Reference Memory Task Research Articles

Effects of Head-Only Exposure to 900 MHz GSM Electromagnetic Fields in Rats: Changes in Neuronal Activity as Revealed by c-Fos Imaging without Concomitant Cognitive Impairments.

Over the last two decades, animal models have been used to evaluate the physiological and cognitive effects of mobile phone exposure. Here, we used a head-only exposure system in rats to determine whether exposure to 900 MHz GSM electromagnetic fields (EMFs) induces regional changes in neuronal activation as revealed by c-Fos imaging. In a first study, rats were exposed for 2 h to brain average specific absorption rates (BASARs) ranging from 0.5 to 6 W/kg. Changes in neuronal activation were found to be dose-dependent, with significant increases in c-Fos expression occurring at BASAR of 1 W/kg in prelimbic, infralimbic, frontal, and cingulate cortices. In a second study, rats were submitted to either a spatial working memory (WM) task in a radial maze or a spatial reference memory (RM) task in an open field arena. Exposures (45 min) were conducted before each daily training session (BASARs of 1 and 3.5 W/kg). Control groups included sham-exposed and control cage animals. In both tasks, behavioral performance evolved similarly in the four groups over testing days. However, c-Fos staining was significantly reduced in cortical areas (prelimbic, infralimbic, frontal, cingulate, and visual cortices) and in the hippocampus of animals engaged in the WM task (BASARs of 1 and 3.5 W/kg). In the RM task, EMF exposure-induced decreases were limited to temporal and visual cortices (BASAR of 1 W/kg). These results demonstrate that both acute and subchronic exposures to 900 MHz EMFs can produce region-specific changes in brain activity patterns, which are, however, insufficient to induce detectable cognitive deficits in the behavioral paradigms used here.

Cognitive and hippocampal effects of adult male mice exposure to environmentally relevant doses of phthalates

We recently showed that chronic exposure of adult male mice to environmental doses of DEHP alone or in a phthalate mixture altered blood brain barrier integrity and induced an inflammatory profile in the hippocampus. Here, we investigate whether such exposure alters hippocampus-dependent behavior and underlying cellular mechanisms. Adult C57BL/6 J male mice were continuously exposed orally to the vehicle or DEHP alone (5 or 50 μg/kg/d) or to DEHP (5 μg/kg/d) in a phthalate mixture. In the Morris water maze, males showed reduced latencies across days to find the platform in the cue and spatial reference memory tasks, regardless of their treatment group. In the probe test, DEHP-50 exposed males displayed a higher latency to find the platform quadrant. In the temporal order memory test, males exposed to DEHP alone or in a phthalate mixture were unable to discriminate between the most recently and previously seen objects. They also displayed reduced ability to show a preference for the new object in the novel object recognition test. These behavioral alterations were associated with a lowered dendritic spine density and protein levels of glutamate receptors and postsynaptic markers, and increased protein levels of the presynaptic synaptophysin in the hippocampus. Metabolomic analysis of the hippocampus indicated changes in amino acid levels including reduced tryptophan and L-kynurenine and elevated NAD + levels, respectively, a precursor, intermediate and endproduct of the kynurenine pathway of tryptophan metabolism. Interestingly, the protein amounts of the xenobiotic aryl hydrocarbon receptor, a target of this metabolic pathway, were elevated in the CA1 area. These data indicate that chronic exposure of adult male mice to environmental doses of DEHP alone or in a phthalate mixture impacted hippocampal function and structure, associated with modifications in amino acid metabolites with a potential involvement of the kynurenine pathway of tryptophan metabolism.

The Impact of Chronic Unpredictable Mild Stress-Induced Depression on Spatial, Recognition and Reference Memory Tasks in Mice: Behavioral and Histological Study.

