Glutamatergic Lateral Habenula Neurons Modulate Consolidation of Associative Memories

Authors

Snigdha Srivastava
I-Ching Wang
Mikhail Y Kochukov
Jessica L Swanson
Mauro Costa-Mattioli
Benjamin R Arenkiel

Language

English

Publication Date

1-1-2025

Journal

Frontiers in Behavioral Neuroscience

DOI

10.3389/fnbeh.2025.1646689

PMID

40799491

PMCID

PMC12339511

PubMedCentral® Posted Date

7-29-2025

PubMedCentral® Full Text Version

Post-print

Abstract

INTRODUCTION: Despite the rise in psychiatric disorders worldwide, the underlying brain circuits responsible for these devastating conditions remain elusive. The lateral habenula (LHb) has emerged as a key brain structure in depression studies due to its hyperactive state in both patients and animal models. While this aligns with known roles in driving aversive states and regulating serotonin release, it is still unclear how acute and transient activity changes in the LHb can influence higher order cognitive processes such as learning, memory, and behavioral adaptation. Given the importance of these processes to psychiatric conditions, understanding how LHb activity impacts cognitive function allows novel insights into the neurobiological mechanisms of disorders like depression.

METHODS: Towards this goal, we used chemogenetic activation to temporarily excite glutamatergic neurons in the mouse LHb and assessed impacts on associative memory.

RESULTS AND DISCUSSION: Surprisingly, we found that transient activation of LHb impaired long-term memory, without affecting anxiety or depression-like behaviors. Specifically, post-training activation of LHb glutamatergic neurons disrupted object recognition and reward-based associative long-term memory, while sparing fear associated long-term memory. The memory impairment was restricted to a critical temporal window post-training/conditioning that corresponded with the consolidation stage of long-term memory. Strikingly, pairing LHb glutamatergic neuronal activation with systemic ketamine administration rescued the long-term memory deficits, indicating that LHb glutamatergic neurons modulate consolidation of associative memories via a NMDA-mediated mechanism. Together, these findings support a novel role for LHb glutamatergic neuronal activity in the consolidation of associative long-term memories.

Keywords

lateral habenula, ketamine, memory, glutamatergic, chemogenetics

Published Open-Access

yes

Recommended Citation

Srivastava, Snigdha; Wang, I-Ching; Kochukov, Mikhail Y; et al., "Glutamatergic Lateral Habenula Neurons Modulate Consolidation of Associative Memories" (2025). Duncan NRI Faculty and Staff Publications. 131.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/131