Contributions of nonhuman primate research to understanding the consequences of human brain injury during development.

In this introductory review we first present a theoretical framework as well as a clinical perspective regarding the effects of early brain injury on the development of cognitive and behavioral functions in humans. Next, we highlight the contributions that nonhuman primate research make toward identifying some of the variables that influence long-term cognitive outcome after developmental disease, or damage. We start our review by arguing that in contrast to adult-onset injury, developmental brain insults alter the ontogenetic pattern of brain organization and circuit specialization depending on the variables of age at injury, the focality of the lesion, and the potential for reorganization. We then introduce the 2 nonhuman primate studies in this section (Kiorpes on vision; Bachevalier on cognitive memory), and highlight the relevance of their findings to our understanding of developmental conditions or injuries in humans, with the ultimate goal of improving the health and development of the young.

Visual boundary cues suffice to anchor place and grid cells in virtual reality.

The hippocampal formation contains neurons responsive to an animal's current location and orientation, which together provide the organism with a neural map of space.1,2,3 Spatially tuned neurons rely on external landmark cues and internally generated movement information to estimate position.4,5 An important class of landmark cue are the boundaries delimiting an environment, which can define place cell field position6,7 and stabilize grid cell firing.8 However, the precise nature of the sensory information used to detect boundaries remains unknown. We used 2-dimensional virtual reality (VR)9 to show that visual cues from elevated walls surrounding the environment are both sufficient and necessary to stabilize place and grid cell responses in VR, when only visual and self-motion cues are available. By contrast, flat boundaries formed by the edges of a textured floor did not stabilize place and grid cells, indicating only specific forms of visual boundary stabilize hippocampal spatial firing. Unstable grid cells retain internally coherent, hexagonally arranged firing fields, but these fields "drift" with respect to the virtual environment over periods >5 s. Optic flow from a virtual floor does not slow drift dynamics, emphasizing the importance of boundary-related visual information. Surprisingly, place fields are more stable close to boundaries even with floor and wall cues removed, suggesting invisible boundaries are inferred using the motion of a discrete, separate cue (a beacon signaling reward location). Subsets of place cells show allocentric directional tuning toward the beacon, with strength of tuning correlating with place field stability when boundaries are removed.

Episodic memory development: Bridging animal and human research.

Human episodic memory is not functionally evident until about 2 years of age and continues to develop into the school years. Behavioral studies have elucidated this developmental timeline and its constituent processes. In tandem, lesion and neurophysiological studies in non-human primates and rodents have identified key neural substrates and circuit mechanisms that may underlie episodic memory development. Despite this progress, collaborative efforts between psychologists and neuroscientists remain limited, hindering progress. Here, we seek to bridge human and non-human episodic memory development research by offering a comparative review of studies using humans, non-human primates, and rodents. We highlight critical theoretical and methodological issues that limit cross-fertilization and propose a common research framework, adaptable to different species, that may facilitate cross-species research endeavors.

Environment geometry alters subiculum boundary vector cell receptive fields in adulthood and early development.

Boundaries to movement form a specific class of landmark information used for navigation: Boundary Vector Cells (BVCs) are neurons which encode an animal's location as a vector displacement from boundaries. Here we characterise the prevalence and spatial tuning of subiculum BVCs in adult and developing male rats, and investigate the relationship between BVC spatial firing and boundary geometry. BVC directional tunings align with environment walls in squares, but are uniformly distributed in circles, demonstrating that environmental geometry alters BVC receptive fields. Inserted barriers uncover both excitatory and inhibitory components to BVC receptive fields, demonstrating that inhibitory inputs contribute to BVC field formation. During post-natal development, subiculum BVCs mature slowly, contrasting with the earlier maturation of boundary-responsive cells in upstream Entorhinal Cortex. However, Subiculum and Entorhinal BVC receptive fields are altered by boundary geometry as early as tested, suggesting this is an inherent feature of the hippocampal representation of space.

Place cell firing correlates with memory deficits and amyloid plaque burden in Tg2576 Alzheimer mouse model.

