Single units in the medial prefrontal cortex with anxiety-related firing patterns are preferentially influenced by ventral hippocampal activity

The medial prefrontal cortex (mPFC) and ventral hippocampus (vHPC) functionally interact during innate anxiety tasks. To explore the consequences of this interaction, we examined task-related firing of single units from the mPFC of mice exploring standard and modified versions of the elevated plus maze (EPM), an innate anxiety paradigm. Hippocampal local field potentials (LFPs) were simultaneously monitored. The population of mPFC units distinguished between safe and aversive locations within the maze, regardless of the nature of the anxiogenic stimulus. Strikingly, mPFC units with stronger task-related activity were more strongly coupled to theta-frequency activity in the vHPC LFP. Lastly, task-related activity was inversely correlated with behavioral measures of anxiety. These results clarify the role of the vHPC-mPFC circuit in innate anxiety and underscore how specific inputs may be involved in the generation of behaviorally relevant neural activity within the mPFC.     

Olfactory preference in the male rat depends on multiple chemosensory inputs converging on the preoptic area

Both volatile and nonvolatile molecules are involved in chemosensory communication in rodents. Volatile odors from physically inaccessible estrous females induced increased numbers of c-Fos-positive cells in the preoptic area (POA) and in the cortical nucleus of the amygdala (CoA) of male rats. The numbers of c-Fos-positive cells in the medial nucleus of the amygdala (MeA) increased in response to the nonvolatile odors of bedding soiled with the excreta of estrous females. In an alternate choice paradigm, male rats carrying ibotenic acid lesions in either the MeA or the CoA—or a combination of both—distinguished the odors of estrous females from those of males, although the time spent sniffing the stimuli was diminished. Males with POA lesions showed complete loss of this capability. Males carrying either of the lesions did not detect differences between estrous and anestrous females or between intact and orchidectomized males. Lesions in the POA or MeA severely impaired male sexual behavior, whereas a CoA lesion had no effects. Thus, c-Fos-positive cells in the CoA might be involved in chemosensory transmission relevant to certain social contexts, but not in the execution of male sexual behavior. The POA is indispensable for both olfactory preferences and sexual behavior. The residual olfactory preference in males with MeA or CoA lesions or the combination of both could reflect an additional route for chemosensory transmission from the main olfactory bulb to the POA.     

Bisphenol-A exposure during adolescence leads to enduring alterations in cognition and dendritic spine density in adult male and female rats

We have previously demonstrated that adolescent exposure of rats to bisphenol-A (BPA), an environmental endocrine disrupter, increases anxiety, impairs spatial memory, and decreases dendritic spine density in the CA1 region of the hippocampus (CA1) and medial prefrontal cortex (mPFC) when measured in adolescents in both sexes. The present study examined whether the behavioral and morphological alterations following BPA exposure during adolescent development are maintained into adulthood. Male and female, adolescent rats received BPA, 40 μg/kg/bodyweight, or control treatments for one week. In adulthood, subjects were tested for anxiety and locomotor activity, spatial memory, non-spatial visual memory, and sucrose preference. Additionally, stress-induced serum corticosterone levels and dendritic spine density in the mPFC and CA1 were measured. BPA-treated males, but not females, had decreased arm visits on the elevated plus maze, but there was no effect on anxiety. Non-spatial memory, object recognition, was also decreased in BPA treated males, but not in females. BPA exposure did not alter spatial memory, object placement, but decreased exploration during the tasks in both sexes. No significant group differences in sucrose preference or serum corticosterone levels in response to a stress challenge were found. However, BPA exposure, regardless of sex, significantly decreased spine density of both apical and basal dendrites on pyramidal cells in CA1 but had no effect in the mPFC. Current data are discussed in relation to BPA dependent changes, which were present during adolescence and did, or did not, endure into adulthood. Overall, adolescent BPA exposure, below the current reference safe daily limit set by the U.S.E.P.A., leads to alterations in some behaviors and neuronal morphology that endure into adulthood.     

