Sex differences in circadian timing systems: Implications for disease

Virtually every eukaryotic cell has an endogenous circadian clock and a biological sex. These cell-based clocks have been conceptualized as oscillators whose phase can be reset by internal signals such as hormones, and external cues such as light. The present review highlights the inter-relationship between circadian clocks and sex differences. In mammals, the suprachiasmatic nucleus (SCN) serves as a master clock synchronizing the phase of clocks throughout the body. Gonadal steroid receptors are expressed in almost every site that receives direct SCN input. Here we review sex differences in the circadian timing system in the hypothalamic–pituitary–gonadal axis (HPG), the hypothalamic–adrenal–pituitary (HPA) axis, and sleep–arousal systems. We also point to ways in which disruption of circadian rhythms within these systems differs in the sexes and is associated with dysfunction and disease. Understanding sex differentiated circadian timing systems can lead to improved treatment strategies for these conditions.     

Hypoactive Sexual Desire Disorder: International Society for the Study of Women's Sexual Health (ISSWSH) Expert Consensus Panel Review

The objective of the International Society for the Study of Women's Sexual Health expert consensus panel was to develop a concise, clinically relevant, evidence-based review of the epidemiology, physiology, pathogenesis, diagnosis, and treatment of hypoactive sexual desire disorder (HSDD), a sexual dysfunction affecting approximately 10% of adult women. Etiologic factors include conditions or drugs that decrease brain dopamine, melanocortin, oxytocin, and norepinephrine levels and augment brain serotonin, endocannabinoid, prolactin, and opioid levels. Symptoms include lack or loss of motivation to participate in sexual activity due to absent or decreased spontaneous desire, sexual desire in response to erotic cues or stimulation, or ability to maintain desire or interest through sexual activity for at least 6 months, with accompanying distress. Treatment follows a biopsychosocial model and is guided by history and assessment of symptoms. Sex therapy has been the standard treatment, although there is a paucity of studies assessing efficacy, except for mindfulness-based cognitive behavior therapy. Bupropion and buspirone may be considered off-label treatments for HSDD, despite limited safety and efficacy data. Menopausal women with HSDD may benefit from off-label testosterone treatment, as evidenced by multiple clinical trials reporting some efficacy and short-term safety. Currently, flibanserin is the only Food and Drug Administration–approved medication to treat premenopausal women with generalized acquired HSDD. Based on existing data, we hypothesize that all these therapies alter central inhibitory and excitatory pathways. In conclusion, HSDD significantly affects quality of life in women and can effectively be managed by health care providers with appropriate assessments and individualized treatments.     

The medial preoptic area is necessary for motivated choice of pup- over cocaine-associated environments by early postpartum rats

Converging evidence suggests that the motivation to seek cocaine during the postpartum period is significantly impacted by the competing incentives of offspring, a stimulus unique to this life stage. In the present study, the functional role of the medial preoptic area (mPOA), a critical site involved in maternal responsiveness, on processing incentive value of pup-associated cues and influencing response allocation for pup- over cocaine-associated environments was investigated using a concurrent pup/cocaine choice conditioned place preference (CPP) paradigm. Early postpartum females with bilateral guide cannulae aimed into the mPOA or into anatomical control sites were conditioned, from postpartum days (PPD) 4 to 7, to associate different uniquely featured environments with pups or cocaine. CPP was tested on PPD8 following intra-mPOA infusions of either 2% bupivacaine or saline vehicle. In two additional experiments, the effects of intra-mPOA infusions of bupivacaine on expression of conditioned responding induced by environments associated with either pups or cocaine were examined separately. Transient inactivation of the mPOA selectively blocked the conditioned preferences for pup-associated environments, significantly contrasting the robust pup-CPP found in non-surgical and intra-mPOA vehicle-treated females. In contrast, mPOA inactivation failed to alter cocaine-CPP in postpartum females. When given a choice between environments associated with pups or cocaine, transient functional inactivation of the mPOA altered choice behavior, biasing the preference of females toward cocaine-associated environments, such that almost all preferred cocaine- and none the pup-associated option. The anatomical specificity was revealed when inactivation of adjacent regions to the mPOA did not affect CPP responses for pups. The findings support a critical role for the mPOA in mediating pup-seeking behavior, and further suggest that the competing properties of pups over alternative incentives, including drugs of abuse, rely on mPOA integrity to provide relevant pup-related information to the circuitry underlying the choice behavior between pups and alternative stimuli.     

