 3D-printing supporting components, an odor-delivery unit with fast response, Arduino based hardware-controlling and data-acquisition unit. Furthermore, the customized software was designed to enable automatic training in all training phases, including lick-teaching, shaping and learning. Using HATS, we trained mice to perform delayed non-match to sample (DNMS), delayed paired association (DPA), Go/No-go (GNG), and GNG reversal tasks. These tasks probed cognitive functions including sensory discrimination, working memory, decision making and cognitive flexibility. Mice reached stable levels of performance within several days in the tasks. HATS enabled an experimenter to train eight mice simultaneously, therefore greatly enhanced the experimental efficiency. Combined with causal perturbation and activity recording techniques, HATS can greatly facilitate our understanding of the neural-circuitry mechanisms underlying learned behaviors.

Early brain connectivity alterations and cognitive impairment in a rat model of Alzheimer\u2019s disease

BackgroundAnimal models of Alzheimer’s disease (AD) are essential to understanding the disease progression and to development of early biomarkers. Because AD has been described as a disconnection syndrome, magnetic resonance imaging (MRI)-based connectomics provides a highly translational approach to characterizing the disruption in connectivity associated with the disease. In this study, a transgenic rat model of AD (TgF344-AD) was analyzed to describe both cognitive performance and brain connectivity at an early stage (5 months of age) before a significant concentration of β-amyloid plaques is present.MethodsCognitive abilities were assessed by a delayed nonmatch-to-sample (DNMS) task preceded by a training phase where the animals learned the task. The number of training sessions required to achieve a learning criterion was recorded and evaluated. After DNMS, MRI acquisition was performed, including diffusion-weighted MRI and resting-state functional MRI, which were processed to obtain the structural and functional connectomes, respectively. Global and regional graph metrics were computed to evaluate network organization in both transgenic and control rats.ResultsThe results pointed to a delay in learning the working memory-related task in the AD rats, which also completed a lower number of trials in the DNMS task. Regarding connectivity properties, less efficient organization of the structural brain networks of the transgenic rats with respect to controls was observed. Specific regional differences in connectivity were identified in both structural and functional networks. In addition, a strong correlation was observed between cognitive performance and brain networks, including whole-brain structural connectivity as well as functional and structural network metrics of regions related to memory and reward processes.ConclusionsIn this study, connectivity and neurocognitive impairments were identified in TgF344-AD rats at a very early stage of the disease when most of the pathological hallmarks have not yet been detected. Structural and functional network metrics of regions related to reward, memory, and sensory performance were strongly correlated with the cognitive outcome. The use of animal models is essential for the early identification of these alterations and can contribute to the development of early biomarkers of the disease based on MRI connectomics.

Remifentanil maintains lower initial delayed nonmatching-to-sample accuracy compared to food pellets in male rhesus monkeys.

Emerging human laboratory and preclinical drug self-administration data suggest that a history of contingent abused drug exposure impairs performance in operant discrimination procedures, such as delayed nonmatching-to-sample (DNMTS), that are hypothesized to assess components of executive function. However, these preclinical discrimination studies have exclusively used food as the reinforcer and the effects of drugs as reinforcers in these operant procedures are unknown. The present study determined effects of contingent intravenous remifentanil injections on DNMTS performance hypothesized to assess 1 aspect of executive function, working memory. Daily behavioral sessions consisted of 2 components with sequential intravenous remifentanil (0, 0.01-1.0 μg/kg/injection) or food (0, 1-10 pellets) availability in nonopioid dependent male rhesus monkeys (n = 3). Remifentanil functioned as a reinforcer in the DNMTS procedure. Similar delay-dependent DNMTS accuracy was observed under both remifentanil- and food-maintained components, such that higher accuracies were maintained at shorter (0.1-1.0 s) delays and lower accuracies approaching chance performance were maintained at longer (10-32 s) delays. Remifentanil maintained significantly lower initial DNMTS accuracy compared to food. Reinforcer magnitude was not an important determinant of DNMTS accuracy for either remifentanil or food. These results extend the range of experimental procedures under which drugs function as reinforcers. Furthermore, the selective remifentanil-induced decrease in initial DNMTS accuracy is consistent with a selective impairment of attentional, but not memorial, processes. (PsycINFO Database Record

Gamma oscillations in the superior colliculus and pulvinar in response to faces support discrimination performance in monkeys