Anxiety-Related Behaviours Associated with microRNA-206-3p and BDNF Expression in Pregnant Female Mice Following Psychological Social Stress

Stress during pregnancy can induce various psychological disorders in women. However, the association linking psychological stress during pregnancy with abnormal behaviours in females remains largely unknown. We employed a novel psychological stress model by introducing pregnant mice to witness the defeat process of their mated partner (WDPMP) and examined the effects of WDPMP on depression-/anxiety-like behaviours and on the expression of brain-derived neurotrophic factor (BDNF) and miR-206-3p in the hippocampus, medial prefrontal cortex (mPFC) and amygdala. Compared to pregnant control (PC) mice, pregnant stressed (PS) mice showed decreased sucrose preference during the late period of gestation, and after lactation, they spent less time in the open arms of the elevated plus maze and in the light chamber of the light/dark box. After lactation, decreased BDNF expression in both the hippocampus and mPFC of PS mice was found to be associated with enhanced miR-206-3p levels; meanwhile, elevated BDNF associated with decreased miR-206-3p expression was evident in the amygdala of the same PS mice. DNA methylation level in the Bdnf promoter did not show difference between PC and PS mice in the hippocampus. Transfection of miR-206-3p resulted in decreased BDNF levels in vitro. These results suggest that WDPMP stress during gestation can induce long-term mood alterations in pregnant mice, which may correlate with changes in miR-206-3p and BDNF expression in the hippocampus, mPFC and amygdala.     

Sex differences in cell migration in the preoptic area/anterior hypothalamus of mice

The preoptic area/anterior hypothalamus (POA/AH) sits as a boundary region rostral to the classical diencephalic hypothalamus and ventral to the telencephalic septal region. Numerous studies have pointed to the region's importance for sex‐dependent functions. Previous studies suggested that migratory guidance cues within this region might be particularly unique in their diversity. To better understand the early development and differentiation of the POA/AH, cytoarchitectural, birthdate, immunocytochemical, and cell migration studies were conducted in vivo and in vitro using embryonic C57BL/6J mice. A medial preoptic nucleus became discernible using Nissl stain in males and females between embryonic days (E) E15 and E17. Cells containing immunoreactive estrogen receptor‐α were detected in the POA/AH by E13, and increased in number with age in both sexes. From E15 to E17, examination of the radial glial fiber pattern by immunocytochemistry confirmed the presence of dual orientations for migratory guidance ventral to the anterior commissure (medial‐lateral and dorsal‐ventral) and uniform orientation more caudally (medial‐lateral). Video microscopy studies followed the migration of DiI‐labeled cells in coronal 250‐μm brain slices from E15 mice maintained in serum‐free media for 1–3 days. Analyses showed significant migration along a dorsal‐ventral orientation in addition to medial‐lateral. The video analyses showed significantly more medial‐lateral migration in males than females in the caudal POA/AH. In vivo, changes in the distribution of cells labeled by the mitotic indicator bromodeoxyuridine (BrdU) suggested their progressive migration through the POA/AH. BrdU analyses also indicated significant movement from dorsal to ventral regions ventral to the anterior commissure. The significant dorsal‐ventral migration of cells in the POA/AH provides additional support for the notion that the region integrates developmental information from both telencephalic and diencephalic compartments. The sex difference in the orientation of migration of cells in the caudal POA/AH suggests one locus for the influence of gonadal steroids in the embryonic mouse forebrain. © 1999 John Wiley & Sons, Inc. J Neurobiol 41: 252–266, 1999     

Neonatal infection produces significant changes in immune function with no associated learning deficits in juvenile rats

The current experiments examined the impact of early‐life immune activation and a subsequent mild immune challenge with lipopolysaccharide (LPS; 25µg/kg) on hippocampal‐dependent learning, proinflammatory cytokine expression in the brain, and peripheral immune function in juvenile male and female rats at P24, an age when hippocampal‐dependent learning and memory first emerges. Our results indicate that neonatal infection did not produce learning deficits in the hippocampal‐dependent context pre‐exposure facilitation effect paradigm in juvenile males and females, contrary to what has been observed in adults. Neonatal infection produced an increase in baseline IL‐1β expression in the hippocampus (HP) and medial prefrontal cortex (mPFC) of juvenile rats. Furthermore, neonatally infected rats showed exaggerated IL‐1β expression in the HP following LPS treatment as juveniles; and juvenile females, but not males, showed exaggerated IL‐1β expression in the mPFC following LPS treatment. Neonatal infection attenuated the production of IL‐6 expression following LPS treatment in both the brain and the spleen, and neonatal infection decreased the numbers of circulating white blood cells in juvenile males and females, an effect that was further exacerbated by subsequent LPS treatment. Together, our data indicate that the consequences of neonatal infection are detectable even early in juvenile development, though we found no concomitant hippocampal‐dependent learning deficits at this young age. These findings underscore the need to consider age and associated on‐going neurodevelopmental processes as important factors contributing to the emergence of cognitive and behavioral disorders linked to early‐life immune activation. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1221–1236, 2017     

