The virtues of youth and maturity (in dentate granule cells).

How does adult neurogenesis contribute to memory? Nakashiba and colleagues generated mutant mice in which synaptic output from older hippocampal granule cells was specifically blocked. Experiments with these mice reveal an unpredicted age-dependent specialization of function, demonstrating that recently born cells support pattern separation, whereas older cells support pattern completion.

Neural correlates of distinct levels of predatory threat in dorsal periaqueductal grey neurons.

The dorsal periaqueductal grey (PAG) is an important site for integrating predatory threats. However, it remains unclear whether predator-related activation in PAG primarily reflects threat itself and thus can distinguish between various degrees of threat, or rather reflects threat-oriented behaviours, with the PAG potentially orchestrating different types of defensive repertoire. To address this issue, we performed extracellular recording of dorsal PAG neurons in freely behaving rats and examined neuronal and behavioural responses to stimulus conditions with distinct levels of predatory threat. Animals were sequentially exposed to a nonthreatening stimulus familiar environment (exposure to habituated environment) and to a novel nonthreatening stimulus (i.e., a toy animal-plush) and to conditions with high (exposure to a live cat), intermediate (exposure to the environment just visited by the cat, with remnant predator scent), and low (exposure on the following day to the predatory context) levels of predatory threat. To test for contributions of both threat stimuli and behaviour to changes in firing rate, we applied a Poisson generalized linear model regression, using the different predator stimulus conditions and defensive repertoires as predictor variables. Analysis revealed that the different predator stimulus conditions were more predictive of changes in firing rate (primarily threat-induced increases) than the different defensive repertoires. Thus, the dorsal PAG may code for different levels of predatory threat, more than it directly orchestrates distinct threat-oriented behaviours. The present results open interesting perspectives to investigate the role of the dorsal PAG in mediating primal emotional and cognitive responses to fear-inducing stimuli.

Hippocampal CA1 activity correlated with the distance to the goal and navigation performance.

Coding the distance to a future goal is an important function of a neural system supporting navigation. While some evidence indicates the hippocampus increases activity with proximity to the goal, others have found activity to decrease with proximity. To explore goal distance coding in the hippocampus we recorded from CA1 hippocampal place cells in rats as they navigated to learned goals in an event arena with a win-stay lose-shift rule. CA1 activity was positively correlated with the distance - decreasing with proximity to the goal. The stronger the correlation between distance to the goal and CA1 activity, the more successful navigation was in a given task session. Acceleration, but not speed, was also correlated with the distance to the goal. However, the relationship between CA1 activity and navigation performance was independent of variation in acceleration and variation in speed. These results help clarify the situations in which CA1 activity encodes navigationally relevant information and the extent to which it relates to behavior.

Evidence for encoding versus retrieval scheduling in the hippocampus by theta phase and acetylcholine.

The formation of new memories requires new information to be encoded in the face of proactive interference from the past. Two solutions have been proposed for hippocampal region CA1: (1) acetylcholine, released in novelty, selectively suppresses excitatory projections to CA1 from CA3 (mediating the products of retrieval), while sparing entorhinal inputs (mediating novel sensory information) and (2) encoding preferentially occurs at the pyramidal-layer theta peak, coincident with input from entorhinal cortex, and retrieval occurs at the trough, coincident with input from CA3, consistent with theta phase-dependent synaptic plasticity. We examined three predictions of these models: (1) in novel environments, the preferred theta phase of CA1 place cell firing should shift closer to the CA1 pyramidal-layer theta peak, shifting the encoding-retrieval balance toward encoding; (2) the encoding-related shift in novel environments should be disrupted by cholinergic antagonism; and (3) in familiar environments, cholinergic antagonism should shift the preferred theta firing phase closer to the theta trough, shifting the encoding-retrieval balance even further toward retrieval. We tested these predictions by recording from CA1 pyramidal cells in freely moving rats as they foraged in open field environments under the influence of scopolamine (an amnestic cholinergic antagonist) or vehicle (saline). Results confirmed all three predictions, supporting both the theta phase and cholinergic models of encoding versus retrieval dynamics. Also consistent with cholinergic enhancement of encoding, scopolamine attenuated the formation of distinct spatial representations in a new environment, reducing the extent of place cell "remapping."

