Deficits In Pattern Separation Research Articles

Impaired neurogenesis of the dentate gyrus is associated with pattern separation deficits: A computational study.

The separation of input patterns received from the entorhinal cortex (EC) by the dentate gyrus (DG) is a well-known critical step of information processing in the hippocampus. Although the role of interneurons in separation pattern efficiency of the DG has been theoretically known, the balance of neurogenesis of excitatory neurons and interneurons as well as its potential role in information processing in the DG is not fully understood. In this work, we study separation efficiency of the DG for different rates of neurogenesis of interneurons and excitatory neurons using a novel computational model in which we assume an increase in the synaptic efficacy between excitatory neurons and interneurons and then its decay over time. Information processing in the EC and DG was simulated as information flow in a two layer feed-forward neural network. The neurogenesis rate was modeled as the percentage of new born neurons added to the neuronal population in each time bin. The results show an important role of an optimal neurogenesis rate of interneurons and excitatory neurons in the DG in efficient separation of inputs from the EC in pattern separation tasks. The model predicts that any deviation of the optimal values of neurogenesis rates leads to different decreased levels of the separation deficits of the DG which influences its function to encode memory.

Overactive Pattern Separation Memory Associated with Negative Emotionality in Adults Diagnosed with Autism Spectrum Disorder.

Bowler et al. (Journal of Autism and Developmental Disorders 44(9):2355-2362. doi:10.1007/s10803-014-2105-y, 2014) have suggested that a specific memory impairment in autism spectrum disorders (ASD) arises from hippocampal failure to consolidate multiple related pieces of information. Twenty-four adults diagnosed with ASD and matched healthy controls completed a pattern separation memory task that is known to critically depend on hippocampal involvement. They additionally completed questionnaires regarding anxiety, depression, and behavioral motivation. Specific deficits in pattern separation were significantly correlated with negative emotionality; the best predictor of memory deficit was from a measure of achievement motivation that has also been associated with hyperactivity and impulsivity. In the context of impaired emotion regulation in ASD, there is a need for integrated cognitive, affective, and neural systems approaches to build targeted interventions.

Presenilin-1 Dependent Neurogenesis Regulates Hippocampal Learning and Memory.

Presenilin-1 (PS1), the catalytic core of the aspartyl protease γ-secretase, regulates adult neurogenesis. However, it is not clear whether the role of neurogenesis in hippocampal learning and memory is PS1-dependent, or whether PS1 loss of function in adult hippocampal neurogenesis can cause learning and memory deficits. Here we show that downregulation of PS1 in hippocampal neural progenitor cells causes progressive deficits in pattern separation and novelty exploration. New granule neurons expressing reduced PS1 levels exhibit decreased dendritic branching and dendritic spines. Further, they exhibit reduced survival. Lastly, we show that PS1 effect on neurogenesis is mediated via β-catenin phosphorylation and notch signaling. Together, these observations suggest that impairments in adult neurogenesis induce learning and memory deficits and may play a role in the cognitive deficits observed in Alzheimer’s disease.

Acquisition of Contextual Discrimination Involves the Appearance of a RAS-GRF1/p38 Mitogen-activated Protein (MAP) Kinase-mediated Signaling Pathway That Promotes Long Term Potentiation (LTP)

RAS-GRF1 is a guanine nucleotide exchange factor with the ability to activate RAS and RAC GTPases in response to elevated calcium levels. We previously showed that beginning at 1 month of age, RAS-GRF1 mediates NMDA-type glutamate receptor (NMDAR)-induction of long term depression in the CA1 region of the hippocampus of mice. Here we show that beginning at 2 months of age, when mice first acquire the ability to discriminate between closely related contexts, RAS-GRF1 begins to contribute to the induction of long term potentiation (LTP) in the CA1 hippocampus by mediating the action of calcium-permeable, AMPA-type glutamate receptors (CP-AMPARs). Surprisingly, LTP induction by CP-AMPARs through RAS-GRF1 occurs via activation of p38 MAP kinase rather than ERK MAP kinase, which has more frequently been linked to LTP. Moreover, contextual discrimination is blocked by knockdown of Ras-Grf1 expression specifically in the CA1 hippocampus, infusion of a p38 MAP kinase inhibitor into the CA1 hippocampus, or the injection of an inhibitor of CP-AMPARs. These findings implicate the CA1 hippocampus in the developmentally dependent capacity to distinguish closely related contexts through the appearance of a novel LTP-supporting signaling pathway.

