Polyethylene glycol treated allografts not tissue matched nor immunosuppressed rapidly repair sciatic nerve gaps, maintain neuromuscular functions, and restore voluntary behaviors in female rats.

Many publications report that ablations of segments of peripheral nerves produce the following unfortunate results: (1) Immediate loss of sensory signaling and motor control; (2) rapid Wallerian degeneration of severed distal axons within days; (3) muscle atrophy within weeks; (4) poor behavioral (functional) recovery after many months, if ever, by slowly-regenerating (∼1mm/d) axon outgrowths from surviving proximal nerve stumps; and (5) Nerve allografts to repair gap injuries are rejected, often even if tissue matched and immunosuppressed. In contrast, using a female rat sciatic nerve model system, we report that neurorrhaphy of allografts plus a well-specified-sequence of solutions (one containing polyethylene glycol: PEG) successfully addresses each of these problems by: (a) Reestablishing axonal continuity/signaling within minutes by nonspecific ally PEG-fusing (connecting) severed motor and sensory axons across each anastomosis; (b) preventing Wallerian degeneration by maintaining many distal segments of inappropriately-reconnected, PEG-fused axons that continuously activate nerve-muscle junctions; (c) maintaining innervation of muscle fibers that undergo much less atrophy than otherwise-denervated muscle fibers; (d) inducing remarkable behavioral recovery to near-unoperated levels within days to weeks, almost certainly by CNS and PNS plasticities well-beyond what most neuroscientists currently imagine; and (e) preventing rejection of PEG-fused donor nerve allografts with no tissue matching or immunosuppression. Similar behavioral results are produced by PEG-fused autografts. All results for Negative Control allografts agree with current neuroscience data 1-5 given above. Hence, PEG-fusion of allografts for repair of ablated peripheral nerve segments expand on previous observations in single-cut injuries, provoke reconsideration of some current neuroscience dogma, and further extend the potential of PEG-fusion in clinical practice.

Polyethylene glycol solutions rapidly restore and maintain axonal continuity, neuromuscular structures, and behaviors lost after sciatic nerve transections in female rats.

Complete severance of major peripheral mixed sensory-motor nerve proximally in a mammalian limb produces immediate loss of action potential conduction and voluntary behaviors mediated by the severed distal axonal segments. These severed distal segments undergo Wallerian degeneration within days. Denervated muscles atrophy within weeks. Slowly regenerating (∼1 mm/day) outgrowths from surviving proximal stumps that often nonspecifically reinnervate denervated targets produce poor, if any, restoration of lost voluntary behaviors. In contrast, in this study using completely transected female rat sciatic axons as a model system, we provide extensive morphometric, immunohistochemical, electrophysiological, and behavioral data to show that these adverse outcomes are avoided by microsuturing closely apposed axonal cut ends (neurorrhaphy) and applying a sequence of well-specified solutions, one of which contains polyethylene glycol (PEG). This "PEG-fusion" procedure within minutes reestablishes axoplasmic and axolemmal continuity and signaling by nonspecifically fusing (connecting) closely apposed open ends of severed motor and/or sensory axons at the lesion site. These PEG-fused axons continue to conduct action potentials and generate muscle action potentials and muscle twitches for months and do not undergo Wallerian degeneration. Continuously innervated muscle fibers undergo much less atrophy compared with denervated muscle fibers. Dramatic behavioral recovery to near-unoperated levels occurs within days to weeks, almost certainly by activating many central nervous system and peripheral nervous system synaptic and other plasticities, some perhaps to a greater extent than most neuroscientists would expect. Negative control transections in which neurorrhaphy and all solutions except the PEG-containing solution are applied produce none of these remarkably fortuitous outcomes observed for PEG-fusion.

The agonistic adrenal: melatonin elicits female aggression via regulation of adrenal androgens.