Novelty and anxiolytic drugs dissociate two components of hippocampal theta in behaving rats.

Hippocampal processing is strongly implicated in both spatial cognition and anxiety and is temporally organized by the theta rhythm. However, there has been little attempt to understand how each type of processing relates to the other in behaving animals, despite their common substrate. In freely moving rats, there is a broadly linear relationship between hippocampal theta frequency and running speed over the normal range of speeds used during foraging. A recent model predicts that spatial-translation-related and arousal/anxiety-related mechanisms of hippocampal theta generation underlie dissociable aspects of the theta frequency-running speed relationship (the slope and intercept, respectively). Here we provide the first confirmatory evidence: environmental novelty decreases slope, whereas anxiolytic drugs reduce intercept. Variation in slope predicted changes in spatial representation by CA1 place cells and novelty-responsive behavior. Variation in intercept predicted anxiety-like behavior. Our findings isolate and doubly dissociate two components of theta generation that operate in parallel in behaving animals and link them to anxiolytic drug action, novelty, and the metric for self-motion.

Anxiolytic drugs and altered hippocampal theta rhythms: the quantitative systems pharmacological approach.

The spirit of systems pharmacology was adopted to study the possible mechanisms of anxiolytic drugs on hippocampal electric patterns. The frequency of the hippocampal theta rhythm increases linearly with the intensity of electrical stimulation to the brainstem. The reduction of mean theta frequency in this paradigm predicts the clinical efficacy of anxiolytic drugs. The purpose of this study was to investigate the mechanisms by which anxiolytics produce their characteristic effects on the slope and intercept of the stimulus-frequency relationship of hippocampal theta. A network of neuron populations that generates septo-hippocampal theta rhythm was modeled using a compartmental modeling technique. The influence of cellular and synaptic parameters on network frequency was studied. Results show that halving the rate of rise and fall of pyramidal hyperpolarization-activated (Ih) conductance lowers nPO elicited theta frequency at low levels of stimulation. Results also suggest that increasing the decay time constant of inhibitory post-synaptic current can reduce the frequency of low nPO stimulation elicited theta rhythm, while maximal synaptic conductance of GABA-mediated synapses has little effect on frequency. Given their similar effect on network dynamics as by known anxiolytics, these parameter manipulations may mimic or predict the biophysical manifestations of anxiolytic action within the septo-hippocampal system.

Frequency matters: how changes in hippocampal theta frequency can influence temporal coding, anxiety-reduction, and memory.

Hippocampal theta frequency is a somewhat neglected topic relative to theta power, phase, coherence, and cross-frequency coupling. Accordingly, here we review and present new data on variation in hippocampal theta frequency, focusing on functional associations (temporal coding, anxiety reduction, learning, and memory). Taking the rodent hippocampal theta frequency to running-speed relationship as a model, we identify two doubly-dissociable frequency components: (a) the slope component of the theta frequency-to-stimulus-rate relationship ("theta slope"); and (b) its y-intercept frequency ("theta intercept"). We identify three tonic determinants of hippocampal theta frequency. (1) Hotter temperatures increase theta frequency, potentially consistent with time intervals being judged as shorter when hot. Initial evidence suggests this occurs via the "theta slope" component. (2) Anxiolytic drugs with widely-different post-synaptic and pre-synaptic primary targets share the effect of reducing the "theta intercept" component, supporting notions of a final common pathway in anxiety reduction involving the hippocampus. (3) Novelty reliably decreases, and familiarity increases, theta frequency, acting upon the "theta slope" component. The reliability of this latter finding, and the special status of novelty for learning, prompts us to propose a Novelty Elicits Slowing of Theta frequency (NEST) hypothesis, involving the following elements: (1) Theta frequency slowing in the hippocampal formation is a generalised response to novelty of different types and modalities; (2) Novelty-elicited theta slowing is a hippocampal-formation-wide adaptive response functioning to accommodate the additional need for learning entailed by novelty; (3) Lengthening the theta cycle enhances associativity; (4) Even part-cycle lengthening may boost associativity; and (5) Artificial theta stimulation aimed at enhancing learning should employ low-end theta frequencies.

