Effects of paternal deprivation on empathetic behavior and the involvement of oxytocin receptors in the anterior cingulate cortex.

Paternal deprivation (PD) impairs social cognition and sociality and increases levels of anxiety-like behavior. However, whether PD affects the levels of empathy in offspring and its underlying mechanisms remain unknown. The present study found that PD increased anxiety-like behavior in mandarin voles (Microtus mandarinus), impaired sociality, reduced the ability of emotional contagion, and the level of consolation behavior. Meanwhile, PD reduced OT neurons in the paraventricular nucleus (PVN) in both male and female mandarin voles. PD decreased the level of OT receptor (OTR) mRNA in the anterior cingulate cortex (ACC) of male and female mandarin voles. Besides, OTR overexpression in the ACC reversed the PD-induced changes in anxiety-like behavior, social preference, emotional contagion, and consolation behavior. Interference of OTR expression in the ACC increased levels of anxiety-like behaviors, while it reduced levels of sociality, emotional contagion, and consolation. These results revealed that the OTR in the ACC is involved in the effects of PD on empathetic behaviors, and provide mechanistic insight into how social experiences affect empathetic behaviors.

Paternal deprivation induces vigilance-avoidant behavior and accompanies sex-specific alterations in stress reactivity and central proinflammatory cytokine response in California mice (Peromyscus californicus).

RATIONALE: Early-life stress (ELS) can increase anxiety, reduce prosocial behaviors, and impair brain regions that facilitate emotional and social development. This knowledge greatly stems from assessing disrupted mother-child relationships, while studies investigating the long-term effects of father-child relationships on behavioral development in children are scarce. However, available evidence suggests that fathers may uniquely influence a child's behavioral development in a sex-specific manner. Rodent models examining mother-offspring interaction demonstrate relationships among ELS, neuroinflammatory mediators, and behavioral development; yet, the role paternal care may play in neuroimmune functioning remains unreported. OBJECTIVES: Using the biparental California mouse (Peromyscus californicus), we examined to what extent paternal deprivation impairs social and anxiety-like behaviors, augments peripheral corticosterone (CORT) response, and alters central proinflammatory cytokine production following an acute stressor in adulthood. METHODS: Biparentally reared and paternally deprived (permanent removal of the sire 24 h post-birth) adult mice were assessed for sociability, preference for social novelty, social vigilance, and social avoidance behaviors, followed by novelty-suppressed feeding (NSF) testing for general anxiety-like behavior. Following an acute stressor, circulating CORT concentrations and region-specific proinflammatory cytokine concentrations were determined via radioimmunoassay and Luminex multianalyte analysis, respectively. RESULTS: In response to a novel same-sex conspecific, social vigilance behavior was associated with reduced sociability and increased avoidance in paternally deprived mice-an effect not observed in biparentally reared counterparts. Yet, in response to a familiar same-sex conspecific, social vigilance persisted but only in paternally deprived females. The latency to consume during NSF testing was not significantly altered by paternal deprivation. In response to an acute physical stressor, lower circulating CORT concentrations were observed in paternally deprived females. Compared to control-reared males, paternal deprivation increased hypothalamic interleukin-1ß, but decreased hippocampal IL-6 protein concentration. CONCLUSION: Greater social vigilance behavior was demonstrated in paternally deprived mice while they avoided social interaction with a novel same-sex conspecific; however, in response to a familiar same-sex conspecific, paternal deprivation increased social vigilance behavior but only in females. It is possible that different neurobiological mechanisms underlie these observed behavioral outcomes as sex-specific central proinflammatory cytokine and stress responsivity were observed in paternally deprived offspring.

Ausencia paterna en la infancia: vivencias en personas con enfermedad mental / Paternal absence in childhood: experiences of people with mental illnesses / Ausência paterna na infância: viver em pessoas com doença mental

Resumen (analítico) El objetivo del estudio consistió en comprender los fenómenos que emergen de la experiencia de la ausencia paterna durante la infancia del adulto con diagnóstico de enfermedad mental. La investigación se desarrolló mediante el análisis cualitativo de las narrativas recogidas en ocho entrevistas semiestructuradas; estas se realizaron a cuatro mujeres y cuatro hombres. Se expusieron los resultados según las seis categorías que emergieron del análisis: universo de la ausencia, miedo e incertidumbre, representación e idealización del padre, tristeza y soledad, estigma y diferencia e ícono del sustituto. Según los hallazgos, la ausencia del padre en la infancia de personas con enfermedad mental origina sentimientos y cogniciones de depresión, estigmatización, soledad y desprotección; estas se asocian a vivencias dolorosas e invitan a profundizar en su comprensión y abordaje terapéutico.

