Dll1 haploinsufficiency causes brain abnormalities with functional relevance.

Introduction: The Notch pathway is fundamental for the generation of neurons during development. We previously reported that adult mice heterozygous for the null allele of the gene encoding the Delta-like ligand 1 for Notch (Dll1lacZ ) have a reduced neuronal density in the substantia nigra pars compacta. The aim of the present work was to evaluate whether this alteration extends to other brain structures and the behavioral consequences of affected subjects. Methods: Brains of Dll1 +/lacZ embryos and mice at different ages were phenotypically compared against their wild type (WT) counterpart. Afterwards, brain histological analyses were performed followed by determinations of neural cell markers in tissue slices. Neurological deficits were diagnosed by applying different behavioral tests to Dll1 +/lacZ and WT mice. Results: Brain weight and size of Dll1 +/lacZ mice was significantly decreased compared with WT littermates (i.e., microcephaly), a phenotype detected early after birth. Interestingly, enlarged ventricles (i.e., hydrocephalus) was a common characteristic of brains of Dll1 haploinsufficient mice since early ages. At the cell level, general cell density and number of neurons in several brain regions, including the cortex and hippocampus, of Dll1 +/lacZ mice were reduced as compared with those regions of WT mice. Also, fewer neural stem cells were particularly found in the adult dentate gyrus of Dll1 +/lacZ mice but not in the subventricular zone. High myelination levels detected at early postnatal ages (P7-P24) were an additional penetrant phenotype in Dll1 +/lacZ mice, observation that was consistent with premature oligodendrocyte differentiation. After applying a set of behavioral tests, mild neurological alterations were detected that caused changes in motor behaviors and a deficit in object categorization. Discussion: Our observations suggest that Dll1 haploinsufficiency limits Notch signaling during brain development which, on one hand, leads to reduced brain cell density and causes microcephaly and hydrocephalus phenotypes and, on the other, alters the myelination process after birth. The severity of these defects could reach levels that affect normal brain function. Therefore, Dll1 haploinsufficiency is a risk factor that predisposes the brain to develop abnormalities with functional consequences.

Behavioral consequences of postnatal undernutrition and enriched environment during later life.

In rat models, large litter groups during suckling are used in the study of undernutrition. Large litter sizes are known to promote alterations in memory processes and anxiety-like behavior. Nevertheless, the effect of large litter size on sexual behavior and the reproductive system is still unknown. Environmental enrichment has been reported to (EE) enhance behavior and to correct some of the alterations produced by postnatal undernutrition. We used the Elevated Plus Maze (EPN), Morris Water Maze (MWM), Object Recognition test (OR) and several parameters of sexual behavior to determine the effect of large litter size on rats exposed to enriched and non-enriched environments. Newborn Wistar rats of both sexes were assigned to be suckled under lactation conditions, in litters of 8 pups or 16 pups. The large litter size (16 pups) caused a reduction in weight gain during the lactation period. On PND 45, four experimental groups were established for both sexes: Well-nourished Non-enriched (WN); Well-nourished Enriched (WE); undernourished Non-enriched (UN); Undernourished Enriched (UE). On PND 90, the UN males spent more time in the open arms on EPM. On PND 100, the UE females increased the latency to find the platform in training days (D1-4) in MWM. On probe day (D5) the UE males spent more time in the target quadrants in MWM. On PND 110, irrespective of EE the large litter size had increased the exploration time in both groups (UN) and (UE) in OR test. On PND 120, the performance of sexual behavior was more evident by effect of EE irrespective of the litter size. In conclusion, the large litter size showed no effects on sexual behavior, in contrast, EE has a sharp influence on sexual behavior. Conversely, memory processes and anxiety-like behavior are altered by large litter size.

Chronic sleep loss disrupts blood-testis and blood-epididymis barriers, and reduces male fertility.

