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Hippocampal input to the nucleus accumbens shell enhances palatability

Angela Yang

Integrated Program in Neuroscience

McGill University, Montreal

April, 2020

A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Master of Science.

© Angela Yang 2020

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TABLE OF CONTENTS

Abstract

3

Résumé

4

Acknowledgements

6

Contribution of authors

7

Introduction

8

Methods and materials

10

Results

i. Number of licks per bout of consumption correlates with palatability 13 ii. Photoinhibition of NAcSh neurons alters consumption without affective hedonic impact 15 iii. Low-frequency photostimulation of vHipp afferents in the NAcSh increases palatability 19 iv. vHipp input to the NAcSh increases palatability independent of opioid signalling 23
v. vHipp-NAc enhancement in palatability is not recapitulated by

NAcSh or dopamine neuron stimulation

25
vi. vHipp-NAcSh activity is sufficient and necessary to condition a flavor preference 28

Discussion

32

Final conclusion and summary

36

References

37

Supplemental methods and references

44
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ABSTRACT

Background: Insight into the neural basis of hedonic processing has come from stud ies of food palatability in rodents. Pharmacological manipulations of the nu cleus accumbens shell (NAcSh) have repeatedly been demonstrated to increase hedonic taste reactivity, yet the contribution of specific NAcSh circuit compone nts is unknown.

Methods

: Bidirectional optogenetic manipulations are targeted to the principal NAcSh projection neurons and afferent pathways of mice during free feeding assays. Number of licks per bout of consumption is used as a measure of food palatabili ty, as it is confirmed to track sucrose concentration and subjective flavor preferenc es.

Results

: Photoinhibition of NAcSh neurons, whether general or cell-type specifi c, is found to alter consumption without affecting its hedonic impact. Among t he principal excitatory afferent pathways, we show that ventral hippocampal (vHipp) input alone enhances palatability upon low-frequency photostimulation time-locked to consumption. This enhancement in palatability is independent of opioid signalling and not recapitulated by NAcSh or dopamine neuron photostimulation. We further d emonstrate that vHipp input photostimulation is sufficient to condition a flavor preference, while its inhibition impedes sucrose-driven flavor preference conditioning. C onclusions: These results demonstrate a novel contribution of vHipp-NAcSh pathway activity to palatability that may relate to its innervation of a particu lar region or neuronal ensemble in the NAcSh. These findings are consistent with the evidence that vHipp- NAcSh activity contributes to the pathophysiology of anhedonia and depression as well as the increasing appreciation of hippocampal involvement in people's food pleasantness ratings, hunger, and weight. 4

Contexte:

Un aperçu de la base neurale des processus de la hédonie provient d'études

sur la palatabilité des aliments chez les rongeurs. Il a été démontré à plusieurs repris

es que les manipulations pharmacologiques de la coque du noyau accumbens (

NAcSh)

augmentent la réactivité du goût hédonique, mais la contribu tion de composants spécifiques du circuit NAcSh est inconn ue.

MŽthodes:

Les manipulations optogénétiques bidirectionnelles sont ciblée s sur les principaux neurones de projection NAcSh et les voies afférentes des s ouris pendant les tests d'alimentation libre. Le nombre de coups de langue par épisode de consommation est utilisé comme mesure de la palatabilité des aliments, car il e st confirmé de suivre la concentration de saccharose et les préférences de saveur subjectiv es.