Maternal dexamethasone exposure during pregnancy in rats disrupts gonadotropin-releasing hormone neuronal development in the offspring

The migration of gonadotropin-releasing hormone (GnRH) neurons from the olfactory placode to the preoptic area (POA) from embryonic day 13 is important for successful reproduction during adulthood. Whether maternal glucocorticoid exposure alters GnRH neuronal morphology and number in the offspring is unknown. This study determines the effect of maternal dexamethasone (DEX) exposure on enhanced green fluorescent protein (EGFP) driven by GnRH promoter neurons (TG-GnRH) in transgenic rats dual-labelled with GnRH immunofluorescence (IF-GnRH). The TG-GnRH neurons were examined in intact male and female rats at different postnatal ages, as a marker for GnRH promoter activity. Pregnant females were subcutaneously injected with DEX (0.1 mg/kg) or vehicle daily during gestation days 13–20 to examine the number of GnRH neurons in P0 male offspring. The total number of TG-GnRH neurons and TG-GnRH/IF-GnRH neuronal ratio increased from P0 and P5 stages to P47–52 stages, suggesting temporal regulation of GnRH promoter activity during postnatal development in intact rats. In DEX-treated P0 males, the number of IF-GnRH neurons decreased within the medial septum, organum vasculosom of the lamina terminalis (OVLT) and anterior hypothalamus. The percentage of TG-GnRH neurons with branched dendritic structures decreased in the OVLT of DEX-P0 males. These results suggest that maternal DEX exposure affects the number and dendritic development of early postnatal GnRH neurons in the OVLT/POA, which may lead to altered reproductive functions in adults.     

Peri-pubertal exposure to testicular hormones organizes response to novel environments and social behaviour in adult male rats

Previous research has shown that exposure to testicular hormones during the peri-pubertal period of life has long-term, organizational effects on adult sexual behaviour and underlying neural mechanisms in laboratory rodents. However, the organizational effects of peri-pubertal testicular hormones on other aspects of behaviour and brain function are less well understood. Here, we investigated the effects of manipulating peri-pubertal testicular hormone exposure on later behavioural responses to novel environments and on hormone receptors in various brain regions that are involved in response to novelty. Male rodents generally spend less time in the exposed areas of novel environments than females, and this sex difference emerges during the peri-pubertal period. Male Lister-hooded rats (Rattus norvegicus) were castrated either before puberty or after puberty, then tested in three novel environments (elevated plus-maze, light–dark box, open field) and in an object/social novelty task in adulthood. Androgen receptor (AR), oestrogen receptor (ER1) and corticotropin-releasing factor receptor (CRF-R2) mRNA expression were quantified in the hypothalamus, hippocampus and medial amygdala. The results showed that pre-pubertally castrated males spent more time in the exposed areas of the elevated-plus maze and light–dark box than post-pubertally castrated males, and also confirmed that peri-pubertal hormone exposure influences later response to an opposite-sex conspecific. Hormone receptor gene expression levels did not differ between pre-pubertally and post-pubertally castrated males in any of the brain regions examined. This study therefore demonstrates that testicular hormone exposure during the peri-pubertal period masculinizes later response to novel environments, although the neural mechanisms remain to be fully elucidated.     

