Searching for cognitive enhancement in the Morris water maze: better and worse performance in D-amino acid oxidase knockout (Dao(-/-)) mice.

A common strategy when searching for cognitive-enhancing drugs has been to target the N-methyl-d-aspartate receptor (NMDAR), given its putative role in synaptic plasticity and learning. Evidence in favour of this approach has come primarily from studies with rodents using behavioural assays like the Morris water maze. D-amino acid oxidase (DAO) degrades neutral D-amino acids such as D-serine, the primary endogenous co-agonist acting at the glycine site of the synaptic NMDAR. Inhibiting DAO could therefore provide an effective and viable means of enhancing cognition, particularly in disorders like schizophrenia, in which NMDAR hypofunction is implicated. Indirect support for this notion comes from the enhanced hippocampal long-term potentiation and facilitated water maze acquisition of ddY/Dao(-) mice, which lack DAO activity due to a point mutation in the gene. Here, in Dao knockout (Dao(-/-) ) mice, we report both better and worse water maze performance, depending on the radial distance of the hidden platform from the side wall of the pool. Dao(-/-) mice displayed an increased innate preference for swimming in the periphery of the maze (possibly due to heightened anxiety), which facilitated the discovery of a peripherally located platform, but delayed the discovery of a centrally located platform. By contrast, Dao(-/-) mice exhibited normal performance in two alternative assays of long-term spatial memory: the appetitive and aversive Y-maze reference memory tasks. Taken together, these results question the proposed relationship between DAO inactivation and enhanced long-term associative spatial memory. They also have generic implications for how Morris water maze studies are performed and interpreted.

Aversive prediction error signals in the amygdala.

Prediction error signals are fundamental to learning. Here, in mice, we show that aversive prediction signals are found in the hemodynamic responses and theta oscillations recorded from the basolateral amygdala. During fear conditioning, amygdala responses evoked by footshock progressively decreased, whereas responses evoked by the auditory cue that predicted footshock concomitantly increased. Unexpected footshock evoked larger amygdala responses than expected footshock. The magnitude of the amygdala response to the footshock predicted behavioral responses the following day. The omission of expected footshock led to a decrease below baseline in the amygdala response suggesting a negative aversive prediction error signal. Thus, in mice, amygdala activity conforms to temporal difference models of aversive learning.

Variation in serotonin transporter expression modulates fear-evoked hemodynamic responses and theta-frequency neuronal oscillations in the amygdala.

BACKGROUND: Gene association studies detect an influence of natural variation in the 5-hydroxytryptamine transporter (5-HTT) gene on multiple aspects of individuality in brain function, ranging from personality traits through to susceptibility to psychiatric disorders such as anxiety and depression. The neural substrates of these associations are unknown. Human neuroimaging studies suggest modulation of the amygdala by 5-HTT variation, but this hypothesis is controversial and unresolved, and difficult to investigate further in humans. METHODS: We used a mouse model in which the 5-HTT is overexpressed throughout the brain and recorded hemodynamic responses (using a novel in vivo voltammetric monitoring method, analogous to blood oxygen level-dependent functional magnetic resonance imaging) and local field potentials during Pavlovian fear conditioning. RESULTS: Increased 5-HTT expression impaired, but did not prevent, fear learning and significantly reduced amygdala hemodynamic responses to aversive cues. Increased 5-HTT expression was also associated with reduced theta oscillations, which were a feature of aversive cue presentation in controls. Moreover, in control mice, but not those with high 5-HTT expression, there was a strong correlation between theta power and the amplitude of the hemodynamic response. CONCLUSIONS: Direct experimental manipulation of 5-HTT expression levels throughout the brain markedly altered fear learning, amygdala hemodynamic responses, and neuronal oscillations.

Genetic mouse models of depression.

This chapter focuses on the use of genetically modified mice in investigating the neurobiology of depressive behaviour. First, the behavioural tests commonly used as a model of depressive-like behaviour in rodents are described. These tests include those sensitive to antidepressant treatment such as the forced swim test and the tail suspension test, as well as other tests that encompass the wider symptomatology of a depressive episode. A selection of example mutant mouse lines is then presented to illustrate the use of these tests. As our understanding of depression increases, an expanding list of candidate genes is being investigated using mutant mice. Here, mice relevant to the monoamine and corticotrophin-releasing factor hypotheses of depression are covered as well as those relating to the more recent candidate, brain-derived neurotrophic factor. This selection provides interesting examples of the use of complimentary lines, such as those that have genetic removal or overexpression, and also opposing behavioural changes seen following manipulation of closely related genes. Finally, factors such as the issue of background strain and influence of environmental factors are reflected upon, before considering what can realistically be expected of a mouse model of this complex psychiatric disorder.

Opposing alterations in anxiety and species-typical behaviours in serotonin transporter overexpressor and knockout mice.