Classic findings have demonstrated an important role for sex steroids as regulators of aggression, but this relationship is lacking within some environmental contexts. In mammals and birds, the adrenal androgen dehydroepiandrosterone (DHEA), a non-gonadal precursor of biologically active steroids, has been linked to aggression. Although females, like males, use aggression when competing for limited resources, the mechanisms underlying female aggression remain understudied. Here, we propose a previously undescribed endocrine mechanism regulating female aggression via direct action of the pineal hormone melatonin on adrenal androgens. We examined this in a solitary hamster species, Phodopus sungorus, in which both sexes are highly territorial across the seasons, and display increased aggression concomitant with decreased serum levels of sex steroids in short 'winter-like' days. Short- but not long-day females had increased adrenal DHEA responsiveness co-occurring with morphological changes in the adrenal gland. Further, serum DHEA and total adrenal DHEA content were elevated in short days. Lastly, melatonin increased DHEA and aggression and stimulated DHEA release from cultured adrenals. Collectively, these findings demonstrate that DHEA is a key peripheral regulator of aggression and that melatonin coordinates a 'seasonal switch' from gonadal to adrenal regulation of aggression by direct action on the adrenal glands.

Oxytocin increases VTA activation to infant and sexual stimuli in nulliparous and postpartum women.

After giving birth, women typically experience decreased sexual desire and increased responsiveness to infant stimuli. These postpartum changes may be viewed as a trade-off in reproductive interests, which could be due to alterations in brain activity including areas associated with reward. The goal of this study was to describe the roles of oxytocin and parity on reward area activation in response to reproductive stimuli, specifically infant and sexual images. Because they have been shown to be associated with reward, the ventral tegmental area (VTA) and nucleus accumbens (NAc) were targeted as areas of expected alterations in activity. Oxytocin was chosen as a potential mediator of reproductive trade-offs because of its relationship to both mother-infant interactions, including breastfeeding and bonding, and sexual responses. We predicted that postpartum women would show higher reward area activation to infant stimuli and nulliparous women would show higher activation to sexual stimuli and that oxytocin would increase activation to infant stimuli in nulliparous women. To test this, we measured VTA and NAc activation using fMRI in response to infant photos, sexual photos, and neutral photos in 29 postpartum and 30 nulliparous women. Participants completed the Sexual Inhibition (SIS) and Sexual Excitation (SES) Scales and the Brief Index of Sexual Function for Women (BISF-W), which includes a sexual desire dimension, and received either oxytocin or placebo nasal spray before viewing crying and smiling infant and sexual images in an fMRI scanner. For both groups of women, intranasal oxytocin administration increased VTA activation to both crying infant and sexual images but not to smiling infant images. We found that postpartum women showed lower SES, higher SIS, and lower sexual desire compared to nulliparous women. Across parity groups, SES scores were correlated with VTA activation and subjective arousal ratings to sexual images. In postpartum women, sexual desire was positively correlated with VTA activation to sexual images and with SES. Our findings show that postpartum decreases in sexual desire may in part be mediated by VTA activation, and oxytocin increased activation of the VTA but not NAc in response to sexual and infant stimuli. Oxytocin may contribute to the altered reproductive priorities in postpartum women by increasing VTA activation to salient infant stimuli.

Polyethylene glycol fusion repair of severed rat sciatic nerves reestablishes axonal continuity and reorganizes sensory terminal fields in the spinal cord.

ABSTRACT: Peripheral nerve injuries result in the rapid degeneration of distal nerve segments and immediate loss of motor and sensory functions; behavioral recovery is typically poor. We used a plasmalemmal fusogen, polyethylene glycol (PEG), to immediately fuse closely apposed open ends of severed proximal and distal axons in rat sciatic nerves. We have previously reported that sciatic nerve axons repaired by PEG- fusion do not undergo Wallerian degeneration, and PEG-fused animals exhibit rapid (within 2-6 weeks) and extensive locomotor recovery. Furthermore, our previous report showed that PEG-fusion of severed sciatic motor axons was non-specific, i.e., spinal motoneurons in PEG- fused animals were found to project to appropriate as well as inappropriate target muscles. In this study, we examined the consequences of PEG-fusion for sensory axons of the sciatic nerve. Young adult male and female rats (Sprague-Dawley) received either a unilateral single cut or ablation injury to the sciatic nerve and subsequent repair with or without (Negative Control) the application of PEG. Compound action potentials recorded immediately after PEG-fusion repair confirmed conduction across the injury site. The success of PEG-fusion was confirmed through Sciatic Functional Index testing with PEG-fused animals showing improvement in locomotor function beginning at 35 days postoperatively. At 2-42 days postoperatively, we anterogradely labeled sensory afferents from the dorsal aspect of the hindpaw following bilateral intradermal injection of wheat germ agglutinin conjugated horseradish peroxidase. PEG-fusion repair reestablished axonal continuity. Compared to unoperated animals, labeled sensory afferents ipsilateral to the injury in PEG-fused animals were found in the appropriate area of the dorsal horn, as well as inappropriate mediolateral and rostrocaudal areas. Unexpectedly, despite having intact peripheral nerves, similar reorganizations of labeled sensory afferents were also observed contralateral to the injury and repair. This central reorganization may contribute to the improved behavioral recovery seen after PEG-fusion repair, supporting the use of this novel repair methodology over currently available treatments.