Sleep loss increases blood-brain barrier permeability. As the blood-brain barrier and the blood-tissue barriers in the reproductive tract (blood-testis and blood-epididymis barriers) share common characteristics, we hypothesized that sleep restriction may also modify their barrier function. Previous reports showed that sleep loss decreased sperm viability and progressive fast mobility, which may be a consequence of altered blood-testis and blood-epididymis barrier. Therefore, we quantified changes in blood-testis and blood-epididymis barrier after sleep loss and related them to male fertility. Adult male Wistar rats were sleep restricted using the multiple-platform technique in a protocol of 20 hr daily sleep deprivation plus 4 hr of sleep recovery in the home-cage. At the 10th day, barrier permeability assays were performed with Na-fluorescein, 10 kDa Cascade blue-dextrans and Evans blue, and the expression of tight junction proteins, actin and androgen receptor was quantified. At the 10th day of sleep restriction and after sleep recovery days 1-7, males were placed with sexually receptive females, sexual behaviour was tested, and the percentage of pregnancies was calculated. Sleep restriction increased the barrier permeability to low- and high-molecular-weight tracers, and decreased the expression of tight junction proteins, actin and androgen receptor. Concomitantly, sleep restriction reduced the percentage of ejaculating males and the number of pregnancies. Sleep recovery for 2-3 days progressively re-established fertility, as indicated by a higher percentage of ejaculating males and impregnated females. In conclusion, chronic sleep loss alters fertility concomitantly with the disruption of the blood-tissue barriers at the reproductive tract, the mechanism involves androgen signalling.

Protein kinase inhibitors infused intraventricularly or into the ventromedial hypothalamus block short latency facilitation of lordosis by oestradiol.

An injection of unesterified oestradiol (E2 ) facilitates receptive behaviour in E2 benzoate (EB)-primed, ovariectomised female rats when it is administered i.c.v. or systemically. The present study tested the hypothesis that inhibitors of protein kinase A (PKA), protein kinase G (PKG) or the Src/mitogen-activated protein kinase (MAPK) complex interfere with E2 facilitation of receptive behaviour. In Experiment 1, lordosis induced by i.c.v. infusion of E2 was significantly reduced by i.c.v. administration of Rp-cAMPS, a PKA inhibitor, KT5823, a PKG inhibitor, and PP2 and PD98059, Src and MAPK inhibitors, respectively, between 30 and 240 minutes after infusion. In Experiment 2, we determined whether the ventromedial hypothalamus (VMH) is one of the neural sites at which those intracellular pathways participate in lordosis behaviour induced by E2 . Administration of each of the four protein kinase inhibitors into the VMH blocked facilitation of lordosis induced by infusion of E2 also into the VMH. These data support the hypothesis that activation of several protein kinase pathways is involved in the facilitation of lordosis by E2 in EB-primed rats.

Cyclic alternating pattern in infants with congenital hypothyroidism.

Congenital hypothyroidism is defined as thyroid hormone deficiency present at birth which is crucial for brain development. Recently, the cyclic alternating pattern, a rhythm present in electroencephalography recordings in non-Rapid eye movement sleep, has been related to brain development and cognition in different pediatric conditions. Therefore, we evaluated the cyclic alternating pattern rate in infants with congenital hypothyroidism, thyroxine supplementation, and healthy controls. The parameters of the cyclic alternating pattern were evaluated in 19 healthy infants (10 female, mean age 25.5 ±â€¯15.5 months) and 21 infants diagnosed with congenital hypothyroidism (19 female, mean age 24.3 ±â€¯19.0 months). We considered the transient electro-cortical activations (phase A of the cycle) in non-Rapid eye movement sleep and the subdivisions of the A phase in: A1, A2 and A3, based on their frequency content. All subjects were subjected to polysomnography recording in a standard laboratory setting. Sleep data were stored computer following the International 10-20 System. Data showed that congenital hypothyroidism infants exhibited higher frequency of central apnea, hypopnea, and arousals in comparison to controls. Particularly, central apnea index decreased with age in the control group but not in congenital hypothyroidism group. Regarding to cyclic alternating pattern measurements, congenital hypothyroidism infants exhibit a higher frequency in the percentage of A3 subtype (electroencephalographic desynchrony) and conversely a lower percentage of A1 subtype (electroencephalographic synchrony), than healthy infants. An important finding of this study is the positive correlation between A1 mean duration and age, which is bigger in control group than in congenital hypothyroidism group (time duration in control group (0.52 s/month) versus congenital hypothyroidism group (0.1 s/month). Infants with congenital hypothyroidism showed an increase of A3 subtype, of central apnea, and of arousals. The reduction of percentage and mean duration of A1 subtype could be a valuable indicator of sleep development in patients with congenital hypothyroidism and healthy infants.