Alzheimer's disease (AD) is associated with progressive memory decline. Hippocampal place cells are a well understood candidate for the neural basis of one type of memory in rodents; these cells identify the animal's location in an environment and are crucial for spatial memory and navigation. We have recorded place cells in the Tg2576 mouse model of AD, and we report that aged (16 mo) but not young (3 mo) transgenic mice show degraded neuronal representations of the environment. The level of place cell degradation correlates with the animals' (poorer) spatial memory as tested in a forced-choice spatial alternation T-maze task and with hippocampal, but not neocortical, amyloid plaque burden. Place cell recording provides a sensitive assay for measuring the amount and rate of functional deterioration in animal models of dementia as well as providing a quantifiable physiological indication of the beneficial effects of potential therapies.

Environmental novelty elicits a later theta phase of firing in CA1 but not subiculum.

The mechanism supporting the role of the hippocampal formation in novelty detection remains controversial. A comparator function has been variously ascribed to CA1 or subiculum, whereas the theta rhythm has been suggested to separate neural firing into encoding and retrieval phases. We investigated theta phase of firing in principal cells in subiculum and CA1 as rats foraged in familiar and novel environments. We found that the preferred theta phase of firing in CA1, but not subiculum, was shifted to a later phase of the theta cycle during environmental novelty. Furthermore, the amount of phase shift elicited by environmental change correlated with the extent of place cell remapping in CA1. Our results support a relationship between theta phase and novelty-induced plasticity in CA1.

Coordinated Emergence of Hippocampal Replay and Theta Sequences during Post-natal Development.

Hippocampal place cells encode an animal's current position in space during exploration [1]. During sleep, hippocampal network activity recapitulates patterns observed during recent experience: place cells with overlapping spatial fields show a greater tendency to co-fire ("reactivation") [2], and temporally ordered and compressed sequences of place cell firing observed during wakefulness are reinstated ("replay") [3-5]. Reactivation and replay may underlie memory consolidation [6-10]. Compressed sequences of place cell firing also occur during exploration: during each cycle of the theta oscillation, the set of active place cells shifts from those signaling positions behind to those signaling positions ahead of an animal's current location [11, 12]. These "theta sequences" have been linked to spatial planning [13]. Here, we demonstrate that, before weaning (post-natal day [P]21), offline place cell activity associated with sharp-wave ripples (SWRs) reflects predominantly stationary locations in recently visited environments. By contrast, sequential place cell firing, describing extended trajectories through space during exploration (theta sequences) and subsequent rest (replay), emerge gradually after weaning in a coordinated fashion, possibly due to a progressive decrease in the threshold for experience-driven plasticity. Hippocampus-dependent learning and memory emerge late in altricial mammals [14-17], appearing around weaning in rats and slowly maturing thereafter [14,15]. In contrast, spatially localized firing is observed 1 week earlier (with reduced spatial tuning and stability) [18-21]. By examining the development of hippocampal reactivation, replay, and theta sequences, we show that the coordinated maturation of offline consolidation and online sequence generation parallels the late emergence of hippocampal memory in the rat.

Differential influences of environment and self-motion on place and grid cell firing.

Place and grid cells in the hippocampal formation provide foundational representations of environmental location, and potentially of locations within conceptual spaces. Some accounts predict that environmental sensory information and self-motion are encoded in complementary representations, while other models suggest that both features combine to produce a single coherent representation. Here, we use virtual reality to dissociate visual environmental from physical motion inputs, while recording place and grid cells in mice navigating virtual open arenas. Place cell firing patterns predominantly reflect visual inputs, while grid cell activity reflects a greater influence of physical motion. Thus, even when recorded simultaneously, place and grid cell firing patterns differentially reflect environmental information (or 'states') and physical self-motion (or 'transitions'), and need not be mutually coherent.

Effects of rising amyloidß levels on hippocampal synaptic transmission, microglial response and cognition in APPSwe/PSEN1M146V transgenic mice.