Polyethylene glycol fusion repair of severed sciatic nerves accelerates recovery of nociceptive sensory perceptions in male and female rats of different strains.

ABSTRACT: Successful polyethylene glycol fusion (PEG-fusion) of severed axons following peripheral nerve injuries for PEG-fused axons has been reported to: (1) rapidly restore electrophysiological continuity; (2) prevent distal Wallerian Degeneration and maintain their myelin sheaths; (3) promote primarily motor, voluntary behavioral recoveries as assessed by the Sciatic Functional Index; and, (4) rapidly produce correct and incorrect connections in many possible combinations that produce rapid and extensive recovery of functional peripheral nervous system/central nervous system connections and reflex (e.g., toe twitch) or voluntary behaviors. The preceding companion paper describes sensory terminal field reorganization following PEG-fusion repair of sciatic nerve transections or ablations; however, sensory behavioral recovery has not been explicitly explored following PEG-fusion repair. In the current study, we confirmed the success of PEG-fusion surgeries according to criteria (1-3) above and more extensively investigated whether PEG-fusion enhanced mechanical nociceptive recovery following sciatic transection in male and female outbred Sprague-Dawley and inbred Lewis rats. Mechanical nociceptive responses were assessed by measuring withdrawal thresholds using von Frey filaments on the dorsal and midplantar regions of the hindpaws. Dorsal von Frey filament test was a more reliable method than plantar von Frey filament test to assess mechanical nociceptive sensitivity following sciatic nerve transections. Baseline withdrawal thresholds of the sciatic-mediated lateral dorsal region differed significantly across strain but not sex. Withdrawal thresholds did not change significantly from baseline in chronic Unoperated and Sham-operated rats. Following sciatic transection, all rats exhibited severe hyposensitivity to stimuli at the lateral dorsal region of the hindpaw ipsilateral to the injury. However, PEG-fused rats exhibited significantly earlier return to baseline withdrawal thresholds than Negative Control rats. Furthermore, PEG-fused rats with significantly improved Sciatic Functional Index scores at or after 4 weeks postoperatively exhibited yet-earlier von Frey filament recovery compared with those without Sciatic Functional Index recovery, suggesting a correlation between successful pPEG-fusion and both motor-dominant and sensory-dominant behavioral recoveries. This correlation was independent of the sex or strain of the rat. Furthermore, our data showed that the acceleration of von Frey filament sensory recovery to baseline was solely due to the PEG-fused sciatic nerve and not saphenous nerve collateral outgrowths. No chronic hypersensitivity developed in any rat up to 12 weeks. All these data suggest that PEG-fusion repair of transection peripheral nerve injuries could have important clinical benefits.

Lower sexual interest in postpartum women: relationship to amygdala activation and intranasal oxytocin.

