In the research domain framework (RDoC), dysfunctional reward expectation has been proposed to be a cross-diagnostic domain in psychiatry, which may contribute to symptoms common to various neuropsychiatric conditions, such as anhedonia or apathy/avolition. We used a modified version of the Monetary Incentive Delay (MID) paradigm to obtain functional MRI images from 22 patients with schizophrenia, 24 with depression and 21 controls. Anhedonia and other symptoms of depression, and overall positive and negative symptomatology were also measured. We hypothesized that the two clinical groups would have a reduced activity in the ventral striatum when anticipating reward (compared to anticipation of a neutral outcome) and that striatal activation would correlate with clinical measures of motivational problems and anhedonia. Results were consistent with the first hypothesis: two clusters in both the left and right ventral striatum were found to differ between the groups in reward anticipation. Post-hoc analysis showed that this was due to higher activation in the controls compared to the schizophrenia and the depression groups in the right ventral striatum, with activation differences between depression and controls also seen in the left ventral striatum. No differences were found between the two patient groups, and there were no areas of abnormal cortical activation in either group that survived correction for multiple comparisons. Reduced ventral striatal activity was related to greater anhedonia and overall depressive symptoms in the schizophrenia group, but not in the participants with depression. Findings are discussed in relation to previous literature but overall are supporting evidence of reward system dysfunction across the neuropsychiatric continuum, even if the specific clinical relevance is still not fully understood. We also discuss how the RDoC approach may help to solve some of the replication problems in psychiatric fMRI research.

Amyloid-β (Aβ) is a prime suspect for causing cognitive deficits during the early phases of Alzheimer’s disease (AD). Experiments in AD mouse models have shown that soluble oligomeric clusters of Aβ degrade synapses and impair memory formation. We show that all Aβ-driven effects measured in these mice depend on AMPA receptor (AMPAR) subunit GluA3. Hippocampal neurons that lack GluA3 were resistant against Aβ-mediated synaptic depression and spine loss. In addition, Aβ oligomers blocked long-term synaptic potentiation only in neurons that expressed GluA3. Furthermore, although Aβ-overproducing mice showed significant memory impairment, memories in GluA3-deficient congenics remained unaffected. These experiments indicate that the presence of GluA3-containing AMPARs is critical for Aβ-mediated synaptic and cognitive deficits.

Alterations in reward processes may underlie motivational and anhedonic symptoms in depression and schizophrenia. However it remains unclear whether these alterations are disorder-specific or shared, and whether they clearly relate to symptom generation or not. We studied brain responses to unexpected rewards during a simulated slot-machine game in 24 patients with depression, 21 patients with schizophrenia, and 21 healthy controls using functional magnetic resonance imaging. We investigated relationships between brain activation, task-related motivation, and questionnaire rated anhedonia. There was reduced activation in the orbitofrontal cortex, ventral striatum, inferior temporal gyrus, and occipital cortex in both depression and schizophrenia in comparison with healthy participants during receipt of unexpected reward. In the medial prefrontal cortex both patient groups showed reduced activation, with activation significantly more abnormal in schizophrenia than depression. Anterior cingulate and medial frontal cortical activation predicted task-related motivation, which in turn predicted anhedonia severity in schizophrenia. Our findings provide evidence for overlapping hypofunction in ventral striatal and orbitofrontal regions in depression and schizophrenia during unexpected reward receipt, and for a relationship between unexpected reward processing in the medial prefrontal cortex and the generation of motivational states.

Excitatory synaptic transmission is mediated by AMPA-type glutamate receptors (AMPARs). In CA1 pyramidal neurons of the hippocampus two types of AMPARs predominate: those that contain subunits GluA1 and GluA2 (GluA1/2), and those that contain GluA2 and GluA3 (GluA2/3). Whereas subunits GluA1 and GluA2 have been extensively studied, the contribution of GluA3 to synapse physiology has remained unclear. Here we show in mice that GluA2/3s are in a low-conductance state under basal conditions, and although present at synapses they contribute little to synaptic currents. When intracellular cyclic AMP (cAMP) levels rise, GluA2/3 channels shift to a high-conductance state, leading to synaptic potentiation. This cAMP-driven synaptic potentiation requires the activation of both protein kinase A (PKA) and the GTPase Ras, and is induced upon the activation of β-adrenergic receptors. Together, these experiments reveal a novel type of plasticity at CA1 hippocampal synapses that is expressed by the activation of GluA3-containing AMPARs.

Neurexin-1 alpha (NRXN1α) belongs to the family of cell adhesion molecules (CAMs), which are involved in the formation of neuronal networks and synapses. NRXN1α gene mutations have been identified in neuropsychiatric diseases including Schizophrenia (SCZ) and Autism Spectrum Disorder (ASD). In order to get a better understanding of the pleiotropic behavioral manifestations caused by NRXN1α gene mutations, we performed a behavioral study of Nrxn1α heterozygous knock-out (+/−) mice and observed increased responsiveness to novelty and accelerated habituation to novel environments compared to wild type (+/+) litter-mates. However, this effect was mainly observed in male mice, strongly suggesting that gender-specific mechanisms play an important role in Nrxn1α-induced phenotypes.

Normal anxiety is an adaptive emotional response. However, when anxiety appears to lack adaptive value, it might be defined as pathological. Adaptation in animals can be assessed for example by changes in behavioural responses over time, i.e. habituation. We hypothesize that non-adaptive anxiety might be reflected by impaired habituation. To test our hypothesis, we repeatedly exposed male mice from two inbred strains to a novel environment, the modified hole board. BALB/cJ mice were found to be initially highly anxious, but subsequently habituated to the test environment. In contrast, 129P3/J mice initially showed less anxiety-related behaviour compared with the BALB/cJ mice but no habituation in anxiety-related behaviour was observed. Notably, anxiety-related behaviour even increased during the experimental period. Complementary, 129P3/J mice did not show habituation in other parameters such as locomotor and exploratory activity, whereas significant changes appeared in these behaviours in BALB/c mice. Finally, the expression of the immediate early gene c-fos differed between the two strains in distinct brain areas, known to regulate the integration of emotional and cognitive processes. These results suggest that 129P3/J mice might be a promising (neuro)-behavioural animal model for non-adaptive, i.e. pathological anxiety.

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