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  • Unilateral medial frontal cortex lesions cause a cognitive decision-making deficit in rats.

    29 December 2017

    The medial frontal cortex (MFC) is critical for cost-benefit decision-making. Generally, cognitive and reward-based behaviour in rodents is not thought to be lateralised within the brain. In this study, however, we demonstrate that rats with unilateral MFC lesions show a profound change in decision-making on an effort-based decision-making task. Furthermore, unilateral MFC lesions have a greater effect when the rat has to choose to put in more effort for a higher reward when it is on the contralateral side of space to the lesion. Importantly, this could not be explained by motor impairments as these animals did not show a turning bias in separate experiments. In contrast, rats with unilateral dopaminergic midbrain lesions did exhibit a motoric turning bias, but were unimpaired on the effort-based decision-making task. This rare example of a cognitive deficit caused by a unilateral cortical lesion in the rat brain indicates that the MFC may have a specialised and lateralised role in evaluating the costs and benefits of actions directed to specific spatial locations.

  • Alterations in spatial memory and anxiety in the MAM E17 rat model of hippocampal pathology in schizophrenia.

    6 February 2018

    Adult rats exposed to methylazoxymethanol acetate (MAM) at embryonic day 17 (E17) display robust pathological alterations in the hippocampus. However, discrepancies exist in the literature regarding the behavioural effects of this pre-natal manipulation. Therefore, a systematic assessment of MAM E17-induced behavioural alterations was conducted using a battery of dorsal and ventral hippocampus-dependent tests. Compared to saline controls, MAM E17-treated rats displayed deficits in spatial reference memory in both the aversive hidden platform watermaze task and an appetitive Y-maze task. Deficits in the spatial reference memory watermaze task were replicated across three different cohorts and two laboratories. In contrast, there was little, or no, effect on the non-spatial, visible platform watermaze task or an appetitive, non-spatial, visual discrimination task, respectively. MAM rats were also impaired in the spatial novelty preference task which assesses short-term memory, and displayed reduced anxiety levels in the elevated plus maze task. Thus, MAM E17 administration resulted in abnormal spatial information processing and reduced anxiety in a number of hippocampus-dependent behavioural tests, paralleling the effects of dorsal and ventral hippocampal lesions, respectively. These findings corroborate recent pathological and physiological studies, further highlighting the usefulness of MAM E17 as a model of hippocampal dysfunction in at least some aspects of schizophrenia.

  • The effect of US signalling and the US-CS interval on backward conditioning in mice.

    15 December 2017

    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.

  • Hippocampal circuit dysfunction in the Tc1 mouse model of Down syndrome.

    14 February 2018

    Hippocampal pathology is likely to contribute to cognitive disability in Down syndrome, yet the neural network basis of this pathology and its contributions to different facets of cognitive impairment remain unclear. Here we report dysfunctional connectivity between dentate gyrus and CA3 networks in the transchromosomic Tc1 mouse model of Down syndrome, demonstrating that ultrastructural abnormalities and impaired short-term plasticity at dentate gyrus-CA3 excitatory synapses culminate in impaired coding of new spatial information in CA3 and CA1 and disrupted behavior in vivo. These results highlight the vulnerability of dentate gyrus-CA3 networks to aberrant human chromosome 21 gene expression and delineate hippocampal circuit abnormalities likely to contribute to distinct cognitive phenotypes in Down syndrome.

  • Hippocampal acetylcholine depletion has no effect on anxiety, spatial novelty preference, or differential reward for low rates of responding (DRL) performance in rats.

    9 February 2018

    We investigated the role of the septo-hippocampal cholinergic projection in anxiety, spatial novelty preference, and differential reward for low rates of responding (DRL) performance. Cholinergic neurons of the rat medial septum (MS) and the vertical limb of the diagonal band of Broca (VDB) were lesioned using the selective immunotoxin, 192 IgG-saporin. Rats were then tested on several behavioral tests previously shown to be sensitive to either (a) hippocampal lesions or (b) nonselective MS/VDB lesions which target both cholinergic and γ-aminobutyric acid (GABA)-ergic projections, or both. Saporin lesions substantially reduced hippocampal cholinergic innervation, resulting in an absence of acetyl cholinesterase staining and markedly reduced choline acetyltransferase activity (mean reduction: 80 ± 5%; range: 50-97%). However, the saporin-lesioned rats did not differ from control rats in any of the behavioral tests. Thus we found no evidence from these lesion studies that the septo-hippocampal cholinergic projection plays an essential role in anxiety, spatial novelty preference, or DRL.

  • SERT and uncertainty: serotonin transporter expression influences information processing biases for ambiguous aversive cues in mice.