Abstract (analytical) The objective of the research was to understand the phenomena that emerged from the experiences of paternal absence during childhood in adults with mental illnesses. This qualitative research was conducted through semi-structured interviews conducted with men and women. The results are grouped into six categories that emerged from the analysis: the universe of absence, fear and uncertainty, representation and idealization of the father, sadness and loneliness, stigma and difference and the icon that is the substitute. Based on the results of the study, the absence of the father in childhood for people with mental illness contributes to feelings of depression, stigmatization, loneliness and lack of protection and are associated with painful experiences that require improved comprehension and a therapeutic approach.

Resumo (analítico) O objetivo do estudo foi compreender os fenômenos que emergem da vivência da ausência paterna na infância do adulto com diagnóstico de doença mental. A pesquisa foi desenvolvida por meio da análise qualitativa das narrativas coletadas em oito entrevistas semiestruturadas, realizadas em quatro mulheres e quatro homens. Os resultados são apresentados de acordo com as seis categorias que emergiram da análise: universo da ausência, medo e incerteza, representação e idealização do pai, tristeza e solidão, estigma e diferença e ícone do substituto. Baseado em descobertas, a ausência do pai na infância de pessoas com transtorno mental provoca sentimentos e cognições de depressão, estigmatização, solidão e falta de proteção, os quais estão associados a experiências dolorosas e convidam a aprofundar sua compreensão e abordagem terapêutica.

Compositional variation in early-life parenting structures alters oxytocin and vasopressin 1a receptor development in prairie voles (Microtus ochrogaster).

Paternal absence can significantly alter bio-behavioural development in many biparental species. This effect has generally been demonstrated by comparing the development of offspring reared under biparental care with those reared by a single mother. However, studies employing this design conflate two significant modifications to early-life experience: removal of father-specific qualities and the general reduction of offspring-directed care. In the socially monogamous prairie vole (Microtus ochrogaster), the experience of paternal absence without substitution during development inhibits partner preference formation in adulthood, a hallmark of social monogamy, in females and males. Employing alloparents as substitutes for fathers, our previous work demonstrated that paternal absence affects pair-bond formation in female offspring via reduced quantity of care, although it affects pair-bond formation in male offspring by means of a missing paternal quality (or qualities). Here, we present evidence that paternal absence (with and without alloparental substitution) may alter the ontogeny of neural oxytocin receptor (OXTR) and/or vasopressin 1a receptor (AVPR1a) distribution in male and female prairie voles. Compared to biparentally reared controls (BPC), male offspring reared in mother only (MON) and maternal-plus-alloparental (MPA) conditions show lower densities of OXTR in the central amygdala; and MPA males show lower densities of OXTR in the caudate putamen and nucleus accumbens. Early-life experience was not associated with differences in AVPR1a density in males. However, MON and MPA females show greater densities of AVPR1a in the medial amygdala than BPC; and MPA females show greater densities of AVPR1a in the ventromedial nucleus of the hypothalamus. We also demonstrate with corticosterone concentrations that MON and MPA offspring are not differentially susceptible to a stressor (ie, social isolation) than BPC offspring. These findings suggest that paternal absence, although likely not a salient early-life stressor, has neuroendocrine consequences for offspring, some of which may affect partner preference formation.

Paternal Deprivation and Female Biparental Family Rearing Induce Dendritic and Synaptic Changes in Octodon degus: I. Medial Prefrontal Cortex.

