# CRCNS: A mechanistic theory of serotonergic modulation of cortical processing

> **NIH NIH R01** · UNIVERSITY OF OREGON · 2021 · $318,135

## Abstract

Serotonergic neuromodulation is a crucial factor in regulating several aspects of brain function, from
mood disorders to appetite, reward and motivation, and in maintaining balance of sensory perception.
However, the network mechanisms by which it modulates brain dynamics are elusive. In this project,
we will develop and experimentally test a mechanistic theory explaining the observed modulations of
cortical activity induced by the serotonergic activation via hallucinogenic agonists. Existing evidence
paints an apparently contradictory picture, where a hallucinogenic HT2AR agonist increases pyramidal
cells’ excitability and glutamatergic levels while, at the same time, leading to a reduction in visually
evoked responses. Our central hypothesis is that these puzzling effects of serotonergic activation are
due to gain modulation induced in visual cortex (V1) circuits. The proposed mechanism is
counterintuitive as it leads to decreased evoked responses by way of increasing pyramidal cell
excitability, due to a counterintuitive effect produced by strong recurrent dynamics in cortical circuits; it
also leads to increased variability of network activity, and changes in brain-wide connectivity. By
expanding the repertoire of cortical states, it may explain the onset of hallucinations driven by
serotonergic activation. We will show how this mechanistic theory can reconcile the tension in the
literature and we will design and perform new experiments to test the model predictions in behaving
animals. Together, this project provides a link between cellular-level neuromodulation and the impact
on network dynamics and, ultimately, sensory perception.

## Key facts

- **NIH application ID:** 10396147
- **Project number:** 1R01DA055439-01
- **Recipient organization:** UNIVERSITY OF OREGON
- **Principal Investigator:** Luca Mazzucato
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $318,135
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10396147

## Citation

> US National Institutes of Health, RePORTER application 10396147, CRCNS: A mechanistic theory of serotonergic modulation of cortical processing (1R01DA055439-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10396147. Licensed CC0.

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