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.

Dorsolateral striatal lesions impair navigation based on landmark-goal vectors but facilitate spatial learning based on a "cognitive map".

In three experiments, the nature of the interaction between multiple memory systems in rats solving a variation of a spatial task in the water maze was investigated. Throughout training rats were able to find a submerged platform at a fixed distance and direction from an intramaze landmark by learning a landmark-goal vector. Extramaze cues were also available for standard place learning, or "cognitive mapping," but these cues were valid only within each session, as the position of the platform moved around the pool between sessions together with the intramaze landmark. Animals could therefore learn the position of the platform by taking the consistent vector from the landmark across sessions or by rapidly encoding the new platform position on each session with reference to the extramaze cues. Excitotoxic lesions of the dorsolateral striatum impaired vector-based learning but facilitated cognitive map-based rapid place learning when the extramaze cues were relatively poor (Experiment 1) but not when they were more salient (Experiments 2 and 3). The way the lesion effects interacted with cue availability is consistent with the idea that the memory systems involved in the current navigation task are functionally cooperative yet associatively competitive in nature.

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.

Spontaneous object-location memory based on environmental geometry is impaired by both hippocampal and dorsolateral striatal lesions.

We examined the role of the hippocampus and the dorsolateral striatum in the representation of environmental geometry using a spontaneous object recognition procedure. Rats were placed in a kite-shaped arena and allowed to explore two distinctive objects in each of the right-angled corners. In a different room, rats were then placed into a rectangular arena with two identical copies of one of the two objects from the exploration phase, one in each of the two adjacent right-angled corners that were separated by a long wall. Time spent exploring these two objects was recorded as a measure of recognition memory. Since both objects were in different locations with respect to the room (different between exploration and test phases) and the global geometry (also different between exploration and test phases), differential exploration of the objects must be a result of initial habituation to the object relative to its local geometric context. The results indicated an impairment in processing the local geometric features of the environment for both hippocampus and dorsolateral striatum lesioned rats compared with sham-operated controls, though a control experiment showed these rats were unimpaired in a standard object recognition task. The dorsolateral striatum has previously been implicated in egocentric route-learning, but the results indicate an unexpected role for the dorsolateral striatum in processing the spatial layout of the environment. The results provide the first evidence that lesions to the hippocampus and dorsolateral striatum impair spontaneous encoding of local environmental geometric features.

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.

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.

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.

Spontaneous object recognition memory is maintained following transformation of global geometric properties.

Studies of spontaneous behavior to assess memory are widespread, but often the relationships of objects to contexts and spatial locations are poorly defined. We examined whether object-location memory was maintained following global, but not local, changes to the geometric shape of an arena. Rats explored two trial-unique objects in a distinctively shaped arena before being exposed to two identical copies of one of these objects in a different shape in a different physical location. Rats preferentially explored objects that were novel in relation to their local geometric context rather than identifying both locations as novel in the global geometric context.