Depression-induced cognitive impairment has recently been given more attention in research. However, the relationship between depression and different types of memory is still not clear. Chronic unpredictable mild stress (CUMS) is a commonly used animal model of depression in which animals are exposed to chronic unpredictable environmental and psychological stressors, which mimics daily human life stressors. This study investigated the impact of different durations of CUMS on various types of memory (short- and long-term spatial memory and recognition memory) and investigated CUMS’ impact on the ultrastructural level by histological assessment of the hippocampus and prefrontal cortex. Twenty male C57BL/J6 mice (6 weeks old, 21.8 ± 2 g) were randomly divided into two groups (n = 10): control and CUMS (8 weeks). A series of behavioral tasks were conducted twice at weeks 5–6 (early CUMS) and weeks 7–8 (late CUMS). A tail-suspension test (TST), forced swimming test (FST), elevated zero maze (EZM), elevated plus maze (EPM), open field test (OFT), and sucrose-preference test (SPT) were used to assess anxiety and depressive symptoms. The cognitive function was assessed by the novel object recognition test (NORT; for recognition memory), Y-maze (for short-term spatial memory), and Morris water maze (MWM: for long-term spatial memory) with a probe test (for reference memory). Our data showed that 8 weeks of CUMS increased the anxiety level, reported by a significant increase in anxiety index in both EPM and EZM and a significant decrease in central preference in OFT, and depression was reported by a significant increase in immobility in the TST and FST and sucrose preference in the SPT. Investigating the impact of CUMS on various types of memory, we found that reference memory is the first memory to be affected in early CUMS. In late CUMS, all types of memory were impaired, and this was consistent with the abnormal histological features of the memory-related areas in the brain (hippocampus and prefrontal cortex).

Ventral hippocampus lesions and allocentric spatial memory in the radial maze: Anterograde and retrograde deficits

Although the dorsal hippocampus (DHip) has been clearly implicated in spatial learning and memory, there is currently debate as to whether the ventral hippocampus (VHip) is also necessary in allocentric-based navigation tasks. To differentiate between these two subregions of the hippocampal dorsoventral axis, we examined the effect of neurotoxic lesions to the DHip and VHip in different learning situations, using a four-arm plus-shaped maze. In experiment 1 a spatial reference memory task was used, with results showing an acquisition deficit in DHip-lesioned rats but perfect learning in VHip-lesioned rats. However, in experiment 2 an acquisition deficit was found in VHip-lesioned rats using a doubly marked training protocol. In this case the position of the goal arm during training was marked simultaneously by the extramaze constellation of stimuli around the maze and an intramaze cue. The main results indicated that DHip and VHip groups presented significantly more allocentric errors in the probe test than the control rats. In experiments 3 and 4, animals with their brains still intact learned, respectively, a spatial reference memory task or a purely cue-guided navigation task, and DHip and VHip lesions were made 2–3 days after reaching learning criterion. Results indicated a profound retrograde deficit in both lesioned groups but only with regard to allocentric information. So, depending on the training protocol used, our results point to increased integration and cooperation throughout the hippocampal dorsoventral axis when allocentric learning and memory is involved. These data support the existence of a functional continuum from the dorsal to the ventral hippocampus.

Neonatal Anesthesia by Ketamine in Neonatal Rats Inhibits the Proliferation and Differentiation of Hippocampal Neural Stem Cells and Decreases Neurocognitive Function in Adulthood via Inhibition of the Notch1 Signaling Pathway.

