Sex differences in the rodent medial prefrontal cortex - What Do and Don't we know?

The prefrontal cortex, particularly its medial subregions (mPFC), mediates critical functions such as executive control, behavioral inhibition, and memory formation, with relevance for everyday functioning and psychopathology. Despite broad characterization of the mPFC in multiple model organisms, the extent to which mPFC structure and function vary according to an individual's sex is unclear - a knowledge gap that can be attributed to a historical bias for male subjects in neuroscience research. Recent efforts to consider sex as a biological variable in basic science highlight the great need to close this gap. Here we review the knowns and unknowns about how rodents categorized as male or female compare in mPFC neuroanatomy, pharmacology, as well as in aversive, appetitive, and goal- or habit-directed behaviors that recruit the mPFC. We propose that long-standing dogmatic concepts of mPFC structure and function may not remain supported when we move beyond male-only studies, and that empirical challenges to these dogmas are warranted. Additionally, we note some common pitfalls in this work. Most preclinical studies operationalize sex as a binary categorization, and while this approach has furthered the inclusion of non-male rodents it is not as such generalizable to what we know of sex as a multidimensional, dynamic variable. Exploration of sex variability may uncover both sex differences and sex similarities, but care must be taken in their interpretation. Including females in preclinical research needs to go beyond the investigation of sex differences, improving our knowledge of how this brain region and its subregions mediate behavior and health. This article is part of the Special Issue on "PFC circuit function in psychiatric disease and relevant models".

Rodent models of stress and dendritic plasticity - Implications for psychopathology.

Stress, as commonplace as it is, is a major environmental risk factor for psychopathology. While this association intuitively, anecdotally, and empirically makes sense, we are still very early in the process of understanding what the neurobiological manifestations of this risk truly are. Seminal work from the past few decades has established structural plasticity in the brain as a potential key mechanism. In this review we discuss evidence linking particularly chronic stress exposure in rodent models to plasticity at the dendrites, like remodeling of dendritic branches and spines, in a range of brain regions. A number of candidate mechanisms that seek to explain how stress influences neuroanatomy at this level have been proposed, utilizing in vivo, ex vivo and in vitro methods. However, a large gap still remains in our knowledge of how such dynamic structural changes ultimately relate to downstream effects such as altered affective and cognitive states relevant for psychopathology. We propose that future work expand our understanding of plasticity of specific stress-related brain circuits and cell-types. We also note that the vast majority of the work has been conducted solely on male rodents. The next big strides in our understanding of the neurobiology of psychopathology will require the inclusion of female subjects, as several studies have suggested both sex divergent and convergent features. By understanding plasticity, we can harness it. The growth of this body of knowledge will inform our efforts to improve the therapeutic options for stress-related psychopathology.

Sex-specific effects of early life stress on social interaction and prefrontal cortex dendritic morphology in young rats.

Early life stress has been linked to depression, anxiety, and behavior disorders in adolescence and adulthood. The medial prefrontal cortex (mPFC) is implicated in stress-related psychopathology, is a target for stress hormones, and mediates social behavior. The present study investigated sex differences in early-life stress effects on juvenile social interaction and adolescent mPFC dendritic morphology in rats using a maternal separation (MS) paradigm. Half of the rat pups of each sex were separated from their mother for 4h a day between postnatal days 2 and 21, while the other half remained with their mother in the animal facilities and were exposed to minimal handling. At postnatal day 25 (P25; juvenility), rats underwent a social interaction test with an age and sex matched conspecific. Distance from conspecific, approach and avoidance behaviors, nose-to-nose contacts, and general locomotion were measured. Rats were euthanized at postnatal day 40 (P40; adolescence), and randomly selected infralimbic pyramidal neurons were filled with Lucifer yellow using iontophoretic microinjections, imaged in 3D, and then analyzed for dendritic arborization, spine density, and spine morphology. Early-life stress increased the latency to make nose-to-nose contact at P25 in females but not males. At P40, early-life stress increased infralimbic apical dendritic branch number and length and decreased thin spine density in stressed female rats. These results indicate that MS during the postnatal period influenced juvenile social behavior and mPFC dendritic arborization in a sex-specific manner.

Estrogen mediates sex differences in stress-induced prefrontal cortex dysfunction.

Many anxiety disorders, as well as major depressive disorder (MDD), are at least twice as prevalent in women as in men, but the neurobiological basis of this discrepancy has not been well studied. MDD is often precipitated by exposure to uncontrollable stress, and is frequently characterized by abnormal or disrupted prefrontal cortex (PFC) function. In animals, exposure to stress has been shown to cause PFC dysfunction, but sex differences in this effect have not been investigated. The present study tested male and female rats on a PFC-dependent working memory task after administration of FG7142, a benzodiazepine inverse agonist that activates stress systems in the brain. Female rats were impaired by lower doses than males during proestrus (high estrogen), but not during estrus (low estrogen). Similarly, ovariectomized females showed increased stress sensitivity only after estrogen replacement. These results suggest that estrogen amplifies the stress response in PFC, which may increase susceptibility to stress-related disorders.

The radiology identification card and charge card: an addressographic radiographic film borrowing system.

We describe a system using an addressograph card and tickler file to facilitate the lending and returning of radiographic jackets, which brings into accountability both the borrower and the lender.

Severe hypertension. Treatment with minoxidil.

Seventeen patients who were partially or totally refractory to maximal doses of conventional antihypertensive agents were treated with minoxidil. Three patients were receiving long-term maintenance dialysis. Propranolol and diuretics were given to prevent reflex tachycardia and fluid retention. Initial control of blood pressure was excellent in 16 patient. In one patient, diastolic blood pressure remained unchanged (120 mm Hg) despite 60 mg of minoxidil and volume depletion. In three other patients, secondary resistance developed, and the addition of guanethidine was necessary. The main side-effects were fluid retention (in eight) and hypertrichosis (in ten), accompanied in some by a peculiar coarsening of the facial features. Renal function stabilized or improved in most, and urine output increased in the three hemodialysis patients. We conclude that minoxidil is a valuable drug in severe hypertension.