Non-spatial Memory Tasks Research Articles

Nucleus reuniens transiently synchronizes memory networks at beta frequencies

Episodic memory-based decision-making requires top-down medial prefrontal cortex and hippocampal interactions. This integrated prefrontal-hippocampal memory state is thought to be organized by synchronized network oscillations and mediated by connectivity with the thalamic nucleus reuniens (RE). Whether and how the RE synchronizes prefrontal-hippocampal networks in memory, however, remains unknown. Here, we recorded local field potentials from the prefrontal-RE-hippocampal network while rats engaged in a nonspatial sequence memory task, thereby isolating memory-related activity from running-related oscillations. We found that synchronous prefrontal-hippocampal beta bursts (15–30 Hz) dominated during memory trials, whereas synchronous theta activity (6–12 Hz) dominated during non-memory–related running. Moreover, RE beta activity appeared first, followed by prefrontal and hippocampal synchronized beta, suggesting that prefrontal-hippocampal beta could be driven by the RE. To test whether the RE is capable of driving prefrontal-hippocampal beta synchrony, we used an optogenetic approach (retroAAV-ChR2). RE activation induced prefrontal-hippocampal beta coherence and reduced theta coherence, matching the observed memory-driven network state in the sequence task. These findings are the first to demonstrate that the RE contributes to memory by driving transient synchronized beta in the prefrontal-hippocampal system, thereby facilitating interactions that underlie memory-based decision-making.

Sex differences in cognition following variations in endocrine status.

Spatial memory, mediated primarily by the hippocampus, is responsible for orientation in space and retrieval of information regarding location of objects and places in an animal's environment. Since the hippocampus is dense with steroid hormone receptors and is capable of robust neuroplasticity, it is not surprising that changes in spatial memory performance occur following a variety of endocrine alterations. Here, we review cognitive changes in both spatial and nonspatial memory tasks following manipulations of the hypothalamic-pituitary-adrenal and gonadal axes and after exposure to endocrine disruptors in rodents. Chronic stress impairs male performance on numerous behavioral cognitive tasks and enhances or does not impact female cognitive function. Sex-dependent changes in cognition following stress are influenced by both organizational and activational effects of estrogen and vary depending on the developmental age of the stress exposure, but responses to gonadal hormones in adulthood are more similar than different in the sexes. Also discussed are possible underlying neural mechanisms for these steroid hormone-dependent, cognitive effects. Bisphenol A (BPA), an endocrine disruptor, given at low levels during adolescent development, impairs spatial memory in adolescent male and female rats and object recognition memory in adulthood. BPA's negative effects on memory may be mediated through alterations in dendritic spine density in areas that mediate these cognitive tasks. In summary, this review discusses the evidence that endocrine status of an animal (presence or absence of stress hormones, gonadal hormones, or endocrine disruptors) impacts cognitive function and, at times, in a sex-specific manner.

Proximal CA1 20-40 Hz power dynamics reflect trial-specific information processing supporting nonspatial sequence memory.

The hippocampus is known to play a critical role in processing information about temporal context. However, it remains unclear how hippocampal oscillations are involved, and how their functional organization is influenced by connectivity gradients. We examined local field potential activity in CA1 as rats performed a nonspatial odor sequence memory task. We found that odor sequence processing epochs were characterized by distinct spectral profiles and proximodistal CA1 gradients of theta and 20-40 Hz power than track running epochs. We also discovered that 20-40 Hz power was predictive of sequence memory performance, particularly in proximal CA1 and during the plateau of high power observed in trials in which animals had to maintain their decision until instructed to respond. Altogether, these results provide evidence that dynamics of 20-40 Hz power along the CA1 axis are linked to trial-specific processing of nonspatial information critical to order judgments and are consistent with a role for 20-40 Hz power in gating information processing.