Postnatal overnutrition alters the orexigenic effects of melanin-concentrating hormone (MCH) and reduces MCHR1 hypothalamic expression on spontaneous feeding and fasting.

One of the approaches to induce obesity in rodents consists in reducing litter size to 3 pups during the lactation period. Animals submitted to this manipulation are heavier, hyperphagic and develop several metabolic diseases for the rest of their lives. In the present study, under the premise that melanin-concentrating hormone (MCH), an orexigenic peptide synthesized by neurons of the lateral hypothalamus, is involved in food intake regulation, we aimed to measure the hypothalamic expression of its receptor, MCHR1, in adult early overfed obese animals and normoweight controls at both ad libitum and food deprived conditions. Additionally, we administered MCH, or an antiMCH antibody, into the third ventricle of ad libitum-fed rats, or fasted rats, respectively, and evaluated chow consumption. Typical nocturnal hyperphagia in rodents was elevated in obese animals compared to normoweight controls, accompanied by a lower expression of MCHR1 and leptin receptor (Ob-R). Following a 24 h fasting, MCHR1 remained lower in SL rats. After 4 h of re-feeding, obese animals ate more than normoweight controls. MCH failed to enhance appetite in early overfed obese animals and immunoneutralization of the peptide only reduced fasted induced-hyperphagia in normoweight controls. These results support the notion that both peptide and brain endogenous MCH exert a physiological relevant action in food intake regulation in normoweight rats, but that postnatal overnutrition disturbs this system, as reflected by MCHR1 downregulation at both ad libitum and fasted conditions and in the lack of response to MCH in both positive- and negative-energetic states in early overfed obese animals.

A2A Adenosine Receptor Antagonism Reverts the Blood-Brain Barrier Dysfunction Induced by Sleep Restriction.

Chronic sleep restriction induces blood-brain barrier disruption and increases pro-inflammatory mediators in rodents. Those inflammatory mediators may modulate the blood-brain barrier and constitute a link between sleep loss and blood-brain barrier physiology. We propose that adenosine action on its A2A receptor may be modulating the blood-brain barrier dynamics in sleep-restricted rats. We administrated a selective A2A adenosine receptor antagonist (SCH58261) in sleep-restricted rats at the 10th day of sleep restriction and evaluated the blood-brain barrier permeability to dextrans coupled to fluorescein (FITC-dextrans) and Evans blue. In addition, we evaluated by western blot the expression of tight junction proteins (claudin-5, occludin, ZO-1), adherens junction protein (E-cadherin), A2A adenosine receptor, adenosine-synthesizing enzyme (CD73), and neuroinflammatory markers (Iba-1 and GFAP) in the cerebral cortex, hippocampus, basal nuclei and cerebellar vermis. Sleep restriction increased blood-brain barrier permeability to FITC-dextrans and Evans blue, and the effect was reverted by the administration of SCH58261 in almost all brain regions, excluding the cerebellum. Sleep restriction increased the expression of A2A adenosine receptor only in the hippocampus and basal nuclei without changing the expression of CD73 in all brain regions. Sleep restriction reduced the expression of tight junction proteins in all brain regions, except in the cerebellum; and SCH58261 restored the levels of tight junction proteins in the cortex, hippocampus and basal nuclei. Finally, sleep restriction induced GFAP and Iba-1 overexpression that was attenuated with the administration of SCH58261. These data suggest that the action of adenosine on its A2A receptor may have a crucial role in blood-brain barrier dysfunction during sleep loss probably by direct modulation of brain endothelial cell permeability or through a mechanism that involves gliosis with subsequent inflammation and increased blood-brain barrier permeability.

D1-like antagonist blocks conditioned place preference induced by ejaculation in male rats.

Mating behavior, particularly ejaculation, induces a state of sexual reward, which is evaluated by the conditioned place preference test. Several studies have shown that opioid receptors are involved in inducing the state of sexual reward, mainly because this state is blocked with naloxone, a mu opioid receptor antagonist. Dopamine has been implicated in sexual motivation, coital behavior and sexual reward, however, some experiments show that D2-like or non-specific dopaminergic antagonists are not capable of blocking the conditioned place preference induced by ejaculation; therefore, the role of dopamine on sexual reward has not been demonstrated, or has been frequently discarded. We show that a dose of SCH 23390 (a specific dopamine D1-like receptor antagonist), which does not modify locomotion, blocks the conditioned place preference induced by ejaculation and the conditioned place preference induced by SKF 38393 (D1-like agonist). Our results indicate that dopamine, across the D1-like receptors, is involved in the sexual reward induced by ejaculation.

