# Claustral Control of Cortical Networks by Serotonin

> **NIH NIH F31** · UNIVERSITY OF MARYLAND BALTIMORE · 2022 · $39,040

## Abstract

Project Summary
Cognitive flexibility deficits are a major contributor to diminished life and therapeutic outcomes across myriad
neuropsychiatric disorders including Alzheimer’s, depression, and schizophrenia. The classical psychedelic,
psilocybin, induces long-lasting improvement of cognitive flexibility, but widespread use is infeasible due to
legislative restrictions and undesirable non-therapeutic effects. Ideally, the therapeutic pro-cognitive effects of
psychedelics could be dissociated from the psychedelic trip, though this requires investigation as to the
mechanisms of psychedelic cognitive effects. Cognition, and cognitive flexibility, is achieved through cortical
networks: frontal cortically-directed coactivated cortical regions that engage in cooperative processing to meet
cognitive demands. Understanding how psychedelics impact neural circuits underlying cortical network
regulation is necessary for the development of therapeutics that reproduce the pro-cognitive psychedelic effect.
The claustrum, a subcortical nucleus, connects frontal cortical and parietal cortical network nodes via “cortico-
claustro-cortical circuits”, is required for optimal task performance in cognitively demanding tasks over
nondemanding tasks, and is activated at the emergence of a task-positive cortical networks in response to a
difficult cognitive task. The claustrum expresses serotonin receptors targeted by psilocin, the active metabolite
of psilocybin (5-HTR2a,1d, and 1b) and claustrum deactivation during psilocybin administration is associated
with psilocybin-mediated cortical network dysfunction. As such the claustrum represents a prime target for
investigation of the cognitive effects of psychedelics. Our preliminary data in mice leads to our hypothesis that
serotonin signaling acutely suppresses cortico-claustro-cortical circuits by: suppression of frontal cortical input
to claustrum (Aim 1), increased local inhibition of claustrum projection neurons (Aim 2), and decreasing
excitability of claustrum projection neurons (Aim 3). To test this novel hypothesis, I will determine the receptor
responsible for each serotonin mediated neuromodulatory effect, confirm that the effect is also recruited by the
psylocibin metabolite psilocin, and assess corresponding changes to the cortico-claustro-cortical circuit strength
for each Aim/neuromodulatory effect. This will be performed using a combination of optogenetics, viral tract-
tracing, and whole-cell electrophysiology. Whole-cell electrophysiology and optogenetics represent the primary
technical training in this proposal. The results of this study stand to introduce a novel circuit mechanism for the
pro-cognitive effects of psychedelics and set the foundation for the development of pro-cognitive therapies
applicable across a wide range of neuropsychiatric disorders. Taken together, this innovative proposal will
provide substantial conceptual and technical training opportunities that are necessary for the PI to u...

## Key facts

- **NIH application ID:** 10607081
- **Project number:** 1F31MH132297-01
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Maxwell Blair Madden
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $39,040
- **Award type:** 1
- **Project period:** 2022-09-12 → 2024-09-11

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10607081

## Citation

> US National Institutes of Health, RePORTER application 10607081, Claustral Control of Cortical Networks by Serotonin (1F31MH132297-01). Retrieved via AI Analytics 2026-07-29 from https://api.ai-analytics.org/grant/nih/10607081. Licensed CC0.

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