Quantitative analysis of pre‐ and postsynaptic sex differences in the nucleus accumbens

Abstract

The nucleus accumbens (NAc) plays a central role in motivation and reward. While there is ample evidence for sex differences in addiction-related behaviors, little is known about the neuroanatomical substrates that underlie these sexual dimorphisms. We investigated sex differences in synaptic connectivity of the NAc by evaluating pre- and postsynaptic measures in gonadally intact male and proestrous female rats. We used DiI labeling and confocal microscopy to measure dendritic spine density, spine head size, dendritic length and branching of medium spiny neurons (MSNs) in the NAc, and quantitative immunofluorescence to measure glutamatergic innervation using pre- (vesicular glutamate transporter 1 and 2) and postsynaptic (post synaptic density 95) markers, as well as dopaminergic innervation of the NAc. We also utilized electron microscopy to complement the above measures. Clear but subtle sex differences were identified, namely in distal dendritic spine density and the proportion of large spines on MSNs, both of which are greater in females. Sex differences in spine density and spine head size are evident in both the core and shell subregions, but are stronger in the core. This study is the first demonstration of neuroanatomical sex differences in the NAc and provides evidence that structural differences in synaptic connectivity and glutamatergic input may contribute to behavioral sex differences in reward and addiction.

Anabolic-androgenic steroids decrease dendritic spine density in the nucleus accumbens of male rats

“…The current findings suggest that AAS also enhance the effects of physiologic testosterone on Acb. In Acb, females have greater spine density than males (Forlano and Woolley, 2010; Wissman et al 2011), and vehicle-treated males have greater spine density than AAS-treated males (current study). Thus, higher testosterone corresponds to lower spine density in Acb.…”

“…Although previous studies report higher Acb spine densities in male rats compared with vehicle-treated males in the present study, this likely reflects the different methods (DiI vs Golgi) used to visualize neuronal morphology. In particular, the DiI labeling used by Forlano and Woolley (2010) and Wissman et al (2011) yields higher spine densities than Golgi impregnation in pyramidal cells of CA1. (Woolley et al 1997).…”

“…In particular, the increase in CA1 persists weeks after treatment cessation, suggesting long-term effects of AAS on neural anatomy. Although the effects of AAS on dendritic spine density in Acb are unknown, male rats have decreased spine density in Acb compared to females (Forlano and Woolley, 2010; Wissman et al 2011). This suggests that testosterone at normal physiologic levels reduces Acb spine density.…”

Mechanisms of Psychostimulant-Induced Structural Plasticity

“…It has been suggested that sexually dimorphic responses are due to sex differences in gonadal hormones, monoaminergic levels, metabolic processes, or D1 receptor sensitivity (Sell et al 2000;Festa et al 2004;Nazarian et al 2004). More recently, a structural and functional basis for these behavioral differences has been identified in the NAc, where cocaine promotes greater induction of dendritic spine density and proportionally more large spines in both the core and shell in female compared with male rats (Forlano and Woolley 2010). Cocaine also promotes a larger increase in miniature excitatory postsynaptic current (EPSC) frequency, a functional correlate of increased spine density along with enhanced behavioral sensitization (Wissman et al 2011).…”

Effects of tetra hydro cannabinol to the dendritc tree and synapses of the accumbens nucleus of wistar rats

“…Two parts of the accumbens nucleus are reported to be sexually dimorphic: core/shell gender differences have been outlined as more expressed in the core region (Forlano and Wooley, 2010).…”