Carmen Pérez-Laso

The development of brain sex differences : a multisignaling process

In order to account for the development of sex differences in the brain, we took, as an integrative model, the vomeronasal pathway, which is involved in the control of reproductive physiology and behavior. The fact that brain sex differences take place in complex neural networks will help to develop a motivational theory of sex differences in reproductive behaviors. We also address the classic genomic actions in which three agents (the hormone, the intracellular receptor, and the transcription function) play an important role in brain differentiation, but we also point out refinements that such a theory requires if we want to account of the existence of two morphological patterns of sex differences in the brain, one in which males show greater morphological measures (neuron numbers and/or volume) than females and the opposite. Moreover, we also consider very important processes closely related to neuronal afferent input and membrane excitability for the developing of sex differences. Neurotransmission associated to metabotropic and ionotropic receptors, neurotrophic factors, neuroactive steroids that alter membrane excitability, cross-talk (and/or by-pass) phenomena, and second messenger pathways appear to be involved in the development of brain sex differences. The sexual differentiation of the brain and reproductive behavior is regarded as a cellular multisignaling process.

Maternal care counteracts behavioral effects of prenatal environmental stress in female rats

There is extensive evidence in rats that prenatal environmental stress (PES) exposure and early postnatal altered maternal care, as a consequence of stress during gestation, can detrimentally affect the brain and behavioral development of the offspring. In order to separate the effect of PES on the fetuses from that on the behavior of the mother, in the present study, we used a cross-fostering procedure in which PES-fetuses were raised by non-stressed mothers and non PES-fetuses were raised by stressed mothers. In Experiment 1, non-stressed mothers showed significantly more maternal behavior than stressed mothers. In Experiment 2, when the female offspring from Experiment 1 reached maturity, they were tested for: (1) induced maternal behavior (MB), (2) plasma levels of corticosterone (Cpd B), progesterone (P), and estradiol (E(2)), (3) number of accessory olfactory bulb (AOB) mitral cells, and (4) c-fos expression measured in AOB and medial preoptic area (MPOA) neurons. We replicated our previous findings that the PES group reared by their own stressed mothers, when adult, attacked the young, expressed disorganized MB and showed altered Cpd B, P and E(2) levels, plus a male-like neuro-morphological pattern in the AOB, by comparison with the non-PES group, reared by their own non-stressed mothers. By contrast, when adult, the PES group reared by non-stressed mothers showed hormonal and morphological neuronal alterations, but they displayed appropriate (full) MB. The non-PES group raised by stressed mothers also showed altered hormone levels, but showed full MB and no morphological neuronal changes. Significant differences in the AOB and MPOA c-fos activity, related to whether or not MB was expressed, were found in the non-PES groups, but not in the PES group reared by non-stressed mothers. To our knowledge, this is the first study to document that adequate maternal care, early in development, can shape the subsequent expression of induced MB, overcoming neuro-morphological and hormonal alterations that are produced by prenatal environmental stress. We conclude that maternal care during early postnatal development can counteract detrimental effects of prenatal environmental stress, exerting long-lasting effects that modulate the behavioral phenotype of the offspring.

Sexual dimorphism in the vomeronasal system of the rabbit.

Studies have shown that the vomeronasal system (VNS), an olfactory neural network that participates in the control of reproductive physiology and behavior, is sexually dimorphic in the rat. These works have also shown two main characteristics of brain sexual dimorphism: (a) dimorphism appears in neural networks related to reproduction and (b) it can present two morphological patterns: one in which males present greater morphological measures than females (male > female) and another in which the opposite is true (female > male). The present work extends the hypothesis to the rabbit, as a representative species of Lagomorpha. In addition, the locus coeruleus (LC), which is known to send rich noradrenergic projections to VNS structures, was also studied. Sex differences were found in: (a) the number of mitral, and dark and light granule cells (female > male) of the accessory olfactory bulb (AOB); (b) the medial amygdala (Me) and its dorsal (Med) and ventral (Mev) subdivisions, males showing greater values than females in volume and number of neurons, while in the posteromedial cortical amygdala (PMCo or C(3)), females show greater density of neurons than males and (c) the posteromedial division of the bed nucleus of the stria terminalis (BSTMP) in which males have more neurons than females. No sex differences were seen in the bed nucleus of the accessory olfactory tract (BAOT) and the LC. These results evidence that, as it was observed in rodents, sex differences are also seen in the VNS of Lagomorpha and that these sex differences present the two morphological patterns seen in Rodentia. Differences between orders are discussed with respect to the species-specific physiological and behavioral peculiarities.

Early postnatal diazepam exposure alters sex differences in the rat brain

The volume and neuron number of the sexually dimorphic accessory olfactory bulb and locus coeruleus are altered by early postnatal exposure (from the day of birth to postnatal day 16) to diazepam. After diazepam treatment, both volume and neuron number were decreased in the male accessory olfactory bulb and in the female locus coeruleus. These results indicate that early postnatal diazepam administration can bear gender-dependent teratogenic effects upon sexually dimorphic nuclei and suggest that endogenous benzodiazepines may be involved in the sexual differentiation of the brain.

