Thyroid hormones mediate the impact of early-life stress on ventral tegmental area gene expression and behavior.

Proper thyroid function is essential to the developing brain, including dopamine neuron differentiation, growth, and maintenance. Stress across the lifespan impacts thyroid hormone signaling and anxiety disorders and depression have been associated with thyroid dysfunction (both hypo- and hyper-active). However, less is known about how stress during postnatal development impacts thyroid function and related brain development. Our previous work in mice demonstrated that early-life stress (ELS) transiently impinged on expression of a transcription factor in dopamine neurons, Otx2, shown to be regulated by thyroid hormones. We hypothesized that thyroid hormone signaling may link experience of ELS with transcriptional dysregulation within the dopaminergic midbrain, and ultimately behavior. Here, we find that ELS transiently increases thyroid-stimulating hormone levels (inversely related to thyroid signaling) in both male and female mice at P21, an effect which recovers by adolescence. We next tested whether transient treatment of ELS mice with synthetic thyroid hormone (levothyroxine, LT4) could ameliorate the impact of ELS on sensitivity to future stress, and on expression of genes related to dopamine neuron development and maintenance, thyroid signaling, and plasticity within the ventral tegmental area. Among male mice, but not females, juvenile LT4 treatment prevented hypersensitivity to adult stress. We also found that rescuing developmental deficits in thyroid hormone signaling after ELS restored levels of some genes altered directly by ELS, and prevented alterations in expression of other genes sensitive to the second hit of adult stress. These findings suggest that thyroid signaling mediates the deleterious impact of ELS on VTA development, and that temporary treatment of hypothyroidism after ELS may be sufficient to prevent future stress hypersensitivity.

Thyroid hormones mediate the impact of early-life stress on ventral tegmental area gene expression and behavior.

Proper thyroid function is essential to the developing brain, including dopamine neuron differentiation, growth, and maintenance. Stress across the lifespan impacts thyroid hormone signaling and anxiety disorders and depression have been associated with thyroid dysfunction (both hypo- and hyper-active). However, less is known about how stress during postnatal development impacts thyroid function and related brain development. Our previous work in mice demonstrated that early-life stress (ELS) transiently impinged on expression of a transcription factor in dopamine neurons shown to be regulated by thyroid hormones. We hypothesized that thyroid hormone signaling may link experience of ELS with transcriptional dysregulation within the dopaminergic midbrain, and ultimately behavior. Here, we find that ELS transiently increases thyroid-stimulating hormone levels (inversely related to thyroid signaling) in both male and female mice at P21, an effect which recovers by adolescence. We next tested whether transient treatment of ELS mice with synthetic thyroid hormone (levothyroxine, LT4) could ameliorate the impact of ELS on sensitivity to future stress, and on expression of genes related to dopamine neuron development and maintenance, thyroid signaling, and plasticity within the ventral tegmental area. Among male mice, but not females, juvenile LT4 treatment prevented hypersensitivity to adult stress. We also found that rescuing developmental deficits in thyroid hormone signaling after ELS restored levels of some genes altered directly by ELS, and prevented alterations in expression of other genes sensitive to the second hit of adult stress. These findings suggest that thyroid signaling mediates the deleterious impact of ELS on VTA development, and that temporary treatment of hypothyroidism after ELS may be sufficient to prevent future stress hypersensitivity.

Reactivation of Early-Life Stress-Sensitive Neuronal Ensembles Contributes to Lifelong Stress Hypersensitivity.

Early-life stress (ELS) is one of the strongest lifetime risk factors for depression, anxiety, suicide, and other psychiatric disorders, particularly after facing additional stressful events later in life. Human and animal studies demonstrate that ELS sensitizes individuals to subsequent stress. However, the neurobiological basis of such stress sensitization remains largely unexplored. We hypothesized that ELS-induced stress sensitization would be detectable at the level of neuronal ensembles, such that cells activated by ELS would be more reactive to adult stress. To test this, we leveraged transgenic mice to genetically tag, track, and manipulate experience-activated neurons. We found that in both male and female mice, ELS-activated neurons within the nucleus accumbens (NAc), and to a lesser extent the medial prefrontal cortex, were preferentially reactivated by adult stress. To test whether reactivation of ELS-activated ensembles in the NAc contributes to stress hypersensitivity, we expressed hM4Dis receptor in control or ELS-activated neurons of pups and chemogenetically inhibited their activity during experience of adult stress. Inhibition of ELS-activated NAc neurons, but not control-tagged neurons, ameliorated social avoidance behavior following chronic social defeat stress in males. These data provide evidence that ELS-induced stress hypersensitivity is encoded at the level of corticolimbic neuronal ensembles.SIGNIFICANCE STATEMENT Early-life stress enhances sensitivity to stress later in life, yet the mechanisms of such stress sensitization are largely unknown. Here, we show that neuronal ensembles in corticolimbic brain regions remain hypersensitive to stress across the life span, and quieting these ensembles during experience of adult stress rescues stress hypersensitivity.

Oxytocin receptor is not required for social attachment in prairie voles.

Prairie voles are among a small group of mammals that display long-term social attachment between mating partners. Many pharmacological studies show that signaling via the oxytocin receptor (Oxtr) is critical for the display of social monogamy in these animals. We used CRISPR mutagenesis to generate three different Oxtr-null mutant prairie vole lines. Oxtr mutants displayed social attachment such that males and females showed a behavioral preference for their mating partners over a stranger of the opposite sex, even when assayed using different experimental setups. Mothers lacking Oxtr delivered viable pups, and parents displayed care for their young and raised them to the weanling stage. Together, our studies unexpectedly reveal that social attachment, parturition, and parental behavior can occur in the absence of Oxtr signaling in prairie voles.