The subcortical visual pathway including the superior colliculus (SC), pulvinar, and amygdala has been implicated in unconscious visual processing of faces, eyes, and gaze direction in blindsight. Our previous studies reported that monkey SC and pulvinar neurons responded preferentially to images of faces while performing a delayed non-matching to sample (DNMS) task to discriminate different visual stimuli (Nguyen et al., 2013, 2014). However, the contribution of SC and pulvinar neurons to the discrimination of the facial images and subsequent behavioral performance remains unknown. Since gamma oscillations have been implicated in sensory and cognitive processes as well as behavioral execution, we hypothesized that gamma oscillations during neuronal responses might contribute to achieving the appropriate behavioral performance (i.e., a correct response). In the present study, we re-analyzed those neuronal responses in the monkey SC and pulvinar to investigate possible relationships between gamma oscillations in these neurons and behavioral performance (correct response ratios) during the DNMS task. Gamma oscillations of SC and pulvinar neuronal activity were analyzed in three phases around the stimulus onset [inter-trial interval (ITI): 1000ms before trial onset; Early: 0–200ms after stimulus onset; and Late: 300–500ms after stimulus onset]. We found that human facial images elicited stronger gamma oscillations in the early phase than the ITI and late phase in both the SC and pulvinar neurons. Furthermore, there was a significant correlation between strengths of gamma oscillations in the early phase and behavioral performance in both the SC and pulvinar. The results suggest that gamma oscillatory activity in the SC and pulvinar contributes to successful behavioral performance during unconscious perceptual and behavioral processes.

THE EFFECTS OF A NOVEL NON-CATECHOL DOPAMINE PARTIAL AGONIST ON WORKING MEMORY IN THE AGED RHESUS MONKEY

Deficient D1 receptor signaling, particularly in the PFC, has been directly implicated in age-related decline in cognitive functions, including memory capacity and flexibility in nonhuman primates (Goldman-Rakic and Brown, 1981) and humans (Ota et al., 2006). Working memory in both aged and experimentally-depleted monkeys are improved by the partial D1 receptor agonist (D1R) SKF38393 (Arnsten et al., 1994). Accordingly, the PFC DA system is a strong target for therapeutic intervention to slow or reverse cognitive decline. In this study, we assess the effect of a novel class of non-catechol D1R agonists with favorable drug-like properties, PF-6294, on the performance of aged female rhesus monkeys in tasks of working memory and executive function. This study was divided into three drug/testing sessions. Each monkey received daily administration of one of three doses (0.0021, 0.021 and 0.24 mg/kg) or a placebo during each of the three sessions. A cross-over design was used and each monkey received two of the three doses and the placebo once during the study. Doses were randomly assigned to each monkey and treatments were administered daily over 3 weeks by subcutaneous injection one hour prior to the testing session which occurred 5 days/week. A six-week wash-out period occurred between each session during which no drug was administered and monkeys were not tested. During each session, we administered 2 tasks: Delayed Non-Matching to Sample (DNMS), with and without delays, and Delayed Recognition Span Task (DRST). No significant effect of treatment was observed in the basic DNMS or delayed version of task. However, the mid-range dose significantly affected DRST performance. Specifically, monkeys administered the 0.021 mg/kg dose achieved a significantly greater span of correct responses than monkeys receiving placebo or other doses both acutely on day 1, and after repeated administration at day 4. These data demonstrate that this new class of non-catechol D1R agonists improves working memory spans in aged monkeys and that this effect is maintained over time. D1R-based pharmacotherapies represent an attractive target for the treatment of cognitive decline associated with neurological disorders and warrant further investigation.

Intra-perirhinal cortex administration of estradiol, but not an ERβ agonist, modulates object-recognition memory in ovariectomized rats

