A Ventral Hippocampal to Lateral Septum Pathway Regulates Social Novelty- Familiarity Preference Restricted; Files Only

Abstract

The ability to recognize familiar conspecifics from strangers is crucial for the survival of most mammalian species. In humans, an inability to recognize kin is associated with several types of dementia, including Alzheimer's disease. Despite the debilitating nature of social recognition deficits, the neural circuits underlying social memory remain poorly understood. Recent evidence has determined the ventral hippocampus (vHPC) is necessary for social recognition. vHPC projections to the lateral septum (LS), a major output of the vHPC, is of particular interest given its involvement in aiding recognition of kin and non-kin odors. However, the exact contribution of vHPC projections to the LS in allowing an animal to discriminate between familiar and novel conspecifics remains unknown. In this study, we used a combination of chemogenetic and optogenetic methods to determine the role of the vHPC-LS projections in mediating social recognition. To evaluate whether vHPC-LS was necessary for social recognition we chemogenetically inhibited using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). We found that inhibition of this pathway disrupted the ability of mice to prefer a novel conspecific over a familiar conspecific. To further evaluate the function of vHPC-LS neurons, we optogenetically inhibited these neurons in a spatially and temporally specific manner in the proximity of either a novel or a familiar mouse in a social discrimination assay. We found that inhibition of vHPC-LS neurons disrupted a mouse’s ability to discriminate between a familiar and novel mouse. Additionally, vHPC-LS neuron inhibition increased the investigation of the conspecific paired with stimulation when presented with two novel conspecifics. These effects were specific to social investigation and not observed when inhibition was paired with one of two novel objects. Next, we focused on identifying which downstream target might mediate the increased social investigation observed with inhibition of vHPC-LS neurons. Using monosynaptic rabies tracing, we found that vHPC makes direct monosynaptic connections onto LS neurons projecting to the ventral tegmental area (VTA). To evaluate if LS-VTA was necessary for social recognition, we chemogenetically inhibited LS-VTA neurons during the interaction between a novel and familiar conspecific. Interestingly, inhibition of LS-VTA neurons disrupts social recognition between novel and familiar conspecifics but also disrupts the ability of mice to preferentially investigate familiar foods over novel foods. We hypothesized that LS inhibition could exert effects on social and food preference by directly synapsing onto dopamine neurons in the VTA. Since dopamine has been known to influence approach behaviors of a wide variety of salient stimulating. Using monosynaptic rabies tracing in a Th-Cre+ mice, we found that LS neurons synapse directly onto dopaminergic VTA neurons. Thus, we discovered that the vHPC-LS-VTA a novel pathway for social memory, more important we discovered that information seems to be transformed within the pathway leading to non-specific novel-familiar discrimination.

Table of Contents

ABSTRACT

ACKNOWLEDGEMENTS

TABLE OF CONTENTS

CHAPTER I

HISTORICAL BACKGROUND

Defining Social Memory

Brain Regions Involved in Social Memory

Anatomy of the Hippocampus

Function of the Hippocampus in Social Memory

Hippocampus Projections Involved in Social Memory

vHPC-mPFC Pathway

vHPC to Nucleus Accumbens Pathway

vHPC to Lateral Septum Pathway

Anatomy of the LS

Functions of the LS

LS in Social Memory

History of the VTA

CHAPTER II

INTRODUCTION

METHODS

Experimental Model and Subject Details

Stereotactic Surgeries

DREADDs

Clozapine-N-Oxide (CNO)

Optogenetics

Rabies Tracing

Histology and Imaging

Behavioral Assays

Social Discrimination Task

Open Field

ANALYSES

Discrimination Score

Velocity

Whole Brain

Statistics

RESULTS

Inhibiting vHPC-LS neurons disrupts the preference for social novelty

vHPC-LS neuron inhibition increases investigation of mouse when using paired inhibition

LS-VTA neurons receive dense monosynaptic input from the vHPC

LS-VTA neurons play a role in social discrimination and food discrimination

GABAergic Neurons in LS Synapse Directly onto Dopamine Neurons in VTA

DISCUSSION

The Hippocampus in Social Memory

Hippocampal-septal Pathway Role in Social Memory

VTA in Social Memory

CHAPTER III

FUTURE DIRECTIONS

Hippocampus

Lateral Septum & Ventral Tegmental Area

CONCLUSION

REFERENCES

APPENDIX

A.    Complete list of publications to which the author has contributed during her graduate training

B. Male vHPC-LS hM4Di

C. Female vHPC-LS hM4Di

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience
Parola chiave	hippocampus optogenetics social memory chemogenetics
Committee Chair / Thesis Advisor	Malavika Murugan, Emory University
Committee Members	Larry Young, Emory University Annabelle Singer, Emory University Robert Liu, Emory University Shannon Gourley, Emory University

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