The Notch signaling pathway plays an important role in the regulation of neurogenesis. The objective of this study was to investigate whether the Notch signaling pathway was involved in the neurogenesis impairment and long-term neurocognitive dysfunction caused by neonatal exposure to ketamine. On postnatal day 7 (PND-7), male Sprague-Dawley (SD) rats were intraperitoneally injected with 40mg/kg ketamine four consecutive times (40mg/kg × 4) at 1-h intervals. Notch ligand Jagged1 (0.5mg/kg) and lentivirus overexpressing the Notch1 intracellular domain (LV-NICD1) were microinjected into the hippocampal dentate gyrus (DG) 1h or 4days before ketamine administration, respectively. The expression of Notch1 signaling pathway-related proteins was detected by Western blotting 24h after ketamine administration. The proliferation and differentiation of the neural stem cells (NSCs) in the hippocampal DG were evaluated by double immunofluorescence staining 24h after treatment. Moreover, changes in hippocampus-dependent spatial memory of 2-month-old rats were investigated with the Morris water maze test. Ketamine anesthesia in neonatal rats decreased the expression levels of Jagged1, Notch1, NICD1, and hairy enhancer of split 1 (Hes1); inhibited the proliferation and astrocytic differentiation of NSCs; and promoted the differentiation of neurons. Neonatal exposure to ketamine caused deficits in hippocampus-dependent spatial reference memory tasks in 2-month-old rats. Microinjection of Jagged1 or LV-NICD1 reversed the inhibitory effect of ketamine on the expression of Notch1-related proteins in the hippocampal DG, attenuated the ketamine-mediated decrease in NSC proliferation and differentiation, and improved the cognitive function of 2-month-old rats after neonatal exposure to ketamine. These results suggest that neonatal exposure to ketamine in rats inhibits the proliferation and differentiation of hippocampal NSCs and impairs neurocognitive function in adulthood. The Notch1 signaling pathway may be involved in the impairment of hippocampus-dependent learning and memory during adulthood caused by neonatal exposure to ketamine. These findings contribute to further understanding the neurotoxicity induced by neonatal exposure to ketamine and the underlying mechanisms.

Repetitive transcranial magnetic stimulation during a spatial memory task leads to a decrease in brain metabolic activity

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that is able to generate causal-based interferences between brain networks and cognitive or behavioral responses. It has been used to improve cognition in several disease models. However, although its exploration in healthy animals is essential to attribute its pure effect in learning and memory processes, studies in this regard are scarce. We aimed to evaluate whether rTMS leads to memory facilitation in healthy rats, and to explore the brain-related oxidative metabolism. We stimulated healthy Wistar rats with a high-frequency (100 Hz) and low-intensity (0.33 T) protocol during three consecutive days and evaluated the effect on the performance of an allocentric spatial reference learning and memory task. Following the last day of learning, we assessed oxidative brain metabolism through quantitative cytochrome c oxidase (CCO) histochemistry. The results showed that rTMS did not improve spatial memory in healthy rats, but the behavioral outcome was accompanied by a CCO reduction in the prefrontal, retrosplenial, parietal, and rhinal cortices, as well as in the striatum, amygdala, septum, mammillary bodies, and the hippocampus, reflecting a lower metabolic activity. In conclusion, rTMS induces a highly efficient use of brain regions associated with spatial memory.

Are Anti-Inflammatory Cytokines Associated with Cognitive Impairment in Patients with Insomnia Comorbid with Depression? A Pilot Study.

