What causes aberrant salience in schizophrenia? A role for impaired short-term habituation and the GRIA1 (GluA1) AMPA receptor subunit.

The GRIA1 locus, encoding the GluA1 (also known as GluRA or GluR1) AMPA glutamate receptor subunit, shows genome-wide association to schizophrenia. As well as extending the evidence that glutamatergic abnormalities have a key role in the disorder, this finding draws attention to the behavioural phenotype of Gria1 knockout mice. These mice show deficits in short-term habituation. Importantly, under some conditions the attention being paid to a recently presented neutral stimulus can actually increase rather than decrease (sensitization). We propose that this mouse phenotype represents a cause of aberrant salience and, in turn, that aberrant salience (and the resulting positive symptoms) in schizophrenia may arise, at least in part, from a glutamatergic genetic predisposition and a deficit in short-term habituation. This proposal links an established risk gene with a psychological process central to psychosis and is supported by findings of comparable deficits in short-term habituation in mice lacking the NMDAR receptor subunit Grin2a (which also shows association to schizophrenia). As aberrant salience is primarily a dopaminergic phenomenon, the model supports the view that the dopaminergic abnormalities can be downstream of a glutamatergic aetiology. Finally, we suggest that, as illustrated here, the real value of genetically modified mice is not as ‘models of schizophrenia’ but as experimental tools that can link genomic discoveries with psychological processes and help elucidate the underlying neural mechanisms

Dissociations within short-term memory in GluA1 AMPA receptor subunit knockout mice

GluA1 AMPA receptor subunit knockout mice display a selective impairment on short-term recognition memory tasks. In this study we tested whether GluA1 is important for short-term memory that is necessary for bridging the discontiguity between cues in trace conditioning. GluA1 knockout mice were not impaired at using short-term memory traces of T-maze floor inserts, made of different materials, to bridge the temporal gap between conditioned stimuli and reinforcement during appetitive discrimination tasks. Thus, different aspects of short-term memory are differentially sensitive to GluA1 deletion. This dissociation may reflect processing of qualitatively different short-term memory traces. Memory that results in performance of short-term recognition (e.g. for objects or places) may be different from the memory required for associative learning in trace conditioning

BDNF-TrkB signaling in striatopallidal neurons controls inhibition of locomotor behaviour

The physiology of brain-derived neurotrophic factor signaling in enkephalinergic striatopallidal neurons is poorly understood. Changes in cortical Bdnf expression levels, and/or impairment in brain-derived neurotrophic factor anterograde transport induced by mutant huntingtin (mHdh) are believed to cause striatopallidal neuron vulnerability in early-stage Huntington’s disease. Although several studies have confirmed a link between altered cortical brain-derived neurotrophic factor signaling and striatal vulnerability, it is not known whether the effects are mediated via the brain-derived neurotrophic factor receptor TrkB, and whether they are direct or indirect. Using a novel genetic mouse model, here, we show that selective removal of brain-derived neurotrophic factor–TrkB signaling from enkephalinergic striatal targets unexpectedly leads to spontaneous and drug-induced hyperlocomotion. This is associated with dopamine D2 receptor-dependent increased striatal protein kinase C and MAP kinase activation, resulting in altered intrinsic activation of striatal enkephalinergic neurons. Therefore, brain-derived neurotrophic factor/TrkB signaling in striatopallidal neurons controls inhibition of locomotor behavior by modulating neuronal activity in response to excitatory input through the protein kinase C/MAP kinase pathway

Close temporal coupling of neuronal activity and tissue oxygen responses in rodent whisker barrel cortex

Neuronal activity elicits metabolic and vascular responses, during which oxygen is first consumed and then supplied to the tissue via an increase in cerebral blood flow. Understanding the spatial and temporal dynamics of blood and tissue oxygen (To(2)) responses following neuronal activity is crucial for understanding the physiological basis of functional neuroimaging signals. However, our knowledge is limited because previous To(2) measurements have been made at low temporal resolution (>100 ms). Here we recorded To(2) at high temporal resolution (1 ms), simultaneously with co-localized field potentials, at several cortical depths from the whisker region of the somatosensory cortex in anaesthetized rats and mice. Stimulation of the whiskers produced rapid, laminar-specific changes in To(2). Positive To(2) responses (i.e. increases) were observed in the superficial layers within 50 ms of stimulus onset, faster than previously reported. Negative To(2) responses (i.e. decreases) were observed in the deeper layers, with maximal amplitude in layer IV, within 40 ms of stimulus onset. The amplitude of the negative, but not the positive, To(2) response correlated with local field potential amplitude. Disruption of neurovascular coupling, via nitric oxide synthase inhibition, abolished positive To(2) responses to whisker stimulation in the superficial layers and increased negative To(2) responses in all layers. Our data show that To(2) responses occur rapidly following neuronal activity and are laminar dependent

Worsening cognitive impairment and neurodegenerative pathology progressively increase risk for delirium