Chronic bryostatin-1 rescues autistic and cognitive phenotypes in the fragile X mice

Fragile X syndrome (FXS), an X-chromosome linked intellectual disability, is the leading monogenetic cause of autism spectrum disorder (ASD), a neurodevelopmental condition that currently has no specific drug treatment. Building upon the demonstrated therapeutic effects on spatial memory of bryostatin-1, a relatively specific activator of protein kinase C (PKC)ε, (also of PKCα) on impaired synaptic plasticity/maturation and spatial learning and memory in FXS mice, we investigated whether bryostatin-1 might affect the autistic phenotypes and other behaviors, including open field activity, activities of daily living (nesting and marble burying), at the effective therapeutic dose for spatial memory deficits. Further evaluation included other non-spatial learning and memory tasks. Interestingly, a short period of treatment (5 weeks) only produced very limited or no therapeutic effects on the autistic and cognitive phenotypes in the Fmr1 KO2 mice, while a longer treatment (13 weeks) with the same dose of bryostatin-1 effectively rescued the autistic and non-spatial learning deficit cognitive phenotypes. It is possible that longer-term treatment would result in further improvement in these fragile X phenotypes. This effect is clearly different from other treatment strategies tested to date, in that the drug shows little acute effect, but strong long-term effects. It also shows no evidence of tolerance, which has been a problem with other drug classes (mGluR5 antagonists, GABA-A and -B agonists). The results strongly suggest that, at appropriate dosing and therapeutic period, chronic bryostatin-1 may have great therapeutic value for both ASD and FXS.

Fenfluramine acts as a positive modulator of sigma-1 receptors

ObjectiveAdjunctive fenfluramine hydrochloride, classically described as acting pharmacologically through a serotonergic mechanism, has demonstrated a unique and robust clinical response profile with regard to its magnitude, consistency, and durability of effect on seizure activity in patients with pharmacoresistant Dravet syndrome. Recent findings also support long-term improvements in executive functions (behavior, emotion, cognition) in these patients. The observed clinical profile is inconsistent with serotonergic activity alone, as other serotonergic medications have not been demonstrated to have these clinical effects. This study investigated a potential role for σ1 receptor activity in complementing fenfluramine's serotonergic pharmacology. MethodsRadioligand binding assays tested the affinity of fenfluramine for 47 receptors associated with seizures in the literature, including σ receptors. Cellular function assays tested fenfluramine and norfenfluramine (its major metabolite) activity at various receptors, including adrenergic, muscarinic, and serotonergic receptors. The σ1 receptor activity was assessed by the mouse vas deferens isometric twitch and by an assay of dissociation of the σ1 receptor from the endoplasmic reticulum stress protein binding immunoglobulin protein (BiP). In vivo mouse models assessed fenfluramine activity at σ1 receptors in ameliorating dizocilpine-induced learning deficits in spatial and nonspatial memory tasks, alone or in combination with the reference σ1 receptor agonist PRE-084. ResultsFenfluramine and norfenfluramine bound ≥30% to β2-adrenergic, muscarinic M1, serotonergic 5-HT1A, and σ receptors, as well as sodium channels, with a Ki between 266 nM (σ receptors) and 17.5 μM (β-adrenergic receptors). However, only σ1 receptor isometric twitch assays showed a positive functional response, with weak stimulation by fenfluramine and inhibition by norfenfluramine. Fenfluramine, but not the 5-HT2C agonist lorcaserin, showed a positive modulation of the PRE-084-induced dissociation of σ1 protein from BiP. Fenfluramine also showed dose-dependent antiamnesic effects against dizocilpine-induced learning deficits in spontaneous alternation and passive avoidance responses, which are models of σ1 activation. Moreover, low doses of fenfluramine synergistically potentiated the low-dose effect of PRE-084, confirming a positive modulatory effect at the σ1 receptor. Finally, all in vivo effects were blocked by the σ1 receptor antagonist NE-100. SignificanceFenfluramine demonstrated modulatory activity at σ1 receptors in vitro and in vivo in addition to its known serotonergic activity. These studies identify a possible new σ1 receptor mechanism underpinning fenfluramine's central nervous system effects, which may contribute to its antiseizure activity in Dravet syndrome and positive effects observed on executive functions in clinical studies.

