Ben Vermaercke

Vesicular Glutamate Transporter VGLUT1 Has a Role in Hippocampal Long-Term Potentiation and Spatial Reversal Learning

Vesicular glutamate transporters 1 and 2 (VGLUT1, VGLUT2) show largely complementary distribution in the mature rodent brain and tend to segregate to synapses with different physiological properties. In the hippocampus, VGLUT1 is the dominate subtype in adult animals, whereas VGLUT2 is transiently expressed during early postnatal development. We generated and characterized VGLUT1 knockout mice in order to examine the functional contribution of this transporter to hippocampal synaptic plasticity and hippocampus-dependent spatial learning. Because complete deletion of VGLUT1 resulted in postnatal lethality, we used heterozygous animals for analysis. Here, we report that deletion of VGLUT1 resulted in impaired hippocampal long-term potentiation (LTP) in the CA1 region in vitro. In contrast, heterozygous VGLUT2 mice that were investigated for comparison did not show any changes in LTP. The reduced ability of VGLUT1-deficient mice to express LTP was accompanied by a specific deficit in spatial reversal learning in the water maze. Our data suggest a functional role of VGLUT1 in forms of hippocampal synaptic plasticity that are required to adapt and modify acquired spatial maps to external stimuli and changes.

Homologous involvement of striatum and prefrontal cortex in rodent and human water maze learning

The multiple memory systems hypothesis posits that dorsal striatum and hippocampus are central nodes in independent memory systems, supporting response-based and place-based learning, respectively. Although our understanding of the function of hippocampus within this framework is relatively well established, the contribution of dorsal striatum is less clear. This in part seems to be due to the heterogeneous nature of dorsal striatum, which receives extensive topographically organized projections from higher cortical areas. Here we quantified neural activity in the intact brain while mice and humans acquired analogous versions of the Morris water maze. We found that dorsomedial striatum and medial prefrontal cortex support the initial acquisition of what is typically considered a hippocampus-dependent spatial learning task. We suggest that the circuit involving dorsomedial striatum and medial prefrontal cortex identified here plays a more task-independent role in early learning than currently thought. Furthermore, our results demonstrate that dorsomedial and dorsolateral striatum serve fundamentally different roles during place learning. The remarkably high degree of anatomical overlap in brain function between mouse and human observed in our study emphasizes the extent of convergence achievable with a well-matched multilevel approach.

Sex differences in human virtual water maze performance: novel measures reveal the relative contribution of directional responding and spatial knowledge.

Sex differences in humans on virtual water maze navigation are well established when overall performance is measured, e.g., by the total time taken to find the hidden platform, total path length, or quadrant dwell time during probe trials. Currently, it is unknown whether males are better spatial learners than females, or if overall performance differences reflect other aspects of the task unrelated to spatial memory. Here, males and females were tested on a virtual analogue of the Morris water maze. We devised a novel method of analysis in which each trial was divided into an initial trajectory phase and search phase. We also implemented a new measure of spatial learning during early and late training, by including trials in which subjects were only required to indicate where they thought the hidden target zone was located. Consistent with previous reports, males outperformed females on overall measures of task performance. Males also performed significantly better on all initial trajectory phase variables. Interestingly, only small (non-significant) differences were observed during the search phase and when spatial learning was tested without the constraints of a typical water maze trial. Our results suggest that spatial knowledge regarding the location of the hidden target zone is not the main factor responsible for overall sex differences in virtual water maze performance. Instead, the largest sex differences were observed during the initial trajectory phase of the trial, which is thought to depend on effective processing of distal features of the environment.

LPA5 receptor plays a role in pain sensitivity, emotional exploration and reversal learning

Lysophosphatidic acid (LPA) is a bioactive lipid acting on the nervous system through at least 6 different G protein‐coupled receptors. In this study, we examined mice lacking the LPA5 receptor using an extensive battery of behavioral tests. LPA5‐deficient mice showed decreased pain sensitivity in tail withdrawal, faster recovery in one inflammatory pain procedure (complete Freunds adjuvant‐induced inflammation) and attenuated responses under specific neuropathic pain conditions. Notably, deletion of LPA5 also induced nocturnal hyperactivity and reduced anxiety in the mutant mice. Several exploratory tasks revealed signs of reduced anxiety in LPA5 knockout mice including increased visits to the arena center and reduced thigmotaxis in the open field, and more open arm entries in the elevated plus maze. Finally, LPA5 knockout mice also displayed marked reduction in social exploration, although several other tests indicated that these mice were able to respond normally to environmental stimuli. While learning and memory performance was not impaired in LPA5‐deficient mice, we found differences, e.g., targeted swim strategy and reversal learning, as well as scheduled appetitive conditioning that might indicate differential motivational behavior. These results imply that LPA5 might be involved in both nociception and mechanisms of pain hypersensitivity, as well as in anxiety‐related and motivational behaviors. These observations further support the proposed involvement of LPA signaling in psychopathology.

Progressive age-related cognitive decline in tau mice.

Age-related cognitive decline and neurodegenerative diseases are a growing challenge for society. Accumulation of tau pathology has been proposed to partially contribute to these impairments. This study provides a behavioral characterization during aging of transgenic mice bearing tau mutations. THY-Tau22 mice were evaluated at ages wherein tau neuropathology in this transgenic mouse model is low (3-4 months), moderate (6-7 months), or extensive (>9 months). Spatial memory was found to be impaired only after 9 months of age in THY-Tau22 mice, whereas non-spatial memory was affected as early as 6 months, appearing to offer an opportunity for assessing potential therapeutic agents in attenuating or preventing tauopathies through modulation of tau kinetics.

