Pathfinder: open source software for analyzing spatial navigation search strategies

Spatial navigation is a universal behavior that varies depending on goals, experience and available sensory stimuli. Spatial navigational tasks are routinely used to study learning, memory and goal-directed behavior, in both animals and humans. One popular paradigm for testing spatial memory is the Morris water maze, where subjects learn the location of a hidden platform that offers escape from a pool of water. Researchers typically express learning as a function of the latency to escape, though this reveals little about the underlying navigational strategies. Recently, a number of studies have begun to classify water maze search strategies in order to clarify the precise spatial and mnemonic functions of different brain regions, and to identify which aspects of spatial memory are disrupted in disease models. However, despite their usefulness, strategy analyses have not been widely adopted due to the lack of software to automate analyses. To address this need we developed Pathfinder, an open source application for analyzing spatial navigation behaviors. In a representative dataset, we show that Pathfinder effectively characterizes the development of highly-specific spatial search strategies as male and female mice learn a standard spatial water maze. Pathfinder can read data files from commercially- and freely-available software packages, is optimized for classifying search strategies in water maze paradigms, and can also be used to analyze 2D navigation by other species, and in other tasks, as long as timestamped xy coordinates are available. Pathfinder is simple to use, can automatically determine pool and platform geometry, generates heat maps, analyzes navigation with respect to multiple goal locations, and can be updated to accommodate future developments in spatial behavioral analyses. Given these features, Pathfinder may be a useful tool for studying how navigational strategies are regulated by the environment, depend on specific neural circuits, and are altered by pathology.

Spatial navigation and orientation are emerging as promising markers for altered cognition in prodromal Alzheimer’s disease, and even in cognitively normal individuals at risk for Alzheimer’s disease. The different APOE gene alleles confer various degrees of risk. The APOE2 allele is considered protective, APOE3 is seen as control, while APOE4 carriage is the major known genetic risk for Alzheimer’s disease. We have used mouse models carrying the three humanized APOE alleles and tested them in a spatial memory task in the Morris water maze. We introduce a new metric, the absolute winding number, to characterize the spatial search strategy, through the shape of the swim path. We show that this metric is robust to noise, and works for small group samples. Moreover, the absolute winding number better differentiated APOE3 carriers, through their straighter swim paths relative to both APOE2 and APOE4 genotypes. Finally, this novel metric supported increased vulnerability in APOE4 females. We hypothesized differences in spatial memory and navigation strategies are linked to differences in brain networks, and showed that different genotypes have different reliance on the hippocampal and caudate putamen circuits, pointing to a role for white matter connections. Moreover, differences were most pronounced in females. This departure from a hippocampal centric to a brain network approach may open avenues for identifying regions linked to increased risk for Alzheimer’s disease, before overt disease manifestation. Further exploration of novel biomarkers based on spatial navigation strategies may enlarge the windows of opportunity for interventions. The proposed framework will be significant in dissecting vulnerable circuits associated with cognitive changes in prodromal Alzheimer’s disease.

Visually guided and context-dependent spatial navigation in the translucent fish Danionella cerebrum

Impairments in the acquisition, retention and selection of spatial navigation strategies after medial caudate-putamen lesions in rats.

Representation of Spatial Goals in Rat Orbitofrontal Cortex

Effects of combined block of α1-adrenoceptors and NMDA receptors on spatial and passive avoidance behavior in rats

To navigate in space, an animal must reference external sensory landmarks to the spatial orientation of its body and head. Circuit and synaptic mechanisms that integrate external cues with internal head-direction (HD) signals to drive navigational behavior remain, however, poorly described. We identify an excitatory synaptic projection from the presubiculum and retrosplenial cortex to the anterodorsalmost sector of the thalamic reticular nucleus (TRN), so far classically implied in gating sensory information flow. Projections to TRN showed driver characteristics and involved AMPA/NMDA-type glutamate receptors that initiated TRN cell burst discharge and feedforward inhibition of anterior thalamic nuclei, where HD-tuned cells relevant for egocentric navigation reside. Chemogenetic anterodorsal TRN inhibition broadened the tuning of thalamic HD cells and compromised egocentric search strategies in the Morris water maze. Besides sensory gating, TRN-dependent thalamic inhibition is an integral part of limbic navigational circuits to recruit HD-cell-dependent search strategies during spatial navigation.

The effects of buspirone on the execution of step-through passive avoidance and spatial navigation learning tasks were assessed. In view of the anxiolytic properties of the drug, its effects on shock induced ultrasonic vocalizations and shock suppressed locomotor activity in a hole-board were also determined. Doses (0.5, 1 and 2 mg/kg, IP) which did not affect exploratory activity in a novel environment (light/dark box and hole-board apparatus) were used. Buspirone (1 and 2 mg/kg) impaired performance on the 24 h passive avoidance recall test when given prior to the training and the test sessions or prior to the test session only but not when given before the training trial only. The stress response to the mild footshock, as measured in terms of suppressed locomotor activity in the hole-board apparatus and post-shock ultrasonic vocalizations, was reduced by buspirone (at 1 and 2 mg/kg, respectively), indicating that its effect on behavior in the passive avoidance learning task is probably due to its anxiolytic properties. Evidence for a possible amnesic effect of buspirone (2 mg/kg) was found on the acquisition and probe test trials in the spatial navigation task. During training the latency to find a submerged escape platform in a water maze was increased. Performance on a probe test was also impaired but this effect was not apparent in animals which had received buspirone only prior to the probe test. Although these changes may be attributable to alterations in many aspects of cognitive processing, the possibility of a direct effect on memory warrants further investigation.

