1. Understanding the brain and behavior The Neurobiology of Social Recognition, Approach, and Avoidance Larry J. Young

2. Introduction • Understanding how the brain processes social information and regulates social behavior helps us understand psychiatric disorders specifically affecting social behavior. • Animal models provide an opportunity for experimental manipulations that are not possible in human patients.

3. Several rodent model systems that have proven particularly useful for understanding how the brain processes social information and regulates social behavior. • Not necessarily models of any specific human condition • Instead contribute to our understanding of the social brain.

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5. The first model, the oxytocin knockout mouse, demonstrates the role of the neuropeptide oxytocin and the amygdala in the differential processing of social verses nonsocial information in the context of social recognition.

6. Social Recognition and the Neural Processing of Social Stimuli • Several studies suggest that the brain has specific neural circuits involved in processing social information rather than nonsocial stimuli. • Human brain imaging studies have demonstrated that the brain processes social visual stimuli differently from nonsocial stimuli. • For example, the lateral fusiform gyrus is activated to a greater degree when subjects view faces than when viewing nonface objects

7. Social recognition in mice, unlike primates, is primarily based on olfactory cues. • During the first social encounter, a male mouse will investigate a novel mouse by sniffing the head and anogenital region for approximately 1 min.

8. If the male encounters the same mouse again, it will investigate the stimulus mouse for only a few seconds and then quickly engage in different behaviors.

9. Neuropeptide oxytocin • Oxytocin is a neuropeptide • Oxytocin induces maternal behavior, uterine contraction and lactation • Young et al. used mice genetically engineered to lack a functional oxytocin (OT) gene to investigate the role of OT in social behavior

11. OT knockout mouse fail to habituate to, or recognize, a stimulus mouse even after repeated exposures • This deficit in social memory is not due to problems with general olfactory processing because these mice habituate normally to nonsocial scents, such as a cotton ball scented with lemon extract

13. OT knockout mice appear to have normal general learning and memory abilities because they perform as well as normal mice in the Morris water maze, which quantifies performance on a spatial learning task. • The specific deficit in social recognition suggests that although general cognitive abilities and olfactory processing are intact, the processing of social stimuli is abnormal.

14. Social recognition in the OT knockout mouse can be fully restored by a single infusion of 1.0 ng OT into the brain just minutes before the initial social encounter. • Infusion of a specific OT antagonist into the brain of wildtype mice prevents the expression of a social memory.

15. Injection of the OT after the initial exposure fails to restore social recognition, demonstrating the OT must be present during the initial processing of the social information, rather than for the retrieval of that information during subsequent exposures

16. What part of the brain controls social recognition using OT? • Use Fos staining to see which brain neurons are activated

17. Experiment • Normal and OT knockout mice were either • left alone in their cages, or • presented with a social stimulus animal for 90 sec.

18. Fos staining indicates neuron activation • Wildtype mice: amygdala activated • OT knockout: amygdala not activated

19. The medial amygdala receives olfactory input directly from the olfactory bulbs and is rich in OT. • Suggest that the amygdala differentially processes social and nonsocial information, • Differential processing is dependent on the presence of OT.

20. Brain imaging studies with high-functioning autistic patients also suggest that the amygdala is involved in processing social information. • Functional magnetic resonance imaging (fMRI) was performed on healthy and autistic subjects to examine brain activity during the processing of facial expressions • Autistic subjects failed to display an activation of the left amygdala during this task, whereas the healthy subjects had significant activation of this region.

21. Neuropeptides in social interest and attachment

22. Montane vole Elizabeth Hadly Stanford University

23. Once the brain gathers and processes social information, it must decide how to react to the situation. • In other words, should the individual engage in social interactions, such as grooming, or attack or flee? • What is it about interacting with other individuals in a social context that is rewarding to most individuals?

24. A rodent about the size of a golden hamster known as a vole has provided an excellent system for understanding affiliative behavior as well as social attachment • There are several species of voles that inhabit various regions of North America, and these species display a range of social behaviors.

25. Prairie voles (Microtus ochrogaster), found naturally in the Midwestern United States, are highly social, form long-lasting social attachments with their mates, and are monogamous

26. Like humans, prairie voles seek social contact. In nature, these rodents live in colonial nests consisting of a mating pair and several generations of offspring. • Prairie voles prefer to spend much of their time in physical contact with another prairie vole, typically in a side-by-side posture referred to as huddling. • In large, naturalistic enclosures, prairie voles spend more than 50% of their time interacting or huddling with another prairie vole

27. In contrast to prairie voles, montane voles (M. montanus), which inhabit the Rocky Mountain region, appear to avoid social contact except for the purpose of mating. Montane voles do not form social attachments between mates. • Female montane voles rear their young in isolated nests and abandon their offspring after 2 to 3 weeks

28. In a similar naturalistic enclosure as described above, montane voles spent only around 5% of the time socially interacting with other montane voles

29. Because prairie and montane voles are genetically very similar, yet so different socially, together they provide an excellent comparative model system for examining the brain mechanisms involved in promoting social contact.