Oxytocin: The great facilitator of life

Oxytocin (Oxt) is a nonapeptide hormone best known for its role in lactation and parturition. Since 1906 when its uterine-contracting properties were described until 50 years later when its sequence was elucidated, research has focused on its peripheral roles in reproduction. Only over the past several decades have researchers focused on what functions Oxt might have in the brain, the subject of this review.     

Both neural and global androgen receptor overexpression affect sexual dimorphism in the mouse brain

Testosterone is the main endocrine mechanism mediating sexual differentiation of the mammalian brain, although testosterone signalling is complex and important mechanistic questions remain. Notably, the extent to which testosterone acts via androgen receptors (AR) in this process remains unknown and it is also not clear where testosterone acts in the body to produce sexual dimorphisms in neuroanatomy. To address these questions, we used a transgenic mouse model of Cre/loxP‐driven AR overexpression in which AR was induced selectively in neural tissue (Nestin‐cre) or in all tissues (CMV‐cre). We then studied sexually dimorphic features of several well‐characterised sexual dimorphisms: calbindin‐immunoreactive neurones in the medial preoptic area (CALB‐SDN), tyrosine hydroxylase neurones in the anteroventral periventricular nucleus, and vasopressin‐immunoreactive neurones originating in the bed nucleus of the stria terminalis and their projections in the lateral septum. We additionally evaluated oestrogen receptor α immunoreactivity in these nuclei. Briefly, we found that global but not neural overexpression of AR resulted in masculinisation of CALB‐SDN nucleus volume, cell number and cell size in transgenic females. Furthermore, neural AR overexpression resulted in increased oestrogen receptor α staining in females compared to males in the medial preoptic area. AR overexpression did not affect other measures. Overall, the results of the present study provide support for the hypothesis that androgenic mechanisms external to the nervous system can affect sexual differentiation of the brain.     

A neurobehavioral evolutionary perspective on the mechanisms underlying empathy

In mammals, empathy is crucial for living in social groups and caring for others. In this paper, we consider the structural and functional organization of empathy. We propose that empathy subsumes a variety of neurobiological processes and partially dissociable information processing subsystems, each of which has a unique evolutionary history. Even the most advanced and flexible forms of empathy in humans are built on more basic forms and remain connected to core subcortical and neurohormonal mechanisms associated with affective communication, parental care and social attachment processes. Considering empathy within a framework that recognizes both the continuities and the changes within a phylogenetic perspective provides a richer understanding of empathy and related neurobehavioral processes.     

苯丙氨酸对家兔内侧视前区VCI神经元电活动的影响

在三碘季胺酚制动的雌性家兔上进行实验。用玻璃微电极记录内侧视前区(mPOA)单位放电。观察mPOA中对阴道宫颈刺激(Vaginocervical stimulation,VC刺激)发生抑制反应的神经元(Vaginocervical inhibitoty neurons,VCI神经元),在脑室内注射苯丙氨酸后放电活动发生的变化。结果表明,苯丙氨酸能加强VC刺激对VCI神经元的抑制作用。     

The effects of lesions of lateral tegmental noradrenergic neurons on components of sexual behaviour and pseudopregnancy in female rats

Lesions (electrolytic and neurotoxic, using 6-hydroxydopamine) have been made of the projections of medullary noradrenergic neurons in the ascending ventral noradrenergic pathway in female rats. The lesions caused major depletion of noradrenaline in sub-cortical structures, notably the hypothalamus. In behavioural tests, these lesions selectively impaired sexual receptivity, measured as lordosis responses, but did not abolish proceptivity (soliciting). The impaired behaviour is critically dependent on somatosensory stimulation generated by the male during a mount. So, too, is pseudopregnancy since stimulation of the uterine cervix during coitus is essential for the prolongation of luteal life which underlies it. The ability to induce a pseudopregnant state was also abolished by the same ventral noradrenergic pathway lesion.These data, together with supportive evidence from experiments using procaine anaesthesia, have led us to suggest an important function of subcortically projecting noradrenergic neurons in the central transmission and/or processing of somatosensory information in neuroendocrine systems. We also present data suggesting that the effects of noradrenergic neuron activity are dependent on dopaminergic mechanisms more directly concerned with the control of motivated behaviour and anterior pituitary function.