During the postpartum period, women experience significant changes in their neuroendocrine profiles and social behavior compared to before pregnancy. A common experience with motherhood is a decrease in sexual desire. Although the lifestyle and peripheral physiological changes associated with parturition might decrease a woman's sexual interest, we hypothesized that there are also hormone-mediated changes in women's neural response to sexual and infant stimuli with altered reproductive priorities. We predicted that amygdala activation to sexually arousing stimuli would be suppressed in postpartum versus nulliparous women, and altered with intranasal oxytocin administration. To test this, we measured amygdala activation using fMRI in response to sexually arousing pictures, infant pictures, and neutral pictures in 29 postpartum and 30 nulliparous women. Half of the women received a dose of exogenous oxytocin before scanning. As predicted, nulliparous women subjectively rated sexual pictures to be more arousing, and infant pictures to be less arousing, than did postpartum women. However, nulliparous women receiving the nasal oxytocin spray rated the infant photos as arousing as did postpartum women. Right amygdala activation was lower in postpartum versus nulliparous women in response to sexual, infant, and neutral images, suggesting a generalized decrease in right amygdala responsiveness to arousing images with parturition. There was no difference in right amygdala activation with nasal spray application. Postpartum women therefore appear to experience a decrease in sexual interest possibly as a feature of a more generalized decrease in amygdala responsiveness to arousing stimuli.

EMG Testing throughout behavioral recovery after rat sciatic nerve crush injury results in exuberant motoneuron dendritic hypertrophy.

Background: Peripheral nerve injury (PNI) is the most common type of nerve trauma yet, while injured motoneurons exhibit a robust capacity for regeneration, behavioral recovery is protracted and typically poor. Neurotherapeutic approaches to PNI and repair have primarily focused on the enhancement of axonal regeneration, in terms of rate, axonal sprouting, and reconnection connectivity. Both electrical stimulation (ES) and treatment with androgens [e.g., testosterone propionate (TP)] have been demonstrated to enhance axonal sprouting, regeneration rate and functional recovery following PNI. To date, very little work has been done to examine the effects of ES and/or TP on dendritic morphology and organization within the spinal cord after PNI. Objective: The objective of the current study was to examine the impact of treatment with TP and ES, alone or in combination, on the dendritic arbor of spinal motoneurons after target disconnection via sciatic nerve crush injury in the rat. Methods: Rats received a crush injury to the sciatic nerve. Following injury, some animals received either (1) no further treatment beyond implantation with empty Silastic capsules, (2) electrical nerve stimulation immediately after injury, (3) implantation with Silastic capsules filled with TP, or (4) electrical nerve stimulation immediately after injury as well as implantation with TP. All of these groups of axotomized animals also received bi-weekly electromyography (EMG) testing. Additional groups of intact untreated animals as well as a group of injured animals who received no further treatment or EMG testing were also included. Eight weeks after injury, motoneurons innervating the anterior tibialis muscle were labeled with cholera toxin-conjugated horseradish peroxidase, and dendritic arbors were reconstructed in three dimensions. Results: After nerve crush and ES and/or TP treatment, motoneurons innervating the anterior tibialis underwent marked dendritic hypertrophy. Surprisingly, this dendritic hypertrophy occurred in all animals receiving repeated bi-weekly EMG testing, regardless of treatment. When the EMG testing was eliminated, the dendritic arbor extent and distribution after nerve crush in the treated groups did not significantly differ from intact untreated animals. Conclusions: The ability of repeated EMG testing to so dramatically affect central plasticity following a peripheral nerve injury was unexpected. It was also unexpected that gonadal steroid hormones and/or ES, two neurotherapeutic approaches with demonstrated molecular/behavioral changes consistent with peripheral improvements in axonal repair and target reconnection, do not appear to impact central plasticity in a similar manner. The significance of peripheral EMG testing and resulting central plasticity reorganization remains to be determined.

A "Four Core Genotypes" rat model to distinguish mechanisms underlying sex-biased phenotypes and diseases.

Background: We have generated a rat model similar to the Four Core Genotypes mouse model, allowing comparison of XX and XY rats with the same type of gonad. The model detects novel sex chromosome effects (XX vs. XY) that contribute to sex differences in any rat phenotype. Methods: XY rats were produced with an autosomal transgene of Sry , the testis-determining factor gene, which were fathers of XX and XY progeny with testes. In other rats, CRISPR-Cas9 technology was used to remove Y chromosome factors that initiate testis differentiation, producing fertile XY gonadal females that have XX and XY progeny with ovaries. These groups can be compared to detect sex differences caused by sex chromosome complement (XX vs. XY) and/or by gonadal hormones (rats with testes vs. ovaries). Results: We have measured numerous phenotypes to characterize this model, including gonadal histology, breeding performance, anogenital distance, levels of reproductive hormones, body and organ weights, and central nervous system sexual dimorphisms. Serum testosterone levels were comparable in adult XX and XY gonadal males. Numerous phenotypes previously found to be sexually differentiated by the action of gonadal hormones were found to be similar in XX and XY rats with the same type of gonad, suggesting that XX and XY rats with the same type of gonad have comparable levels of gonadal hormones at various stages of development. Conclusion: The results establish a powerful new model to discriminate sex chromosome and gonadal hormone effects that cause sexual differences in rat physiology and disease.

