CA3 Retrieves Coherent Representations from Degraded Input: Direct Evidence for CA3 Pattern Completion and Dentate Gyrus Pattern Separation

Two experiments examined how locations in environmental spaces, which cannot be overseen from one location, are represented in memory: by global reference frames, multiple local reference frames, or orientation-free representations. After learning an immersive virtual environment by repeatedly walking a closed multisegment route, participants pointed to seven previously learned targets from different locations. Contrary to many conceptions of survey knowledge, local reference frames played an important role: Participants performed better when their body or pointing targets were aligned with the local reference frame (corridor). Moreover, most participants turned their head to align it with local reference frames. However, indications for global reference frames were also found: Participants performed better when their body or current corridor was parallel/orthogonal to a global reference frame instead of oblique. Participants showing this pattern performed comparatively better. We conclude that survey tasks can be solved based on interconnected local reference frames. Participants who pointed more accurately or quickly additionally used global reference frames.

Neural Population Evidence of Functional Heterogeneity along the CA3 Transverse Axis: Pattern Completion versus Pattern Separation

Parametrized post-Newtonian theory of reference frames, multipolar expansions and equations of motion in the N-body problem

Computational Influence of Adult Neurogenesis on Memory Encoding

Neuronal plasticity and antidepressant actions

S.02.02 - Adult hippocampal neurogenesis and cognitive flexibility - linking memory and mood

Navigation using global or local reference frames in rats with medial and lateral entorhinal cortex lesions

Manipulation of spatial reference frames is a common experimental tool to investigate the nature of hippocampal information coding and to investigate high-order processes, such as cognitive coordination. However, it is unknown how the hippocampus afferents represent the local and global reference frames of an environment. To address these issues, single units were recorded in freely moving rats with multi-tetrode arrays targeting the superficial layers of the lateral entorhinal cortex (LEC) and medial entorhinal cortex (MEC), the two primary cortical inputs to the hippocampus. Rats ran clockwise laps around a circular track partitioned into quadrants covered by different textures (the local reference frame). The track was centered in a circular environment with distinct landmarks on the walls (the global reference frame). Here we demonstrate a novel dissociation between MEC and LEC in that the global frame controlled the MEC representation and the local frame controlled the LEC representation when the reference frames were rotated in equal, but opposite, directions. Consideration of the functional anatomy of the hippocampal circuit and popular models of attractor dynamics in CA3 suggests a mechanistic explanation of previous data showing a dissociation between the CA3 and CA1 regions in their responses to this local–global conflict. Furthermore, these results are consistent with a model of the LEC providing the hippocampus with the external sensory content of an experience and the MEC providing the spatial context, which combine to form conjunctive codes in the hippocampus that form the basis of episodic memory.

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.

The complementary processes of pattern completion and pattern separation are thought to be essential for successful memory storage and recall. The dentate gyrus (DG) and proximal CA3 (pCA3) regions have been implicated in pattern separation, in part through extracellular recording studies of these areas. However, the DG contains two types of excitatory cells: granule cells of the granule layer and mossy cells of the hilus. Little is known about the firing properties of mossy cells in freely moving animals, and it is unclear how their activity may contribute to the mnemonic functions of the hippocampus. Furthermore, tetrodes in the dentate granule layer and pCA3 pyramidal layer can also record mossy cells, thus introducing ambiguity into the identification of cell types recorded. Using a random forests classifier, we classified cells recorded in DG (Neunuebel and Knierim, 2014) and pCA3 (Lee et al., 2015) of 16 male rats and separately examined the responses of granule cells, mossy cells, and pCA3 pyramidal cells in a local/global cue mismatch task. All three cell types displayed low correlations between the population representations of the rat's position in the standard and cue-mismatch sessions. These results suggest that all three excitatory cell types within the DG/pCA3 circuit may act as a single functional unit to support pattern separation.SIGNIFICANCE STATEMENT Mossy cells in the dentate gyrus (DG) are an integral component of the DG/pCA3 circuit. While the role of granule cells in the circuitry and computations of the hippocampus has been a focus of study for decades, the contributions of mossy cells have been largely overlooked. Recent studies have revealed the spatial firing properties of mossy cells in awake behaving animals, but how the activity of these highly active cells contributes to the mnemonic functions of the DG is uncertain. We separately analyzed mossy cells, granule cells, and pCA3 cells and found that all three cell types respond similarly to a local/global cue mismatch, suggesting that they form a single functional unit supporting pattern separation.

