# Endocannabinoid regulation of a septohabenular circuit in anxiety and depression

> **NIH NIH F30** · MEDICAL COLLEGE OF WISCONSIN · 2021 · $46,730

## Abstract

Project Summary
Anxiety and depression are highly prevalent neuropsychiatric disorders which cause substantial morbidity and
mortality. A top priority of NIMH is to elucidate the molecules, cells, and neural circuits associated with complex
behaviors, including anxiety and depression (NIMH Strategic Objective 1.1). The medial habenula (MHb) is a
well-conserved epithalamic structure known to be a powerful modulator of fear and escape behavior in
zebrafish and anxiety- and depressive-like behaviors in rodents, and has been shown by MRI to be decreased
in volume in humans with depression. The output of MHb neurons is impacted by their synaptic inputs, such as
from the medial septum and nucleus of the diagonal band (MSDB), which provides the sole identified
GABAergic input to the MHb. We have generated preliminary data showing that CB1 receptor activation by
endocannabinoids or by a CB1 receptor agonist suppresses GABAergic inputs in the MHb. Guided by these
exciting findings, we hypothesized that 2-AG/CB1 signaling increases the output of MHb neurons via
suppression of the MSDB input and disinhibition of MHb neurons, resulting in anxiolytic and antidepressant-like
behavioral effects. This hypothesis will be tested via two Specific Aims. In Aim I, we will determine if functional
CB1 receptors are expressed on MSDB to MHb axon terminals and how their activation affects MHb neuronal
output. We will use viral vectors to express ChR2 in the MSDB and selectively activate MSDB axonal terminals
that innervate MHb neurons through optogenetic stimulation. We will then examine whether CB1 receptor
activation alters light-induced inhibitory postsynaptic currents (IPSCs) and action potential firing in MHb
neurons. In Aim II, we will determine how gain- or loss-of-function in 2-AG/CB1 signaling in the MSDB to MHb
circuit affects CB1-mediated suppression of MSDB inputs, and test the hypothesis that this bi-directionally
alters anxiety- and depression-like behaviors. Loss-of-function is achieved via targeted deletion of CB1
receptors, while gain-of-function is achieved by targeted deletion of the enzyme that degrades 2-AG,
monoacylglycerol lipase. In completing this project, the trainee will master a wide range of powerful
experimental techniques, such as ex vivo slice electrophysiology, optogenetics, confocal imaging, in situ
hybridization and immunohistochemistry, viral microinjection, pharmacology, and animal behavior assays.
Further, the proposed research will expand our knowledge of the neural substrates underlying anxiety and
depressive disorders, and how they are regulated by eCB signaling.

## Key facts

- **NIH application ID:** 10226894
- **Project number:** 5F30MH115536-05
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Casey R Vickstrom
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,730
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10226894

## Citation

> US National Institutes of Health, RePORTER application 10226894, Endocannabinoid regulation of a septohabenular circuit in anxiety and depression (5F30MH115536-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10226894. Licensed CC0.

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