Spatial Coding in the Subiculum Requires Anterior Thalamic Inputs

Hippocampal function relies on the anterior thalamic nuclei, yet the reasons remain poorly understood. While anterior thalamic lesions disrupt parahippocampal spatial signalling, their impact on the subiculum is unknown, despite the importance of this area for hippocampal networks. We recorded subiculum cells in rats with either permanent (N-methyl-D-aspartic acid) or reversible (muscimol) anterior thalamic lesions. The diverse spatial signals normally found in the subiculum, including place cells, disappeared following permanent thalamic lesions and showed marked disruption during transient lesions. Meanwhile, permanent anterior thalamic lesions had no discernible impact on CA1 place fields. Thalamic lesions reduced spatial alternation performance (permanently or reversibly) to chance levels, while leaving a non-spatial recognition memory task unaffected. These findings, which help to explain why anterior thalamic damage is so deleterious for spatial memory, cast a new spotlight on the importance of subiculum function, and reveal its dependence on anterior thalamic signalling.

Nonspatial sequence coding varies along the CA1 transverse axis

The hippocampus plays a critical role in the memory for sequences of events, a defining feature of episodic memory. To shed light on the fundamental mechanisms supporting this capacity, we recently recorded neural activity in CA1 as rats performed a nonspatial odor sequence memory task. Our main finding was that, while the animals’ location and behavior remained constant, a proportion of CA1 neurons fired differentially to odors depending on whether they were presented in or out of sequence (sequence cells). Here, we further examined if such sequence coding varied along the distal-to-proximal axis of the dorsal CA1 region (distal: toward subiculum; proximal: toward CA3). Differences in information processing along this axis have been suggested by recent anatomical and electrophysiological evidence that odor information may be more strongly represented in the distal segment, whereas spatial information may be more strongly represented in the proximal segment. Recorded neurons were grouped into four arbitrary sections of dorsal CA1, ranging from distal to proximal. We found that, although sequence cell coding was observed across the distal-to-proximal extent of CA1 from which we recorded, it was significantly higher in intermediate CA1, a region with more balanced anatomical input from lateral and medial entorhinal regions. More specifically, in that particular segment of CA1, we observed a significant increase in the magnitude of sequence coding of all cells, as well as in the sequential information content of sequence cells. Importantly, a different pattern was observed when examining the distribution of spatial coding from the same electrodes. Consistent with previous reports, our results suggest that spatial information was more strongly represented in the proximal section of CA1 (higher proportion of cells with place fields). These findings indicate that nonspatial sequence memory coding is not uniformly distributed along the transverse axis of CA1, and that this distribution does not simply follow the expected gradient based on the stimulus modality or the degree of spatial selectivity. Instead, the observed distribution suggests this form of sequence coding may be associated with convergent input from lateral and medial entorhinal regions, which is present throughout the proximodistal axis but greater in intermediate CA1.

Sex differences in aerobic exercise efficacy to improve cognition: A systematic review and meta-analysis of studies in older rodents.

Research in humans indicates that women may show greater cognitive benefits from aerobic training (AT) than men. To determine whether this sex difference extends to rodents, we conducted a systematic review and meta-analysis of studies in healthy, older rodents. Results indicate that compared to controls, AT improved hippocampus-dependent and -independent learning and memory. A sex difference was found with males showing larger benefits from AT on conditioned-avoidance and non-spatial memory tasks. AT also increased brain-derived neurotrophic factor compared to controls, with larger effects in females. As an exploratory analysis, sex differences in voluntary AT were examined separately from forced AT. Voluntary AT enhanced non-spatial memory to a greater extent in males. Forced AT enhanced hippocampus-dependent learning and memory more so in females. These findings suggest that sex is an important factor to consider, and studies directly assessing sex differences in the ability of exercise to improve brain function are needed.

