Abstract
Conceptual and computational models have been advanced that propose that perceptual disturbances in psychosis, such as hallucinations, may arise due to a disruption in the balance between bottom-up (ie sensory) and top-down (ie from higher brain areas) information streams in sensory cortex. However, the neural activity underlying this hypothesized alteration remains largely unexplored. Pharmacological N-methyl-d-aspartate receptor (NMDAR) antagonism presents an attractive model to examine potential changes as it acutely recapitulates many of the symptoms of schizophrenia including hallucinations, and NMDAR hypofunction is strongly implicated in the pathogenesis of schizophrenia as evidenced by large-scale genetic studies. Here we use in vivo 2-photon imaging to measure frontal top-down signals from the anterior cingulate cortex (ACC) and their influence on activity of the primary visual cortex (V1) in mice during pharmacologically induced NMDAR hypofunction. We find that global NMDAR hypofunction causes a significant increase in activation of top-down ACC axons, and that surprisingly this is associated with an ACC-dependent net suppression of spontaneous activity in V1 as well as a reduction in V1 sensory-evoked activity. These findings are consistent with a model in which perceptual disturbances in psychosis are caused in part by aberrant top-down frontal cortex activity that suppresses the transmission of sensory signals through early sensory areas.
Highlights
Schizophrenia is a neuropsychiatric disease characterized by psychotic symptoms including hallucinations; the specific disturbances in neural activity that underpin these perceptual abnormalities are unclear
To investigate the effects of global N-methyl-d-aspartate receptor (NMDAR) hypofunction on top-down anterior cingulate cortex (ACC)→V1 signals, we used in vivo calcium imaging in awake mice to record from ACC axon terminals in V1
In contrast to our observations of ACC axons, and in vivo reports from prefrontal cortex (PFC),[10,30] we found that NMDAR block reduced spontaneous activity in V1 by approximately 35%, whereas no significant effect was observed after saline treatment (Kruskal–Wallis test: P < 10–9; figures 2B and C; see Supplementary Figure S1-1B for analysis of moving periods)
Summary
Schizophrenia is a neuropsychiatric disease characterized by psychotic symptoms including hallucinations (false perceptions); the specific disturbances in neural activity that underpin these perceptual abnormalities are unclear. A number of computational theories based around predictive processing have been advanced, which propose that perceptual disturbances may arise due to a disruption in the balance between bottom-up (ie sensory) and top-down (ie from higher brain areas) information streams in sensory cortex. This imbalance could result in inappropriate or false inference because of an abnormal balance in perceptual processing between top-down signals and sensory evidence.[1,2,3,4,5,6,7]. Alterations in the influence of top-down predictive signals could result both from changes in activity in higher cortical regions providing descending signals and/or from alterations in local circuitry (such as shifts in excitatory/inhibitory balance) in lower brain regions in which comparisons between predictions and bottom-up signals are performed and prediction errors are encoded.[5,6,7] At present, there remains little direct evidence of changes in psychosis of activity of neurons providing top-down signals to sensory cortex, or understanding of the influence this may have on sensory cortex activity
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