Apoptosis during sexual differentiation of the bed nucleus of the stria terminalis in the rat brain

The bed nucleus of the stria terminalis (BST) in the rat forebrain differs between males and females. To test whether apoptosis may contribute to the development of sex differences in the BST, the incidence of apoptosis was determined in sham-treated males and sham-treated females sacrificed on postnatal days (PN) 2, 4, 6, 8, 10, and 12 (PN 1 being day of birth). More apoptotic nuclei were found in the principal nucleus of the BST (BSTpr) in females than in males, whereas the reverse was true for the lateral division of the BST (BSTl). Moreover, the volume of the BSTpr was larger in males than in females, whereas there was no sex difference in the volume of the BSTl. Our results also confirmed earlier reports indicating that the incidence of apoptosis in the central part of the medial preoptic nucleus (MPNc) is higher in females than in males. No sex difference in apoptosis was found in the ventromedial hypothalamus (VMH) and paraventricular nucleus (PVN). The volume of the MPNc and VMH was larger in males than in females, whereas the PVN volume did not differ between males and females. To test whether sex differences in neonatal levels of gonadal steroids may cause sex differences in the incidence of apoptosis in the BSTpr, the incidence of apoptosis was compared between castrated males and females that were treated with testosterone propionate or vehicle on the day of birth. In the BSTpr of gonadal steroid-treated animals, the incidence of apoptosis was lower when compared to animals treated with vehicle, which was also true for the MPNc. These results are consistent with the hypothesis that gonadal steroids contribute to the sexually dimorphic differentiation of the BST by controlling the incidence of apoptosis.     

Anxiety-like behaviors in adulthood are altered in male but not female rats exposed to low dosages of polychlorinated biphenyls in utero

Exposure to polychlorinated biphenyls (PCBs), a class of endocrine-disrupting chemicals, can result in altered reproductive behavior in adulthood, especially when exposure occurs during critical periods of brain sexual differentiation in the fetus. Whether PCBs alter other sexually dimorphic behaviors such as those involved in anxiety is poorly understood. To address this, pregnant rat dams were injected twice, on gestational days 16 and 18, with the weakly estrogenic PCB mixture Aroclor 1221 (A1221) at one of two low dosages (0.5 mg/kg or 1.0 mg/kg, hereafter 1.0 and 0.5), estradiol benzoate (EB; 50 μg/kg) as a positive estrogenic control, or the vehicle (3% DMSO in sesame oil). We also conducted a comprehensive assessment of developmental milestones of the F1 male and female offspring. There were no effects of treatment on sex ratio at birth and age at eye opening. Puberty, assessed by vaginal opening in females and preputial separation in males, was not affected in females but was advanced in males treated with A1221 (1.0). Males and females treated with A1221 (both dosages) were heavier in early adulthood relative to controls. The earliest manifestation of this effect developed in males prior to puberty and in females slightly later, during puberty. Anxiety-like behaviors were tested using the light:dark box and elevated plus maze tests in adulthood. In females, anxiety behaviors were unaffected by treatment. Males treated with A1221 (1.0) showed reduced indices of anxiety and increased activity in the light:dark box but not the elevated plus maze. EB failed to replicate the phenotype produced by A1221 for any of the developmental and behavioral endpoints. Collectively, these results indicate that PCBs increase body weight in both sexes, but their effects on anxiety-like behaviors are specific to males. Furthermore, differences between the results of A1221 and EB suggest that the PCBs are likely acting through mechanisms distinct from their estrogenic activity.     

Ontogeny of the sexually dimorphic male nucleus in the preoptic/anterior hypothalamus of ferrets and its manipulation by gonadal steroids

A sexually dimorphic nucleus exists in the dorsal region of the ferret preoptic/anterior hypothalamic area (POA/AH), and is called the male nucleus of the POA/AH (MN-POA/AH) because it is found only in males. Development of the MN-POA/AH was studied in male ferrets, and for comparison a sexually nondimorphic ventral POA/AH nucleus was studied in both sexes. The MN-POA/AH was conspicuous in males as early as embryonic day 37 (E37) of a 41-day gestation, and its volume increased until postnatal day 56 (P56). No nucleus was present in the dorsal POA/AH of females at any age. The densities and average somal areas of cells in the dorsal POA/AH were similar in males and females at E33, before the MN-POA/AH could be visualized. However, at E37 and E41 dorsal cells were greater in density and/or somal area in males than in females, accounting for the appearance of a nucleus in males at these ages. To insure that the dorsal POA/AH nucleus seen in males at E37 and E41 was the presumptive MN-POA/AH present in adult males, pregnant ferrets were given progesterone and either implanted subcutaneously (s.c.) with testosterone (T) or ovariectomized and implanted s.c. with the aromatase inhibitor, 1,4,6-androstatriene-3,17-dione (ATD), on day 30 of gestation. As predicted from previous studies in which subjects were sacrificed in adulthood, formation of a dorsal POA/AH nucleus was promoted in female ferrets by T, and blocked in males by maternal ovariectomy and ATD treatment for animals sacrificed at E41. Much evidence suggests that behavioral sexual differentiation is accomplished in the male ferret between age E28 and P20. The MN-POA/AH is present and potentially functional in males during a considerable portion of this perinatal period.     

