Ultrastructural analysis of sex differences in nucleus accumbens synaptic connectivity

Abstract

Despite robust sex differences in behavioral responses to drugs of abuse, relatively little is known about structural sex differences in synaptic connectivity of reward circuits such as in the nucleus accumbens (NAc). Previously, we showed that distal dendritic spine density on medium spiny neurons in the NAc is higher in females than males, suggesting that sex differences in NAc excitatory synapses could play a role in differential behavioral responses to drugs. In the current study, we used electron microscopy and stereological counting methods to evaluate dendritic spine and shaft synapses, as well as tyrosine hydroxylase-immunoreactive (TH-IR) profiles, in the NAc core of male and female rats. We found an unanticipated rostro-caudal gradient in spine synapse density in females but not males, resulting in a sex difference favoring females in the caudal NAc core. The volume of the NAc was not different between males and females. We also found that the percentage of spines with large spine heads was greater in females in the rostral core. The density of shaft synapses was low compared to spine synapses, and sex differences were minor. The density of TH-IR profiles was not different between males and females, but females had a higher proportion of spines with large heads near TH suggesting a potential sex difference in dopaminergic modulation of large spine synapses. These findings underscore the importance of including both males and females in studies of reward circuitry, and of considering variation along the rostro-caudal axis of the NAc in future studies.

Cocaine-and-Amphetamine Regulated Transcript (CART) peptide attenuates dopamine- and cocaine-mediated locomotor activity in both male and female rats: Lack of sex differences

“…While sex differences in cocaine-mediated LMA have been observed, there are numerous reports that indicate that there are no sex differences in basal DA receptor mRNA (DA D1, D2), dopamine transporter binding levels and tyrosine hydroxylase profile in the NAc of adult rats (Festa et al, 2006, Wissman et al, 2012). Also, there are no sex differences in DA (D1 and D2) receptor density in the NAc in adult rats (Andersen et al, 1997) though there are sex differences during development (Andersen et al, 1997, Andersen and Teicher, 2000).…”

“…This observation may be partly due to higher basal levels of DA in the NAc of females compared to males (Duchesne et al, 2009). It may also be partly due to sex differences in cocaine-induced enhancement of structural changes in spine density in the medium spiny neurons of the NAc, with greater female vs male changes correlating with greater female vs male behavioral responses to cocaine (Wissman et al, 2011, Wissman et al, 2012). But, as discussed in the previous paragraph, one can infer that these sex differences may not even be due to DA because there is ample evidence that DA systems in the NAc in males and females are not much different.…”

Basal regulation of HPA and dopamine systems is altered differentially in males and females by prenatal alcohol exposure and chronic variable stress

“…Findings from basic animal models similarly demonstrate sex differences in response to drugs. Specifically, female rats typically show enhanced: 1) DA release to stress or substances with abuse potential (Becker et al, 2012); 2) medium spiny neuron density in the NAc (Wissman et al, 2012); and 3) and sensitization to stimulants (Zhao and Becker, 2010). Together, these findings support enhanced neurobiological vulnerability to SUD in females compared to males, with females entering the cycle of addiction at a more advanced stage because of the connection between their substance use and stress reduction.…”

Differential striatal spine pathology in Parkinson’s disease and cocaine addiction: A key role of dopamine?

“…In rats, MSNs in female NAc harbor a larger density of spines than males, but neither the dendritic length nor any aspect of dendritic branching is sexually dimorphic (Forlano and Woolley, 2010), suggesting that changes in spine density are representative of genuine differences in dendritic spine number per MSN. In rats treated with daily cocaine for 5 weeks followed by 17–21 days withdrawal, the magnitude of the cocaine-induced increase in spine density is larger in females than males, particularly in the core of the NAc (Wissman et al, 2011, 2012; Li et al, 2012), which was correlated with a higher frequency of mEPSC in NAc core MSNs in females than males. These differential cocaine-induced morphological changes of spines between males and females can be due to various factors including sex differences in hormonal regulation of BDNF, CAMKII and/or delta Fos B (Wissman et al, 2011).…”