In most mammalian species parent-offspring interactions during early life periods primarily comprise social contacts with the mother, whereas the role of males in parental care is one of the most overlooked and understudied topics. The present study addressed the hypothesis that the complete deprivation of paternal care delays or permanently retards synaptic connectivity in the brain, particularly in the medial prefrontal cortex (mPFC) of the offspring in a sex-specific manner. Another aim of this study was to address the question whether and in which way replacing the father with a female caregiver (in our experiments the "aunt") can "buffer" the detrimental effects of paternal deprivation on neuronal development. The comparison of: (a) single mother rearing; (b) biparental rearing by father and mother; and (c) biparental rearing by two female caregivers revealed that: (i) paternal care represents a critical environmental factor for synaptic and dendritic development of pyramidal neurons in the vmPFC of their offspring; (ii) a second female caregiver ("aunt") does not "buffer" the neuronal consequences of paternal deprivation; and that (iii) neuronal development in the vmPFC is differentially affected in male and female offspring in response to different family constellations.

Preweaning Paternal Deprivation Impacts Parental Responses to Pups and Alters the Serum Oxytocin and Corticosterone Levels and Oxytocin Receptor, Vasopressin 1A Receptor, Oestrogen Receptor, Dopamine Type I Receptor, Dopamine Type II Receptor Levels in Relevant Brain Regions in Adult Mandarin Voles.

Although maternal separation and neonatal paternal deprivation (PD) have been found to exert a profound and persistent effects on the physiological and behavioural development of offspring, whether preweaning PD (PPD; from PND 10 to 21) affects maternal and parental responses to pups and the underlying neuroendocrine mechanism are under-investigated. Using monogamous mandarin voles (Microtus mandarinus), the present study found that PPD increased the latency to approach a pup-containing ball, decreased the total durations of sniffing and contacting a pup-containing ball and walking and increased the total duration of inactivity in both sexes. Moreover, PPD decreased serum oxytocin levels and increased corticosterone levels, but only in females. Furthermore, in both males and females, PPD decreased the expression of oxytocin receptor mRNA and protein in the medial preoptic area (MPOA), nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC), but increased it in the medial amygdala (MeA) and decreased the expression of oestrogen receptor mRNA and protein in the MPOA. PPD increased the expression of dopamine type I receptor in the NAcc, but decreased it in the mPFC. PPD decreased dopamine type II receptor (D2R) in the NAcc both in males and females, but increased D2R in the mPFC in females and decreased D2R protein expression in males. Moreover, PPD decreased vasopressin 1A receptor (V1AR) in the MPOA, MeA and mPFC, but only in males. Our results suggest that the reduction of parental responses to pups induced by PPD may be associated with the sex-specific alteration of several neuroendocrine parameters in relevant brain regions.

Revisiting paternal absence: Female alloparental replacement of fathers recovers partner preference formation in female, but not male prairie voles (Microtus ochrogaster).

In prairie voles (Microtus ochrogaster), biparental care of offspring is typical, and paternal absence in the pre-weaning development of offspring alters biobehavioral development. We sought to determine whether this altered development is due to the absence of specific paternal qualities or a general reduction in pup-directed care. We compared the biobehavioral development of pups reared under conditions of biparental (BPC), maternal-plus-alloparental (MPA; i.e., mother and older sister), and maternal only (MON) care. Older sisters provided a quantity of care equal to or greater than that of fathers. Growth rate and developmental milestones were unaffected by family composition, with the exception of earlier fur growth in MON conditions. In adulthood, we tested behaviors on an elevated plus maze, spontaneous alloparental care, and partner preference formation. We found no significant differences on the elevated plus maze and only marginal differences in alloparental care. While both female and male MON individuals showed deficits in partner preference formation, MPA females showed typical partner preference formation. However, the alloparental substitution of fathers was not sufficient for the typical development of partner preference formation in males. We conclude that paternal care plays a differentially important role in the social development of female and male prairie vole offspring.

Pre-weaning paternal deprivation impairs social recognition and alters hippocampal neurogenesis and spine density in adult mandarin voles.