Sleep loss as a factor to induce cellular and molecular inflammatory variations.

A reduction in the amount of time spent sleeping occurs chronically in modern society. Clinical and experimental studies in humans and animal models have shown that immune function is impaired when sleep loss is experienced. Sleep loss exerts a strong regulatory influence on peripheral levels of inflammatory mediators of the immune response. An increasing number of research projects support the existence of reciprocal regulation between sleep and low-intensity inflammatory response. Recent studies show that sleep deficient humans and rodents exhibit a proinflammatory component; therefore, sleep loss is considered as a risk factor for developing cardiovascular, metabolic, and neurodegenerative diseases (e.g., diabetes, Alzheimer's disease, and multiple sclerosis). Circulating levels of proinflammatory mediators depend on the intensity and duration of the method employed to induce sleep loss. Recognizing the fact that the concentration of proinflammatory mediators is different between acute and chronic sleep-loss may expand the understanding of the relationship between sleep and the immune response. The aim of this review is to integrate data from recent published reports (2002-2013) on the effects of sleep loss on the immune response. This review may allow readers to have an integrated view of the mechanisms involved in central and peripheral deficits induced by sleep loss.

Role of sleep in the regulation of the immune system and the pituitary hormones.

Sleep is characterized by a reduced response to external stimuli and a particular form of electroencephalographic (EEG) activity. Sleep is divided into two stages: REM sleep, characterized by muscle atonia, rapid eye movements, and EEG activity similar to wakefulness, and non-REM sleep, characterized by slow EEG activity. Around 80% of total sleep time is non-REM. Although it has been intensely studied for decades, the function (or functions) of sleep remains elusive. Sleep is a highly regulated state; some brain regions and several hormones and cytokines participate in sleep regulation. This mini-review focuses on how pituitary hormones and cytokines regulate or affect sleep and how sleep modifies the plasma concentration of hormones as well as cytokines. Also, we review the effects of hypophysectomy and some autoimmune diseases on sleep pattern. Finally, we propose that one of the functions of sleep is to maintain the integrity of the neuro-immune-endocrine system.

Perinatal inhibition of aromatization enhances the reward value of sex.

Paced mating reduces the aversive properties and increases the positive characteristics of mating, inducing a reward state. Pacing is able to induce conditioned place preference (CPP), whereas nonpaced mating does not. The authors hypothesized that the aversive properties of mating are caused by androgens from adjacent males or from the mother during fetal life. To test whether aromatization of androgens induces the aversive properties of mating, female rats were treated perinatally with 1,4,6-androstatriene-3, 17-dione (ATD) to inhibit aromatization. When adults, these females were ovariectomized and hormonally primed to evaluate CPP after paced and nonpaced mating. During paced mating, control females showed higher return latencies after ejaculation, whereas ATD-treated females did not show a similar increase. In CPP tests, both paced and nonpaced mating induced a reward state in ATD-treated females, whereas only paced mating induced a reward state in control females. These results show that the perinatal inhibition of aromatization enhances the rewarding properties of mating, suggesting that estradiol induced the aversive properties of mating and/or modified the perinatal organization of the neuronal pathways in females.

Prenatal blockade of androgen receptors reduces the number of intromissions needed to induce conditioned place preference after paced mating in female rats.

Estrous female rats pace their coital contacts to control the rate of cervical/vaginal stimulation. Females that receive at least 10 paced intromissions develop a reward state, evaluated by conditioned place preference (CPP), whereas females that do not pace their coital contacts do not develop CPP. We asked if the blockade of androgen receptors could modify the number of intromissions needed during paced mating to develop CPP. Pregnant females received daily injections of the androgen receptor antagonist flutamide from day 12 of pregnancy until pups were born. When adults, females exposed prenatally to flutamide or vehicle were ovariectomized and hormonally primed to evaluate if paced and non-paced mating induced CPP. The prenatal flutamide treatment did not affect the capacity of females to develop CPP to a systemic morphine injection. Flutamide-treated females that paced their sexual contacts developed CPP with fewer intromissions than control females. No effect on conditioning was observed when females were not allowed to pace their sexual contacts. The results suggest the existence of a threshold of cervical/vaginal stimulation that correlates with the induction of a reward state and that this threshold can be reduced by prenatal blockade of androgen receptors.