BackgroundTo distinguish insomnia comorbid with depression (ICD) from chronic insomnia disorder (CID) by exploring the relationship between serum levels of frequently overlooked anti-inflammatory cytokines and cognitive function.MethodsA total of 42 ICD patients, 63 CID patients, and 42 healthy control subjects were enrolled in the study. The Pittsburgh Sleep Quality Index and Hamilton Depression Rating Scale were used to assess sleep quality and depression severity, respectively. The Chinese-Beijing version of Montreal Cognitive Assessment scale (MoCA-C) and Nine-Box Maze Test (NBMT) were used to assess cognitive function. Serum levels of anti-inflammatory interleukins (IL-1RA, IL-4, IL-5, IL-10, IL-13, and IL-28A), transforming growth factor (TGF)-β1, granulocyte-macrophage colony-stimulating factor, interferon-γ, and the chemokine regulated upon activation, normal T cell expressed and secreted (RANTES) were measured by enzyme-linked immunosorbent assay.ResultsThe ICD group had significantly more errors in the spatial reference task (H=2.55, Ps=0.03) and spatial working memory task (H=5.67, Ps<0.01) of the NBMT, as well as lower levels of IL-1RA (H=−2.85, Ps=0.01), IL-4 (H=−3.28, Ps<0.01), IL-5 (H=−3.35, Ps<0.01), IL-10 (H=−4.46, Ps<0.01), and IL-28A (H=−2.75, Ps=0.02) than control subjects. Compared with the CID group, the ICD group had significantly more errors in the spatial reference memory task (H=−2.84, Ps=0.01) of the NBMT, and lower levels of IL-5 (H=3.41, Ps<0.01), IL-10 (H=5.30, Ps<0.01), IL-13 (H=3.89, Ps<0.01), and GM-CSF (H=2.72, Ps=0.02). A partial correlation analysis showed that the level of one or more of IL-4, IL-5, IL-10, IL-13, and TGF-β1 was positively correlated with cognitive function (MoCA-C score and/or performance in spatial memory task) in ICD patients.ConclusionICD is a distinct condition that can be distinguished from CID based on immune dysfunction and specific types of cognitive dysfunction.

Working and Reference Memory Tasks Trigger Opposed Long-Term Synaptic Changes in the Rat Dentate Gyrus.

Long-term storage of information into memory is supposed to rely on long-term synaptic plasticity processes. The detection of such synaptic changes after training in long-term/reference memory (RM) tasks has yet been scarce, variable and only studied on a short time scale. Short-term or working memory (WM) is largely known to depend on persistent neuronal activity or short-term plasticity. However, processing information into WM could also involve long-term synaptic changes that could be responsible for the erasure/forgetting of items previously stored in WM and acting as proactive interference. In order to study long-term synaptic changes associated with RM or WM, we trained chronically implanted rats in 3 different radial maze tasks: a classical RM task and 2 WM tasks involving different levels of proactive interference. Synaptic responses in the dentate gyrus were recorded during 2×24 h in freely moving rats after training. We found that consolidation of long-term information leads first to a delayed synaptic potentiation, occurring 9h after RM training that is replaced by a synaptic depression once the RM rule is fully acquired. In contrast, optimal information processing into WM triggers a synaptic depression immediately after training and lasting 3h that could act as a mechanism for interference erasure/forgetting.

Reconfiguration of the cortical-hippocampal interaction may compensate for Sharp-Wave Ripple deficits in APP/PS1 mice and support spatial memory formation.

Hippocampal-cortical dialogue, during which hippocampal ripple oscillations support information transfer, is necessary for long-term consolidation of spatial memories. Whereas a vast amount of work has been carried out to understand the cellular and molecular mechanisms involved in the impairments of memory formation in Alzheimer’s disease (AD), far less work has been accomplished to understand these memory deficiencies at the network-level interaction that may underlie memory processing. We recently demonstrated that freely moving 8 to 9-month-old APP/PS1 mice, a model of AD, are able to learn a spatial reference memory task despite a major deficit in Sharp-Wave Ripples (SWRs), the integrity of which is considered to be crucial for spatial memory formation. In order to test whether reconfiguration of hippocampal-cortical dialogue could be responsible for the maintenance of this ability for memory formation, we undertook a study to identify causal relations between hippocampal and cortical circuits in epochs when SWRs are generated in hippocampus. We analyzed the data set obtained from multielectrode intracranial recording of transgenic and wild-type mice undergoing consolidation of spatial memory reported in our previous study. We applied Directed Transfer Function, a connectivity measure based on Granger causality, in order to determine effective coupling between distributed circuits which express oscillatory activity in multiple frequency bands. Our results showed that hippocampal-cortical coupling in epochs containing SWRs was expressed in the two frequency ranges corresponding to ripple (130–180 Hz) and slow gamma (20–60 Hz) band. The general features of connectivity patterns were similar in the 8 to 9-month-old APP/PS1 and wild-type animals except that the coupling in the slow gamma range was stronger and spread to more cortical sites in APP/PS1 mice than in the wild-type group. During the occurrence of SWRs, the strength of effective coupling from the cortex to hippocampus (CA1) in the ripple band undergoes sharp increase, involving cortical areas that were different in the two groups of animals. In the wild-type group, retrosplenial cortex and posterior cingulate cortex interacted with the hippocampus most strongly, whereas in the APP/PS1 group more anterior structures interacted with the hippocampus, that is, anterior cingulate cortex and prefrontal cortex. This reconfiguration of cortical-hippocampal interaction pattern may be an adaptive mechanism responsible for supporting spatial memory consolidation in AD mice model.