Disruption of the early social environment, such as maternal separation or early deprivation, can impair cognitive function, alter offspring neurogenesis and restrict dendritic architecture in the hippocampus. However, whether paternal deprivation during the pre-weaning period affects adult neurogenesis, synaptogenesis and social recognition remains unclear in monogamous species. In the present study, mandarin vole (Microtus mandarinus) pups were deprived of fathers during postnatal day 14-21. Then social recognition, hippocampal neurogenesis and spine density, basal levels of corticosterone (CORT) and oxytocin (OT) were examined at adulthood. We found that paternal deprivation impaired social recognition at adulthood. In addition, paternal deprivation significantly reduced 5-bromo-2-deoxyuidine (BrdU) immunoreactive cells (p < 0.01) and Brdu/Neun-labeled cells (p < 0.05) in the dentate gyrus compared to those of biparental care group in females, but not in males (p > 0.05). Meanwhile, paternal deprivation group had fewer double-staining cells with BrdU and the immature neuron marker doublecortin than biparental care group both in male (p < 0.01) and female (p < 0.05) voles. Paternal deprivation also decreased the number of dendritic spines in the dentate gyrus at adulthood. Paternal deprivation reduced circulating levels of OT and increased CORT only in females. These results demonstrated that impaired social recognition induced by paternal deprivation may be linked with alterations in neurogenesis and spine densityof the dentate gyrus and levels of OT and CORT, especially in females.

Enduring Effects of Paternal Deprivation in California Mice (Peromyscus californicus): Behavioral Dysfunction and Sex-Dependent Alterations in Hippocampal New Cell Survival.

Early-life experiences with caregivers can significantly affect offspring development in human and non-human animals. While much of our knowledge of parent-offspring relationships stem from mother-offspring interactions, increasing evidence suggests interactions with the father are equally as important and can prevent social, behavioral, and neurological impairments that may appear early in life and have enduring consequences in adulthood. In the present study, we utilized the monogamous and biparental California mouse (Peromyscus californicus). California mouse fathers provide extensive offspring care and are essential for offspring survival. Non-sibling virgin male and female mice were randomly assigned to one of two experimental groups following the birth of their first litter: (1) biparental care: mate pairs remained with their offspring until weaning; or (2) paternal deprivation (PD): paternal males were permanently removed from their home cage on postnatal day (PND) 1. We assessed neonatal mortality rates, body weight, survival of adult born cells in the dentate gyrus of the hippocampus, and anxiety-like and passive stress-coping behaviors in male and female young adult offspring. While all biparentally-reared mice survived to weaning, PD resulted in a ~35% reduction in survival of offspring. Despite this reduction in survival to weaning, biparentally-reared and PD mice did not differ in body weight at weaning or into young adulthood. A sex-dependent effect of PD was observed on new cell survival in the dentate gyrus of the hippocampus, such that PD reduced cell survival in female, but not male, mice. While PD did not alter classic measures of anxiety-like behavior during the elevated plus maze task, exploratory behavior was reduced in PD mice. This observation was irrespective of sex. Additionally, PD increased some passive stress-coping behaviors (i.e., percent time spent immobile) during the forced swim task-an effect that was also not sex-dependent. Together, these findings demonstrate that, in a species where paternal care is not only important for offspring survival, PD can also contribute to altered structural and functional neuroplasticity of the hippocampus. The mechanisms contributing to the observed sex-dependent alterations in new cell survival in the dentate gyrus should be further investigated.

Effects of paternal deprivation on cocaine-induced behavioral response and hypothalamic oxytocin immunoreactivity and serum oxytocin level in female mandarin voles.

Early paternal behavior plays a critical role in behavioral development in monogamous species. The vast majority of laboratory studies investigating the influence of parental behavior on cocaine vulnerability focus on the effects of early maternal separation. However, comparable studies on whether early paternal deprivation influences cocaine-induced behavioral response are substantially lacking. Mandarin vole (Microtus mandarinus) is a monogamous rodent with high levels of paternal care. After mandarin vole pups were subjected to early paternal deprivation, acute cocaine- induced locomotion, anxiety- like behavior and social behavior were examined in 45day old female pups, while hypothalamic oxytocin immunoreactivity and serum oxytocin level were also assessed. We found that cocaine increased locomotion and decreased social investigation, contact behavior and serum oxytocin level regardless of paternal care. Cocaine increased anxiety levels and decreased oxytocin immunoreactive neurons of the paraventricular nuclei and supraoptic nuclei in the bi-parental care group, whilst there were no specific effects in the paternal deprivation group. These results indicate that paternal deprivation results in different behavioral response to acute cocaine exposure in adolescents, which may be in part associated with the alterations in oxytocin immunoreactivity and peripheral OT level.

