The neurobiology of parenting and infant-evoked aggression

Abstract

Parenting behavior comprises a variety of adult-infant and adult-adult interactions across multiple timescales. The state transition from nonparent to parent requires an extensive reorganization of individual priorities and physiology and is facilitated by combinatorial hormone action on specific cell types that are integrated throughout interconnected and brainwide neuronal circuits. In this review, we take a comprehensive approach to integrate historical and current literature on each of these topics across multiple species, with a focus on rodents. New and emerging molecular, circuit-based, and computational technologies have recently been used to address outstanding gaps in our current framework of knowledge on infant-directed behavior. This work is raising fundamental questions about the interplay between instinctive and learned components of parenting and the mutual regulation of affiliative versus agonistic infant-directed behaviors in health and disease. Whenever possible, we point to how these technologies have helped gain novel insights and opened new avenues of research into the neurobiology of parenting. We hope this review will serve as an introduction for those new to the field, a comprehensive resource for those already studying parenting, and a guidepost for designing future studies.

Keywords: behavior; cell types; circuits; hormones; parenting.

FIGURE 1.

The many facets of parenting. Here we describe 3 broad categories of parenting behaviors: (1) offspring-directed behaviors; (2) adult-directed behaviors; and (3) physiological changes. (1) Parenting involves many distinct behaviors directed towards offspring. These behaviors are highly dependent on the species, sex, and mating status of the individual, as well as the social structure of the group. Often, but not always, the specific behavior is similar in males vs. females or parents vs. alloparents. Finally, infanticide is an offspring-directed behavior observed in both males and females, but typically for distinct purposes. (2) Becoming a parent changes how animals interact not only with offspring, but also with other adults. These changes span from affiliative (e.g. pair bonding in voles or coordination of alloparenting behavior in mice or primates), to reduced interaction, to antagonistic or aggressive behaviors. (3) Parents, especially mammalian mothers, also undergo a suite of changes to their internal physiology upon pregnancy and parturition and throughout lactation. To support growing offspring, mothers often dramatically increase food intake, and show various metabolic adaptations to increase nutrient uptake. Rodent mothers show constitutively increased body temperature, likely as a by-product of milk production, as BAT thermogenesis actually drops (likely to prevent overheating). Parents of many species including humans show reduced sleep and weaker circadian cycles, as well as reduced anxious behavior. However, various factors in humans can contribute to increased rather than decreased anxiety and even postpartum depression (see main text for examples).

FIGURE 2.

Switches in parental behavior. Animals can switch from minimally parental, or even infanticidal, to parental; they can also switch from parental to non-parental. Often, these switches are driven by specific events. Six examples of behavioral switches are displayed here, three from mice (upper) and three from other species (lower). For each example, the flow diagram describes the animal’s parental state before an event that causes a behavioral switch (“Pre”), the event itself (“Switch event”), and the animal’s parental state after the event (“Post”).

FIGURE 3.

Timeline, production and release of parenting related hormones. Top: Hormone levels in women change throughout pregnancy and lactation. Placental lactogens increase during gestation as the placental mass increases and drop significantly when the placenta is expelled during birth. Prolactin rises shortly before childbirth and then promotes milk production through secretion in heavy pulses in between bouts of nursing. Oxytocin rises sharply at childbirth and then increases with bouts of nursing. Bottom: Estrogen and progesterone are secreted by granulosa cells in the ovaries and testosterone is secreted by leydig cells in the testes. These steroid hormones travel through the bloodstream, cross the blood brain barrier, and affect cells with the appropriate receptor throughout the brain. Prolactin is secreted from lactotrophs in the anterior pituitary. Prolactin release is regulated by inhibitory release of dopamine from TIDA neurons in the arcuate nucleus. Once released into the bloodstream, prolactin crosses the blood brain barrier to affect cells with the appropriate receptors throughout the brain. Oxytocin is released from parvocellular and magnocellular neurons in the PVH, SON, and AN which send projections to the posterior pituitary for release into the bloodstream. These neurons also project to discrete areas of the brain, brain stem, and spinal cord allowing for time-locked oxytocin signaling in specific brain areas on cells with the appropriate receptor. In addition, magnocellular neurons in the PVH and SON release oxytocin somatodendritically to signal locally within these nuclei. Abbreviations: TIDA = tuberoinfundibular dopamine neurons, Arc = arcuate nucleus, SON = supraoptic nucleus, PVH = paraventricular nucleus of the hypothalamus, AN = accessory nuclei of the hypothalamus, Parvo = parvocellular neurons, Magno = magnocellular neurons.

FIGURE 4.

