Sexual dimorphism in locus coeruleus dendritic morphology: A structural basis for sex differences in emotional arousal

Abstract

Stress-related psychiatric disorders, such as depression and anxiety, affect a disproportionate number of women. We previously demonstrated that the major brain norepinephrine (NE)-containing nucleus, locus coeruleus (LC) is more sensitive to stressors and to the stress-related neuropeptide, corticotropin-releasing factor (CRF) in female compared to male rats. Because the LC-NE system is a stress-responsive system that is thought to be dysregulated in affective disorders, sex differences in LC structure or function could play a role in female vulnerability to these diseases. The present study used different approaches to compare LC dendritic characteristics between male and female rats. Immunofluorescence labeling of tyrosine hydroxylase, the norepinephrine synthetic enzyme, revealed that LC dendrites of female rats extend further into the peri-LC region, covering a significantly greater area than those of males. Optical density measurements of dendrites in the peri-LC revealed increased dendritic density in females compared to their male counterparts. Additionally, immunoreactivity for synaptophysin, a synaptic vesicle protein, was significantly greater in the LC in female rats, suggesting an increased number of synaptic contacts onto LC processes. Individual LC neurons were juxtacellularly labeled with neurobiotin in vivo for morphological analysis. LC dendritic trees of females were longer and had more branch points and ends. Consistent with this, Sholl analysis determined that, compared to males, LC dendrites of females had a more complex pattern of branching. The greater dendritic extension and complexity seen in females predicts a higher probability of communication with diverse afferents that terminate in the peri-LC. This may be a structural basis for heightened arousal in females, an effect which may, in part, account for the sex bias in incidence of stress-related psychiatric disorders.

Sex-Biased Stress Signaling: The Corticotropin-Releasing Factor Receptor as a Model

“…With respect to the morphologic effects of CRF on LC neurons, it is noteworthy that LC dendrites of female rats are longer and more complex, having more branch points and extending further into the peri-LC than LC dendrites of male rats (Bangasser et al, 2011). This is reminiscent of the effects of CRF on LC dendrites and would result in a greater magnitude of arousal in response to emotion-related stimuli by favoring more contacts with limbic terminals that convey emotionrelated information (Fig.…”

“…BNST, bed nucleus of the stria terminalis; CNA, central nucleus of the amygdala; PGi, paragigantocellularis; PVN, paraventricular nucleus of the hypothalamus. Reproduced with permission from Bangasser et al (2011).…”

Stress Effects on Neuronal Structure: Hippocampus, Amygdala, and Prefrontal Cortex

“…The authors speculate that, in females, the sex differences in PFC to amygdala circuitry (Shansky et al, 2010) underlie the female HF vs LF difference at the time of conditioning. The fact that estrogen's and androgen's effects are widespread in the central nervous system via both genomic and non-genomic receptors (McEwen and Milner, 2007), there are likely to be many more examples of sex × stress interactions related to many brain regions and multiple functions, as well as developmentally programmed sex differences that affect how the brain responds to stress, eg, in the locus coeruleus (Bangasser et al, 2010(Bangasser et al, , 2011.…”

Orexin-1 Receptor Mediation of Cocaine Seeking in Male and Female Rats

“…In the hypothalamus, female rats express higher levels of orexin-A and OX1R than males (Taheri et al, 1999;Jöhren et al, 2001), a difference that may affect response to yohimbine. On the other hand, stress-induced cocaine seeking probably is influenced by interactions between orexin, corticotropin-releasing factor, and norepinephrine (Ida et al, 2000;Walling et al, 2004;Boutrel et al, 2005), possibly at the locus coeruleus (Abercrombie et al, 1988;Britton et al, 1992), a sexually dimorphic area (Bangasser et al, 2011) with the highest OX1R expression in the brain (Hervieu et al, 2001). Because females show different patterns of locus coeruleus activity than males upon stress stimulation (Curtis et al, 2006;Bangasser et al, 2010), this may account for somewhat different orexin-mediated changes during yohimbine-induced stress.…”