Vector trace cells in the subiculum of the hippocampal formation.

Successfully navigating in physical or semantic space requires a neural representation of allocentric (map-based) vectors to boundaries, objects and goals. Cognitive processes such as path-planning and imagination entail the recall of vector representations, but evidence of neuron-level memory for allocentric vectors has been lacking. Here, we describe a novel neuron type, vector trace cell (VTC), whose firing generates a new vector field when a cue is encountered and a 'trace' version of that field for hours after cue removal. VTCs are concentrated in subiculum, distal to CA1. Compared to non-trace cells, VTCs fire at further distances from cues and exhibit earlier-going shifts in preferred theta phase in response to newly introduced cues, which demonstrates a theta-linked neural substrate for memory encoding. VTCs suggest a vector-based model of computing spatial relationships between an agent and multiple spatial objects, or between different objects, freed from the constraints of direct perception of those objects.

Boundary vector cells in the subiculum of the hippocampal formation.

"Boundary vector cells" were predicted to exist by computational models of the environmental inputs underlying the spatial firing patterns of hippocampal place cells (O'Keefe and Burgess, 1996; Burgess et al., 2000; Hartley et al., 2000). Here, we report the existence of cells fulfilling this description in recordings from the subiculum of freely moving rats. These cells may contribute environmental information to place cell firing, complementing path integrative information. Their relationship to other cell types, including medial entorhinal "border cells," is discussed.

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.

Novel insights into false recollection: a model of déjà vécu.

The thesis of this paper is that déjà experiences can be separated into two forms: déjà vu, arising from the erroneous sensation of familiarity, and déjà vécu, arising from the erroneous sensation of recollection. We summarise a series of cases for whom déjà vécu is experienced frequently and for extended periods, and seek to differentiate their experiences from "healthy" déjà experiences by non-brain-damaged participants. In reviewing our cases, we stress two novel ideas: that déjà vécu in these cases is delusion-like; and that these cases experience déjà vécu for stimuli that are especially novel or unusual. Here we present a novel cognitive neuroscientific hypothesis of déjà vécu. This hypothesis assumes that the signal of retrieval from memory is neurally dissociable from the contents of retrieval. We suggest that a region downstream of the hippocampus signals "recollection" by detecting the timing of firing in hippocampal output neurons relative to the theta oscillation. Disruptions to this "temporal coding" mechanism result in false signals of recollection which may occur without actual retrieval and which, ironically, may arise particularly during situations of contextual novelty.

Acetylcholine and Spontaneous Recognition Memory in Rodents and Primates.

Whilst acetylcholine has long been linked to memory, there have been significant questions about its specific role. In particular, the effects of cholinergic manipulations in primates and rodents has often been at odds. Here, we review the work in primates and rodents on the specific function of acetylcholine in memory, and episodic memory in particular. We propose that patterns of impairment can best be understood in terms of a role for hippocampal acetylcholine in resolving spatial interference and we discuss the benefits of new tasks of episodic memory in animals allowing clearer translation of findings to the clinic.

Distinct and combined responses to environmental geometry and features in a working-memory reorientation task in rats and chicks.