Intra-rhinal cortical infusion of 17-β estradiol (E2, 244.8pg/μl) enhances performance on the Novel-Object Preference (NOP) test and impairs accuracy on the delayed nonmatching-to-sample (DNMS) task in the same set of ovariectomized rats (Gervais, Jacob, Brake, & Mumby, 2013). These results appear paradoxical, as normal performance on both tests require intact object-recognition memory (ORM) ability. While demonstrating a preference for the novel object requires recognizing the sample object, rodents can recognize the sample object and still fail to demonstrate a preference. Therefore, enhanced NOP test performance is consistent with both improved ORM and increased novel-object exploration independent of memory processes. There is some evidence suggesting that estrogen receptor (ER) β agonists enhance NOP test performance (Jacome et al., 2010), but no study to date has examined the role of this receptor in DNMS task performance in rodents. The aim of the present study was to determine whether intra-PRh infusion of an ER β agonist, diarylpropionitrile (DPN, 2μg/μl), has divergent effects on novel-object preference (i.e. novelty preference) and accuracy on the DNMS task. Ovariectomized (OVX) rats (n=7) received chronic low E2 (∼22pg/ml serum) replacement, then intra-PRh infusion of DPN (2μg/μl), E2 (244.8pg/μl), or vehicle before each mixed-delay session (0.5–5min) of the DNMS task. A different set of OVX rats (n=10) received the same infusions before each NOP test trial, and were tested either 4 or 72h later. Consistent with Gervais et al. (2013), intra-PRh E2 reduced accuracy on the DNMS task following a 5-min retention delay and enhanced novelty preference on both tests. Intra-PRh DPN was associated with accuracy that was similar to the vehicle-infusion condition, despite enhancing novelty preference on both tests. The accuracy results suggest that while intra-PRh E2 impairs ORM, ERβ does not play a role. However, ERβ in the PRh appears to be important for the expression of novelty preference, in a manner that is unaffected by retention delay. These findings suggest that the modulation of novelty preference by intra-PRh E2/ERβ may be due to factors unrelated to ORM.

Nicotine ameliorates schizophrenia-like cognitive deficits induced by maternal LPS exposure: a study in rats.

ABSTRACTMaternal exposure to infectious agents is a predisposing factor for schizophrenia with associated cognitive deficits in offspring. A high incidence of smoking in these individuals in adulthood might be, at least in part, due to the cognitive-enhancing effects of nicotine. Here, we have used prenatal exposure to maternal lipopolysaccharide (LPS, bacterial endotoxin) at different time points as a model for cognitive deficits in schizophrenia to determine whether nicotine reverses any associated impairments. Pregnant rats were treated subcutaneously with LPS (0.5 mg/kg) at one of three neurodevelopmental time periods [gestation days (GD) 10-11, 15-16, 18-19]. Cognitive assessment in male offspring commenced in early adulthood [postnatal day (PND) 60] and included: prepulse inhibition (PPI), latent inhibition (LI) and delayed non-matching to sample (DNMTS). Following PND 100, daily nicotine injections (0.6 mg/kg, subcutaneously) were administered, and animals were re-tested in the same tasks (PND 110). Only maternal LPS exposure early during fetal neurodevelopment (GD 10-11) resulted in deficits in all tests compared to animals that had been prenatally exposed to saline at the same gestational time point. Repeated nicotine treatment led to global (PPI) and selective (LI) improvements in performance. Early but not later prenatal LPS exposure induced consistent deficits in cognitive tests with relevance for schizophrenia. Nicotine reversed the LPS-induced deficits in selective attention (LI) and induced a global enhancement of sensorimotor gating (PPI).

Object and spatial memory after neonatal perirhinal lesions in monkeys

The contribution of the perirhinal cortex (PRh) to recognition memory is well characterized in adults, yet the same lesions have limited effect on recognition of spatial locations. Here, we assessed whether the same outcomes will follow when perirhinal lesions are performed in infancy. Monkeys with neonatal perirhinal (Neo-PRh) lesions and control animals were tested in three operant recognition tasks as they reached adulthood: Delayed Nonmatching-to-Sample (DNMS) and Object Memory Span (OMS), measuring object recognition, and Spatial Memory Span (SMS), measuring recognition of spatial locations. Although Neo-PRh lesions did not impact acquisition of the DNMS rule, they did impair performance when the delays were extended from 30s to 600s. In contrast, the same neonatal lesions had no impact on either the object or spatial memory span tasks, suggesting that the lesions impacted the maintenance of information across longer delays and not memory capacity. Finally, the magnitude of recognition memory impairment after the Neo-PRh lesions was similar to that previously observed after adult-onset perirhinal lesions, indicating minimal, or no, functional compensation after the early PRh lesions. Overall, the results indicate that the PRh is a cortical structure that is important for the normal development of mechanisms supporting object recognition memory. Its contribution may be relevant to the memory impairment observed with human cases of temporal lobe epilepsy without hippocampal sclerosis, but not to the memory impairment found in developmental amnesia cases.