The Role of the Neuropeptide Galanin in Locus Coeruleus Degeneration Open Access

Abstract

The neuropeptide galanin, which is widely expressed in both the brain and periphery, appears to have both neuromodulatory and neurotrophic activity in the nervous system. In its neurotrophic role, galanin can convey a protective effect to neurons under some conditions, presenting a potential therapeutic target for various common neurodegenerative diseases such as Alzheimer’s Disease (AD) and Parkinson’s Disease (PD). The locus coeruleus (LC), the major noradrenergic nucleus in the brain, co-expresses galanin in about 80% of its neurons. The LC is one of the first regions to show signs of damage in neurodegenerative diseases such as AD, and galanin-containing LC neurons are relatively spared in AD compared to LC neurons that do not express galanin. Therefore, the goal of the present research was to further elucidate the potential neuroprotective role of galanin in response to LC damage. This work assessed whether genetic overexpression (Gal OX) or knockout (Gal^cKO-Dbh) of LC-derived galanin in mice altered the neurotoxicity induced by the LC-specific neurotoxin, DSP-4. DSP-4 was administered either acutely (1 injection) or chronically (5 injections over 3 months). LC neuron and fiber integrity were assessed in the LC and several of its forebrain targets using immunohistochemistry for the norepinephrine transporter (NET). Microglial activation was also assessed using immunohistochemistry for ionized calcium binding adaptor molecule 1 (IBA-1), a protein expressed in microglia which is upregulated during microglial activation. In general, chronic DSP-4 caused more damage to LC neurons than acute DSP-4, and the effects were similar between genotypes. However, there was a consistent trend for a greater reduction of NET immunoreactivity and a failure to increase IBA-1 in Gal^cKODbh mice following acute DSP-4 administration, suggesting that endogenous galanin protects LC neurons against neurotoxin-induced degeneration under certain conditions, potentially via a microglial mechanism. Future work should further elucidate the role of galanin in response to LC damage by exploring its relationship to microglial pro- and anti-inflammatory activity.

Table of Contents

Introduction....................................................................................................................................1

The Locus Coeruleus………………......……………………….....................................................................2

Norepinephrine...............................................................................................................................5

Galanin...........................................................................................................................................6

Hypothesis and Expected Results………………………….…….…………………….…………………………..…….8

Materials and Methods.....................................................................................................................9

Results..........................................................................................................................................14

Discussion.....................................................................................................................................18

Conclusion.....................................................................................................................................23

Tables and Figures..........................................................................................................................24

Table 1- Two-Way ANOVA Results……………………………………….……………………………………….........24

Figure 1- Experimental Groups…………………………………………………………………………………….........25

Figure 2- Injection Timeline………………………………………………………………………………………….......25

Figure 3- Acute Gal OX Representative Images…………..…………….……………………………….............…26

Figure 4- Acute Gal OX Results……………………….……………………………………………………………........27

Figure 5- Chronic Gal OX Representative Images…………………….……………………………………............28

Figure 6- Chronic Gal OX Results…………………………………………………………………………………........29

Figure 7- Acute Gal^cKO-Dbh Representative Images…………………………………..…………………................31

Figure 8- Acute Gal^cKO-Dbh Results………………………………………………………………………………….......32

Figure 9- Chronic Gal^cKO-Dbh Representative Images……………..……………………………..……….............34

Figure 10- Chronic Gal^cKO-Dbh Results……………………………………………………………………………........35

Works Cited....................................................................................................................................36

About this Honors Thesis

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School	Emory College
Department	Neuroscience and Behavioral Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Neuroscience
Keyword	Locus Coeruleus Neurodegeneration Galanin
Committee Chair / Thesis Advisor	David Weinshenker, PhD, Emory University
Committee Members	Yoland Smith, PhD, Emory University Lary Walker, PhD, Emory University

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