30. Do oxytocin (OT) and arginine vasopressin (AVP) explain the differences in social behavior of voles?

31. Vasopressin and OT are 9–amino acid peptides with a ring structure connected by a disulfide bond. • The peptides differ only at two amino acid residues and the OT and AVP genes are located adjacent to each other on the same chromosome • Both peptides are synthesized in neurons in the hypothalamus that project to the posterior pituitary and are released into the peripheral blood supply where they regulate functions such as blood pressure, urine concentration, uterine contraction, and lactation

32. These neuropeptides are also synthesized in separate hypothalamic and extrahypothalamic neurons that release the peptides independently within the brain to modulate a number of social behaviors

33. OT and AVP effects on social interaction • OT or AVP infusions increase the amount of time that a vole spends in olfactory investigation and huddling in a side-by-side posture with another animal

34. OT and AVP effects on pair bonding • The prairie vole, which is monogamous, forms a permanent pair bond after mating. • In the laboratory, pair bond formation is assessed in a three chambered testing arena by quantifying the amount of time the experimental animals spends during a 3-hour test with either the mate (confined to one chamber) or with a novel animal (confined in separate chamber).

35. Intracerebroventricular infusions of an OT antagonist into a female prairie vole before mating prevents the formation of a partner preference (Insel and Hulihan 1995), whereas OT injections facilitate partner preference formation, even in the absence of mating • Similar results have been obtained using AVP antagonists and agonists in male prairie voles

36. Both OT and AVP are present in all mammalian species, and prairie and montane voles appear to have similar levels of these peptides • So what explains the differences in affiliative behavior in these species?

37. The answer appears to lie within the regional expression of the receptors for these peptides within the brain. • Receptor autoradiography studies show that prairie and montane voles have dramatically different distributions of OT and AVP receptors within the brain

38. prairie voles have higher levels of OT receptor in the nucleus accumbens (the ‘s brain“pleasure center”) and the basolateral amygdala relative to montane voles • prairie voles have higher densities of the V1a subtype of the AVP receptor in the ventral pallidum and the medial amygdala compared with montane voles,

39. Differential localization of receptors in brain might lead to the activation of different circuits upon peptide release and ultimately to different behavioral responses.

40. Experiment • Male prairie and montane voles were given either • 1.0 ng of AVP in artificial cerebrospinal fluid • artificial cerebrospinal fluid alone (control) • Behavioral response: affiliation test

41. Prairie voles • Prairie voles injected with AVP exhibited significantly higher levels of social interactions than control prairie voles injected with artificial cerebrospinal fluid

42. Montane voles • In contrast, the injection of AVP had no impact on social interactions in montane voles. • Instead montane voles respond to AVP injections by exhibiting increased levels of nonsocial behaviors such as autogrooming

43. Do other species show the same effects of vasopressin? • Young et al. created transgenic mice carrying the prairie vole vasopressin receptor • Test if there is a direct relationship between the behavioral response to AVP and the specific pattern of V1a vasopressin receptors (V1aR)

44. The transgene contained the regulatory sequences that direct the expression of the gene in a tissue-specific manner.

45. Mice transgenic for the prairie vole V1aR gene expressed the V1aR in a pattern that was similar (but not identical) to that of prairie voles, but markedly different from that of nontransgenic mice

46. The transgenic mice, which share some of the regional distribution of AVP receptors with the prairie vole, responded to the AVP treatment by displaying increased affiliative behavior (Figure 3, next slide). • Nontransgenic littermates showed no increase in affiliative behavior after AVP injection.

48. The transgenic mice did not respond to vasopressin in exactly the same way as prairie voles. • Mice not display elevated V1aR binding, compared with nontransgenic mice, in some of the areas that may be critical specific aspects of social behavior, such as the amygdala and ventral pallidum. • These mice also did not display partner preferences as prairie voles do.

49. This is the first study to demonstrate that the regional distribution and density of a neurotransmitter or neuropeptide receptor is directly associated with the social behavior displayed by an individual.

50. How do the the differential distribution of OT and AVP receptors in prairie and montane vole brains promote social interactions?