BACKGROUND: Progression of Alzheimer's disease is thought initially to depend on rising amyloidß and its synaptic interactions. Transgenic mice (TASTPM; APPSwe/PSEN1M146V) show altered synaptic transmission, compatible with increased physiological function of amyloidß, before plaques are detected. Recently, the importance of microglia has become apparent in the human disease. Similarly, TASTPM show a close association of plaque load with upregulated microglial genes. METHODS: CA1 synaptic transmission and plasticity were investigated using in vitro electrophysiology. Microglial relationship to plaques was examined with immunohistochemistry. Behaviour was assessed with a forced-alternation T-maze, open field, light/dark box and elevated plus maze. FINDINGS: The most striking finding is the increase in microglial numbers in TASTPM, which, like synaptic changes, begins before plaques are detected. Further increases and a reactive phenotype occur later, concurrent with development of larger plaques. Long-term potentiation is initially enhanced at pre-plaque stages but decrements with the initial appearance of plaques. Finally, despite altered plasticity, TASTPM have little cognitive deficit, even with a heavy plaque load, although they show altered non-cognitive behaviours. INTERPRETATION: The pre-plaque synaptic changes and microglial proliferation are presumably related to low, non-toxic amyloidß levels in the general neuropil and not directly associated with plaques. However, as plaques grow, microglia proliferate further, clustering around plaques and becoming phagocytic. Like in humans, even when plaque load is heavy, without development of neurofibrillary tangles and neurodegeneration, these alterations do not result in cognitive deficits. Behaviours are seen that could be consistent with pre-diagnosis changes in the human condition. FUNDING: GlaxoSmithKline; BBSRC; UCL; ARUK; MRC.

Experience-dependent increase in CA1 place cell spatial information, but not spatial reproducibility, is dependent on the autophosphorylation of the alpha-isoform of the calcium/calmodulin-dependent protein kinase II.

Place cells in hippocampal area CA1 are essential for spatial learning and memory. Here, we examine whether daily exposure to a previously unexplored environment can alter place cell properties. We demonstrate two previously unreported slowly developing plasticities in mouse place fields: both the spatial tuning and the trial-to-trial reproducibility of CA1 place fields improve over days. We asked whether these two components of improved spatial coding rely on the alpha-isoform of the calcium/calmodulin-dependent protein kinase II (alphaCaMKII) autophosphorylation, an effector mechanism of NMDA receptor-dependent long-term potentiation and an essential molecular process for spatial memory formation. We show that, in mice with deficient autophosphorylation of alphaCaMKII, the spatial tuning of place fields is initially similar to that of wild-type mice, but completely fails to show the experience-dependent increase over days. In contrast, place field reproducibility in the mutants, although impaired, does show the experience-dependent increase over days. Consequently, the progressive improvement in spatial coding in new hippocampal place cell maps depends on the existence of two molecularly dissociable, experience-dependent processes.

Self-Organized Attractor Dynamics in the Developing Head Direction Circuit.

Head direction (HD) cells are neurons found in an extended cortical and subcortical network that signal the orientation of an animal's head relative to its environment [1-3]. They are a fundamental component of the wider circuit of spatially responsive hippocampal formation neurons that make up the neural cognitive map of space [4]. During post-natal development, HD cells are the first among spatially modulated neurons in the hippocampal circuit to exhibit mature firing properties [5, 6], but before eye opening, HD cell responses in rat pups have low directional information and are directionally unstable [7, 8]. Using Bayesian decoding of HD cell ensemble activity recorded in the anterodorsal thalamic nucleus (ADN), we characterize this instability and identify its source: under-signaling of angular head velocity, which incompletely shifts the directional signal in proportion to head turns. We find evidence that geometric cues (the corners of a square environment) can be used to mitigate this under-signaling and, thereby, stabilize the directional signal even before eye opening. Crucially, even when directional firing cannot be stabilized, ensembles of unstable HD cells show short-timescale (1-10 s) temporal and spatial couplings consistent with an adult-like HD network. The HD network is widely modeled as a continuous attractor whose output is one coherent activity peak, updated during movement by angular head velocity signals and anchored by landmark cues [9-11]. Our findings present strong evidence for this model, and they demonstrate that the required network circuitry is in place and functional early during development, independent of reference to landmark information.

Spatial cell firing during virtual navigation of open arenas by head-restrained mice.

