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In response to NIH initiatives to investigate sex as a biological variable in preclinical animal studies, researchers have increased their focus on male and female differences in neurotrauma. Inclusion of both sexes when modeling neurotrauma is leading to the identification of novel areas for therapeutic and scientific exploitation. Here, we review the organizational and activational effects of sex hormones on recovery from injury and how these changes impact the long-term health of spinal cord injury SCI patients. When determining how sex affects SCI it remains imperative to expand outcomes beyond locomotor recovery and consider other complications plaguing the quality of life of patients with SCI.

Interestingly, the SCI field predominately utilizes female rodents for basic science research which contrasts most other male-biased research fields. We discuss the unique caveats this creates to the translatability of preclinical research in the SCI field. We also review current clinical and preclinical data examining sex as biological variable in SCI. Further, we report how technical considerations such as housing, size, care management, and age, confound the interpretation of sex-specific effects in animal studies of SCI.

We have uncovered novel findings regarding how age differentially affects mortality and injury-induced anemia in males and females after SCI, and further identified estrus cycle dysfunction in mice after injury. Emerging concepts underlying sexually dimorphic responses to therapy are also discussed. Through a combination of literature review and primary research observations we present a practical guide for considering and incorporating sex as biological variable in preclinical neurotrauma studies.

In most areas of scientific study, knowledge gained from both pre-clinical and clinical research is based upon a disproportionate inclusion of male subjects. Implications of this male-dominated research are that guidelines developed from medical literature often neglect sex-based differences in basic pathophysiology of disease and treatment responses. Modeling medical practice on such limited demographics and failure to advance our understanding of disease, injury, and treatment in the context of sex-based differences have manifested into practices that are emerging as not just ineffective, but sometimes dangerous, to the health of women.

In recent years, likely owing to this mandate, findings from animal models of many neurological conditions have begun exposing exactly how important sex-dependent effects in medicine can be. This manuscript evaluates work that has considered sex as a biological variable in neurotrauma with specific emphasis on spinal cord injury SCI. Further, we provide novel primary data demonstrating that sex effects in SCI can depend on age at time of injury. Because pre-clinical work comparing male and female responses to SCI is limited, outcomes are frequently paralleled to findings in traumatic brain injury TBI.

A recent and more thorough review of sex effects on TBI can be found elsewhere 2. Finally, methodological considerations for assimilating sex as a biological variable in SCI studies are discussed owing to a substantial increase in the complexity of study de and interpretation. Materials and methods used to construct Figures 2 — 5 have been provided in Supplementary Materials.

Data provided in Figures 2 — 5 is primary data used to articulate sex-dependent relationships important for the consideration of studying sex in pre-clinical models of SCI. The first observations of sex differences in neurotrauma found that men experience a higher frequency of cerebral infarcts 3 and increased mortality compared to women 45.

Meta-analyses of clinical data in SCI patients have found mixedwith a tendency for females to experience improved recovery compared to male counterparts in measures of motor capabilities and independence 6. Differences in demographic characteristics between males and females, however, introduce several caveats that complicate the interpretation of how sex affects SCI recovery.

In contrast, on average females tend to receive SCI at an older age 89. Older age at time of SCI can exacerbate injuries 10 — 12 and mechanisms of primary trauma at older ages are often caused by less forceful events such as slip and fall accidents compared to vehicular and sporting accidents or acts of violence However, even when age is controlled, in the clinical setting, females recover better than males 6. Finally, emergent work in animal models has also reproduced a small but ificant protective effect of being female following SCI 14 — The extent to which sex influences outcomes following SCI remains controversial based on existing clinical and pre-clinical data.

Several rodent studies have confirmed a female-biased protection on locomotor outcomes after SCI 14 — 17while others have found no differences 18 Most prior work supporting sex-dependent effects after SCI have limited evaluations to locomotor outcomes and white matter sparing, which found marginal improvements favoring females. However, problems facing patients suffering from SCI extend beyond an inability to walk. Following cervical SCI, which makes up Indeed, relieving these secondary complications is of highest priority for individuals with SCI Therefore, it is necessary to expand pre-clinical outcomes beyond locomotor disability to determine if sex differences exist in other modalities of SCI-induced dysfunction and to understand what underlying biological processes mediate these effects.

Unlike reports of locomotor functions, clinical reports suggest that no differences exist between males and females in the development or severity of bowel or bladder incontinence 25or in the frequency of developing urinary tract infections However, females do have a higher clinical incidence for reporting development of SCI-induced pain 27 What little work has been done in animal models to compare a sex-dependency of pain development after SCI has also demonstrated controversial .

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Female rats have been reported to both increase 29 and decrease 30 the prevalence of developing mechanical and thermal allodynia after SCI, while no sex-dependent effects have been found in mice 31 Importantly, several studies investigating analgesic strategies to reduce pain caused by peripheral nerve injury have converging evidence that many pain-relieving agents exert sexually dichotomous effects 33 — A similar sex-dependent effect was found using pioglitazone to treat SCI-induced pain in mice which found a female-specific analgesic influence These findings suggest that while the experience of SCI-induced pain may not differ between sexes in mice, biological mechanisms regulating pain may differ between males and females.