Objects learned within single enclosed spaces (e.g., rooms) can be represented within a single reference frame. Contrarily, the representation of navigable spaces (multiple interconnected enclosed spaces) is less well understood. In this study we examined different levels of integration within memory (local, regional, global), when learning object locations in navigable space. Participants consecutively learned two distinctive regions of a virtual environment that eventually converged at a common transition point and subsequently solved a pointing task. In Experiment 1 pointing latency increased with increasing corridor distance to the target and additionally when pointing into the other region. Further, when pointing within a region alignment with local and regional reference frames, when pointing across regional boundaries alignment with a global reference frame was found to accelerate pointing. Thus, participants memorized local corridors, clustered corridors into regions, and integrated globally across the entire environment. Introducing the transition point at the beginning of learning each region in Experiment 2 caused previous region effects to vanish. Our findings emphasize the importance of locally confined spaces for structuring spatial memory and suggest that the opportunity to integrate novel into existing spatial information early during learning may influence unit formation on the regional level. Further, global representations seem to be consulted only when accessing spatial information beyond regional borders. Our results are inconsistent with conceptions of spatial memory for large scale environments based either exclusively on local reference frames or upon a single reference frame encompassing the whole environment, but rather support hierarchical representation of space. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

North in the head: spatial reference frame and map orientation

Aim: Aging and early Alzheimer’s disease (AD) affect pattern separation (PS) based mnemonic discrimination in humans. PS function involves the dentate gyrus (DG), a brain region producing new neurons during adulthood. Aging and AD presumably affect PS and DG function through different mechanisms, although it has never been clearly shown within the same study. Passive immunotherapy targeting β-amyloid peptides (Aβ) was used to determine the relative contribution of abnormal levels of Aβ to early PS deficits in two mouse models of aging and amyloid pathology, and potential involvement of adult neurogenesis. Methods: Female Tg2576 mice were tested in a spatial PS task from the age of three months to determine the age of onset of PS deficits. A cohort of five-month-old female Tg2576 mice and a cohort of 20-month-old male C57BL/6J mice were treated with passive immunization for four weeks, and then tested for PS performance. ELISA assays were used to quantify Aβ levels in CA3/DG regions of these mouse models. DG recruitment during PS testing was assessed with an Egr-1 ex vivo imagery. The contribution of adult-born neurons to a potential rescue of PS performances was evaluated using bromodeoxyuridine and doublecortin co-immunostainings. Results: Spatial PS deficits appeared first in four-month-old female Tg2576 mice, an early pre-plaque stage of Alzheimer pathology. Aβ immunotherapy restored PS performance in Tg2576 mice, but not in aged male C57BL/6J mice. PS impairments were associated with an overactivation of the DG in both models and a potentially abnormal level of immature adult-born neurons in Tg2576 mice. Conclusions: Alleviation of PS deficits following Aβ immunotherapy in Tg2576 mice is associated with reduced DG activation and improved adult-born neurons maturation. The absence of beneficial effects in aged mice suggests that PS deficits in aging and AD may be related to different underlying mechanisms.

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.

The article presents a critical analysis of the Special and General Relativity Theories. Both theories are found incomplete and need a revision. The general relativity principle is currently understood as meaning that there is no preferred frame of reference and equations of motion must be Lorentz invariant. These interpretations should be modified to the form that there is no global preferred frame of reference, but there is a local preferred frame of reference given by the local gravitation field, and the equations of motion should be invariant in conformal mappings. The reason why there is a local preferred frame of reference is that the Lorentz transform does not define a valid time for a moving frame and therefore cannot give a set of frames of reference where there is no preferred local frame of reference. As light travels along geodesics of the gravitational field, this local preferred frame is given by the local gravitation field. Much of relativity theory remains after this revision, including the geometric interpretation of gravity, the equivalence principle, time and length dilation in gravitational fields and accelerating frames, time and length dilation between frames in constant relative motion if the local gravitation field is strong enough.