Visual categorization of natural movies by rats.

Visual categorization of complex, natural stimuli has been studied for some time in human and nonhuman primates. Recent interest in the rodent as a model for visual perception, including higher-level functional specialization, leads to the question of how rodents would perform on a categorization task using natural stimuli. To answer this question, rats were trained in a two-alternative forced choice task to discriminate movies containing rats from movies containing other objects and from scrambled movies (ordinate-level categorization). Subsequently, transfer to novel, previously unseen stimuli was tested, followed by a series of control probes. The results show that the animals are capable of acquiring a decision rule by abstracting common features from natural movies to generalize categorization to new stimuli. Control probes demonstrate that they did not use single low-level features, such as motion energy or (local) luminance. Significant generalization was even present with stationary snapshots from untrained movies. The variability within and between training and test stimuli, the complexity of natural movies, and the control experiments and analyses all suggest that a more high-level rule based on more complex stimulus features than local luminance-based cues was used to classify the novel stimuli. In conclusion, natural stimuli can be used to probe ordinate-level categorization in rats.

Impulsivity, decreased social exploration, and executive dysfunction in a mouse model of frontotemporal dementia

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder, a major subset of which is characterized by the accumulation of abnormal forms of the protein tau, leading to impairments in motor functions as well as language and behavioral alterations. Tau58-2/B mice express human tau with the P301S mutation found in familial forms of FTLD in neurons. By assessing three age cohorts of Tau58-2/B mice in a comprehensive behavioral test battery, we found that the tauopathy animals showed age-dependent signs of impulsivity, decreased social exploration and executive dysfunction. The deficit in executive function was first limited to decreased spatial working memory, but with aging this was extended to impaired instrumental short-term memory. Tau pathology was prominent in brain regions underlying these behaviors. Thus, Tau-58-2/B mice recapitulate neurological deficits of the behavioral variant of frontotemporal dementia (bvFTD), presenting them as a suitable model to test therapeutic interventions for the amelioration of this variant.

More complex brains are not always better: rats outperform humans in implicit category-based generalization by implementing a similarity-based strategy

Generalization from previous experiences to new situations is a hallmark of intelligent behavior and a prerequisite for category learning. It has been proposed that category learning in humans relies on multiple brain systems that compete with each other, including an explicit, rule-based system and an implicit system. Given that humans are biased to follow rule-based strategies, a counterintuitive prediction of this model is that other animals, in which this rule-based system is less developed, might generalize better to new stimuli in implicit category-learning tasks that are not rule-based. To test this prediction, rats and humans were trained in rule-based and information-integration category-learning tasks with visual stimuli. The generalization performance of rats and humans was equal in rule-based categorization, but rats outperformed humans on generalization in the information-integration task. The performance of rats was consistent with a nondimensional, similarity-based categorization strategy. These findings illustrate through a comparative approach that the bias toward rule-based strategies can impede humans’ performance on generalization tasks.

Inability to acquire spatial information and deploy spatial search strategies in mice with lesions in dorsomedial striatum

Dorsal striatum has been shown to contribute to spatial learning and memory, but the role of striatal subregions in this important aspect of cognitive functioning remains unclear. Moreover, the spatial-cognitive mechanisms that underlie the involvement of these regions in spatial navigation have scarcely been studied. We therefore compared spatial learning and memory performance in mice with lesions in dorsomedial (DMS) and dorsolateral striatum (DLS) using the hidden-platform version of the Morris water maze (MWM) task. Compared to sham-operated controls, animals with DMS damage were impaired during MWM acquisition training. These mice displayed delayed spatial learning, increased thigmotaxis, and increased search distance to the platform, in the absence of major motor dysfunction, working memory defects or changes in anxiety or exploration. They failed to show a preference for the target quadrant during probe trials, which further indicates that spatial reference memory was impaired in these animals. Search strategy analysis moreover demonstrated that DMS-lesioned mice were unable to deploy cognitively advanced spatial search strategies. Conversely, MWM performance was barely affected in animals with lesions in DLS. In conclusion, our results indicate that DMS and DLS display differential functional involvement in spatial learning and memory. Our results show that DMS, but not DLS, is crucial for the ability of mice to acquire spatial information and their subsequent deployment of spatial search strategies. These data clearly identify DMS as a crucial brain structure for spatial learning and memory, which could explain the occurrence of neurocognitive impairments in brain disorders that affect the dorsal striatum.

Comparison of the spatial-cognitive functions of dorsomedial striatum and anterior cingulate cortex in mice

Neurons in anterior cingulate cortex (aCC) project to dorsomedial striatum (DMS) as part of a corticostriatal circuit with putative roles in learning and other cognitive functions. In the present study, the spatial-cognitive importance of aCC and DMS was assessed in the hidden-platform version of the Morris water maze (MWM). Brain lesion experiments that focused on areas of connectivity between these regions indicated their involvement in spatial cognition. MWM learning curves were markedly delayed in DMS-lesioned mice in the absence of other major functional impairments, whereas there was a more subtle, but still significant influence of aCC lesions. Lesioned mice displayed impaired abilities to use spatial search strategies, increased thigmotaxic swimming, and decreased searching in the proximity of the escape platform. Additionally, aCC and DMS activity was compared in mice between the early acquisition phase (2 and 3 days of training) and the over-trained high-proficiency phase (after 30 days of training). Neuroplasticity-related expression of the immediate early gene Arc implicated both regions during the goal-directed, early phases of spatial learning. These results suggest the functional involvement of aCC and DMS in processes of spatial cognition that model associative cortex-dependent, human episodic memory abilities.