Intraneural Topography of Rat Sciatic Axons: Implications for Polyethylene Glycol Fusion Peripheral Nerve Repair.

Peripheral nerve injuries are the most common type of nerve trauma. We have been working with a novel repair technique using a plasmalemmal fusogen, polyethylene glycol (PEG), to re-fuse the membranes of severed axons. PEG-fusion repair allows for immediate re-innervation of distal targets, prevents axonal degeneration, and improves behavioral recovery. PEG-fusion of severed axons is non-specific, and we have previously reported that following injury and PEG-fusion misconnections between spinal motoneurons and their distal targets were present. Surprisingly, appropriately paired proximal and distal motor axons were observed in all PEG-fused animals. We hypothesized that a topographic organization of axons contributing to the sciatic nerve could explain the incidence of appropriate connections. We traced the course of specific axon populations contributing to the sciatic nerve in young adult male and female rats. Following intraneural injection of Fast Blue into the tibial branch, labeled axons were confined to a discrete location throughout the course of the nerve. Following intramuscular injection of cholera toxin-conjugated horseradish peroxidase into the anterior tibialis, labeled axons were confined to a smaller but still discrete location throughout the nerve. In both cases, the relative locations of labeled axons were consistent bilaterally within animals, as well as across animals and sexes. Thus, the relatively consistent location of specific axon populations could allow for realignment of appropriate populations of axons, and enhanced behavioral recovery seen in PEG-fused animals. Knowing the organization of axons within the sciatic nerve promotes accurate territory realignment during repair, therefore aiding in recovery outcomes.

Exercise is neuroprotective on the morphology of somatic motoneurons following the death of neighboring motoneurons via androgen action at the target muscle.

Motoneuron loss is a severe medical problem that can result in loss of motor control and eventually death. We have previously demonstrated that partial motoneuron loss can result in dendritic atrophy and functional deficits in nearby surviving motoneurons, and that an androgen-dependent effect of exercise following injury can be neuroprotective against this dendritic atrophy. In this study, we explored where the necessary site of androgen action is for exercise-driven neuroprotective effects on induced dendritic atrophy. Motoneurons innervating the vastus medialis muscles of adult male rats were selectively killed by intramuscular injection of cholera toxin-conjugated saporin. Simultaneously, some saporin-injected animals were given implants of the androgen receptor antagonist hydroxyflutamide, either directly at the adjacent vastus lateralis musculature ipsilateral to the saporin-injected vastus medialis or interscapularly as a systemic control. Following saporin injections, some animals were allowed free access to a running wheel attached to their home cages. Four weeks later, motoneurons innervating the same vastus lateralis muscle were labeled with cholera toxin-conjugated horseradish peroxidase, and dendritic arbors were reconstructed in three dimensions. Dendritic arbor lengths of saporin-injected animals allowed to exercise were significantly longer than those not allowed to exercise. Androgen receptor blockade locally at the vastus lateralis muscle prevented the protective effect of exercise. These findings indicate that exercise following neural injury exerts a protective effect on motoneuron dendrites, which acts via androgen receptor action at the target muscle.

Inhibition of Cytosolic Phospholipase A2 Has Neuroprotective Effects on Motoneuron and Muscle Atrophy after Spinal Cord Injury.