Father absence in the monogamous california mouse impairs social behavior and modifies dopamine and glutamate synapses in the medial prefrontal cortex.

The role of the father in psycho-affective development is indispensable. Yet, the neurobehavioral effects of paternal deprivation (PD) are poorly understood. Here, we examined the behavioral consequences of PD in the California mouse, a species displaying monogamous bonding and biparental care, and assessed its impact on dopamine (DA), serotonin (5-HT), and glutamate (GLU) transmission in the medial prefrontal cortex (mPFC). In adult males, deficits in social interaction were observed, when a father-deprived (PD) mouse was matched with a PD partner. In adult females, deficits were observed when matching a PD animal with a non-PD control, and when matching 2 PD animals. PD also increased aggression in females. Behavioral abnormalities in PD females were associated with a sensitized response to the locomotor-activating effect of amphetamine. Following immunocytochemical demonstration of DA, 5-HT, and GLU innervations in the mPFC, we employed in vivo electrophysiology and microiontophoresis, and found that PD attenuated the basal activity of low-spiking pyramidal neurons in females. PD decreased pyramidal responses to DA in females, while enhancing responses to NMDA in both sexes. We thus demonstrate that, during critical neurodevelopmental periods, PD leads to sex-dependent abnormalities in social and reward-related behaviors that are associated with disturbances in cortical DA and GLU neurotransmission.

Neuroendocrine responses to social isolation and paternal deprivation at different postnatal ages in Mandarin voles.

Neonatal isolation and paternal deprivation have long lasting effects on the behavior and neuroendocrine system at adulthood. Whether these effects at adulthood are induced by neonatal changes in relevant neuroendocrine parameters lead by these early-life social experiences is not well understood. Whether monogamous rodents exhibit a stress hypo-responsive period (SHRP) also remains unclear. Using the monogamous mandarin vole, we found that 30 min of isolation did not affect levels of corticosterone (CORT) and adrenocorticotropin (ACTH) at postnatal days 8, 10, and 12 displaying a SHRP, but increased these at postnatal days 4, 14, 16, and 18. Isolation increased vasopressin (AVP)-ir neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) from postnatal days 4 to 12, and up-regulated oxytocin (OT)-ir neurons in the PVN at postnatal days 4 and 8 and SON at postnatal day 4. Paternally deprived pups showed increase in ACTH and CORT after 30 min of social isolation from postnatal days 8 to 14, increase in AVP-ir neurons in the PVN from postnatal days 10 to 14, reduction in OT-ir neurons in the PVN from postnatal days 10 to 14 and in the SON at postnatal days 12 and 14. These results indicate that monogamous mandarin voles display a short SHRP which can be disrupted by paternal deprivation. Central AVP and OT levels may also be altered by paternal deprivation and social isolation. We propose that changes in these neuroendocrine parameters induced by early-life social experiences such as those tested here persist and result.

Neonatal paternal deprivation impairs social recognition and alters levels of oxytocin and estrogen receptor α mRNA expression in the MeA and NAcc, and serum oxytocin in mandarin voles.

Paternal care is necessary for the healthy development of social behavior in monogamous rodents and social recognition underpins social behavior in these animals. The effects of paternal care on the development of social recognition and underlying neuroendocrine mechanisms, especially the involvement of oxytocin and estrogen pathways, remain poorly understood. We investigated the effects of paternal deprivation (PD: father was removed from neonatal pups and mother alone raised the offspring) on social recognition in mandarin voles (Microtus mandarinus), a socially monogamous rodent. Paternal deprivation was found to inhibit the development of social recognition in female and male offspring according to a habituation-dishabituation paradigm. Paternal deprivation resulted in increased inactivity and reduced investigation during new encounters with other animals. Paternal deprivation reduced oxytocin receptor (OTR) and estrogen receptor α (ERα) mRNA expression in the medial amygdala and nucleus accumbens. Paternal deprivation reduced serum oxytocin (OT) concentration in females, but had no effect on males. Our results provide substantial evidence that paternal deprivation inhibits the development of social recognition in female and male mandarin voles and alters social behavior later in life. This is possibly the result of altered expression of central OTR and ERα and serum OT levels caused by paternal deprivation.