GABAergic mediation of stress-induced secretion of corticosterone and oxytocin, but not prolactin, by the hypothalamic paraventricular nucleus

The hypothalamus-pituitary-adrenal axis (HPA) participates in mediating the response to stressful stimuli. Within the HPA, neurons in the medial parvocellular region of paraventricular nucleus (PVN) of the hypothalamus integrate excitatory and inhibitory signals triggering secretion of corticotropin-releasing hormone (CRH), the main secretagogue of adrenocorticotropic hormone (ACTH). Stressful situations alter CRH secretion as well as other hormones, including prolactin and oxytocin. Most inputs to the PVN are of local origin, half of which are GABAergic neurons, and both GABA-A and GABA-B receptors are present in the PVN. The objective of the present study was to investigate the role of GABA-A and GABA-B receptors in the PVN's control of stress-induced corticosterone, oxytocin and prolactin secretion. Rats were microinjected with saline or different doses (0.5, 5 and 50 pmol) of GABA-A (bicuculine) or GABA-B (phaclofen) antagonists in the PVN. Ten minutes later, they were subjected to a stressor (ether inhalation) and blood samples were collected 30 min before and 10, 30, 60, 90 and 120 min after the stressful stimulus to measure hormone levels by radioimmunoassay. Our results indicate that GABA acts in the PVN to inhibit stress-induced corticosterone secretion via both its receptor subtypes, especially GABA-B. In contrast, GABA in the PVN stimulates oxytocin secretion through GABA-B receptors and does not alter prolactin secretion.     

Organizational effects of estrogen on male-type vulnerability to early weaning

We previously reported that early-weaned (postnatal day 14) male ICR mice, compared to normally weaned animals, exhibited a persistent increase in anxiety-related behavior in the elevated plus maze test. In this study, we examined whether steroid hormone manipulations on postnatal day 0 and at the ages of 2 or 3 weeks affected male-type vulnerability to early weaning. Neither castration nor ovariectomy at the age of 3 weeks affected male-type vulnerability. However, in males, castration at the age of 2 weeks attenuated the increased anxiety levels induced by early weaning, and the implantation of testosterone or estradiol, but not of dihydrotestosterone, restored the effects of early weaning. In contrast, in females, neonatal treatment with testosterone propionate together with testosterone at the age of 2 weeks, which reversed sexual behavior to the male type, did not affect anxiety levels in response to early weaning. When pregnant females were repeatedly treated with testosterone propionate on embryonic days 14, 17, and 19, in addition to testosterone treatment at the age of 2 weeks, the anxiety levels in female were increased by early weaning. Furthermore, the prenatal treatment of estradiol benzoate, but not dihydrotestosterone, induced enhanced anxiety levels by early weaning in females. These results suggest that neural systems are masculinized by estrogen from the embryonic phase to the early postnatal period and are responsible for the high levels of anxiety elicited by early weaning.     

Long-lasting consequences of neonatal maternal separation on social behaviors in ovariectomized female mice