Surviving motoneurons undergo dendritic atrophy after spinal cord injury (SCI), suggesting an important therapeutic target for neuroprotective strategies to improve recovery of function after SCI. Our previous studies showed that cytosolic phospholipase A2 (PLA2) may play an important role in the pathogenesis of SCI. In the present study, we investigated whether blocking cytosolic PLA2 (cPLA2) pharmacologically with arachidonyl trifluoromethyl ketone (ATK) or genetically using cPLA2 knockout (KO) mice attenuates motoneuron atrophy after SCI. C57BL/6 mice received either sham or contusive SCI at the T10 level. At 30 min after SCI, mice were treated with ATK or vehicle. Four weeks later, motoneurons innervating the vastus lateralis muscle of the quadriceps were labeled with cholera toxin-conjugated horseradish peroxidase, and dendritic arbors were reconstructed in three dimensions. Soma volume, motoneuron number, lesion volume, and tissue sparing were also assessed, as were muscle weight, fiber cross-sectional area, and motor endplate size and density. ATK administration reduced percent lesion volume and increased percent volume of spared white matter, compared to the vehicle-treated control animals. SCI with or without ATK treatment had no effect on the number or soma volume of quadriceps motoneurons. However, SCI resulted in a decrease in dendritic length of quadriceps motoneurons in untreated animals, and this decrease was completely prevented by treatment with ATK. Similarly, vastus lateralis muscle weights of untreated SCI animals were smaller than those of sham surgery controls, and these reductions were prevented by ATK treatment. No effects on fiber cross-sectional areas, motor endplate area, or density were observed across treatment groups. Remarkably, genetically deleting cPLA2 in cPLA2 KO mice attenuated dendritic atrophy after SCI. These findings suggest that, after SCI, cord tissue damage and regressive changes in motoneuron and muscle morphology can be reduced by inhibition of cPLA2, further supporting a role for cPLA2 as a neurotherapeutic target for SCI treatment.

Neuroprotective actions of androgens on motoneurons.

Androgens have a variety of protective and therapeutic effects in both the central and peripheral nervous systems. Here we review these effects as they related specifically to spinal and cranial motoneurons. Early in development, androgens are critical for the formation of important neuromuscular sex differences, decreasing the magnitude of normally occurring cell death in select motoneuron populations. Throughout the lifespan, androgens also protect against motoneuron death caused by axonal injury. Surviving motoneurons also display regressive changes to their neurites as a result of both direct axonal injury and loss of neighboring motoneurons. Androgen treatment enhances the ability of motoneurons to recover from these regressive changes and regenerate both axons and dendrites, restoring normal neuromuscular function. Androgens exert these protective effects by acting through a variety of molecular pathways. Recent work has begun to examine how androgen treatment can interact with other treatment strategies in promoting recovery from motoneuron injury.

Maternal care effects on the development of a sexually dimorphic motor system: the role of spinal oxytocin.

Maternal licking in rats affects the development of the spinal nucleus of the bulbocavernosus (SNB), a sexually dimorphic motor nucleus that controls penile reflexes involved with copulation. Reduced maternal licking results in decreased motoneuron number, size, and dendritic length in the adult SNB, as well as deficits in adult male copulatory behavior. Our previous findings that licking-like tactile stimulation influences SNB dendritic development and upregulates Fos expression in the lumbosacral spinal cord suggest that afferent signaling is changed by differences in maternal stimulation. Oxytocin afferents from the hypothalamus are a possible candidate, given previous research that has shown oxytocin is released following sensory stimulation, oxytocin modulates excitability in the spinal cord, and is a pro-erectile modulator of male sex behavior. In this experiment, we used immunofluorescence and immediate early gene analysis to assess whether licking-like tactile stimulation of the perineum activated parvocellular oxytocinergic neurons in the hypothalamus in neonates. We also used enzyme immunoassay to determine whether this same stroking stimulation produced an increase in spinal oxytocin levels. We found that stroking increased Fos immunolabeling in small oxytocin-positive cells in the paraventricular nucleus of the hypothalamus, in comparison to unstroked or handled control pups. In addition, 60s of licking-like perineal stimulation produced a transient 89% increase in oxytocin levels in the lumbosacral spinal cord. Together, these results suggest that oxytocin afferent activity may contribute to the effects of early maternal care on the masculinization of the SNB and resultant male copulatory behavior.

Exercise promotes recovery after motoneuron injury via hormonal mechanisms.

