Antipsychotic drugs selectively decorrelate long-range interactions in deep cortical layers

Abstract

Psychosis is characterized by a diminished ability of the brain to distinguish externally driven activity patterns from self-generated activity patterns. Antipsychotic drugs are a class of small molecules with relatively broad binding affinity for a variety of neuromodulator receptors that, in humans, can prevent or ameliorate psychosis. How these drugs influence the function of cortical circuits and in particular their ability to identify self-generated activity patterns is still largely unclear. Here we used widefield calcium imaging to determine the cell type specific functional effects of antipsychotic drugs in mouse dorsal cortex during visuomotor integration. By comparing cell type specific activation patterns between locomotion onsets that were experimentally coupled to self-generated visual feedback and locomotion onsets that were not coupled, we show that deep cortical layers were differentially activated in these two conditions. We then show that the antipsychotic drug clozapine disrupted visuomotor integration at locomotion onsets also primarily in deep cortical layers. Given that one of the key components of visuomotor integration in cortex are long-range cortico-cortical connections, we tested whether the effect of clozapine was detectable in the correlation structure of activity patterns across dorsal cortex. We found that clozapine, as well as two other antipsychotic drugs, aripiprazole and haloperidol, resulted in a strong reduction in correlations of layer 5 activity between cortical areas and impaired the spread of visuomotor prediction errors generated in visual cortex. Our results are consistent with the interpretation that a major functional effect of antipsychotic drugs is an alteration of the activation of internal representations as a consequence of reduced long-range layer 5 mediated communication.

Wide-field calcium imaging of cortical activation and functional connectivity in externally- and internally-driven locomotion

“…Here, we confirm our previous findings 6 that locomotion exhibits a widespread decrease in cortical FC compared to rest, even though neural activity in these areas increases [12][13][14][15] . The exception to this global FC decrease is the increase in correlation of M2 nodes with nodes across the cortex, beginning at locomotion onset and persisting until locomotion offset.…”

Neocortical layer 5 subclasses: From cellular properties to roles in behavior

“…It seems that IT neurons are strongly engaged in preparatory stages of various tasks as they are more active in sensory regions during sensory sampling phases ( Musall et al, 2021 ; Mohan et al, 2022 ). This trend is consistent in other areas such as mPFC where they retain goal specific responses prior to action initiation ( Bae et al, 2021 ) and preparatory movement activities in motor structures ( Currie et al, 2021 ; Heindorf and Keller, 2022 ). Inhibiting the IT neurons during sampling periods only weakly affects the behavioral outcome, suggesting a minor role in regulating behavioral output.…”

“…In recent years, there has been a surge of evidence of the distinct functional roles of IT and ET neurons in cognitive behavior ( Li et al, 2015 ; Takahashi et al, 2020 ; Bae et al, 2021 ; Currie et al, 2021 ; Musall et al, 2021 ; Heindorf and Keller, 2022 ; Mohan et al, 2022 ; Park et al, 2022 ). With recent development of combining whole-brain imaging with newly developed mouse lines, it is now possible to record brain-wide activity of IT neurons (including both L5 and L2/3 IT neurons) and L5 ET neurons.…”

Prediction error neurons in mouse cortex are molecularly targetable cell types

“…Interestingly, we find that the third type of excitatory L2/3 neuron, the L2/3 Agmat cell type, does not exhibit responses consistent with visuomotor prediction errors. One possibility is that this population functions to maintain an internal representation, by integrating over negative prediction error and positive prediction error responses, a function that is typically speculated to be performed by L5 neurons (Heindorf and Keller, 2022). Another possibility is that these neurons compute prediction errors that are not visuomotor.…”