Sub-chronic variable stress induces sex-specific effects on glutamatergic synapses in the nucleus accumbens.
Men and women manifest different symptoms of depression and under current diagnostic criteria, depression is twice as prevalent in woman. However, little is known of the mechanisms contributing to these important sex differences. Sub-chronic variable stress (SCVS), a rodent model of depression, induces depression-like behaviors in female mice only, modeling clinical evidence of higher susceptibility to mood disorders in women. Accumulating evidence indicates that altered neuroplasticity of excitatory synapses in the nucleus accumbens (NAc) is a key pathophysiological feature of susceptibility to social stress in males. Here we investigated the effects of SCVS on pre- and post-synaptic protein levels and morphology of glutamatergic synapses of medium spiny neurons (MSNs) in the NAc of female and male mice. Animals underwent six-day exposure to alternating stressors including shock, tail suspension and restraint. MSNs from the NAc were filled with a Lucifer yellow dye and spine density and type were examined using NeuronStudio. In a separate group of animals, immunofluorescence staining was performed for vesicular glutamate transporter 1 (VGLUT1) and vesicular glutamate transporter 2 (VGLUT2), in order to label cortical and subcortical glutamatergic terminals. Immunostaining for post-synaptic density 95 (PSD95) was employed to evaluate post-synaptic density. Females demonstrated circuit-specific pre-synaptic alterations in VGLUT1 and VGLUT2 containing synapses that may contribute to stress susceptibility in the absence of post-synaptic alterations in PSD95 puncta, spine density or type. These data indicate that susceptibility to stress in females is associated with changes in the frequency of distinct glutamatergic inputs to the NAc.
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY 10029, USA; Department of Sciences for Health Promotion and Mother and Child Care, University of Palermo, Palermo 90127, Italy.
Anna
A
Brancato
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY 10029, USA.
Dana
D
Bregman
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY 10029, USA.
H Francisica
HF
Ahn
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY 10029, USA.
Madeline L
ML
Pfau
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY 10029, USA.
Caroline
C
Menard
Department of Sciences for Health Promotion and Mother and Child Care, University of Palermo, Palermo 90127, Italy.
Carla
C
Cannizzaro
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY 10029, USA.
Scott J
SJ
Russo
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY 10029, USA; Department of Neuroscience, Virgina Polytechnic Institute and State University, Blacksburg, VA 20460, USA. Electronic address: ghodes@vt.edu.
Georgia E
GE
Hodes
D000818:Animals; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000502:physiology*; D009714:Nucleus Accumbens / Q000378:metabolism*; D057907:Post-Synaptic Density / Q000378:metabolism*; D012727:Sex Characteristics; D013312:Stress, Physiological; D013569:Synapses / Q000378:metabolism*; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism
D050598:Vesicular Glutamate Transport Protein 1; D050599:Vesicular Glutamate Transport Protein 2
depression; medium spiny neurons; nucleus accumbens; plasticity; sex differences; stress