Injuries to spinal motoneurons manifest in a variety of forms, including damage to peripheral axons, neurodegenerative disease, or direct insult centrally. Such injuries produce a variety of negative structural and functional changes in both the directly affected and neighboring motoneurons. Exercise is a relatively simple behavioral intervention that has been demonstrated to protect against, and accelerate recovery from, these negative changes. In this article, we describe how exercise is neuroprotective for motoneurons, accelerating axon regeneration following axotomy and attenuating dendritic atrophy following the death of neighboring motoneurons. In both of these injury models, the positive effects of exercise have been found to be dependent on gonadal hormone action. Here we describe a model in which exercise, hormones, and brain-derived neurotrophic factor might all interact to produce neuroprotective effects on motoneuron structure following neural injury.

Neural Activation in Women in Response to Masculinized Male Faces: Mediation by Hormones and Psychosexual Factors.

Women's preference for masculine faces varies with hormonal state, sociosexuality, and relationship status, but the underlying mechanisms are poorly understood. We hypothesized that hormones and psychosexual factors (sociosexuality, sexual inhibition/excitation) mediate the perception and evaluation of male faces thereby influencing women's preferences. We used fMRI to measure brain activity in twelve women as they evaluated pictures of male faces (half 30% masculinized, half 30% feminized). Participants were heterosexual women, age 23-28, who were not in a committed relationship and not using hormonal contraception. Women were tested during both the follicular and luteal phase of their menstrual cycle. We found five brain regions related to face and risk processing that responded more to the masculinized than to the feminized faces, including the superior temporal gyrus, precentral gyrus, posterior cingulate cortex, inferior parietal lobule, and anterior cingulate cortex. Increased activation in the anterior cingulate cortex, specifically, may indicate that women perceive masculinized faces to be both more risky and more attractive. We did not see any areas that were more strongly activated by feminized faces. Levels of activation were influenced by hormonal and psychosexual factors. The patterns of hormonally and psychosexually mediated neural activation observed may offer insight into the cognitive processes underlying women's partner preferences.

Neural activation in the orbitofrontal cortex in response to male faces increases during the follicular phase.

Women's sexual interest changes with hormonal fluctuations across the menstrual cycle. It is unclear how hormones modify women's sexual behavior and desire, but one possibility is that they alter women's positive appraisals of stimuli and thus their sexual interest. Using 3 T fMRI, we measured neural activation in women at two time points in their menstrual cycle (late follicular, luteal) while they evaluated photos of men presented as potential sexual partners. Participants were ten heterosexual women aged 23-28 none of who was using hormonal contraceptives or in a committed relationship. In an event-related design, the women were presented with as series of photos of male faces and asked questions to assess their degree of sexual interest in the men depicted. Results demonstrate an overall effect of menstrual cycle phase on neural activation. During their follicular versus luteal phase, women demonstrated increased activation in the right medial orbitofrontal cortex (OFC), suggesting increased positive appraisal. Activation in the OFC was positively correlated with women's estradiol to progesterone ratios. There were no areas that demonstrated increased activation during the luteal versus follicular phase. The observed increase in activation in the OFC during the follicular phase may reflect a hormonally mediated increase in appetitive motivation and may prime women towards increased sexual interest and behavior around ovulation.

The role of the anterior cingulate cortex in women's sexual decision making.

Women's sexual decision making is a complex process balancing the potential rewards of conception and pleasure against the risks of possible low paternal care or sexually transmitted infection. Although neural processes underlying social decision making are suggested to overlap with those involved in economic decision making, the neural systems associated with women's sexual decision making are unknown. Using fMRI, we measured the brain activation of 12 women while they viewed photos of men's faces. Face stimuli were accompanied by information regarding each man's potential risk as a sexual partner, indicated by a written description of the man's number of previous sexual partners and frequency of condom use. Participants were asked to evaluate how likely they would be to have sex with the man depicted. Women reported that they would be more likely to have sex with low compared to high risk men. Stimuli depicting low risk men also elicited stronger activation in the anterior cingulate cortex (ACC), midbrain, and intraparietal sulcus, possibly reflecting an influence of sexual risk on women's attraction, arousal, and attention during their sexual decision making. Activation in the ACC was positively correlated with women's subjective evaluations of sex likelihood and response times during their evaluations of high, but not low risk men. These findings provide evidence that neural systems involved in sexual decision making in women overlap with those described previously to underlie nonsexual decision making.