Characterizing the effects of tonic 17β-estradiol administration on spatial learning and memory in the follicle-deplete middle-aged female rat

17β-estradiol (E2)-containing hormone therapy is a safe, effective way to alleviate unwanted menopause symptoms. Preclinical research has focused upon the role of E2 in learning and memory using a surgically menopausal rodent model whereby the ovaries are removed. Given that most women retain their reproductive tract and undergo a natural menopause transition, it is necessary to understand how exogenous E2 impacts a structurally intact, but follicle-deplete, system. In the current study, 8 month old female rats were administered the ovatoxin 4-vinylcyclohexene diepoxide (VCD), which accelerates ovarian follicular depletion, to model the human menopause transition. After follicular depletion, at 11 months old, rats were administered Vehicle or tonic E2 treatment for 12 days prior to behavioral evaluation on spatial working and reference memory tasks. Results demonstrated that E2 had both enhancing and impairing effects on taxed working memory depending upon the learning or retention phases of the water radial-arm maze, with no impact on reference memory. Relationships between memory scores and circulating estrogen levels were specific to follicle-depleted rats without E2 treatment. Collectively, findings demonstrate the complexity of E2 administration in a follicle-depleted background, with cognitive effects specific to working memory; furthermore, E2 administration altered circulating hormonal milieu and relationships between hormone profiles and memory. In sum, menopausal etiology impacts the parameters of E2 effects on cognition, complementing prior work with other estrogen compounds. Deciphering estrogenic actions in a system wherein the reproductive tract remains intact with follicle-depleted ovaries, thus modeling the majority or menopausal women, is critical for translational perspectives.

The role of learning and environmental geometryin landmark-based spatial reorientationof fish (Xenotoca eiseni).

Disoriented animals and humans use both the environmental geometry and visual landmarks to guide their spatial behavior. Although there is a broad consensus on the use of environmental geometry across various species of vertebrates, the nature of disoriented landmark-use has been greatly debated in the field. In particular, the discrepancy in performance under spontaneous choice conditions (sometimes called "working memory" task) and training over time ("reference memory" task) has raised questions about the task-dependent dissociability of mechanisms underlying the use of landmarks. Until now, this issue has not been directly addressed, due to the inclusion of environmental geometry in most disoriented navigation paradigms. In the present study, therefore, we placed our focus on landmark-based navigation in fish (Xenotoca eiseni), an animal model that has provided fruitful research in spatial reorientation. We began with a test of spontaneous navigation by geometry and landmarks (Experiment 1), showing a preference for the correct corner, even in the absence of reinforced training. We then proceeded to test landmarks without the influence of informative geometry through the use of square environments (Experiment 2-4), varying the numerosity of present landmarks, the distance of landmarks from the target corner, and the type of task (i.e., spontaneous cued memory or reference memory). We found marked differences in landmark-use in the absence of environmental geometry. In the spontaneous memory task, visual landmarks acquired perceptive salience (and attracted the fish) but without serving as a spatial cue to location when they were distal from the target. Across learning in the reference memory task, the fish overcame these effects and gradually improved in their performance, although they were still biased to learn visual landmarks near the target (i.e., as beacons). We discuss these results in relation to the existing literature on dissociable mechanisms of spatial learning.