Maternal separation (MS) stress is known to induce long-lasting alterations in emotional and anxiety-related behaviors, but effects on social behaviors are not well defined. The present study examined MS effects on female social behaviors in the social investigation (SIT) and social preference (SPT) tests, in addition to non-social behaviors in the open-field (OFT) and light-dark transition (LDT) tests in C57BL/6J mice. All females were tested as ovariectomized to eliminate confounding effects of endogenous estrogen during behavioral testing. Daily MS (3 hr) from postnatal day 1 to 14 did not affect anxiety levels in LDT, but were elevated in OFT with modified behavioral responses to the novel environment. Furthermore, MS altered social investigative behaviors and preference patterns toward unfamiliar stimulus mice in SIT and short- and long-term SPT paradigms. In SIT, MS reduced social investigation duration and increased number of stretched approaches towards both female and male unfamiliar stimulus mice, suggesting increased social anxiety levels in MS females. Similarly, MS heightened levels of social anxiety during short-term SPT but no MS effect on social preference was found. On the other hand, MS females displayed a distinctive preference for female stimuli, unlike control females, when tested for long-term SPT over a prolonged period of 5 days. Evaluation of FosB expression in the paraventricular nucleus, medial and central amygdala following stimulus exposure demonstrated greater number of FosB immunopositive cells in all three brain regions in MS females compared to control females. These results suggest that MS females might differ in neuroendocrine responses toward unfamiliar female and male opponents, which may be associated with modifications in social behaviors found in the present study. Taken together, this study provides new evidence that early life stress modifies female social behaviors by highlighting alterations in behavioral responses to situations involving social as well as non-social novelty.     

Changes in the activity budget of cycling female chimpanzees

This study is a preliminary report on the time allocated to various activities by female wild chimpanzees (Pan troglodytes schweinfurthii) during their sexual cycle. Cycling females with maximal tumescence (estrous females) tended to spend more time moving than cycling females with quiescent sexual skin (anestrous females). Although there was no statistically significant decrease in any specific activity that corresponded to the increase in time spent moving, feeding time did decrease in four of the five females. The frequency of approach by females toward males and the frequency of approach by males toward females significantly increased when females were in estrus. Direct aggression by males occurred more frequently toward estrous females than toward anestrous females. The copulation frequency and the frequency of approach to males was not significantly correlated with the increase in time spent moving. There was a high but not significant correlation between the time spent moving and the frequency of direct aggression by males toward females. Mating effort, feeding competition, male aggression, and other possible reasons that might explain the increase in moving time are discussed. Am. J. Primatol. 46:157–166, 1998. © 1998 Wiley-Liss, Inc.     

Effects of 5-HT1A receptor agonist and antagonist on anxiety in intact and ovariectomized female rats

The purpose of this work was to study the role of 5-HT1A receptors on the level of anxiety in adult intact and ovariectomized (OVX) female rats. The influence of chronic administration of 5-HT1A receptor agonist 8-OH-DPAT (0.05 mg/kg, s.c.) and 5-HT1A receptor antagonist NAN-190 (0.1 mg/kg, i.p.) given for 14 days alone or in combination with 17beta-estradiol (0.5 microg i.m./rat/day) was studied on behavior in the elevated plus maze. In intact females administration of NAN-190 resulted in significant increase in the number of enterings and the time spent on the open arms in every phase of the estrous cycle, however, 8-OH-DPAT failed to modify these parameters. In OVX females 8-OH-DPAT alone or in combination with 17beta-estradiol significantly increased the number of enterings and time spent on the open arms. On the contrary, NAN-190 alone or in combination with 17beta-estradiol in OVX females failed to evoke behavioral changes in the elevated plus maze. Thus, the 5-HT1A receptor antagonist NAN-190 induced anxiolytic effect in intact female rats, while 5-HT1A receptor agonist 8-OH-DPAT produced an anxiolytic profile on OVX rats. Results of this work specify the involvement of 5-HT1A receptors in behavioral mechanisms of anxiety in OVX female rats.     

Exploratory patterns of rats on a complex maze provide evidence for topological coding

Rats' exploratory patterns on a complex elevated maze were analyzed in both light and dark conditions. Rats were less active in the light than in the dark. In the light, they spent more time exploring the outer areas of the maze than the inner areas whereas exploration of both regions was similar in the dark. In both light and dark, rats spent more time investigating choice points (which provided multiple directions for movements) than runways that allowed only simple movements. In addition, choice points that provided more connections with other distant places were associated with more exploration. While such effects might be the result of stimulus-seeking of distant information in the light, increased exploration times in the dark presumably reflect the processing of local information associated with the maze connectivity. These results suggest that exploratory patterns in the dark reflect processing of the topological structure of the maze.     

Sex differences in cell migration in the preoptic area/anterior hypothalamus of mice.

