# Hippocampal memory circuits in delusions

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $607,651

## Abstract

SUMMARY
Hippocampal memory circuits are strongly implicated in the formation and persistence of delusions. In
particular, the dentate gyrus (DG) and the CA1 subfield are vulnerable to early developmental stressors that
are risk factors for schizophrenia; postmortem evidence points to deficits in inhibitory input and in
neurogenesis. We hypothesize that delusions result from aberrant associative memory formation due to
impaired functioning of DG/CA3 subfields and persist due to a failure to update false beliefs with new episodic
information due to reduced mnemonic prediction error signaling in CA1 and reduced post-encoding
consolidation of newly formed memories. Because antipsychotics target hippocampal memory circuits, it is
important to study these circuits in unmedicated subjects. We propose to apply three task-based fMRI
paradigms to examine early mnemonic associative processing, prediction error, and plasticity of circuits
associated with encoding and retrieval in three experiments, each including 50 first episode nonaffective
psychosis (FEP) subjects and 50 healthy matched controls. The medication-naïve FEP subjects will be re-
studied after 8 weeks of antipsychotic treatment to examine the relationship between medication effects on
delusional severity and on hippocampal memory circuits. Imaging will also be repeated after 8 weeks in
healthy controls to assess learning effects. The first paradigm, a behavioral pattern separation task, has not
previously been studied in medication-naïve first episode psychosis. The paradigms for assessment of CA1
activation during prediction error and of plasticity of connectivity between hippocampal subfields, the ventral
tegmental area dopamine neurons and cortical regions were recently developed and validated by Dr. Davachi's
team in healthy subjects; we have demonstrated feasibility of these paradigms in schizophrenia subjects. The
proposed project will advance our understanding of circuits involved in delusions and their pharmacologic
response, will provide validated imaging biomarkers for clinical studies and will identify new targets for
treatment development.

## Key facts

- **NIH application ID:** 9921486
- **Project number:** 5R01MH112733-03
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** LILA DAVACHI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $607,651
- **Award type:** 5
- **Project period:** 2018-07-16 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9921486

## Citation

> US National Institutes of Health, RePORTER application 9921486, Hippocampal memory circuits in delusions (5R01MH112733-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9921486. Licensed CC0.

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