Carbonic anhydrase activation enhances object recognition memory in mice through phosphorylation of the extracellular signal-regulated kinase in the cortex and the hippocampus

Rats injected with by d-phenylalanine, a carbonic anhydrase (CA) activator, enhanced spatial learning, whereas rats given acetazolamide, a CA inhibitor, exhibited impairments of fear memory consolidation. However, the related mechanisms are unclear. We investigated if CAs are involved in a non-spatial recognition memory task assessed using the object recognition test (ORT). Systemic administration of acetazolamide to male CD1 mice caused amnesia in the ORT and reduced CA activity in brain homogenates, while treatment with d-phenylalanine enhanced memory and increased CA activity. We provided also the first evidence that d-phenylalanine administration rapidly activated extracellular signal-regulated kinase (ERK) pathways, a critical step for memory formation, in the cortex and the hippocampus, two brain areas involved in memory processing. Effects elicited by d-phenylalanine were completely blunted by co-administration of acetazolamide, but not of 1-N-(4-sulfamoylphenyl-ethyl)-2,4,6-trimethylpyridinium perchlorate (C18), a CA inhibitor that, differently from acetazolamide, does not cross the blood brain barrier. Our results strongly suggest that brain but not peripheral CAs activation potentiates memory as a result of ERK pathway enhanced activation.

The ventral hippocampal muscarinic cholinergic system plays a key role in sexual dimorphisms of spatial working memory in rats

Sex differences in cognitive processing and function have been documented in human and animal studies. Females have been found to perform better than males on non-spatial memory tasks, while males tend to outperform females on spatial memory tasks. The neural mechanisms underlying these sexual dimorphisms are unclear. However, it is known that the cholinergic system is critically involved in memory processes, and there are notable differences between males and females in cholinergic system function and receptor expression. In particular, there are sex differences in the processing of information in the frontal cortex and hippocampus. In this study, we examined the roles of muscarinic and nicotinic acetylcholine receptors in the medial frontal cortex (MfC) and ventral hippocampus (VH) on spatial working memory in male and female rats. Local infusions of scopolamine (SCOP) and mecamylamine (MEC) (10, 20, 50 μg/side) were used to antagonize these receptors in each respective brain region during performance in the 16-arm radial arm maze. Infusions of SCOP into the VH caused a significant increase in memory errors in female rats, but had no significant effect on males, while infusions of MEC into the VH had no effect on either sex. Infusions of both SCOP (50 μg/side) and MEC (20 μg/side) into the MfC caused working memory impairments in both sexes. These results show that muscarinic acetylcholine receptors in the VH are differentially vulnerable to spatial memory impairments in females. Ventral hippocampal muscarinic acetylcholine receptors may play a key role in male-female differences in spatial memory.

Longitudinal Examination of Learning and Memory in Rats Following Adolescent Exposure to 3,4-Methylenedioxymethamphetamine or 5-Methoxy-N,N-Diisopropyltryptamine

A drug of abuse, Foxy or Methoxy Foxy gained popularity among recreational users as an alternative to MDMA (Ecstasy). Considerable research into the consequences of MDMA use is available, yet much remains unknown about the neurobiological consequences of Foxy use. In addition, research into the long-term neuropsychological repercussions associated with these two compounds remains incomplete. The goal of the present research was to explore the effects of MDMA or Foxy on cognitive processes associated with adolescent exposure considered over much of the lifespan. Here we investigated whether the reported effects following adolescent exposure resolved in early adulthood or continued throughout life. The protocol involved repeated doses of either MDMA or Foxy during the period defined as mid-adolescence (postnatal days 34 - 46) in rats, followed by the use of four series of learning and memory tasks repeated at different points in the rodent lifespan. At four time points in adulthood, the animals were trained and tested on a on a series of spatial and non-spatial memory tasks designed to assess the impact and severity of Foxy and MDMA. Oddly, MDMA-treated rats were impaired on a step down passive avoidance task. The performance of the drug-treated rats was markedly inferior to that of the control animals on more demanding water maze tasks, with some results suggesting a lack of flexibility in adapting to changing task demands. MDMA rats were the most impaired. While some persistent cognitive deficits were found, no significant group differences in serotonin or dopamine levels were found in any of the measured regions of the brain changes, cortical or subcortical. These results provide evidence for compromised neurocognition that continues long after drug exposure in the absence of any discernable changes in neurotransmitter levels. Several possible physiological and neurochemical mechanisms associated with these compounds requiring further study are also outlined.

