Impact of Antipsychotic Drugs on Cortical Communication

Core Concepts

The author explores how antipsychotic drugs impact long-range cortical communication, specifically focusing on the role of layer 5 neurons in response to visuomotor integration.

Abstract

The content delves into the influence of antipsychotic drugs on cortical circuits, particularly in distinguishing between self-generated and externally driven activity patterns. Using mouse models and widefield calcium imaging, the study reveals that antipsychotic drugs disrupt visuomotor integration primarily in deep cortical layers. The findings suggest that these drugs alter long-range communication mediated by layer 5 neurons, potentially shedding light on their therapeutic mechanisms in treating psychosis. The experiments involved comparing responses to locomotion and visual flow feedback under different conditions, highlighting distinct activation patterns in deep cortical layers. Antipsychotic drugs like clozapine were found to significantly reduce correlations of layer 5 activity between cortical areas, impacting the spread of visuomotor prediction errors. These results indicate a selective alteration of long-range communication as a major functional effect of antipsychotic drugs. Furthermore, the study suggests that Tlx3 positive layer 5 intratelencephalic (IT) neurons play a crucial role in distinguishing closed and open loop visuomotor coupling. The research also points towards potential implications for understanding schizophrenia pathogenesis and treatment efficacy through alterations in cortical connectivity induced by antipsychotic medications.

Stats

Antipsychotic drugs like clozapine disrupted visuomotor integration at locomotion onsets primarily in deep cortical layers. Clozapine resulted in a strong reduction in correlations of layer 5 activity between cortical areas. Aripiprazole and haloperidol mimicked the decorrelation effects observed with clozapine. Amphetamine did not induce similar changes as seen with antipsychotic drugs.

Quotes

"The remarkable aspect of these findings is not that there are differences between closed and open loop locomotion onsets, particularly in visual regions of cortex one would perhaps expect to find differences, but that these differences are larger specifically in the deep cortical layers." "Given that L5 IT neurons exhibited opposing responses to positive and negative prediction errors, these responses would be consistent with those of internal representation neurons."

Key Insights Distilled From

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

by Heindorf,M.,... at www.biorxiv.org 01-31-2022

https://www.biorxiv.org/content/10.1101/2022.01.31.478462v4

Deeper Inquiries

What implications do the findings have for understanding schizophrenia pathogenesis beyond altered resting-state functional connectivity

The findings from the study provide valuable insights into schizophrenia pathogenesis beyond altered resting-state functional connectivity. The results suggest that antipsychotic drugs, specifically clozapine, aripiprazole, and haloperidol, have a significant impact on long-range cortical communication mediated by layer 5 intratelencephalic (IT) neurons. This alteration in communication could be a key factor in understanding the underlying mechanisms of schizophrenia. By disrupting visuomotor integration at locomotion onsets primarily in deep cortical layers, these drugs may target the misconfiguration of internal models and aberrant activation of internal representations seen in psychosis. Schizophrenia is characterized by hallucinations and delusions resulting from inaccurate predictions of sensory consequences of movements. The differential responses observed in Tlx3 positive L5 IT neurons to positive and negative prediction errors align with the concept of internal representation neurons being involved in processing such errors. Therefore, targeting these specific neuron types with antipsychotic drugs could potentially correct the disturbances in predictive processing that contribute to psychotic symptoms. Understanding how antipsychotics affect long-range cortical communication can shed light on how these medications alleviate symptoms associated with schizophrenia. It suggests that interventions aimed at modulating lateral coupling within cortex, particularly involving L5 IT neurons or similar neuron types, may hold promise for developing more targeted treatments for schizophrenia.

How might lateral coupling within cortex play a more dominant role than vertical coupling based on the study's results

The study's results indicate that lateral coupling within cortex may play a more dominant role than vertical coupling based on several key findings. Firstly, while deep cortical layers (specifically L5 IT neurons) exhibited differential activation patterns between closed and open loop conditions during locomotion onsets, superficial layers showed limited differences. This suggests that interactions within deep cortical layers are more sensitive to changes related to self-generated versus externally generated activity patterns. Secondly, antipsychotic drugs like clozapine significantly impacted long-range correlations between different regions across dorsal cortex but had minimal effects on local correlations within superficial layers like L2/3 or L4 excitatory neurons. This implies that alterations induced by these medications predominantly affect long-range communication mediated by L5 IT neurons rather than local interactions within superficial layers. Overall, these observations point towards a stronger influence of lateral connections among deep cortical layers compared to vertical connections between superficial and deep layers when it comes to processes like visuomotor integration and prediction error signaling implicated in conditions like psychosis.

Could exploring the effects of antipsychotics on other neuron types provide additional insights into their mechanisms of action

Exploring the effects of antipsychotics on other neuron types could offer additional insights into their mechanisms of action beyond those observed in Tlx3 positive L5 IT neurons. Excitatory Neurons: Investigating how antipsychotics impact other subtypes of excitatory neurons such as those found in upper cortical layers (L2/3) or specific subsets like Scnn1a-Cre-expressing cells could reveal whether the observed alterations are unique to certain neuronal populations or if they have broader implications across different excitatory cell types. Inhibitory Neurons: Studying inhibitory neuron populations targeted by PV-Cre-, VIP-Cre-, and SST-Cre lines might provide information about how antipsychotics influence inhibitory circuits within cortex. Understanding changes in inhibition levels due to medication could elucidate their role in regulating network dynamics relevant to psychiatric disorders. By examining diverse neuronal subtypes' responses to antipsychotic drugs alongside their effects on long-range communication patterns similar to what was observed with Tlx3-positive L5 IT cells will help create a comprehensive picture of how these medications modulate neural activity throughout various circuits involved in cognitive processes linked with mental health conditions like schizophrenia