The swimming control group in spatial reference memory task: analysis of its motor cortex activity.

Spatial reference memory in rodents is commonly performed in the Morris Water Maze (MWM). The use of control groups on this task is essential in order to subtract brain activity not related to learning. To study the functional contribution of selected brain areas, we assessed neuronal metabolic activity thorough quantitative cytochrome c oxidase histochemistry. This technique allows the measurement of the oxidative metabolism responsible for ATP production. Our objective is to analyse if the swimming control group is an optimal control for the evaluation of spatial reference memory task. To do so, we explore the behaviour in the MWM and the neuronal metabolic activity of motor cortex and its layers, in addition to hippocampus. For this purpose, three groups of Wistar rats were used: reference memory group, swimming control, and cage control. The behavioural results show significant differences between the experimental group and the swimming control group in time spent in the quadrants and swimming speed. In addition, higher neuronal hippocampal metabolic activity (CA1 subfield) was found in the experimental when compared to both controls. However, there are no differences in the motor cortex neuronal metabolic activity of the groups. Therefore, we can assume that the swimming control group effectively isolates the motor activity during the swim and the behavioural results are due to the hippocampal activity related to learning itself and not the physical activity performed in the labyrinth.

Assembly Responses of Hippocampal CA1 Place Cells Predict Learned Behavior in Goal-Directed Spatial Tasks on the Radial Eight-Arm Maze

Hippocampus is needed for both spatial working and reference memories. Here, using a radial eight-arm maze, we examined how the combined demand on these memories influenced CA1 place cell assemblieswhile reference memories were partially updated. This was contrasted with control tasks requiring only working memory or the update of reference memory. Reference memory update led to the reward-directed place field shifts at newly rewarded arms and to the gradual strengthening of firing in passes between newly rewarded arms but not between those passes that included a familiar-rewarded arm. At the maze center, transient network synchronization periods preferentially replayed trajectories of the next chosen arm in reference memory tasks but the previously visited arm in the working memory task. Hence, reference memory demand was uniquely associated with a gradual, goal novelty-related reorganization of place cell assemblies and with trajectory replay that reflected the animal's decision of which arm to visit next.

Dentate spikes and learning: disrupting hippocampal function during memory consolidation can improve pattern separation.

Hippocampal dentate spikes (DSs) are short-duration, large-amplitude fluctuations in hilar local field potentials and take place while resting and sleeping. During DSs, dentate gyrus granule cells increase firing while CA1 pyramidal cells decrease firing. Recent findings suggest DSs play a significant role in memory consolidation after training on a hippocampus-dependent, nonspatial associative learning task. Here, we aimed to find out whether DSs are important in other types of hippocampus-dependent learning tasks as well. To this end, we trained adult male Sprague-Dawley rats in a spatial reference memory task, a fixed interval task, and a pattern separation task. During a rest period immediately after each training session, we either let neural activity to take place as usual, timed electrical stimulation of the ventral hippocampal commissure (vHC) to immediately follow DSs, or applied the vHC stimulation during a random neural state. We found no effect of vHC stimulation on performance in the spatial reference memory task or in the fixed interval task. Surprisingly, vHC stimulation, especially contingent on DSs, improved performance in the pattern separation task. In conclusion, the behavioral relevance of hippocampal processing and DSs seems to depend on the task at hand. It could be that in an intact brain, offline memory consolidation by default involves associating neural representations of temporally separate but related events. In some cases this might be beneficial for adaptive behavior in the future (associative learning), while in other cases it might not (pattern separation). NEW & NOTEWORTHY The behavioral relevance of dentate spikes seems to depend on the learning task at hand. We suggest that dentate spikes are related to associating neural representations of temporally separate but related events within the dentate gyrus. In some cases this might be beneficial for adaptive behavior in the future (associative learning), while in other cases it might not (pattern separation).