Evolutionary State-Space Model and Its Application to Time-Frequency Analysis of Local Field Potentials.

We propose an evolutionary state space model (E-SSM) for analyzing high dimensional brain signals whose statistical properties evolve over the course of a non-spatial memory experiment. Under E-SSM, brain signals are modeled as mixtures of components (e.g., AR(2) process) with oscillatory activity at pre-defined frequency bands. To account for the potential non-stationarity of these components (since the brain responses could vary throughout the entire experiment), the parameters are allowed to vary over epochs. Compared with classical approaches such as independent component analysis and filtering, the proposed method accounts for the entire temporal correlation of the components and accommodates non-stationarity. For inference purpose, we propose a novel computational algorithm based upon using Kalman smoother, maximum likelihood and blocked resampling. The E-SSM model is applied to simulation studies and an application to a multi-epoch local field potentials (LFP) signal data collected from a non-spatial (olfactory) sequence memory task study. The results confirm that our method captures the evolution of the power for different components across different phases in the experiment and identifies clusters of electrodes that behave similarly with respect to the decomposition of different sources. These findings suggest that the activity of different electrodes does change over the course of an experiment in practice; treating these epoch recordings as realizations of an identical process could lead to misleading results. In summary, the proposed method underscores the importance of capturing the evolution in brain responses over the study period.

Sex differences in chronic stress effects on cognition in rodents

Chronic stress causes deleterious changes in physiological function in systems ranging from neural cells in culture to laboratory rodents, sub-human primates and humans. It is notable, however, that the vast majority of research in this area has been conducted in males. In this review, we provide information about chronic stress effects on cognition in female rodents and contrast it with responses in male rodents. In general, females show cognitive resilience to chronic stressors which impair male cognitive function using spatial tasks including the radial arm maze, radial arm water maze, Morris water maze, Y-maze and object placement. Moreover, stress often enhances female performance in some of these cognitive tasks. Memory in females is not affected by stress in non-spatial memory tasks like recognition memory and temporal order recognition memory while males show impaired memory following stress. We discuss possible bases for these sex-dependent differences including the use of different strategies by the sexes to solve cognitive tasks. Whether the sex differences result from changes in non-mnemonic factors is also considered. Sex-dependent differences in alcohol and drug influences on stress responses are also described. Finally, the role of neurally derived estradiol in driving sex differences and providing resilience to stress in females is shown. The importance of determining the nature and extent of sex differences in stress responses is that such differences may provide vital information for understanding why some stress related diseases have different incidence rates between the sexes and for developing novel therapeutic treatments.

Impaired learning and memory in CD38 null mutant mice.