Visual object pattern separation varies in older adults

Young and nondemented older adults completed a visual object continuous recognition memory task in which some stimuli (lures) were similar but not identical to previously presented objects. The lures were hypothesized to result in increased interference and increased pattern separation demand. To examine variability in object pattern separation deficits, older adults were divided into impaired and unimpaired groups based on performance on a standardized serial list-learning task. Impaired older adults showed intact recognition memory, but were impaired relative to young and unimpaired older adults when identifying similar lure stimuli, demonstrating that object pattern separation varies in older adults.

Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders

Although an influence of adult neurogenesis in mediating some of the effects of antidepressants has received considerable attention in recent years, much less is known about how alterations in this form of plasticity may contribute to psychiatric disorders such as anxiety and depression. One way to begin to address this question is to link the functions of adult-born hippocampal neurons with specific endophenotypes of these disorders. Recent studies have implicated adult-born hippocampal neurons in pattern separation, a process by which similar experiences or events are transformed into discrete, non-overlapping representations. Here we propose that impaired pattern separation underlies the overgeneralization often seen in anxiety disorders, specifically post-traumatic stress disorder and panic disorder, and therefore represents an endophenotype for these disorders. The development of new, pro-neurogenic compounds may therefore have therapeutic potential for patients who display pattern separation deficits.

Pattern separation deficits following damage to the hippocampus

Computational models of hippocampal function propose that the hippocampus is capable of rapidly storing distinct representations through a process known as pattern separation. This prediction is supported by electrophysiological data from rodents and neuroimaging data from humans. Here, we test the prediction that damage to the hippocampus would result in pattern separation deficits by having memory-impaired patients with bilateral hippocampal damage study a series of objects or faces and then perform a modified recognition memory test. In the test phase, participants viewed true repetitions, novel foils, and lures that were perceptually and semantically related to the studied stimuli. Patients with hippocampal damage were unimpaired relative to matched controls in their baseline recognition memory. However, patients were less likely to uniquely identify lures as “similar” than matched controls, indicating an impairment in pattern separation processes following damage to the hippocampus.

Spatial pattern separation in cognitively normal young and older adults

This study examined the ability of cognitively normal young adults (n = 30) and older adults (n = 30) to perform a delayed match-to-sample task involving varying degrees of spatial interference to assess spatial pattern separation. Each trial consisted of a sample phase followed by a choice phase. During the sample phase, a circle appeared briefly on a computer screen. The participant was instructed to remember the location of the circle on the screen. During the choice phase, two circles were displayed simultaneously, and the participant was asked to indicate which circle was in the same location as the sample phase circle. The two circles on choice phase trials were separated by one of four possible spatial separations: 0, 0.5, 1.0, and 1.5 cm. Smaller separations are likely to create increased overlap among memory representations, which may result in heightened interference and a greater need for pattern separation. Consistent with this hypothesis, performance increased as a function of increased spatial separation in both young and older adults. However, young adults outperformed older adults, suggesting that spatial pattern separation may be less efficient in older adults due to potential age-related changes in the dentate gyrus and CA3 hippocampal subregions. Older adults also were divided into older impaired and older unimpaired groups based on their performance on a standardized test of verbal memory. The older impaired group was significantly impaired relative to both the older unimpaired and young groups, suggesting that pattern separation deficits may be variable in older adults. The present findings may have important implications for designing behavioral interventions for older adults that structure daily living tasks to reduce interference, thus improving memory function.

