Table 2.

Summary of anxiety findings in synucleinopathy animal models.

Animal model	Behavior test	Time	Non-motor feature findings vs controls	Mechanism findings
6-OHDA	OFT, EPM	3 weeks	No effect	n.a.123
	OFT, EPM	36 days	Anxiety	n.a.124
	EPM	3 weeks	Anxiety	n.a.117,126
	EPM Contextual fear conditioning	21 days 24 days	Anxiety	Amygdala: reduced dopamine, norepinephrine, increased serotonin Striatum: reduced dopamine, norepinephrine, serotonin Prefrontal cortex: reduced dopamine, norepinephrine, serotonin116
	Marble burying OFT, EPM	3 weeks	Anxiety	Catecholaminergic denervation127
	OFT, EPM	3 weeks	Anxiety	Activation or suppression of AMPA receptor in the lateral habenula led to increase or decrease anxiety, respectively128
MPTP	EPM	26 days	Anxiety	Whole brain lysate: reduced serotonin, dopamine125
	EPM	5 days	Anxiety	n.a.131
Rotenone	EPM, OFT	28 days	Anxiety	Prefrontal cortex, hippocampus: reduced 5-HT+cell and SERT+cell density BLA: reduced 5-HT+cell density134
Paraquat	EPM	1 month	Anxiety	n.a.136
PFF	OFT	6 months	No effect	n.a.139
	Fear conditioning	3, 6 months	No effect	n.a.144
	OFT EPM	30 days	Anxiety	Highest level of αSyn in the amygdala143
	OFT Elevated zero maze Cued and contextual fear conditioning	6 months	Anxiety	Amygdala: 18% neuronal loss, αSyn inclusion colocalized with excitatory neurons Prefrontal cortex: no neuronal loss142
	Fear conditioning Contextual fear retention	9 months	Anxiety	n.a.150
A53T	EPM	12 months	Reduced anxiety	n.a.153
	OFT Stress-induced hyperthermic	2, 6, 12 months	Reduced anxiety	n.a.185
	Open field	12 months	Increased anxiety	n.a.161
	EPM	2, 8, 12 months	Reduced anxiety	Striatum: no change in NE, serotonin, reduced DAT at 8 months145
	OFT, EPM	12, 24 weeks	Reduced anxiety	Striatum: DAT levels significantly decreased and increased dopamine level and its metabolites DOPA146 Hypothalamus: increased serotonin levels146
	EPM	3, 5, 7 months	Reduced anxiety	Hypothalamus and hippocampus: αSyn inclusion colocalized with orexin neurons158 Activation of orexin neurons restores anxiety158
A30P	Fear conditioning	4, 12 months	Reduced freezing	n.a.147
BCA αSyn	EPM	12, 24 months	Reduced anxiety	Striatum: Increased DAT and serotonin148
	Exploratory and feeding behavior	4 months	Anxiety	Hippocampus: reduced serotonin149
A53T αSyn/Tau KO	OFT	2, 6, 12, 18 months	Anxiety	SN: loss of parvalbumin neurons159
Thy1-αSyn	Fear conditioning	3, 4 months	Increased fear	Amygdala: loss of parvalbumin neurons, microgliosis98
αSyn KO	EPM	12 weeks, 12 months	No effect	n.a.153,154
LRRK2	EPM	4, 20 months	No effect	n.a.166
Dj-1 KO	EPM	8, 17 months	No effect	n.a.186
	EPM	3, 5 months	Anxiety	Anxiety-like behaviours were substantially reversed by modulating D2 receptor activity168
Park2 KO	EPM	n.a	Anxiety	n.a.169
Pink1 KO	EPM	4, 8, 12 months	Anxiety	Locus coeruleus: reduced number of cell bodies immunoreactive for TH, and increased expression of the alpha -1 adrenergic receptor170,171

MFB medial forebrain bundle, n.a. not applicable, DAT dopamine transporter, EPM elevated plus maze, OPT open field test, SN substantia nigra, NE norepinephrine, DOPA 3,4-dihydroxyphenylalanine, TH tyrosine hydroxylase, AMPA aminomethylphosphonic acid.