    9 January 2018

    The long allele variant of the serotonin transporter (SERT, 5-HTT) gene-linked polymorphic region (5-HTTLPR) is associated with higher levels of 5-HTT expression and reduced risk of developing affective disorders. However, little is known about the mechanisms underlying this protective effect. One hypothesis is that 5-HTT expression influences aversive information processing, with reduced negative cognitive bias present in those with higher 5-HTT expression. Here we investigated this hypothesis using genetically-modified mice and a novel aversive learning paradigm. Mice with high levels of 5-HTT expression (5-HTT over-expressing, 5-HTTOE mice) and wild-type mice were trained to discriminate between three distinct auditory cues: one cue predicted footshock on all trials (CS+); a second cue predicted the absence of footshock (CS-); and a third cue predicted footshock on 20% of trials (CS20%), and was therefore ambiguous. Wild-type mice exhibited equivalently high levels of fear to the CS+ and CS20% and minimal fear to the CS-. In contrast, 5-HTTOE mice exhibited high levels of fear to the CS+ but minimal fear to the CS- and the CS20%. This selective reduction in fear to ambiguous aversive cues suggests that increased 5-HTT expression reduces negative cognitive bias for stimuli with uncertain outcomes.

  • Worsening cognitive impairment and neurodegenerative pathology progressively increase risk for delirium.

    28 January 2018

    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. CONCLUSION: 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.

  • Prebiotic administration normalizes lipopolysaccharide (LPS)-induced anxiety and cortical 5-HT2A receptor and IL1-β levels in male mice.

    15 February 2018

    The manipulation of the enteric microbiota with specific prebiotics and probiotics, has been shown to reduce the host's inflammatory response, alter brain chemistry, and modulate anxiety behaviour in both rodents and humans. However, the neuro-immune and behavioural effects of prebiotics on sickness behaviour have not been explored. Here, adult male CD1 mice were fed with a specific mix of non-digestible galacto-oligosaccharides (Bimuno®, BGOS) for 3 weeks, before receiving a single injection of lipopolysaccharide (LPS), which induces sickness behaviour and anxiety. Locomotor and marble burying activities were assessed 4h after LPS injection, and after 24h, anxiety in the light-dark box was assessed. Cytokine expression, and key components of the serotonergic (5-Hydroxytryptamine, 5-HT) and glutamatergic system were evaluated in the frontal cortex to determine the impact of BGOS administration at a molecular level. BGOS-fed mice were less anxious in the light-dark box compared to controls 24h after the LPS injection. Elevated cortical IL-1β concentrations in control mice 28 h after LPS were not observed in BGOS-fed animals. This significant BGOS×LPS interaction was also observed for 5HT2A receptors, but not for 5HT1A receptors, 5HT, 5HIAA, NMDA receptor subunits, or other cytokines. The intake of BGOS did not influence LPS-mediated reductions in marble burying behaviour, and its effect on locomotor activity was equivocal. Together, our data show that the prebiotic BGOS has an anxiolytic effect, which may be related to the modulation of cortical IL-1β and 5-HT2A receptor expression. Our data suggest a potential role for prebiotics in the treatment of neuropsychiatric disorders where anxiety and neuroinflammation are prominent clinical features.

  • Left-right dissociation of hippocampal memory processes in mice.

    16 February 2018

    Left-right asymmetries have likely evolved to make optimal use of bilaterian nervous systems; however, little is known about the synaptic and circuit mechanisms that support divergence of function between equivalent structures in each hemisphere. Here we examined whether lateralized hippocampal memory processing is present in mice, where hemispheric asymmetry at the CA3-CA1 pyramidal neuron synapse has recently been demonstrated, with different spine morphology, glutamate receptor content, and synaptic plasticity, depending on whether afferents originate in the left or right CA3. To address this question, we used optogenetics to acutely silence CA3 pyramidal neurons in either the left or right dorsal hippocampus while mice performed hippocampus-dependent memory tasks. We found that unilateral silencing of either the left or right CA3 was sufficient to impair short-term memory. However, a striking asymmetry emerged in long-term memory, wherein only left CA3 silencing impaired performance on an associative spatial long-term memory task, whereas right CA3 silencing had no effect. To explore whether synaptic properties intrinsic to the hippocampus might contribute to this left-right behavioral asymmetry, we investigated the expression of hippocampal long-term potentiation. Following the induction of long-term potentiation by high-frequency electrical stimulation, synapses between CA3 and CA1 pyramidal neurons were strengthened only when presynaptic input originated in the left CA3, confirming an asymmetry in synaptic properties. The dissociation of hippocampal long-term memory function between hemispheres suggests that memory is routed via distinct left-right pathways within the mouse hippocampus, and provides a promising approach to help elucidate the synaptic basis of long-term memory.