Decreased Neurogenesis Increases Spatial Reversal Errors in Chickadees (Poecile atricapillus )

Adult hippocampal neurogenesis has been proposed to both aid memory formation and disrupt memory. We examined the role of adult hippocampal neurogenesis in spatial working and reference memory in black-capped chickadees (Poecile atricapillus), a passerine bird that relies on spatial memory for cache retrieval and foraging. We tested spatial working and spatial reference memory in birds that had received methylazoxymethanol acetate (MAM), a neurotoxin that decreases hippocampal neurogenesis. MAM treatment significantly reduced neurogenesis in the hippocampus quantified by doublecortin (DCX) labeling of newly divided and migrating neurons. MAM treatment had little effect on the working or reference memory but caused an increase in errors on the reference memory task following reversal. Working memory for recently visited spatial locations and reference memory for familiar spatial locations were thus unaffected by a reduction in neurogenesis. An increase in errors following reference memory reversal may indicate that adult hippocampal neurogenesis aids in pattern separation, the differentiation of similar memories at the time of encoding.

Disruption of dorsal hippocampal - prefrontal interactions using chemogenetic inactivation impairs spatial learning.

The hippocampus (HPC) and prefrontal cortex (PFC) are both necessary for learning and memory-guided behavior. Multiple direct and indirect anatomical projections connect the two regions, and HPC - PFC functional interactions are mediated by diverse physiological network patterns, thought to sub serve various memory processes. Disconnection experiments using contralateral inactivation approaches have established the role of direct, ipsilateral projections from ventral and intermediate HPC (vHPC and iHPC) to PFC in spatial memory. However, numerous studies have also prominently implicated physiological interactions between dorsal HPC (dHPC) and PFC regions in spatial memory tasks, and recent reports have identified direct dHPC - PFC connections. Whether dHPC - PFC interactions are necessary for spatial learning and memory has yet to be tested. Here, we used a chemogenetic inactivation approach using virally-expressed DREADDs (designer receptors exclusively activated by designer drugs) in rats to investigate the role of dHPC - PFC interactions in learning a hippocampal - dependent spatial alternation task. We implemented a rapid learning paradigm for a continuous W-track spatial alternation task comprising two components: an outbound, working memory component, and an inbound, spatial reference memory component. We investigated the effect of contralateral inactivation of dHPC and PFC on learning this task as compared with naïve and vehicle injection controls, as well as ipsilateral inactivation of the same regions. Contralateral dHPC - PFC inactivation selectively led to a significant impairment in learning the spatial working memory task compared to control groups, but did not impair learning of the spatial reference memory task. Ipsilateral inactivation animals showed similar learning rates as animals in the control groups. In a separate experiment, we confirmed that bilateral inactivation of PFC also leads to an impairment in learning the spatial working memory task. Our results thus demonstrate that dHPC - PFC interactions are necessary for spatial alternation learning in novel tasks. In addition, they provide crucial evidence to support the view that physiological interactions between dHPC and PFC play a key role in spatial learning and memory.

Why are maternally separated females inflexible? Brain activity pattern of COx and c-Fos

Subjects' early life events will affect them later in life. When these events are stressful, such as child abuse in humans or repeated maternal separation in rodents, subjects can show some behavioral and brain alterations. This study used young adult female Wistar rats that were maternally raised (AFR), maternally separated from post-natal day (PND) 1 to PND10 (MS10), or maternally separated from PND1 to PND21 (MS21), in order to assess the effects of maternal separation (MS) on spatial learning and memory, as well as cognitive flexibility, using the Morris Water Maze (MWM). We performed quantitative cytochrome oxidase (COx) histochemistry on selected brain areas in order to identify whether maternal separation affects brain energy metabolism. We also performed c-Fos immunohistochemistry on the medial prefrontal cortex (mPFC), thalamus, and hippocampus to explore whether this immediate early gene activity was altered in stressed subjects. We obtained a similar spatial learning pattern in maternally raised and maternally separated subjects on the reference memory task, but only the controls were flexible enough to solve the reversal learning successfully. Separated groups showed less c-Fos activity in the mPFC and less complex neural networks on COx.