Background matters: the effects of estrogen receptor alpha gene disruption on male sexual behavior are modified by background strain.

One approach to study interactions between behavior and genetics is to use inbred mice with different genetic backgrounds. To examine the effect of background on a specific gene, we conducted a series of experiments with a well-characterized knockout (KO) mouse, the estrogen receptor alpha KO (ERalphaKO). The ERalphaKO mouse has so far been examined in one inbred line, C57BL/6J. Here, we examined the behavior of ERalphaKO mice within three different backgrounds mixed with C57BL/6J; DBA/2J, BALB/c, and A/J. First, we assessed masculine sexual behavior in both intact male and testosterone-treated female offspring. More ERalphaKO males in the DBA/2J (5/12) and BALB/c (5/13) backcrosses displayed intromissions and many ejaculated as compared with males in a C57BL/6J and A/J mixed background. Many fewer ERalphaKO females than males displayed masculine sexual behavior in any of the three hybrid crosses. We assessed fertility in males from the C57BL/6J by DBA/2J cross and found that one of 12 ERalphaKO males sired a litter. Several other characteristics of sexual behavior and physiology were unaffected by genetic background in ERalphaKO mice. Our data suggest that genetic background has dramatic effects on male sexual behavior and its dependence on the ERalpha gene.

Differential effects of rapid eye movement sleep deprivation and immobilization stress on blood lymphocyte subsets in rats.

OBJECTIVES: There is growing evidence of the relationship between sleep and the immune response. Studies aimed at elucidating the function of rapid eye movement (REM) sleep have found it difficult to separate the effects due to REM sleep deprivation and the effects due to the stress produced by the deprivation procedure. It has been claimed that immobilization is the main stressor that the animals have to face during the deprivation process. In this study, we analyzed the effects of short-term (24 h) and long-term (240 h) REM sleep deprivation on the distribution of lymphocyte subsets in the peripheral blood of rats. In addition, these effects were compared with those obtained after both short- and long-term stress by immobilization. METHODS: Lymphocyte population bearing surface markers such as CD5 (T cells), CD45RA (B cells), CD4 (T helper/inducer cells), CD8 (T suppressor/cytotoxic cells) and CD161 (NK cells) were analyzed using monoclonal antibodies. Lymphocyte subsets were assessed by flow cytometry. RESULTS: Both short- and long-term REM sleep deprivation decreased the percentage of T lymphocytes and induced a significant increase in NK cells. Short-term immobilization induced only a significant increase in the percentage of B lymphocytes and a decrease in the percentage of T lymphocytes, while long-term immobilization did not elicit any change. CONCLUSION: The present results support the notion that REM sleep deprivation and immobilization stress each exert particular effects on the immune system. These data suggest that the characteristics of the immune response will depend on the nature of the behavioral manipulation.

Progestins and place preference conditioning after paced mating.

When female rats pace their coital interaction, a reward state evaluated by conditioned place preference is induced. Progesterone (P) is essential for the expression of proceptive behavior and for the induction of CPP. However, the functional significance of ring A reduction of P for the induction of this state during estrous is unsettled. In the present study, we evaluated whether ring A-reduced metabolites of P are involved in the reward state induced when the females are allowed to pace their sexual contacts. Ovariectomized (ovx) female rats treated with estradiol benzoate (EB, 5 microg) and P (13 microg), Megestrol acetate (MA; 13 microg ), 5 alpha-pregnan-20 dione (5 alphaDHP; 3 microg), or 5 beta-pregnan-3 alpha-ol-20-one (5 beta,3 alpha-Pgl; 3 microg) were used. Progestins were dissolved in propylene glycol and intravenously (iv) injected through an indwelling jugular catheter before females were tested for pacing behavior. After 15 intromissions or one ejaculation, females were gently placed in the nonpreferred compartment of a CPP box. Paced mating in all groups treated with progestins induced a clear change of preference. The administration of progestins alone did not induce CPP. These results suggest that P and ring A-reduced metabolites facilitate the reward state following pacing.

Facilitation of male-like coital behavior in female rats by kindling.