Introduction to Special Issue on Affective Science in Animals: Toward a Greater Understanding of Affective Processes in Non-Human Animals.

How should we characterize the affective lives of non-human animals? There is a large body of work studying affective processes in non-human animals, yet this work is frequently overlooked. Ideas about the affective lives of animals have varied across culture and time and are reflected in literature, theology, and philosophy. Our contemporary ideas about animal affect are philosophically important within the discipline of affective science, and these ideas have consequences in several domains, including animal husbandry, conservation, and human and veterinary medicine. The articles contained within this special volume cover several levels of analysis and broad representation of species, from the non-mammalian, to rodents, to primates; but together, these articles are collectively concerned with the topic of affective processes in non-human animals.

Neuroimaging of human and non-human animal emotion and affect in the context of social relationships.

Long-term relationships are essential for the psychological wellbeing of humans and many animals. Positive emotions and affective experiences (e.g., romantic or platonic love) seem to be closely related to the creation and maintenance of social bonds. When relationships are threatened or terminated, other emotions generally considered to be negative can arise (e.g., jealousy or loneliness). Because humans and animals share (to varying degrees) common evolutionary histories, researchers have attempted to explain the evolution of affect and emotion through the comparative approach. Now brain imaging techniques allow the comparison of the neurobiological substrates of affective states and emotion in human and animal brains using a common methodology. Here, we review brain imaging studies that feature emotions characterized by the context of social bonding. We compare imaging findings associated with affective and emotional states elicited by similar social situations between humans and animal models. We also highlight the role of key neurohormones (i.e., oxytocin, vasopressin, and dopamine) that jointly support the occurrence of socially contextualized emotions and affect across species. In doing so, we seek to explore and clarify if and how humans and animals might similarly experience social emotion and affect in the context of social relationships.

Interactions between the κ opioid system, corticotropin-releasing hormone and oxytocin in partner loss.

Selective adult social attachments, or 'pair bonds', represent central relationships for individuals in a number of social species, including humans. Loss of a pair mate has emotional consequences that may or may not diminish over time, and that often translate into impaired psychological and physical health. In this paper, we review the literature on the neuroendocrine mechanisms for the emotional consequences of partner loss, with a special focus on hypothesized interactions between oxytocin, corticotropin-releasing hormone and the κ opioid system. This article is part of the theme issue 'Interplays between oxytocin and other neuromodulators in shaping complex social behaviours'.

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.

Longitudinal Trajectories and Inter-parental Dynamics of Prairie Vole Biparental Care.

For altricial mammalian species, early life social bonds are constructed principally between offspring and their mothers, and the mother-offspring relationship sets the trajectory for offspring bio-behavioral development. In the rare subset of monogamous and biparental species, offspring experience an expanded social network which includes a father. Accordingly, in biparental species fathers also have the potential to influence trajectories of offspring development. Previous semi-natural and laboratory study of one monogamous and biparental species, the prairie vole (Microtus ochrogaster), has given insight into the role that mothers and fathers play in shaping behavioral phenotypes of offspring. Of particular interest is the influence of biparental care in the development of monogamous behavior in offspring. Here, we first briefly review that influence. We then present novel research which describes how parental investment in prairie voles changes across sequential litters of pups, and the extent to which it is coordinated between mothers and fathers. We use approximately 6 years of archival data on prairie vole parenting to investigate trajectories and inter-parent dynamics in prairie vole parenting. We use a series of latent growth models to assess the stability of parental investment across the first 4 l. Our findings suggest that prairie voles display sexually dimorphic patterns of change in parental behavior: mothers' investment declines linearly whereas fathers' pattern of change is characterized by initial decline between litters 1 and 2 with subsequent increase from litters 2 to 4. Our findings also support a conclusion that prairie vole paternal care may be better characterized as compensatory-that is, fathers may compensate for decline in maternal investment. Opposing trends in investment between mothers and fathers ultimately imply stability in offspring investment across sequential litters. These findings, combined with previous studies, generate a hypothesis that paternal compensation could play an important role in maintaining the development of monogamous behavioral phenotypes in individual offspring and across cohorts of those offspring. Understanding longitudinal and inter-individual dynamics of complex social behaviors is critical for the informed investigation of both proximate and ultimate mechanisms that may subserve these behaviors.

Titi Monkeys as a Novel Non-Human Primate Model for the Neurobiology of Pair Bonding
.

It is now widely recognized that social bonds are critical to human health and well-being. One of the most important social bonds is the attachment relationship between two adults, known as the pair bond. The pair bond involves many characteristics that are inextricably linked to quality of health, including providing a secure psychological base and acting as a social buffer against stress. The majority of our knowledge about the neurobiology of pair bonding comes from studies of a socially monogamous rodent, the prairie vole (Microtus ochrogaster), and from human imaging studies, which inherently lack control. Here, we first review what is known of the neurobiology of pair bonding from humans and prairie voles. We then present a summary of the studies we have conducted in titi monkeys (Callicebus cupreus)-a species of socially monogamous New World primates. Finally, we construct a neural model based on the location of neuropeptide receptors in the titi monkey brain, as well as the location of neural changes in our imaging studies, with some basic assumptions based on the prairie vole model. In this model, we emphasize the role of visual mating stimuli as well as contributions of the dopaminergic reward system and a strong role for the lateral septum. This model represents an important step in understanding the neurobiology of social bonds in non-human primates, which will in turn facilitate a better understanding of these mechanisms in humans.