We present a mouse virtual reality (VR) system which restrains head-movements to horizontal rotations, compatible with multi-photon imaging. This system allows expression of the spatial navigation and neuronal firing patterns characteristic of real open arenas (R). Comparing VR to R: place and grid, but not head-direction, cell firing had broader spatial tuning; place, but not grid, cell firing was more directional; theta frequency increased less with running speed, whereas increases in firing rates with running speed and place and grid cells' theta phase precession were similar. These results suggest that the omni-directional place cell firing in R may require local-cues unavailable in VR, and that the scale of grid and place cell firing patterns, and theta frequency, reflect translational motion inferred from both virtual (visual and proprioceptive) and real (vestibular translation and extra-maze) cues. By contrast, firing rates and theta phase precession appear to reflect visual and proprioceptive cues alone.

Reconciling the different faces of hippocampal theta: The role of theta oscillations in cognitive, emotional and innate behaviors.

The theta oscillation (5-10Hz) is a prominent behavior-specific brain rhythm. This review summarizes studies showing the multifaceted role of theta rhythm in cognitive functions, including spatial coding, time coding and memory, exploratory locomotion and anxiety-related behaviors. We describe how activity of hippocampal theta rhythm generators - medial septum, nucleus incertus and entorhinal cortex, links theta with specific behaviors. We review evidence for functions of the theta-rhythmic signaling to subcortical targets, including lateral septum. Further, we describe functional associations of theta oscillation properties - phase, frequency and amplitude - with memory, locomotion and anxiety, and outline how manipulations of these features, using optogenetics or pharmacology, affect associative and innate behaviors. We discuss work linking cognition to the slope of the theta frequency to running speed regression, and emotion-sensitivity (anxiolysis) to its y-intercept. Finally, we describe parallel emergence of theta oscillations, theta-mediated neuronal activity and behaviors during development. This review highlights a complex interplay of neuronal circuits and synchronization features, which enables an adaptive regulation of multiple behaviors by theta-rhythmic signaling.

Hippocampus: Activity-Driven Maturation of Neural Circuits for Navigation.

New research reveals that neural activity is required for post-natal maturation of hippocampal neural circuits underlying memory and navigation; this activity-dependent maturation occurs sequentially along the classic 'tri-synaptic' pathway, following the direction of information flow found in the adult hippocampus.

The development of spatial and memory circuits in the rat.

We provide a concise review of recent studies related to the development of neural circuits supporting spatial navigation and memory in the rat. We chart the relative timeline of the emergence of the four main classes of spatially tuned neurons within the hippocampus and related limbic areas: head direction cells emerge earliest (postnatal day 12, P12), before the eyes of the rats are even open, followed by place cells and boundary responsive cells; grid cells emerge last, around the age of weaning (P21). The rate of maturation is unique to each type of neuron, with the head direction and grid cells showing rapid developmental spurts, in contrast to place cells, which show a more gradual trend of maturation. Interestingly, the emergence of allocentric spatial abilities occurs only after the full complement of spatial neurons becomes functional at P20-21, whereas associative processing in the place cell network is evident from as early as P16. We also present evidence supporting the view that the sensory inputs, which are particularly salient to adult spatial networks, may not be essential for the immature spatial system. Crucially, visual information, although more salient than other sensory modalities for anchoring the adult head direction system, does not appear to be essential for setting up the immature head direction network. We conclude by highlighting an urgent need for new theoretical models that can account for the sequential emergence of spatial cells, as well as the lack of primacy of vision in the early organization of the head direction network. WIREs Cogn Sci 2017, 8:e1424. doi: 10.1002/wcs.1424 For further resources related to this article, please visit the WIREs website.

Absence of Visual Input Results in the Disruption of Grid Cell Firing in the Mouse.