Kindling is a model of epilepsy and brain plasticity. When applied to the medial preoptic area (MPOA) of non-copulating male rats kindling induces masculine sexual behavior. In order to test if kindling could facilitate male-like coital behavior in female rats, sexually naive females were ovariectomized and kindled in the amygdala (AMG) or the MPOA until an intermediate stage (between 1 and 3, MPOA1-3) or until stage 5 (MPOA5 group). Once kindling was established, females were treated with 2.5 mg/Kg of testosterone propionate (TP) for 15 days. Male-like coital behavior was evaluated on days 5, 10 and 15 of treatment. Subjects were then injected with a TP dose of 5 mg/kg for 15 days and tested in the same way as with the lower dose. The number of mounts was significantly increased and the mount latency was significantly reduced in the MPOA1-3 group when tested 5 days after treatment with the low dose of TP. The same facilitation was observed in MPOA1-3 and MPOA5 groups on day 10 of treatment with the low dose of TP. When the animals were under the high dose of TP treatment, the number of intromissions was increased in all experimental groups (including the AMG kindled group) in comparison to sham animals. In a second experiment we evaluated if the facilitation of male-like coital behavior induced by kindling was produced by a modification of the response of the vomeronasal system to sexually relevant cues. Ovariectomized females were stimulated until they reached kindling stage 2, then they were treated with 2.5 mg/kg of TP for 5 days. After animals were exposed for 90 min to clean sawdust or sawdust soiled by estrous females they were perfused. Fos was detected by immunocytochemistry along the vomeronasal pathway. No differences were found in Fos responses between sham and MPOA kindled females. The facilitation of masculine sexual behavior observed in AMG kindled females may be a consequence of the propagation of the AD to other brain regions involved in the expression of masculine sexual behavior. We propose that masculine sexual behavior is facilitated in MPOA kindled female rats by local neural changes produced by this kind of stimulation without modifying the response of the vomeronasal system to sexually relevant cues.

Effect of prenatal androgen receptor antagonist or aromatase inhibitor on sexual behavior, partner preference and neuronal Fos responses to estrous female odors in the rat accessory olfactory system.

Many socially relevant odors are detected in rodent species by the vomeronasal organ and subsequently processed by the accessory olfactory system (AOS). We previously found that gonadectomized male and female rats treated in adulthood with testosterone propionate (TP) showed equivalent Fos responses in the AOS to odors derived from estrous females. Likewise, in contrast with numerous other mammalian species, gonadectomized female rats show surprisingly high levels of male-typical mounting behavior in response to adult TP. We tested the hypothesis that prenatal testosterone (T) exposure, acting via androgen receptors (ARs) or via estrogen receptors, masculinizes the AOS in rats of both sexes. Pregnant dams were treated with either the AR blocker, Flutamide, the aromatase inhibitor, 1,4,6-androstatriene-3,17-dione (ATD), or nothing (control) to assess the role of prenatal androgen and estradiol receptor activation, respectively, in this masculinization. Beginning at birth, male and female offspring were injected subcutaneously (sc) every other day with either ATD (pre- and neonatal ATD group) or oil vehicle (Flutamide and control groups) until postnatal Day 12. Subjects were gonadectomized as adults, hormonally treated and tested for different behaviors before having their AOS Fos responses to estrous female odors assessed. Prenatal treatment with Flutamide (but not ATD) significantly decreased anogenital distance and severely impaired intromissive and ejaculatory behaviors in males tested after TP replacement without disrupting mounting capacity in either sex. Pre- and neonatal treatment with ATD (but not Flutamide) enhanced lordosis responsiveness in males tested after sc injections of estradiol and progesterone, whereas these perinatal treatments had no effect on any aspect of masculine coital performance in either sex. After TP treatment, male and female control subjects preferred to approach a tethered stimulus female as opposed to a male, and prenatal Flutamide or perinatal ATD treatments did not modify this pattern of partner preference. Neuronal Fos responses to estrous odors were (as in previous studies) identical in the AOS of gonadectomized TP-treated control males and females. Prenatal Flutamide or perinatal ATD treatments failed to disrupt consistently this profile of Fos responses to estrous odors in the AOS of rats of either sex. These behavioral and neuroanatomical findings raise the possibility that the similar level of male-typical responsiveness to social odors that occurs in male and female rats after adult TP treatment results from nonsteroid-hormone-dependent, species-specific factors that act perinatally in the brains of rats of both sexes.