Monosynaptic inputs to new neurons in the dentate gyrus

Adult hippocampal neurogenesis is considered important for cognition. The integration of newborn dentate gyrus granule cells into the existing network is regulated by afferent neuronal activity of unspecified origin. Here we combine rabies virus-mediated retrograde tracing with retroviral labelling of new granule cells (21, 30, 60, 90 days after injection) to selectively identify and quantify their monosynaptic inputs in vivo. Our results show that newborn granule cells receive afferents from intra-hippocampal cells (interneurons, mossy cells, area CA3 and transiently, mature granule cells) and septal cholinergic cells. Input from distal cortex (perirhinal (PRH) and lateral entorhinal cortex (LEC)) is sparse 21 days after injection and increases over time. Patch-clamp recordings support innervation by the LEC rather than from the medial entorhinal cortex. Mice with excitotoxic PRH/LEC lesions exhibit deficits in pattern separation but not in water maze learning. Thus, PRH/LEC input is an important functional component of new dentate gyrus neuron circuitry.

Pattern separation deficits associated with increased hippocampal CA3 and dentate gyrus activity in nondemented older adults

There is widespread evidence that memory deteriorates with aging, however the exact mechanisms that underlie these changes are not well understood. Given the growing size of the aging population, there is an imperative to study age-related neurocognitive changes in order to better parse healthy from pathological aging. Using a behavioral paradigm that taxes pattern separation (the ability to differentiate novel yet similar information from previously learned information and thus avoid interference), we investigated age-related neural changes in the human hippocampus using high-resolution (1.5 mm isotropic) blood-oxygenation level-dependent fMRI. Recent evidence from animal studies suggests that hyperactivity in the CA3 region of the hippocampus may underlie behavioral deficits in pattern separation in aged rats. Here, we report evidence that is consistent with findings from the animal studies. We found a behavioral impairment in pattern separation in a sample of healthy older adults compared with young controls. We also found a related increase in CA3/dentate gyrus activity levels during an fMRI contrast that stresses pattern separation abilities. In a detailed analysis of behavior, we also found that the pattern of impairment was consistent with the predictions of the animal model, where larger changes in the input (greater dissimilarity) were required in order for elderly adults to successfully encode new information as distinct from previously learned information. These findings are also consistent with recent fMRI and behavioral reports in healthy aging, and further suggest that a specific functional deficit in the CA3/dentate network contributes to memory difficulties with aging.

Dorsal vs Ventral Hippocampal Neurogenesis: Implications for Cognition and Mood

An emerging view of the hippocampus is that of a functionally heterogeneous structure along its longitudinal axis. Lesion studies reveal that the dorsal (septal pole) hippocampus is involved in learning and spatial memory, whereas the ventral (temporal pole) hippocampus regulates emotional and motivated behaviors (Fanselow and Dong, 2010). Anatomical connectivity and gene expression analyses support this functional dissociation. For example, serotonergic fibers provide denser input to the ventral hippocampus with a concomitant enrichment of 5-HT1A and 2C receptors ventrally (KF Tanaka and R Hen, unpublished). Efferent connectivity indicates that ventral hippocampus can modulate reward circuitry and emotional behavior through projections to nucleus accumbens, prefrontal cortex and amygdala, and stress responses by regulating the hypothalamic–pituitary–adrenal axis (Sahay and Hen, 2007). In both regions, the subgranular zone of the dentate gyrus (DG) continues to produce new neurons in adulthood. These adult-born granule cells (GCs) functionally integrate into the DG circuit, exhibit enhanced excitability, and have a significant impact on both learning and emotional behavior (Sahay and Hen, 2007). As adult neurogenesis has been implicated in both learning and mood, an exciting possibility is that adult-born GCs in the dorsal and ventral hippocampus may be functionally dissociated. Chronic antidepressant treatment increases neurogenesis in the DG, a requirement for some of their behavioral effects (Santarelli et al, 2003). Recent studies suggest that antidepressants regulate behavior by selectively increasing ventral hippocampal neurogenesis. Chronic treatment with agomelatine, a melatonin receptor agonist, and 5-HT2C receptor antagonist with robust effects in animal models as well as efficacy in human major depressive disorder increases neurogenesis selectively in the ventral DG (Banasr et al, 2006). In humans, selective serotonin reuptake inhibitors and tricyclic antidepressants increase proliferating and neuronal precursor cells more prominently in the anterior portion of the DG of patients with MDD as compared to controls and untreated MDD subjects (Boldrini et al, 2009). These two studies, although correlational, provide exciting preliminary evidence that warrants future studies aimed at selectively blocking or stimulating neurogenesis in the ventral hippocampus. In the cognitive realm, adult neurogenesis has recently been implicated in pattern separation, the ability to distinguish between similar contexts (Deng et al, 2010). Owing to their unique physiological properties, adult-born GCs may contribute to pattern separation by modulation of sparse coding in the DG. A recent report indicates that ablation of adult-born GCs increases the magnitude of spontaneous gamma bursts in the dorsal DG and enhances modulation of single unit firing by these bursts (Lacefield et al, 2010). This increase in spontaneous activity suggests that adult-born GCs may modulate network inhibition of mature GCs through either feedback inhibition or synaptic competition. Thus, young GCs may contribute to sparse coding and pattern separation by modulating inhibitory control of the mature GCs in the DG. Deficits in pattern separation may not only impact cognition, but may also contribute to anxiety disorders by impairing the ability to discriminate between safe and fearful contexts. The resulting inability to respond appropriately to similar situations that have differing emotional valence may lead to the generalization observed in certain anxiety disorders such as PTSD. As adult-born GCs have a role in sparse coding in the DG and pattern separation, it will be of great interest to examine how blocking or stimulating ventral hippocampal neurogenesis may influence emotional behavior by modulating pattern separation.