A Miniaturized, Programmable Deep-Brain Stimulator for Group-Housing and Water Maze Use.

Pre-clinical deep-brain stimulation (DBS) research has observed a growing interest in the use of portable stimulation devices that can be carried by animals. Not only can such devices overcome many issues inherent with a cable tether, such as twisting or snagging, they can also be utilized in a greater variety of arenas, including enclosed or large mazes. However, these devices are not inherently designed for water-maze environments, and their use has been restricted to individually-housed rats in order to avoid damage from various social activities such as grooming, playing, or fighting. By taking advantage of 3D-printing techniques, this study demonstrates an ultra-small portable stimulator with an environmentally-protective device housing, that is suitable for both social-housing and water-maze environments. The miniature device offers 2 channels of charge-balanced biphasic pulses with a high compliance voltage (12 V), a magnetic switch, and a diverse range of programmable stimulus parameters and pulse modes. The device's capabilities have been verified in both chronic pair-housing and water-maze experiments that asses the effects of nucleus reuniens DBS. Theta-burst stimulation delivered during a reference-memory water-maze task (but not before) had induced performance deficits during both the acquisition and probe trials of a reference memory task. The results highlight a successful application of 3D-printing for expanding on the range of measurement modalities capable in DBS research.

Pigeons (Columba livia) know when they will need hints: prospective metacognition for reference memory?

Despite their impressive cognitive abilities, avian species have shown less evidence for metacognition than mammals. We suspect that commonly used tasks such as matching to sample might be too demanding to allow metacognitive processing within birds' working memory. Here, we examined whether pigeons could control their behavior as a function of knowledge levels on a three-item sequence learning task, a reference memory task supposedly requiring fewer working memory resources. The experiment used two types of lists differing in familiarity. One was familiar to the pigeons through repeated exposure, whereas the other was novel in every new session. In test sessions, pigeons could choose between a trial with a hint specifying the next item to peck and one with no hint. However, successful responses in trials with a hint resulted in lowered rates of primary reinforcement: .60 in the first test and .75 in the second. Results showed that two of four pigeons chose the trial with a hint significantly more often before receiving a novel list than the familiar list in the four sessions of the first test, and three did so in the second test. Impressively, one bird showed robust evidence in the very first sessions in both tests. These results suggest that pigeons may monitor their long-term knowledge states and thereby control their environment before starting to solve a task.

Automated dissection of permanent effects of hippocampal or prefrontal lesions on performance at spatial, working memory and circadian timing tasks of C57BL/6 mice in IntelliCage

To evaluate permanent effects of hippocampal and prefrontal cortex lesion on spatial tasks, lesioned and sham-operated female C57BL/6 mice were exposed to a series of conditioning schemes in IntelliCages housing 8–10 transponder-tagged mice from each treatment group. Sequential testing started at 51–172days after bilateral lesions and lasted for 154 and 218days in two batches of mice, respectively. Spontaneous undisturbed behavioral patterns clearly separated the three groups, hippocampals being characterized by more erratic hyperactivity, and strongly impaired circadian synchronization ability. Hippocampal lesions led to deficits in spatial passive avoidance, as well as in spatial reference and working memory tasks. Impairment was minimal in rewarded preference/reversal schemes, but prominent if behavioral responses required precise circadian timing or included punishment of wrong spatial choices. No differences between sham-operated and prefrontally lesioned subjects in conditioning success were discernible. These results corroborate the view that hippocampal dysfunction spares simple spatial learning tasks but impairs the ability to cope with conflicting task-inherent spatial, temporal or emotional cues. Methodologically, the results show that automated testing and data analysis of socially kept mice is a powerful, efficient and animal-friendly tool for dissecting complex features and behavioral profiles of hippocampal dysfunction characterizing many transgenic or pharmacological mouse models.