Molecular mechanisms of hormone action. A Top: Schematic of testosterone molecular signaling through nuclear androgen receptor. Testosterone can bind directly to androgen receptor, be converted to dihydrotestosterone and then bind to androgen receptor or be converted to estrogen. Once bound, the androgen receptor translocates to the nucleus to activate transcription. Bottom: Example of testosterone effect on neuron physiology. Androgen signaling in the hippocampus increases spine size. B Top: Schematic of estrogen molecular signaling through nuclear estrogen receptors. Estrogen can bind to Esr1 or Esr2. Once bound, the estrogen receptor translocates to the nucleus to activate transcription. Bottom: Example of estrogen effect on neuron physiology. Estrogen signaling in the hippocampus increases spine density. C Top: Schematic of progesterone molecular signaling through nuclear progesterone receptor. Progesterone binds to the progesterone receptor. Once bound, the progesterone receptor translocates to the nucleus to activate transcription. Bottom: Example of progesterone effect on neuron physiology. Progesterone signaling in the hippocampus first increases spine density, then decreases it. D Left: Schematic of fast estrogen molecular signaling at synaptic membranes. Estrogen can act at distinct membrane associated receptors in males and females and in inhibitory and excitatory neurons to impact synaptic physiology. Right: Example of estrogen effect on neuron synaptic physiology in females. Estrogen signaling in the hippocampus increases release probability at excitatory synapses and decreases release probability at inhibitory synapses. E Top: Schematic of prolactin molecular signaling through prolactin receptor. Prolactin binds the prolactin receptor to activate JAK/STAT and MAPK/ERK signaling. Through these actions prolactin leads to the closure of small conductance calcium-activated potassium (SK) channels to depolarize neurons. Bottom: Example of prolactin effect on neuron physiology. Prolactin signaling in MPOA depolarizes MPOA^Gal cells and causes them to fire action potentials. F Left: Schematic of oxytocin molecular signaling through oxytocin and vasopressin receptors. Oxytocin can signal through both oxytocin and vasopressin receptors pre- and post-synaptically to affect neuron physiology. The exact effect of oxytocin signaling depends on which Gα protein the receptor is paired with. Right: Example of oxytocin effect on neuron physiology. Oxytocin signaling in the left auditory cortex increases the amplitude of excitatory postsynaptic currents and decreases the amplitude of inhibitory postsynaptic currents. Abbreviations: AR = androgen receptor, ER = estrogen receptor, Esr1 = estrogen receptor alpha, Esr2 = estrogen receptor beta, PR = progesterone receptor, V1aR = vasopressin receptor 1A, V1bR = vasopressin receptor 1B, AEA = anandamide, PLC = phospholipase C, IP3 = inositol triphosphate, mGluR1 = metabotropic glutamate receptor 1, Pr = release probability, JAK = janus kinases, STAT = signal transducer and activator of transcription, MAPK = mitogen-activated protein kinase, ERK = extracellular signal-regulated kinase.

FIGURE 5.

Change in hormone receptor expression throughout the brain across parental state in rodents. Top: Schematic of brain area locations. Bottom: Summary of hormone receptor changes throughout various brain areas in pregnant females, lactating females, and parental males. Abbreviations: OTR = oxytocin receptor, ERa = estrogen receptor alpha (Esr1), ERb = estrogen receptor beta (Esr2), PR = progesterone receptor, PRLR = prolactin receptor, V1aR = vasopressin receptor 1A, OB = olfactory bulb, AvPe = anteroventral periventricular nucleus, MPOA = medial preoptic nucleus, BNST = bed nucleus of the stria terminalis, Arc = arcuate nucleus, SON = supraoptic nucleus, VMH = ventromedial nucleus of the hypothalamus, PVHN = paraventricular nucleus of the hypothalamus, MeA = medial amygdala, VLM = ventrolateral medulla, NTS = nucleus tractus solitarius, Hip = hippocampus, PAG = periaqueductal gray, AHN = anterior hypothalamic nucleus.

FIGURE 6.

Hierarchy of Infant-evoked Behaviors. Adult-pup interactions have a hierarchical and temporal structure. First, parenting and infanticidal behavioral strategies/states last over hours to days. Then, persistent motor actions such as pup grooming, nest-building, nursing for parenting or rough handling and avoiding pups for infanticide or neglect last over minutes. Finally, goal directed motor actions such as pup search and retrieval during parenting and biting the pup during infanticide behaviors last for a few seconds.

FIGURE 7.

Sensory control of parenting. Parenting circuits integrate multimodal sensory and internal information leading to the onset as well as modulation of parenting or infanticidal behaviors. Pup olfactory cues, auditory calls, tactile cues and stimulation due to suckling, as well as chemosensory vomeronasal cues indicate the presence of pup. While vomeronasal cues have been shown to promote infanticidal or neglect behaviors, the other pup cues promote parenting behaviors. Parenting circuits integrate sensory information as well as information about the internal state of the animal. The parental state of the animal enhances parenting behaviors whereas stress inhibits parenting. The metabolic and hormonal state of the animal also modulates parenting. The parenting circuits also integrate surrounding environmental cues such as presence of other conspecific adults. Presence of resources enhances parenting while threat from predators deters parenting behavior.

