# Photostimulation of locus coeruleus CA1 catecholaminergic terminals reversed Spatial memory impairment in an alzheimer’s disease mouse model

## TL;DR

Optogenetic stimulation of brain pathways in a mouse model of Alzheimer's disease improved memory and brain function.

## Contribution

Optogenetic stimulation of LC-CA1 catecholaminergic terminals reversed AD-related memory deficits in a mouse model.

## Key findings

- Optogenetic stimulation reversed spatial memory impairment in AD-TH mice.
- Stimulation restored hippocampal catecholaminergic neurotransmitter levels and enhanced synaptic plasticity.
- LC-hippocampal catecholaminergic circuitry plays a critical role in early AD memory deficits.

## Abstract

One of the earliest changes associated with Alzheimer’s disease (AD) is the loss of catecholaminergic terminals in the cortex and hippocampus originating from the Locus Coeruleus (LC). This decline leads to reduced catecholaminergic neurotransmitters in the hippocampus, affecting synaptic plasticity and spatial memory. However, it is unclear whether restoring catecholaminergic transmission in the terminals from the LC may alleviate the spatial memory deficits associated with AD.

This study aims to investigate the effects of optogenetic stimulation of LC catecholaminergic projections on alleviating spatial memory and synaptic plasticity deficits associated with AD.

We conducted experiments using a 12-month-old 3xTgAD mouse model (AD-TH) that expresses Cre recombinase under the control of the tyrosine hydroxylase (TH) gene. This model enabled us to photostimulate the terminals from the LC in the hippocampal CA1 region before performing two different spatial memory tasks and inducing long-term plasticity.

Optogenetic stimulation successfully reversed the impairment of spatial memory retrieval in aging AD-TH mice. Furthermore, this stimulation restored levels of catecholaminergic neurotransmitters in the hippocampus and enhanced synaptic plasticity, as demonstrated by a long-term potentiation (LTP) protocol.

These findings suggest a critical role for the LC-hippocampal CA1 catecholaminergic circuitry in disrupting synaptic plasticity and the spatial memory deficits characteristic of the early stages of AD. The study highlights the potential for targeting LC catecholaminergic pathways as a therapeutic strategy to improve cognitive deficits experienced by AD patients.

The online version contains supplementary material available at 10.1007/s00213-025-06885-w.