Human gene association studies have produced conflicting findings regarding the relationship between the 5-HT transporter (5-HTT) and anxiety. In the present study genetically modified mice were utilised to examine the effects of changes in 5-HTT expression on anxiety. In addition, the influence of 5-HTT expression on two innate "species-typical" behaviours (burrowing and marble burying) and body weight was explored. Across a range of models, 5-HTT overexpressing mice displayed reduced anxiety-like behaviour whilst 5-HTT knockout mice showed increased anxiety-like behaviour, compared to wildtype controls. In tests of species-typical behaviour 5-HTT overexpressing mice showed some facilitation whilst 5-HTT knockout mice were impaired. Reciprocal effects were also seen on body weight, as 5-HTT overexpressors were lighter and 5-HTT knockouts were heavier than wildtype controls. These findings show that variation in 5-HTT gene expression produces robust changes in anxiety and species-typical behaviour. Furthermore, the data add further support to findings that variation of 5-HTT expression in the human population is linked to changes in anxiety-related personality traits.

Hippocampal NMDA receptors and anxiety: at the interface between cognition and emotion.

David De Wied had a fundamental interest in the brain and behaviour, with a particular interest in the interface between cognition and emotion, and how impairments at this interface could underlie human psychopathology. The NMDA subtype of glutamate receptor is an important mediator of synaptic plasticity and plays a central role in the neurobiological mechanisms of emotionality, as well as learning and memory. NMDA receptor antagonists affect various aspects of emotionality including fear, anxiety and depression, as well as impairing certain forms of learning and memory. The hippocampus is a key brain structure, implicated in both cognition and emotion. Lesion studies in animals have suggested that dorsal and ventral sub-regions of the hippocampus are differentially involved in dissociable aspects of hippocampus-dependent behaviour. Cytotoxic lesions of the dorsal hippocampus (septal pole) in rodents impair spatial learning but have no effect on anxiety, whereas ventral hippocampal lesions reduce anxiety but are without effect on spatial memory. This role for the ventral hippocampus in anxiety is distinct from the role of the amygdala in other aspects of emotional processing, such as fear conditioning. Recent studies with genetically modified mice have shown that NR1 NMDA receptor subunit deletion, specifically from the granule cells of the dentate gyrus, not only impairs short-term spatial memory but also reduces anxiety. This suggests that NMDA receptors in ventral hippocampus may be a key locus supporting the anxiolytic effects of NMDA receptor antagonists. These data support Gray's neuropsychological account of hippocampal function.

Modeling brain reserve: experience-dependent neuronal plasticity in healthy and Huntington's disease transgenic mice.

OBJECTIVE: Experience-dependent modification of neuronal and synaptic connectivity may represent a mechanism of relevance to the theory of brain or cognitive reserve. The authors have investigated structural correlates of synaptic function and plasticity, through analysis of dendritic morphology after environmental enrichment, a paradigm for investigation of experience-dependent plasticity. DESIGN: Using a transgenic mouse model for Huntington's disease (HD), R6/1 and wild-type mice were exposed to either standard housing or environmental enrichment from 4 until 20 weeks of age. MEASUREMENTS: Golgi-stained neurons were analyzed for dendritic branching and spine density in the hippocampus, somatosensory, and motor cortices. RESULTS: Symptomatic R6/1 HD mice showed an absence of dendritic spine pathology, although there were region-specific decreases in dendritic diameter, branching, and complexity, as well as neuronal soma area. Furthermore, the authors demonstrate that environmental enrichment induces subtle, region-specific effects on dendritic morphology and spine density in wild-type control animals, but had less of an effect in HD mice, which has implications for our understanding of the cellular mechanisms mediating experience-dependent plasticity in HD. CONCLUSIONS: These results show that gross structural alterations are less likely to contribute to the cognitive, psychiatric, and motor symptoms in HD, and suggest that subtle molecular and functional changes may underlie HD symptomatology. Furthermore, the enrichment-induced effects on dendritic morphology may contribute to strengthening neuronal and synaptic connectivity, and provide a mechanism for how the brain may more efficiently use existing neuronal networks and recruit alternate networks when required. These findings not only have implications for HD, but the authors also propose that the concept of enrichment and cognitive reserve may be relevant to many brain disorders, including neurologic and psychiatric, where cognitive dysfunction is a part of symptomatology.

Gene-environment interactions modulating cognitive function and molecular correlates of synaptic plasticity in Huntington's disease transgenic mice.

Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by motor, cognitive and psychiatric symptoms. Here, we show that R6/1 (HD) mice have deficits in short-term hippocampal-dependent memory prior to onset of motor symptoms. HD mice also exhibit impaired performance on a test of long-term spatial memory, however, environmental enrichment enhanced spatial learning and significantly ameliorated this memory deficit in HD mice. Analysis of the presynaptic vesicle protein synaptophysin showed no differences between standard-housed wild-type and HD littermates, however, enrichment increased synaptophysin levels in the frontal cortex and hippocampus in both groups. In comparison, analysis of postsynaptic proteins revealed that HD animals show decreased levels of PSD-95 and GluR1, but no change in levels of gephyrin. Furthermore, at 12 weeks of age when we observe a beneficial effect of enrichment on spatial learning in HD mice, enrichment also delays the onset of a deficit in hippocampal PSD-95 levels. Our results show that cognitive deficits in HD mice can be ameliorated by environmental enrichment and suggest that changes in synaptic composition may contribute to the cognitive alterations observed.