Extrapolating these findings to other outcomes may suggest that despite small sex-dependent effects in outcomes of locomotion or pain, the biological mechanisms underlying dysfunction may differ and require different strategies for treatment. The investigation of sex-specific effects in animal models of neurotrauma has predominately focused on how sex hormones mediate tissue protection Due to a higher prevalence and fluctuation of estrogens and progesterone in females, it is reasonable to hypothesize that female sex hormones are neuroprotective.

Two major de strategies have been employed to support this hypothesis in vivo following neurotrauma. These include ovariectomies to partially deplete estrogens and progesterone, as well as exogenous delivery of estrogens and progesterone in both female and male rodents prior to injury 539 — Ovariectomies normalize tissue and functional outcomes between sexes, a finding consistent following both TBI 40 and SCI This supports female sex hormones as being modestly neuroprotective. Using estrogens or high-dose progesterone as treatments for neurotrauma has persistently improved outcomes following SCI, TBI, and stroke in both males and females 53942 — The influence of female hormones on recovery from neurotrauma has led to an appraisal that inclusion of females adds too much variability to data due to the fluctuation of estrogens and progesterone during the estrus cycle, which scientists use as an argument to exclude the use of females in most pre-clinical research.

A belief that hormonal fluctuations during the estrous cycle adds variability to research outcomes is contributing to the exclusion of females in most pre-clinical neurotrauma modeling. Data analyses of NIH-funded, rodent, primary research publications demonstrate that females are the sole sex used in the vast majority of SCI experiments Figure 1.

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This may change, as our data compiled from freely available publicationslikely does not yet reflect NIH programmatic changes enacted in to consider sex as a biological variable in vertebrate animal research. Nonetheless, male rodents are not often used when modeling SCI due to more severe post-operative complications and difficulty with manual bladder expressions which are required after experimental paralysis. These severe, male-specific, postoperative complications confound research efforts by increasing mortality and exclusion of subjects due to adverse health issues.

A bias against male rodents in pre-clinical models of SCI has created a unique incongruence between clinical and pre-clinical demographics because the predominant clinical demographic is young males. In fact, the smallest SCI demographics seen in clinic are young and elderly females 89 This would argue that even if females were to be used, middle-aged female rodents would serve as a more clinically translatable model. Considering that neither young males, nor middle-aged females are commonly used to model SCI, including these additional variables may be essential for improving translatability of pre-clinical findings.

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Figure 1. Of studies utilizing both male and female rodents, only one study explicitly reported on how data between sexes were compared and included in analysis The importance of including both sexes in pre-clinical SCI research is emphasized by findings that support sex-dependent effects in both locomotor 1516and non-locomotor outcomes such as pain 29 An accumulation of recent work is finding that the pathophysiology of injury is fundamentally different between males and females 50 Similarly, males and females have sex-specific considerations for long-term care 2752and biological differences can alter response to treatment 3135 The rest of this manuscript will discuss how several physiological processes differ between males and females and highlight how these differences affect injury, recovery, and living with SCI.

As mentioned above for sex hormones, the investigation of sex-specific effects in animal models of neurotrauma has predominately focused on activational changes. However, sex-specific organizational effects, those that occur during development and throughout life, shape the nervous system at a structural and cellular level and contribute to sex differences in behavior and functional responses In the brain neuronal cell s in discrete areas differ between males and females which are established during the organizational period of hormone exposure Similar sex differences in astrocytes and microglia cell s and morphology have been reported However, little has been performed evaluating sex differences in the spinal cord outside of the regulatory centers controlling male and female sex organs These neuroanatomical differences are hypothesized to be mediated by perinatal exposure to steroids, specifically a prenatal surge of testosterone occurring in males late in gestation and a second surge occurring immediately after birth 57 One example of sex differences arising during spinal cord development is observed in the spinal nucleus of the bulbocavernosus SNB ; a pool of motoneurons in the lower lumbar spinal cord.

SNB motoneurons project to striated muscles of the perineum which attach to the base of the penis and are required for an erection and ejaculation 59 Male rats have more cells in the SNB compared to females Developmentally, SNB motoneurons initially form in both sexes but degenerate in females around the time of birth In addition to the neurotrophic als from the muscles, androgens and estrogens have been shown to permanently establish this sex difference early in development.

The lumbar spinal cord houses neurons and central pattern generators controlling functions that are disrupted by SCI including pain responses as well as locomotor, bowel, and bladder functions. Whether other organizational effects exist within the spinal cord and contribute to sex-specific injury responses remain to be determined. Organizational effects during development also confer innate sex-differences in epigenetic profiles and cell morphology that do not depend on ongoing sex hormone aling 61 For example, early developmental exposure to sex hormones is thought to induce a permanent sexual phenotype of glial cells 62which recently has been demonstrated in brain microglia Microglia display a sex-dependent morphology, with female microglia having a more ramified morphology compared to males

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Considerations for Studying Sex as a Biological Variable in Spinal Cord Injury