Bivalent habenula modulation of human monoaminergic midbrain and cortical pathways

AI Summary

Habenula bidirectionally modulates ventral tegmental area and dorsal raphe nucleus: inhibited by negative feedback, excited by positive feedback.
Effects replicate across reversal learning and perceptual uncertainty tasks, indicating a generalisable mechanism for adaptive behaviour.
Task-specific cortical pathways modulate habenula signalling: VTA to dACC, DRN to medial PFC, and dACC to habenula show context-dependent effects.

TL;DR (AI Generated)

Using ultra-high field (7T) fMRI and dynamic causal modelling across two negative RPE-inducing experimental tasks, we characterize habenula-directed connectivity with monoaminergic midbrain and cortical pathways in healthy adults (n = 47, 24 males and 23 females; n = 43, 23 males and 20 females).

Task-specific modulatory effects emerged in pathways between the subcortical and cortical regions (ventral tegmental area→dorsal anterior cingulate cortex, dorsal raphe nucleus→medial prefrontal cortex, and dorsal anterior cingulate cortex→habenula), revealing context-dependent cortical elaboration of negative RPE-driven habenula signals.

This provides the first evidence in humans, using model-based effective connectivity, for bivalent modulation of habenula function on monoaminergic midbrain and cortical pathways, demonstrating how the brain integrates negative and positive signals to guide adaptive behavior.Significance Statement The habenula - an epithalamic brain region - plays a key role in the encoding of reward and punishment.

Basic summary

J Neurosci. 2026 Oct 29:e0020262026. doi: 10.1523/JNEUROSCI.0020-26.2026. Online ahead of print.

ABSTRACT

The habenula is implicated in signaling negative reward prediction errors (RPE), yet direct evidence demonstrating its influence on downstream human brain circuits is limited. Using ultra-high field (7T) fMRI and dynamic causal modelling across two negative RPE-inducing experimental tasks, we characterize habenula-directed connectivity with monoaminergic midbrain and cortical pathways in healthy adults (n = 47, 24 males and 23 females; n = 43, 23 males and 20 females). Negative feedback drove habenula inhibition of ventral tegmental area and dorsal raphe nucleus activity, while positive feedback had an excitatory effect. These core effects are replicated across reversal learning and perceptual decision uncertainty tasks, establishing a generalizable mechanism for behavioral adaptation. Task-specific modulatory effects emerged in pathways between the subcortical and cortical regions (ventral tegmental area→dorsal anterior cingulate cortex, dorsal raphe nucleus→medial prefrontal cortex, and dorsal anterior cingulate cortex→habenula), revealing context-dependent cortical elaboration of negative RPE-driven habenula signals. This provides the first evidence in humans, using model-based effective connectivity, for bivalent modulation of habenula function on monoaminergic midbrain and cortical pathways, demonstrating how the brain integrates negative and positive signals to guide adaptive behavior.Significance Statement The habenula – an epithalamic brain region – plays a key role in the encoding of reward and punishment. Animal studies have demonstrated the habenula to be bivalently modulated by aversive and appetitive stimuli, resulting in the bidirectional modulation of monoaminergic brain region activity. Despite this evidence, the directional impact of bivalently modulated habenula activity on its circuitry has yet to be investigated in humans. This study leverages ultra-high field (7T) fMRI and dynamic causal modelling to reveal the impact of bivalent habenula modulation on monoaminergic midbrain and cortical regions across two distinct tasks. Through these methodologies, we demonstrate the habenula to have a key role in guiding adaptive behavior.

PMID:42957319 | DOI:10.1523/JNEUROSCI.0020-26.2026

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