The preoptic area/anterior hypothalamus (POA/AH) sits as a boundary region rostral to the classical diencephalic hypothalamus and ventral to the telencephalic septal region. Numerous studies have pointed to the region's importance for sex-dependent functions. Previous studies suggested that migratory guidance cues within this region might be particularly unique in their diversity. To better understand the early development and differentiation of the POA/AH, cytoarchitectural, birthdate, immunocytochemical, and cell migration studies were conducted in vivo and in vitro using embryonic C57BL/6J mice. A medial preoptic nucleus became discernible using Nissl stain in males and females between embryonic days (E) E15 and E17. Cells containing immunoreactive estrogen receptor-alpha were detected in the POA/AH by E13, and increased in number with age in both sexes. From E15 to E17, examination of the radial glial fiber pattern by immunocytochemistry confirmed the presence of dual orientations for migratory guidance ventral to the anterior commissure (medial-lateral and dorsal-ventral) and uniform orientation more caudally (medial-lateral). Video microscopy studies followed the migration of DiI-labeled cells in coronal 250-microm brain slices from E15 mice maintained in serum-free media for 1-3 days. Analyses showed significant migration along a dorsal-ventral orientation in addition to medial-lateral. The video analyses showed significantly more medial-lateral migration in males than females in the caudal POA/AH. In vivo, changes in the distribution of cells labeled by the mitotic indicator bromodeoxyuridine (BrdU) suggested their progressive migration through the POA/AH. BrdU analyses also indicated significant movement from dorsal to ventral regions ventral to the anterior commissure. The significant dorsal-ventral migration of cells in the POA/AH provides additional support for the notion that the region integrates developmental information from both telencephalic and diencephalic compartments. The sex difference in the orientation of migration of cells in the caudal POA/AH suggests one locus for the influence of gonadal steroids in the embryonic mouse forebrain.     

Estrogen receptor alpha influences socially motivated behaviors

Male mice lacking estrogen receptor alpha (ERalphaKO) show reduced social behaviors. We hypothesized that this might be due to either socially elicited or generalized anxiety. Male ERalphaKOs and wild type (WT) mice were given a series of behavioral tests: elevated plus maze, T-maze, and social recognition. Each test included a social dimension by exposing males to ovariectomized (OVX) females. In addition plasma concentrations of corticosterone were measured, and open field activity was assessed. In the elevated plus maze, WT males exposed to an OVX female 1 min prior to the test were more anxious than WT controls. ERalphaKO males showed anxiety in this test whether or not they were preexposed to a female. In the T-maze, WT males increased exploration of a novel arm when it contained an OVX female. The presence or absence of a female in a novel arm did not affect behavior of ERalphaKO males. In social recognition tests, ERalphaKO males spent less time than WT littermates investigating an OVX female that was repeatedly introduced into their home cage. On the final trial, when a novel female was introduced, WT males increased their chemo-investigation but ERalphaKOs did not. Plasma corticosterone levels were lower in ERalphaKO than in WT males when plasma was taken directly after a brief (control) cage disturbance. In the open field WT and ERalphaKO males behaved essentially the same. Taken together, the results of these experiments suggest the ERalphaKO males avoid contact with other conspecifics, perhaps due to an inability to be aroused by social cues.     

HP1BP3 expression determines maternal behavior and offspring survival

Maternal care is an indispensable behavioral component necessary for survival and reproductive success in mammals, and postpartum maternal behavior is mediated by an incompletely understood complex interplay of signals including effects of epigenetic regulation. We approached this issue using our recently established mice with targeted deletion of heterochromatin protein 1 binding protein 3 (HP1BP3), which we found to be a novel epigenetic repressor with critical roles in postnatal growth. Here, we report a dramatic reduction in the survival of pups born to Hp1bp3^?/? deficient mouse dams, which could be rescued by co‐fostering with wild‐type dams. Hp1bp3^?/? females failed to retrieve both their own pups and foster pups in a pup retrieval test, and showed reduced anxiety‐like behavior in the open‐field and elevated‐plus‐maze tests. In contrast, Hp1bp3^?/? females showed no deficits in behaviors often associated with impaired maternal care, including social behavior, depression, motor coordination and olfactory capability; and maintained unchanged anxiety‐associated hallmarks such as cholinergic status and brain miRNA profiles. Collectively, our results suggest a novel role for HP1BP3 in regulating maternal and anxiety‐related behavior in mice and call for exploring ways to manipulate this epigenetic process.