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Taiyou edited this page Jan 24, 2026 · 2 revisions

Project Overview

Background

Serotonin (5-hydroxytryptamine, 5-HT) is a crucial neuromodulator involved in various brain functions including mood regulation, reward processing, and cognitive control. The dorsal raphe nucleus (DRN) is the primary source of serotonergic projections to the forebrain.

This study uses optogenetic functional MRI (ofMRI) to map brain-wide activation patterns induced by selective stimulation of DRN serotonin neurons in transgenic mice.

Experimental Design

Animal Models

Group Description Sample Size
TPH-Cre Transgenic mice expressing Cre recombinase in serotonin neurons (TPH2+) n=8
Control (WT) Wild-type littermate controls n=6-7

Sessions

The experiment consists of four sessions:

Session Condition Purpose
Session 1 Awake state Primary functional mapping
Session 2 Awake state Replication of Session 1
Session 3 Anesthesia (isoflurane) Effect of anesthesia on functional activation
Session 4 Awake state Post-anesthesia recovery

Stimulation Protocol

  • Blue light (473 nm): Activates ChR2, stimulating serotonin neurons
  • Yellow light (593 nm): Control condition (no activation)
  • Stimulation pattern: 20 Hz, 5 ON/OFF cycles per session

Main Findings

1. Brain-wide Activation by DRN Stimulation

Optogenetic activation of DRN serotonin neurons induces:

  • Widespread BOLD signal increases across cortical and subcortical regions
  • Strongest activation in reward-related areas (NAc, VTA, mPFC)
  • Time-locked response to stimulation onset

2. Anesthesia Reverses Activation Patterns

Under isoflurane anesthesia (Session 3):

  • Brain-wide activation is reversed to deactivation
  • This effect is reversible upon awakening (Session 4)
  • Suggests anesthetic-induced changes in receptor responsiveness

3. Structure-Function Correlation

The functional activation pattern correlates with:

  • Structural density of serotonergic projections (from Allen Brain Atlas)
  • Expression levels of specific 5-HT receptors (1A, 1B, 1F, 2A, 2C)

4. Receptor-Specific Effects

Different 5-HT receptor subtypes contribute differently to the observed activation:

  • Excitatory receptors (5-HT2A/2C): Positive contribution to activation
  • Inhibitory receptors (5-HT1A/1B): Negative contribution in some regions

Technical Approach

MRI Acquisition

  • Field strength: 11.7 T (Bruker BioSpec)
  • Sequence: BOLD-fMRI (GE-EPI)
  • Resolution: 0.2 × 0.2 × 0.5 mm³
  • TR/TE: 1000/15 ms

Data Analysis Pipeline

  1. Preprocessing: Motion correction, spatial normalization to mouse brain template
  2. GLM analysis: Contrast of parameter estimates (COPE) for stimulation vs. baseline
  3. ROI analysis: Extraction of activation values for 28 predefined brain regions
  4. Statistical testing: Paired t-tests with FDR correction for multiple comparisons

Publications

Hamada H.T., Abe Y., Takata N., Taira M, Tanaka F.K., and Doya K. (2024). Optogenetic activation of dorsal raphe serotonin neurons induces brain-wide activation. Nature Communications, 15, 4152. DOI: 10.1038/s41467-024-48489-6

Dataset Availability

Raw MRI data is available from OpenNeuro:

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