The original provocative formulation of the 'geometric module' hypothesis was based on a working-memory task in rats which suggested that spontaneous reorientation behavior is based solely on the environmental geometry and is impervious to featural cues. Here, we retested that claim by returning to a spontaneous navigation task with rats and domestic chicks, using a single prominent featural cue (a striped wall) within a rectangular arena. Experiments 1 and 2 tested the influence of geometry and features separately. In Experiment 1, we found that both rats and chicks used environmental geometry to compute locations in a plain rectangular arena. In Experiment 2, while chicks failed to spontaneously use a striped wall in a square arena, rats showed a modest influence of the featural cue as a local marker to the goal. The critical third experiment tested the striped wall inside the rectangular arena. We found that although chicks solely relied on geometry, rats navigated based on both environmental geometry and the featural cue. While our findings with rats are contrary to classic claims of an impervious geometric module, they are consistent with the hypothesis that navigation by boundaries and features may involve distinct underlying cognitive computations. We conclude by discussing the similarities and differences in feature-use across tasks and species.

En route to delineating hippocampal roles in spatial learning.

The precise role played by the hippocampus in spatial learning tasks, such as the Morris Water Maze (MWM), is not fully understood. One theory is that the hippocampus is not required for 'knowing where' but rather is crucial in 'getting there'. To explore this idea in the MWM, we manipulated 'getting there' variables, such as passive transport or active swimming towards the hidden platform, in rats with and without hippocampal lesions. Our results suggested that for intact rats, self-motion cues enroute to the hidden goal were a necessary component for 'place learning' to progress. Specifically, intact rats could not learn the hidden goal location, when passively transported to it, despite extensive training. However, when rats were either given hippocampal lesions, or placed in a light-tight box during transportation to the hidden goal, passive-placement spatial learning was facilitated. In a subsequent experiment, the 'getting there' component of place navigation was simplified, via the placement of two overhead landmarks, one of which served as a beacon. When 'getting there' was made easier in this way, hippocampal lesions did not induce deficits in 'knowing where' the goal was. In fact, similar to the facilitation observed in passive-placement spatial learning, hippocampal lesions improved landmark learning relative to controls. Finally, demonstrating that our lesions were sufficiently deleterious, hippocampal-lesioned rats were impaired, as predicted, in an environmental-boundary based learning task. We interpret these results in terms of competition between multiple memory systems, and the importance of self-generated motion cues in hippocampal spatial mapping.

Insoluble Aß overexpression in an App knock-in mouse model alters microstructure and gamma oscillations in the prefrontal cortex, affecting anxiety-related behaviours.

We studied a new amyloid-beta precursor protein (App) knock-in mouse model of Alzheimer's disease (AppNL-G-F ), containing the Swedish KM670/671NL mutation, the Iberian I716F mutation and the Artic E693G mutation, which generates elevated levels of amyloid beta (Aß)40 and Aß42 without the confounds associated with APP overexpression. This enabled us to assess changes in anxiety-related and social behaviours, and neural alterations potentially underlying such changes, driven specifically by Aß accumulation. AppNL-G-F knock-in mice exhibited subtle deficits in tasks assessing social olfaction, but not in social motivation tasks. In anxiety-assessing tasks, AppNL-G-F knock-in mice exhibited: (1) increased thigmotaxis in the open field (OF), yet; (2) reduced closed-arm, and increased open-arm, time in the elevated plus maze (EPM). Their ostensibly anxiogenic OF profile, yet ostensibly anxiolytic EPM profile, could hint at altered cortical mechanisms affecting decision-making (e.g. 'disinhibition'), rather than simple core deficits in emotional motivation. Consistent with this possibility, alterations in microstructure, glutamatergic-dependent gamma oscillations and glutamatergic gene expression were all observed in the prefrontal cortex, but not the amygdala, of AppNL-G-F knock-in mice. Thus, insoluble Aß overexpression drives prefrontal cortical alterations, potentially underlying changes in social and anxiety-related behavioural tasks.This article has an associated First Person interview with the first author of the paper.

