Attachment--and loss.

Childhood maltreatment has been linked to a variety of changes in brain structure and function and stress–responsive neurobiological systems. Epidemiological studies have documented the impact of childhood maltreatment on health and emotional well–being. After a brief review of the neurobiology of childhood trauma, we use the Adverse Childhood Experiences (ACE) Study as an epidemiological “case example” of the convergence between epidemiologic and neurobiological evidence of the effects of childhood trauma. The ACE Study included 17,337 adult HMO members and assessed 8 adverse childhood experiences (ACEs) including abuse, witnessing domestic violence, and serious household dysfunction. We used the number of ACEs (ACE score) as a measure of cumulative childhood stress and hypothesized a "doseresponse" relationship of the ACE score to 18 selected outcomes and to the total number of these outcomes (comorbidity). Based upon logistic regression analysis, the risk of every outcome in the affective, somatic, substance abuse, memory, sexual,and aggressionrelated domains increased in a graded fashion as the ACE score increased (P <0.001). The mean number of comorbid outcomes tripled across the range of the ACE score. The graded relationship of the ACE score to 18 different outcomes in multiple domains theoretically parallels the cumulative exposure of the developing brain to the stress response with resulting impairment in multiple brain structures and functions.

https://traumasensitiveschools.org/wp-content/uploads/2013/06/Anda-Article-Enduring-Effects-of-Abuse.pdf

The enduring effects of abuse and related adverse experiences in childhood: A convergence of evidence from neurobiology and epidemiology

We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.

/pdf/strong-association-of-de-novo-copy-number-mutations-with-1mq4l4g552.pdf

Strong Association of De Novo Copy Number Mutations with Autism

The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gene expression is the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. In response to a variety of stimuli such as suckling, parturition, or certain kinds of stress, the processed OT peptide is released from the posterior pituitary into the systemic circulation. Such stimuli also lead to an intranuclear release of OT. Moreover, oxytocinergic neurons display widespread projections throughout the central nervous system. However, OT is also synthesized in peripheral tissues, e.g., uterus, placenta, amnion, corpus luteum, testis, and heart. The OT receptor is a typical class I G protein-coupled receptor that is primarily coupled via Gq proteins to phospholipase C-β. The high-affinity receptor state requires both Mg2+ and cholesterol, which probably function as allosteric modulators. The agonist-binding region of the receptor has bee...

The Oxytocin Receptor System: Structure, Function, and Regulation

The human stress response has been characterized, both physiologically and behaviorally, as "fight-or-flight." Although fight-or-flight may characterize the primary physiological responses to stress for both males and females, we propose that, behaviorally, females' responses are more marked by a pattern of "tend-and-befriend." Tending involves nurturant activities designed to protect the self and offspring that promote safety and reduce distress; befriending is the creation and maintenance of social networks that may aid in this process. The biobehavioral mechanism that underlies the tend-and-befriend pattern appears to draw on the attachment-caregiving system, and neuroendocrine evidence from animal and human studies suggests that oxytocin, in conjunction with female reproductive hormones and endogenous opioid peptide mechanisms, may be at its core. This previously unexplored stress regulatory system has manifold implications for the study of stress.

/pdf/biobehavioral-responses-to-stress-in-females-tend-and-2yimakv5ai.pdf

Biobehavioral responses to stress in females: tend-and-befriend, not fight-or-flight.

The development of social familiarity in rodents depends predominantly on olfactory cues and can critically influence reproductive success. Researchers have operationally defined this memory by a reliable decrease in olfactory investigation in repeated or prolonged encounters with a conspecific. Brain oxytocin (OT) and vasopressin (AVP) seem to modulate a range of social behaviour from parental care to mate guarding. Pharmacological studies indicate that AVP administration may enhance social memory, whereas OT administration may either inhibit or facilitate social memory depending on dose, route or paradigm. We found that male mice mutant for the oxytocin gene (Oxt-/-) failed to develop social memory, whereas wild-type (Oxt+/+) mice showed intact social memory. Measurement of both olfactory foraging and olfactory habituation tasks indicated that olfactory detection of non-social stimuli is intact in Oxt-/- mice. Spatial memory and behavioural inhibition measured in a Morris water-maze, Y-maze, or habituation of an acoustic startle also seemed intact. Treatment with OT but not AVP rescued social memory in Oxt-/- mice, and treatment with an OT antagonist produced a social amnesia-like effect in Oxt+/+ mice. Our data indicate that OT is necessary for the normal development of social memory in mice and support the hypothesis that social memory has a neural basis distinct from other forms of memory.

/pdf/social-amnesia-in-mice-lacking-the-oxytocin-gene-3foyz0bav1.pdf

Social amnesia in mice lacking the oxytocin gene.

Infant vocalization, adult aggression, and fear behavior of an oxytocin null mutant mouse.

Faces are one of the most salient classes of stimuli involved in social communication. Three experiments compared face-recognition abilities in chimpanzees (Pan troglodytes) and rhesus monkeys (Macaca mulatta). In the face-matching task, the chimpanzees matched identical photographs of conspecifics' faces on Trial 1, and the rhesus monkeys did the same after 4 generalization trials. In the individual-recognition task, the chimpanzees matched 2 different photographs of the same individual after 2 trials, and the rhesus monkeys generalized in fewer than 6 trials. The feature-masking task showed that the eyes were the most important cue for individual recognition. Thus, chimpanzees and rhesus monkeys are able to use facial cues to discriminate unfamiliar conspecifics. Although the rhesus monkeys required many trials to learn the tasks, this is not evidence that faces are not as important social stimuli for them as for the chimpanzees.

/pdf/recognizing-facial-cues-individual-discrimination-by-58w6tr1fuw.pdf

Recognizing facial cues: individual discrimination by chimpanzees (Pan troglodytes) and rhesus monkeys (Macaca mulatta).

Several lines of evidence support a role for oxytocin and vasopressin in complex social behaviors, including parental care, sex behavior, and aggression. Recent studies in a monogamous mammal, the prairie vole, suggest an additional role for both peptides in the formation of pair bonds. Central administration of oxytocin facilitates and administration of an oxytocin antagonist inhibits partner preference formation in female prairie voles. Conversely, vasopressin facilitates and a V1a receptor antagonist inhibits pair bonding in males. A potential cellular basis for these effects is the species-specific pattern of expression of oxytocin and V1a receptors in reward pathways of the prairie vole brain. At a molecular level, comparative sequencing of the oxytocin and V1a receptors reveals species differences in the promoter sequences that may guide regional expression in the brain. Transgenic mice created with the 5’ flanking region of the prairie vole oxytocin receptor gene demonstrate that sequences in this region influence the pattern of expression within the brain. The unique promoter sequences of the prairie vole OTR and V1a receptor genes and the resulting species-specific pattern of regional expression provide a potential molecular mechanism for the evolution of pair bonding behaviors and a cellular basis for monogamy.

Oxytocin, vasopressin, and the neuroendocrine basis of pair bond formation.

https://tauruspet.med.yale.edu/staff/dl489/IM_18FDG_kinetics_Rilling_2001_1.pdf

James T. Winslow

Papers

Social amnesia in mice lacking the oxytocin gene.

Infant vocalization, adult aggression, and fear behavior of an oxytocin null mutant mouse.

Recognizing facial cues: individual discrimination by chimpanzees (Pan troglodytes) and rhesus monkeys (Macaca mulatta).

Oxytocin, vasopressin, and the neuroendocrine basis of pair bond formation.

Neural correlates of maternal separation in rhesus monkeys.