High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with amnestic Mild Cognitive Impairment

Functional magnetic resonance imaging (fMRI) studies have observed hyperactivity in the hippocampal region in individuals with Mild Cognitive Impairment (MCI). However, the actual source of such hyperactivity is not well understood. Studies of aged rats observed similar hyperactive signals in the CA3 region of the hippocampus that correlated with spatial memory deficits and, in particular, with their ability to represent novel environments as being distinct from familiar ones (pattern separation). In this study, we tested the hypothesis that patients with amnestic MCI (aMCI) have deficits in pattern separation, along with hyperactive fMRI BOLD activity in the CA3 region of the hippocampus. We used high-resolution fMRI during a continuous recognition task designed to emphasize pattern separation. We conducted hippocampal subfield-level region of interest analyses to test for dysfunctional activity in aMCI patients. We found that patients showed impaired performance on trials that taxed their pattern separation abilities. We also observed hyperactive BOLD signals in the CA3/dentate and hypoactive signals in the entorhinal cortex during the separation condition. In a high-resolution morphometric analysis of hippocampal subfields, aMCI patients also had smaller CA3/dentate and CA1 volumes (no difference in the subiculum). The CA3/dentate region bilaterally also exhibited the largest shape deformations in aMCI patients, suggesting that this locus is affected early in the course of the disease. These findings suggest that structural and functional changes in the CA3/dentate region of the hippocampus contribute to the deficits in episodic memory that are observed in patients with aMCI. The functional hyperactivity may be evidence for a dysfunctional encoding mechanism, consistent with the predictions of computational models of hippocampal learning.

Pattern separation deficits may contribute to age-associated recognition impairments.

Normal aging is associated with impairments in stimulus recognition. In the current investigation, object recognition was tested in adult and aged rats with the standard spontaneous object recognition (SOR) task or two variants of this task. On the standard SOR task, adult rats showed an exploratory preference for the novel object over delays up to 24 h, whereas the aged rats only showed significant novelty discrimination at the 2-min delay. This age difference appeared to be because of the old rats behaving as if the novel object was familiar. To test this hypothesis directly, rats participated in a variant of the SOR task that allowed the exploration times between the object familiarization and the test phases to be compared, and this experiment confirmed that aged rats falsely "recognize" the novel object. A final control examined whether or not aged rats exhibited reduced motivation to explore objects. In this experiment, when the environmental context changed between familiarization and test, young and old rats failed to show an exploratory preference because both age groups spent more time exploring the familiar object. Together these findings support the view that age-related impairments in object recognition arise from old animals behaving as if novel objects are familiar, which is reminiscent of behavioral impairments in young rats with perirhinal cortical lesions. The current experiments thus suggest that alterations in the perirhinal cortex may be responsible for reducing aged animals' ability to distinguish new stimuli from ones that have been encountered previously.

Maximal oxygen intake as an objective measure of cardio-respiratory performance.

Maximal oxygen intake as an objective measure of cardio-respiratory performance.