The within-subject application of diffusion tensor MRI and CLARITY reveals brain structural changes in Nrxn2 deletion mice.

Background: Of the many genetic mutations known to increase the risk of autism spectrum disorder, a large proportion cluster upon synaptic proteins. One such family of presynaptic proteins are the neurexins (NRXN), and recent genetic and mouse evidence has suggested a causative role for NRXN2 in generating altered social behaviours. Autism has been conceptualised as a disorder of atypical connectivity, yet how single-gene mutations affect such connectivity remains under-explored. To attempt to address this, we have developed a quantitative analysis of microstructure and structural connectivity leveraging diffusion tensor MRI (DTI) with high-resolution 3D imaging in optically cleared (CLARITY) brain tissue in the same mouse, applied here to the Nrxn2α knockout (KO) model. Methods: Fixed brains of Nrxn2α KO mice underwent DTI using 9.4 T MRI, and diffusion properties of socially relevant brain regions were quantified. The same tissue was then subjected to CLARITY to immunolabel axons and cell bodies, which were also quantified. Results: DTI revealed increases in fractional anisotropy in the amygdala (including the basolateral nuclei), the anterior cingulate cortex, the orbitofrontal cortex and the hippocampus. Axial diffusivity of the anterior cingulate cortex and orbitofrontal cortex was significantly increased in Nrxn2α KO mice, as were tracts between the amygdala and the orbitofrontal cortex. Using CLARITY, we find significantly altered axonal orientation in the amygdala, orbitofrontal cortex and the anterior cingulate cortex, which was unrelated to cell density. Conclusions: Our findings demonstrate that deleting a single neurexin gene (Nrxn2α) induces atypical structural connectivity within socially relevant brain regions. More generally, our combined within-subject DTI and CLARITY approach presents a new, more sensitive method of revealing hitherto undetectable differences in the autistic brain.

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.

The Neurobiology of Mammalian Navigation.

Mammals have evolved specialized brain systems to support efficient navigation within diverse habitats and over varied distances, but while navigational strategies and sensory mechanisms vary across species, core spatial components appear to be widely shared. This review presents common elements found in mammalian spatial mapping systems, focusing on the cells in the hippocampal formation representing orientational and locational spatial information, and 'core' mammalian hippocampal circuitry. Mammalian spatial mapping systems make use of both allothetic cues (space-defining cues in the external environment) and idiothetic cues (cues derived from self-motion). As examples of each cue type, we discuss: environmental boundaries, which control both orientational and locational neuronal activity and behaviour; and 'path integration', a process that allows the estimation of linear translation from velocity signals, thought to depend upon grid cells in the entorhinal cortex. Building cognitive maps entails sampling environments: we consider how the mapping system controls exploration to acquire spatial information, and how exploratory strategies may integrate idiothetic with allothetic information. We discuss how 'replay' may act to consolidate spatial maps, and simulate trajectories to aid navigational planning. Finally, we discuss grid cell models of vector navigation.

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.

Rearing on hind legs, environmental novelty, and the hippocampal formation.

Many mammals spontaneously rear on their hind legs in response to novelty. The current paper is the first review of rearing behaviour, and is intended to collate findings from different perspectives that are not usually brought together. We suggest that rearing is a useful marker of environmental novelty, that the hippocampal formation is a crucial component of the system controlling rearing in novel environments, and that rearing is one of several ethological measures that can profitably be used to assess hippocampal learning and memory. Consideration is given to the following topics: the possible functions of rearing in information-gathering and escape behaviour; the modulation of rearing by various factors such as anxiety/ fear emotionality; comparative perspectives on rearing; neuroanatomical circuits involved in rearing with particular reference to the hippocampal formation and its afferents and efferents; and the role of the hippocampal formation in uncharted and mismatch environmental novelty. The review concludes with testable predictions about rearing, environmental novelty and the hippocampus.