CD38 is an enzyme that catalyzes the formation of cyclic ADP ribose and nicotinic acid adenine dinucleotide phosphate, both of which are involved in the mobilization of Ca2+ from intracellular stores. Recently, CD38 has been shown to regulate oxytocin release from hypothalamic neurons. Importantly, CD38 mutations are associated with autism spectrum disorders (ASD) and CD38 knockout (CD38−/−) mice display ASD-like behavioral phenotypes including deficient parental behavior and poor social recognition memory. Although ASD and learning deficits commonly co-occur, the role of CD38 in learning and memory has not been investigated. We report that CD38−/− mice show deficits in various learning and memory tasks such as the Morris water maze, contextual fear conditioning, and the object recognition test. However, either long-term potentiation or long-term depression is not impaired in the hippocampus of CD38−/− mice. Our results provide convincing evidence that CD38−/− mice show deficits in various learning and memory tasks including spatial and non-spatial memory tasks. Our data demonstrate that CD38 is critical for regulating hippocampus-dependent learning and memory without modulating synaptic plasticity.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0195-5) contains supplementary material, which is available to authorized users.

Nonspatial Sequence Coding in CA1 Neurons.

The ability to remember the order of life events depends on the hippocampus, but the underlying neural mechanisms remain poorly understood. Here we addressed this issue by recording neural activity in hippocampal region CA1 while rats performed a nonspatial sequence memory task. We found that hippocampal neurons code for the temporal context of items (whether odors were presented in the correct or incorrect sequential position) and that this activity is linked with memory performance. The discovery of this novel form of temporal coding in hippocampal neurons advances our fundamental understanding of the neurobiology of episodic memory and will serve as a foundation for our cross-species, multitechnique approach aimed at elucidating the neural mechanisms underlying memory impairments in aging and dementia.

The neurosteroid allopregnanolone impairs object memory and contextual fear memory in male C57BL/6J mice

Allopregnanolone (ALLO, or 3α-hydroxy-5α-pregnan-20-one) is a steroid metabolite of progesterone and a potent endogenous positive allosteric modulator of GABA-A receptors. Systemic ALLO has been reported to impair spatial, but not nonspatial learning in the Morris water maze (MWM) and contextual memory in rodents. These cognitive effects suggest an influence of ALLO on hippocampal-dependent memory, although the specific nature of the neurosteroid's effects on learning, memory or performance is unclear. The present studies aimed to determine: (i) the memory process(es) affected by systemic ALLO using a nonspatial object memory task; and (ii) whether ALLO affects object memory via an influence within the dorsal hippocampus. Male C57BL/6J mice received systemic ALLO either before or immediately after the sample session of a novel object recognition (NOR) task. Results demonstrated that systemic ALLO impaired the encoding and consolidation of object memory. A subsequent study revealed that bilateral microinfusion of ALLO into the CA1 region of dorsal hippocampus immediately following the NOR sample session also impaired object memory consolidation. In light of debate over the hippocampal-dependence of object recognition memory, we also tested systemic ALLO-treated mice on a contextual and cued fear-conditioning task. Systemic ALLO impaired the encoding of contextual memory when administered prior to the context pre-exposure session. Together, these results indicate that ALLO exhibits primary effects on memory encoding and consolidation, and extend previous findings by demonstrating a sensitivity of nonspatial memory to ALLO, likely by disrupting dorsal hippocampal function.

A Sequence of events model of episodic memory shows parallels in rats and humans.

A critical feature of episodic memory is the ability to remember the order of events as they occurred in time, a capacity shared across species including humans, nonhuman primates, and rodents. Accumulating evidence suggests that this capacity depends on a network of structures including the hippocampus and the prefrontal cortex, but their respective contributions remain poorly understood. As addressing this important issue will require converging evidence from complementary investigative techniques, we developed a cross-species, nonspatial sequence memory task suitable for behavioral and neurophysiological studies in rodents and in humans. The task involves the repeated presentation of sequences of items (odors in rats and images in humans) and requires subjects to make a judgment as to whether each item is presented "in sequence" or "out of sequence." To shed light on the cognitive processes and sequence representations supporting performance, different types of "out of sequence" probe trials were used including: (i) repeating an item from earlier in the sequence (Repeats; e.g., ABAD), (ii) skipping ahead in the sequence (Skips; e.g., ABD), and (iii) inserting an item from a different sequence into the same ordinal position (Ordinal Transfers; e.g., A2CD). We found a remarkable similarity in the performance of rats and humans, particularly in the pattern of results across probe trial types. Thus, the results suggest that rats and humans not only remember the sequences of events, but also use similar underlying cognitive processes and mnemonic representations. This strong cross-species correspondence validates this task for use in future basic and clinical interdisciplinary studies aimed at examining the neural mechanisms underlying episodic memory.