Grid cells are spatially modulated neurons within the medial entorhinal cortex whose firing fields are arranged at the vertices of tessellating equilateral triangles [1]. The exquisite periodicity of their firing has led to the suggestion that they represent a path integration signal, tracking the organism's position by integrating speed and direction of movement [2-10]. External sensory inputs are required to reset any errors that the path integrator would inevitably accumulate. Here we probe the nature of the external sensory inputs required to sustain grid firing, by recording grid cells as mice explore familiar environments in complete darkness. The absence of visual cues results in a significant disruption of grid cell firing patterns, even when the quality of the directional information provided by head direction cells is largely preserved. Darkness alters the expression of velocity signaling within the entorhinal cortex, with changes evident in grid cell firing rate and the local field potential theta frequency. Short-term (<1.5 s) spike timing relationships between grid cell pairs are preserved in the dark, indicating that network patterns of excitatory and inhibitory coupling between grid cells exist independently of visual input and of spatially periodic firing. However, we find no evidence of preserved hexagonal symmetry in the spatial firing of single grid cells at comparable short timescales. Taken together, these results demonstrate that visual input is required to sustain grid cell periodicity and stability in mice and suggest that grid cells in mice cannot perform accurate path integration in the absence of reliable visual cues.

Reversal of Synapse Degeneration by Restoring Wnt Signaling in the Adult Hippocampus.

Synapse degeneration occurs early in neurodegenerative diseases and correlates strongly with cognitive decline in Alzheimer's disease (AD). The molecular mechanisms that trigger synapse vulnerability and those that promote synapse regeneration after substantial synaptic failure remain poorly understood. Increasing evidence suggests a link between a deficiency in Wnt signaling and AD. The secreted Wnt antagonist Dickkopf-1 (Dkk1), which is elevated in AD, contributes to amyloid-ß-mediated synaptic failure. However, the impact of Dkk1 at the circuit level and the mechanism by which synapses disassemble have not yet been explored. Using a transgenic mouse model that inducibly expresses Dkk1 in the hippocampus, we demonstrate that Dkk1 triggers synapse loss, impairs long-term potentiation, enhances long-term depression, and induces learning and memory deficits. We decipher the mechanism involved in synapse loss induced by Dkk1 as it can be prevented by combined inhibition of the Gsk3 and RhoA-Rock pathways. Notably, after loss of synaptic connectivity, reactivation of the Wnt pathway by cessation of Dkk1 expression completely restores synapse number, synaptic plasticity, and long-term memory. These findings demonstrate the remarkable capacity of adult neurons to regenerate functional circuits and highlight Wnt signaling as a targetable pathway for neuronal circuit recovery after synapse degeneration.

Theta-modulated place-by-direction cells in the hippocampal formation in the rat.

We report the spatial and temporal properties of a class of cells termed theta-modulated place-by-direction (TPD) cells recorded from the presubicular and parasubicular cortices of the rat. The firing characteristics of TPD cells in open-field enclosures were compared with those of the following two other well characterized cell classes in the hippocampal formation: place and head-direction cells. Unlike place cells, which code only for the animal's location, or head-direction cells, which code only for the animal's directional heading, TPD cells code for both the location and the head direction of the animal. Their firing is also strongly theta modulated, firing primarily at the negative-to-positive phase of the locally recorded theta wave. TPD theta modulation is significantly stronger than that of place cells. In contrast, the firing of head-direction cells is not modulated by theta at all. In repeated exposures to the same environment, the locational and directional signals of TPD cells are stable. When recorded in different environments, TPD locational and directional fields can uncouple, with the locational field shifting unpredictably ("remapping"), whereas the directional preference remains similar across environments.

A Developmental Switch in Place Cell Accuracy Coincides with Grid Cell Maturation.

Place cell firing relies on information about self-motion and the external environment, which may be conveyed by grid and border cells, respectively. Here, we investigate the possible contributions of these cell types to place cell firing, taking advantage of a developmental time window during which stable border cell, but not grid cell, inputs are available. We find that before weaning, the place cell representation of space is denser, more stable, and more accurate close to environmental boundaries. Boundary-responsive neurons such as border cells may, therefore, contribute to stable and accurate place fields in pre-weanling rats. By contrast, place cells become equally stable and accurate throughout the environment after weaning and in adulthood. This developmental switch in place cell accuracy coincides with the emergence of the grid cell network in the entorhinal cortex, raising the possibility that grid cells contribute to stable place fields when an organism is far from environmental boundaries.