Do spatial and recognition memories have a lateralized processing by the dorsal hippocampus CA3?

Spatial Navigation (Water Maze) Tasks

BackgroundThe Morris water maze task is a hippocampus-dependent learning and memory test that typically takes between 3 days to 2 weeks of training. This task is used to assess spatial learning and induces the expression of genes known to be crucial to learning and memory in the hippocampus. A major caveat in the protocol is the prolonged duration of training, and difficulty of assessing the time during training in which animals have learned the task. We introduce here a condensed version of the task that like traditional water maze tasks, creates lasting hippocampus-dependent spatial cognitive maps and elicits gene expression following learning.MethodsThis paradigm was designed for rats to quickly acquire a hippocampus-dependent spatial cognitive map and retain this memory for at least 24 hours. To accomplish this, we interspersed visible and hidden training trials, delivering them in a massed fashion so training takes a maximum of 15 minutes. Learning was assessed based on latencies to the platform during each training trial, as well as time spent in the goal quadrant during probe testing 30 minutes and 24 hours after training. Normal rats were compared to two impaired cohorts (rats with fimbria-fornix lesions and rats administered NMDA receptor antagonist (CPP)). To quantitate hippocampal expression of known learning genes, real-time polymerase chain reaction (RT-PCR) was performed on hippocampal cDNA.ResultsWe show that massed training using alternating visible and hidden training trials generates robust short-term working and long-term reference memories in rats. Like the traditional Morris water maze paradigm, this task requires proper hippocampal function, as rats with fimbria-fornix lesions and rats administered CPP fail to learn the spatial component of the task. Furthermore, training in this paradigm elicits hippocampal expression of genes upregulated following learning in a variety of spatial tasks: homer1a, cfos and zif268.ConclusionsWe introduce here a condensed version of the Morris water maze, which is like a traditional water maze paradigm, in that it is hippocampus-dependent, and elicits hippocampal expression of learning genes. However, this task is administered in 15 minutes and induces spatial memory for at least 24 hours.

Consistency of cognitive performance in spatial navigation and its link to activity and boldness in laboratory rats.

Rats with lesions of the medial prefrontal, posterior parietal, or posterior temporal cortex were tested in five spatial navigation tasks, which varied in egocentric or allocentric demands, a visual discrimination task, and two delayed nonmatching-to-sample tasks. Rats with prefrontal lesions were impaired at every spatial navigation task, whereas rats with posterior parietal lesions had selective spatial navigation impairments. Rats with prefrontal lesions were also impaired at a visual delayed nonmatching-to-sample task, as they were unable to learn the task, even with no delay. The results are consistent with the idea that the basic plan of mammalian cortex includes prefrontal, posterior parietal, and posterior temporal regions, each of which have generally similar functions across mammalian taxa. There are, however, species-typical differences that reflect specific ecological pressures on the development of the different regions.

There is considerable research on the neurobiological mechanisms within the hippocampal system that support spatial navigation. In this article I review the literature on navigational strategies in humans and animals, observations on hippocampal function in navigation, and studies of hippocampal neural activity in animals and humans performing different navigational tasks and tests of memory. Whereas the hippocampus is essential to spatial navigation via a cognitive map, its role derives from the relational organization and flexibility of cognitive maps and not from a selective role in the spatial domain. Correspondingly, hippocampal networks map multiple navigational strategies, as well as other spatial and nonspatial memories and knowledge domains that share an emphasis on relational organization. These observations suggest that the hippocampal system is not dedicated to spatial cognition and navigation, but organizes experiences in memory, for which spatial mapping and navigation are both a metaphor for and a prominent application of relational memory organization.

Cognitive decline is sexually dimorphic in Alzheimer's disease (AD). Men show higher incidences of amnestic mild cognitive impairment yet women disproportionally phenoconvert to AD. It is hypothesized that men maintain greater cognitive reserve than women under comparable amyloid-β (Aβ) challenge. One behavioral aspect of cognitive reserve in mice is the capacity to cope with Aβ-associated stereotypies by switching to increasingly effective navigational search strategies in the Morris water maze. To explore inherent sex differences in this paradigm, however, we require an AβPP mouse model wherein behavioral flexibility is impaired earlier in females than males despite equivalent Aβ load. Here, we show that when F1 C57Bl/6×C3H/HeJ TgCRND8 mice are placed on C57Bl/6 background, N5 Tg males and females exhibit equivalent Aβ pathologies at 2, 4, 6, and 8 months of age yet females display learning and memory deficits earlier than males. We further show that this N5 line does not carry the autosomal recessive pde6brd1 mutation that impairs visual acuity and that the estrous cycle is not disrupted on this genetic background. At 5.5 months of age, Tg males, but not females, compensate for Aβ-associated stereotypic behaviors (i.e., hyperactive tight circling) by alternating navigational search strategies and adopting increasingly productive spatial search strategies. Females fail to overcome Aβ-associated stereotypies and do not efficiently switch from systematic to spatial learning strategies. Together, these data identify a novel AβPP mouse model that can be used for preclinical testing of interventions targeting sexual dimorphisms in behavioral indices of cognitive reserve.