Perinatal administration of diazepam alters sexual dimorphism in the rat accessory olfactory bulb

The present study examines the effects of pre and/or early postnatal administration of diazepam on the mitral cell and on the light and dark granule cell populations in the sexually dimorphic accessory olfactory bulb of the rat. Quantitative differences related to sex were observed in the numbers of the three types of neurons, with vehicle males showing greater numbers of cells than vehicle females. The number of mitral cells in males decreased to the levels shown by female rats following prenatal and pre-postnatal diazepam treatments, whereas the DZ treatments did not affect the females. In addition, the diazepam administration during the prenatal, postnatal and pre-postnatal periods decreased the numbers of both light and dark granule cells in males, while these two granule cell subpopulations were not affected in diazepam treated females. These results indicate that perinatal administration of diazepam can alter the sexual dimorphism in the accessory olfactory bulb and that the GABAA/benzodiazepine receptor complex is involved in the sexual differentiation this part of the brain.

Environmental prenatal stress alters sexual dimorphism of maternal behavior in rats

The prenatal external environment can affect fetuses, altering the maternal behavior that they express when mature. In the present study, environmental prenatal stress (EPS) was applied to pregnant rats in their final week of gestation, and when their female offspring reached maturity, the long latency effect of the stress on those offspring was ascertained on their induced maternal behavior (MB), accessory olfactory bulb (AOB) morphology and plasma levels of ACTH and corticosterone (Cpd B). EPS reduced: the percentage of these virgins that showed induced MB, their retrieval of foster pups, the time spent crouching, and the quality of nest building; it also increased the incidence of their cannibalism of foster pups. The EPS-treated females presented a male-like pattern of induced MB. They showed increased plasma levels of ACTH and Cpd B and increased numbers of mitral cells in the AOB. These findings provide evidence that stress applied to the pregnant rat produces long-lasting behavioral, neuroanatomical and hormonal alterations in the female offspring that can be observed when they reach maturity.

Estradiol Masculinizes the Number of Accessory Olfactory Bulb Mitral Cells in the Rat

Orchidectomized males injected with a single dose of estradiol benzoate on the day of birth (D1) showed mitral cell numbers in the accessory olfactory bulb similar to those of control males. However, orchidectomized males that received no additional estradiol benzoate treatment and those orchidectomized and given a single dose of dihydrotestosterone on D1 showed decreases in the number of accessory olfactory bulb mitral cells compared with control males. These results support the notion that the presence of estradiol immediately after birth induces the masculinization of mitral cells number in the accessory olfactory bulb.

Effects of perinatal diazepam exposure on the sexually dimorphic rat locus coeruleus

Diazepam (DZ) administration over prenatal, postnatal, and pre plus postnatal periods altered the normal expression of the morphological sex differences of the LC. Males were affected only by the prenatal exposure and the effect of this exposure produced an increase in the volume and neuron number of males LC. By contrast, females were affected by both pre and postnatal treatments and the effect of this exposure resulted in a decrease in the volume and neuron number of females LC. However, pre plus postnatal treatment did not affect females LC.

Effects of estradiol on the development of sexual dimorphism in the bed nucleus of the accessory olfactory tract in the rat

Orchidectomized males injected with a single dose of estradiol benzoate (EB) on the day of birth (D1) showed a volume and neuron number in the nucleus of the accessory olfactory tract (BAOT) similar to that of control males. However, orchidectomized males and those orchidectomized and given a single dose of DHT on D1 showed a decrease in BAOT volume and neuron number with respect to control males. These results support the notion that estradiol induces the morphological masculinization of this structure. The inability of DHT in counteracting the effect of orchidectomy is addressed taking into account the inhibitory action of androgens.

Effects of perinatal diazepam administration on two sexually dimorphic nonreproductive behaviors

The effects of prenatal and/or early postnatal diazepam (DZ) administration on open field activity and continuously reinforced lever-pressing response were studied. Rat pups of both sexes were prenatally (during the last week of pregnancy) and/or postnatally (from the day of birth to day 16) daily exposed to a 2.5 mg/kg dose of DZ. At the age of 60 days all groups were tested in the open field for 5 consecutive days and thirty days later they were studied in a continuously reinforced lever-pressing situation during four consecutive days. In the open field test, females showed greater activity than males and prenatal and/or early postnatal DZ treatments did not alter this sexual dimorphism, although all treatments decreased the open field activity in both male and female 60-day-old rats. In the Skinner box, 90-day-old males presented higher rates of lever-pressing response than females, and only the early postnatal DZ treatment was effective in altering this sexual dimorphism, by decreasing the males but not females rates of response. These results are discussed in regard to the possible interaction between DZ and gonadal hormones during the early sexual differentiation period.