RŽsultats:

La photoinhibition des neurones NAcSh, qu'ils soient généraux ou spécifiques au type cellulaire, modifie la consommation sans affecter son impact hédonique. Parmi les principales voies afférentes glutamatergiques, nous montrons que la projection de l'hippocampe ventral (vHipp) à elle seule améli ore la palatabilité lors de la photostimulation à basse fréquence liée à la consommation . Cette amélioration de la palatabilité est indépendante de la signalisation des opioïdes et n'est pas reproduit par NAcSh ou la photostimulation des neurones dopaminergiques. Nous démon trons en outre que la photostimulation d'entrée vHipp est suffisante pour cond itionner une préférence de saveur, tandis l'inhibition empêche le conditionnement de préférence de saveur entraîné par le saccharose. Conclusions: Ces résultats démontrent une nouvelle contribution de l'activité de la voie vHipp-NAcSh à la palatabilité qui peut être liée à son innerva tion d'une région 5 particulière ou d'un ensemble neuronal dans le NAcSh. Ces résultat s sont cohérents avec la preuve que l'activité vHipp-NAcSh contribue à la physiopathologie de l'anhédonie et de la dépression ainsi qu'à l'appréciation cr oissante de l'implication de l'hippocampe dans les cotes d'agrément alimentaire, la faim et le poi ds des gens. 6

ACKNOWLEDGEMENTS

First I would like to thank my supervisor, Jonathan Britt, for constantly inspiring me to ask important questions, and providing the necessary intellectual and material resources to answer them. Thank you for always keeping your office door open. Without your mentorship I could not have achieved this level of completion with my Master's thesis. I am also grateful to my lab mates Christopher Lafferty and Jesse Mendoza, for all the days and nights we spent at the lab, and for demonstrating to me what it truly means to learn and work as a team. I am glad to know that we matured tog ether not only as academics but also as friends. I extend my dear appreciation to fellow graduate students, Thalia Garvock, Thomas Christinck, Matteo Bernado, and Isabell e Groves, for providing fresh perspectives, endless moral support, and sometimes, a healthy dose of distractions to keep me going. I would also like to express my gratitude to the invaluable undergraduates who carried out the daily task of running experiments, namely Shira Mattuck, Veronica Le, Jiamin Song, Camille Bouchard, Ashley Jussaume, Julia Akimoto, and Onur Koçer. Furthermore, I would like to acknowledge my committee members, Paul Clarke and Jeffrey Mogil, for their expertise, insight, and willingness to help during this project. Lastly, I would like to thank my family and friends for their encouragem ent and understanding. I hope I can make up the time. 7

CONTRIBUTION OF AUTHORS

Based on the manuscript, "Hippocampal input to the nucleus accumbens shell enhances palatability":

Angela K. Yang

1,3 , Jesse A. Mendoza 2,3 , Christopher K. Lafferty 2,3 , Franca Lacroix 2

Jonathan P. Britt

2,3 1 Integrated Program in Neuroscience, McGill University, Montreal, QC, Can ada 2 Department of Psychology, McGill University, Montreal, QC, Canada 3 Center for Studies in Behavioural Neurobiology, Concordia University, Montreal, QC,

Canada

The author of this thesis conceived the study and designed the experimen ts with the guidance of Jonathan Britt. The author also collected and analyzed the majority of the work Jesse Mendoza and Christopher Lafferty assisted with surgery for experimentation as well as the codes designed for behavioural tasks and data analysis. Franca Lacroix completed the acquisition of data for the retrograde trac ing study, including surgery and image analysis of brain tissue. 8

INTRODUCTION

Anhedonia is a reduced ability to experience pleasure that it is often o bserved in psychiatric disorders (1). A distributed network of brain regions common across humans and rodents is involved in hedonic processing, but circuit mechanisms ar e unclear (2,3) The nucleus accumbens (NAc) is a site of interest because pathophysiol ogical dysfunction in this region has been associated with anhedonia, drug addi ction, and depression (4- 6) . Moreover, pharmacological manipulations of the NAc have been demonstrated to increase the hedonic impact of food, as measured with fa cial reactivity (2) and number of licks per bout (LPB) of consumpti on (7,8). The drugs that promote positive taste reactions are generally inhibitory, including opioids (8,9), cannabinoids (10), and GABA receptor agonists (11), but their influences on NAc physiology are complex as they differentially modulate the NAc cell types and afferentquotesdbs_dbs35.pdfusesText_40

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