Background: Delirium is a profound neuropsychiatric disturbance precipitated by acute illness. Although dementia is the major risk factor this has typically been considered a binary quantity (i.e., cognitively impaired versus cognitively normal) with respect to delirium risk. We used humans and mice to address the hypothesis that the severity of underlying neurodegenerative changes and/or cognitive impairment progressively alters delirium risk. Methods: Humans in a population-based longitudinal study, Vantaa 85+, were followed for incident delirium. Odds for reporting delirium at follow-up (outcome) were modeled using random-effects logistic regression, where prior cognitive impairment measured by Mini-Mental State Exam (MMSE) (exposure) was considered. To address whether underlying neurodegenerative pathology increased susceptibility to acute cognitive change, mice at three stages of neurodegenerative disease progression (ME7 model of neurodegeneration: controls, 12 weeks, and 16 weeks) were assessed for acute cognitive dysfunction upon systemic inflammation induced by bacterial lipopolysaccharide (LPS; 100 μg/kg). Synaptic and axonal correlates of susceptibility to acute dysfunction were assessed using immunohistochemistry. Results: In the Vantaa cohort, 465 persons (88.4 ± 2.8 years) completed MMSE at baseline. For every MMSE point lost, risk of incident delirium increased by 5% (p = 0.02). LPS precipitated severe and fluctuating cognitive deficits in 16-week ME7 mice but lower incidence or no deficits in 12-week ME7 and controls, respectively. This was associated with progressive thalamic synaptic loss and axonal pathology. Conclusions: A human population-based cohort with graded severity of existing cognitive impairment and a mouse model with progressing neurodegeneration both indicate that the risk of delirium increases with greater severity of pre-existing cognitive impairment and neuropathology

Attentive Learning of Sequential Handwriting Movements: A Neural Network Model

Defense Advanced research Projects Agency and the Office of Naval Research (N00014-95-1-0409, N00014-92-J-1309); National Science Foundation (IRI-97-20333); National Institutes of Health (I-R29-DC02952-01)

Super-smart mice: Surprised or Surprising?: Theoretical comment on Singer, Boison, Möhler, Feldon and Yee.

The glycine transporter (GlyT1) regulates levels of the neurotransmitter glycine, a coagonist of the N-methyl-D-aspartate receptor (NMDAR), and as such may represent a novel site for developing cognition-enhancing drugs. Genetically modified mice with reduced levels of GlyT1 have been generated to test this hypothesis. P. Singer, D. Boison, H. Möhler, J. Feldon, and B. K. Yee now show, through a spontaneous exploration task, that mice in which GlyT1 has been deleted, specifically in neurons in the forebrain, demonstrate enhanced object recognition memory. Whereas both control and mutant mice show a preference for a novel object over a familiar object 2 min after the initial presentation of 1 of the objects, only the mutant mice show a preference for the novel object when tested after a 2-hr delay. The longer-lasting habituation displayed by the GlyT1 mice is consistent with a role for glycine/NMDAR-dependent synaptic plasticity in supporting a nonassociative, short-term memory trace of a recently experienced stimulus. This short-term habituation process may be independent of associative learning mechanisms and may be best described by A. R. Wagner's (1981) sometimes opponent process model.

Competitive short-term and long-term memory processes in spatial habituation

Exposure to a spatial location leads to habituation of exploration such that, in a novelty preference test, rodents subsequently prefer exploring a novel location to the familiar location. According to Wagner's (1981) theory of memory, short-term and long-term habituation are caused by separate and sometimes opponent processes. In the present study, this dual-process account of memory was tested. Mice received a series of exposure training trials to a location before receiving a novelty preference test. The novelty preference was greater when tested after a short, rather than a long, interval. In contrast, the novelty preference was weaker when exposure training trials were separated by a short, rather than a long interval. Furthermore, it was found that long-term habituation was determined by the independent effects of the amount of exposure training and the number of exposure training trials when factors such as the intertrial interval and the cumulative intertrial interval were controlled. A final experiment demonstrated that a long-term reduction of exploration could be caused by a negative priming effect due to associations formed during exploration. These results provide evidence against a single-process account of habituation and suggest that spatial habituation is determined by both short-term, recency-based memory and long-term, incrementally strengthened memory

The effect of US signalling and the US–CS interval on backward conditioning in mice

The effect of US signalling and the US–CS interval in backward conditioning was assessed in mice. For one group of mice the presentation of food was signalled by a tone and for another group, food was unsignalled. For half of the mice, within each group, the presentation of food preceded a visual cue by 10 s. For the other half, food was presented at the start of the visual cue (0-s US–CS interval), resulting in simultaneous pairings of these events. A summation test and a subsequent retardation test were used to assess the inhibitory effects of backward conditioning in comparison to training with a non-reinforced visual cue that controlled for the possible effects of latent inhibition and conditioned inhibition caused as a consequence of differential conditioning. In the summation test unsignalled presentations of the US resulted in inhibition when the US–CS interval was 10 s, but not 0 s. Signalled presentations of the US resulted in inhibition, independent of the US–CS interval. In the retardation test, independent of US signalling, a US–CS interval of 10 s failed to result in inhibition, but an interval of 0 s resulted in greater conditioned responding to the backward CS than the control CS. A generalisation decrement account of the effect of signalling the US with a 0-s US–CS interval, which resulted in reduced responding in the summation test and faster acquisition in the retardation test, is discussed