FIGURE 8.

Parenting circuits. Parenting circuits comprise sensory, cortical, subcortical, modulatory and motor regions. These circuits integrate sensory cues across multiple modalities eventually converging on the medial preoptic area (MPOA) and then reach motor regions to control the execution of behavior. VNO = vomeronasal organ, MOE = main olfactory epithelium, NTS = nucleus of solitary tract, AOB = Accessory Olfactory Bulb, MOB = Main Olfactory Bulb, S1 = Primary somatosensory Cortex, OT = Olfactory Tubercle, AON = Accessory Olfactory Nucleus, ACx = Auditory Cortex, TeA = Temporal association cortex, ACC = Anterior Cingulate Cortex, PBN = Parabrachial Nucleus, CeA = Central Amygdala, MeA = Medial Amygdala, MPOA = Medial preoptic area, vBNST = ventral Bed nucleus of the stria terminalis, BNSTrh = rhomboid Bed nucleus of the stria terminalis, CoA = Cortical Amygdala, PVH = paraventricular nucleus, PIN = posterior intralaminar nucleus, MGM = medial geniculate nucleus, PeFA = Perifornical area, LHb = lateral habenula, VTA = ventral tegmental area, LC = Locus coeruleus, NAc = Nucleus Accumbens, PAG = periaqueductal gray, RRF = reticular formation via the reticulospinal tracts.

FIGURE 9.

Circuit organization of parenting-promoting MPOA^Gal and infanticide-promoting PeFA^Ucn3 neurons. A. Pro-parenting MPOA^Gal neuronal circuit organization. Panels show (1) Fos identification of Gal+ MPOA neurons activated during parenting (image from Ref. and used with permission from Nature), (2) their connectivity with other brain areas (inputs on left, outputs on right), (3) how different MPOA^Gal neurons projecting to different targets were shown to be involved in distinct aspects of parenting, and (4) a circuit diagram summarizing connectivity and functional manipulation experiments (Images for (2), (3) and (4) are from Ref. and used with permission from Nature). B. Infanticide-promoting PeFA^Ucn3 neuronal circuit organization. Panels show (1) Fos identification of Ucn3+ PeFA neurons activated during infanticide, (2) their connectivity with other brain areas, (3) how distinct PeFA^Ucn3 projections mediate distinct aspects of infanticidal behavior, and (4) a circuit diagram summarizing connectivity and functional manipulation experiments (image from Ref. , and used per CC-BY Open Access terms). AAV-FLEx-ChR2 = adeno-associated virus delivery expressing a floxed (“FLEx”) channelrhodopsin-2 gene for light-activated stimulationf. AH = Anterior hypothalamus, Arc = Arcuate nucleus, AHi = Amygdalohippocampal area, AHPM = Posteriomedial amygdalohippocampal area, AVP = Vasopressin, AvPe = Anteroventral preoptic nucleus, BNST = Bed nucleus of the stria terminalis, CRH = Corticotropin-releasing hormone, DM = Dorsomedial hypothalamus, Gal = Galanin, IL = Infralimbic cortex, LC = Locus coeruleus, lHB = Lateral Habenula, LS = lateral septum, MeA = Medial amygdala, MnPO = Median preoptic nucleus, MPOA = Medial preoptic area, MS = medial septum, NAc = Nucleus accumbens core, NAsh = Nucleus accumbens shell, OXT = Oxytocin, PAG = Periaqueductal grey, PeFA = Perifornical area, PMV = Ventral premammillary nucleus, PVH = Paraventricular hypothalamic nucleus (also known as PVH), PVT = Paraventricular thalamic nucleus, RM = Retromammillary nucleus, RMg = Raphe magnus nucleus, RRF = retrorubral field, SFO = Subfornical organ, SNpc = Substantia nigra pars compacta, SON = Supraoptic nucleus, StHy = Striohypothalamic nucleus, Ucn3 = Urocortin 3, VMH = Ventromedial hypothalamic nucleus, VMPO = Ventromedial preoptic nucleus, VTA = Ventral tegmental area.

FIGURE 10.

Transcriptomically defined cell types controlling parenting behavior. A. Schematics depicting the methods used for transcriptomic studies such as Moffitt et al., 2018 (139): scRNA-seq (left) and MERFISH (right). B. MERFISH data from Ref. showing that MPOA^Gal,Calcr neurons are a subset of either MPOA^Gal neurons (left) or MPOA^Esr1 neurons (right). C. MERFISH data from Ref. , showing the spatial distribution of 8 different cell types that are activated during parenting or infanticide according to Fos experiments. D. Summary of cell type involvement in parenting or infanticide, according to sex and/or mating status. Dashed arrow indicates a putative connection. AvPe = Anteroventral preoptic nucleus, BNST = Bed nucleus of the stria terminalis, MPOA = Medial preoptic area, PeFA = Perifornical area. Images in A-C are from Ref. and used with permission from Science.