Monkeys rely on recency of stimulus repetition when solving short-term memory tasks.

Seven monkeys performed variants of two short-term memory tasks that others have used to differentiate between selective and nonselective memory mechanisms. The first task was to view a list of sequentially presented images and identify whether a test matched any image from the list, but not a distractor from a preceding list. Performance was best when the test matched the most recently presented image. Response rates depended linearly on recency of repetition whether the test matched a sample from the current list or a distractor from a preceding list, suggesting nonselective memorization of all images viewed instead of just the sample images. The second task was to remember just the first image in a list selectively and ignore subsequent distractors. False alarms occurred frequently when the test matched a distractor presented near the beginning of the sequence. In a pilot experiment, response rates depended linearly on recency of repetition irrespective of whether the test matched the first image or a distractor, again suggesting nonselective memorization of all images instead of just the first image. Modification of the second task improved recognition of the first image, but did not abolish use of recency. Monkeys appear to perform nonspatial visual short-term memory tasks often (or exclusively) using a single, nonselective, memory mechanism that conveys the recency of stimulus repetition.

Processing of spatial and non-spatial information reveals functional homogeneity along the dorso-ventral axis of CA3, but not CA1

The ventral hippocampus is thought to principally contribute to emotional memory, while its dorsal part would be more involved in spatial processes. However, few studies have investigated ventral hippocampal function in spatial or non-spatial memories devoid of strong emotional components, and conflicting results have emerged regarding the role of the dorsal hippocampus in non-spatial (object) recognition memory. Moreover, even fewer reports have dissociated the contribution of the hippocampal subfields CA1 and CA3 to those processes, despite growing evidence of a functional segregation between these subfields. In a recent study, we detected the immediate-early gene Arc, used as a marker of neuronal activity, during spontaneous spatial and non-spatial recognition memory tasks, and showed that dorsal CA3 was spatially tuned while dorsal CA1 processed spatial and non-spatial information to the same extent (Beer, Chwiesko, Kitsukawa, & Sauvage, 2013). Here, we analyze the pattern of Arc expression detected in ventral CA1 and CA3 to determine their role in spatial or non-spatial recognition memory, and investigate whether ventral CA1 and CA3 activation differs from that of their dorsal counterparts. We report that ventral CA1 and CA3 are recruited for both spatial and non-spatial memories, but more strongly for spatial memory (e.g. were spatially tuned), and that CA3 is functionally homogeneous along the dorso-ventral axis, but not CA1.

Cortical Abnormalities and Non-Spatial Learning Deficits in a Mouse Model of CranioFrontoNasal Syndrome

Eph receptors and their ephrin ligands play critical roles in the development of the nervous system, however, less is known about their functions in the adult brain. Here, we investigated the function of ephrinB1, an ephrinB family member that is mutated in CranioFrontoNasal Syndrome. We show that ephrinB1 deficient mice (EfnB1Y/−) demonstrate spared spatial learning and memory but exhibit exclusive impairment in non-spatial learning and memory tasks. We established that ephrinB1 does not control learning and memory through direct modulation of synaptic plasticity in adults, since it is not expressed in the adult brain. Rather we show that the cortex of EfnB1Y/− mice displayed supernumerary neurons, with a particular increase in calretinin-positive interneurons. Further, the increased neuron number in EfnB1Y/− mutants correlated with shorter dendritic arborization and decreased spine densities of cortical pyramidal neurons. Our findings indicate that ephrinB1 plays an important role in cortical maturation and that its loss has deleterious consequences on selective cognitive functions in the adult.