Prairie Voles HORMONAL CONTROL OF MATERNAL BEHAVIOR, MONOGAMY AND BIRDSONG. Bi 156

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1 Prairie Voles HORMONAL CONTROL OF MATERNAL BEHAVIOR, MONOGAMY AND BIRDSONG Bi 156 January 23, 2012 Paul H. Patterson

2 Tough questions for today Can we envision a neurobiology of love? Is there a molecular basis for monogamy versus promiscuity? Are there biological explanations for good versus bad parenting? How do birds learn to sing? How do hormones control the development of birdsong? Is there a molecular connection between human language and bird (and mouse) song?

3 Prairie voles

4 Behavior of two vole species

5 Vasopressin Vasopressin (arginine vasopressin, AVP) released by the posterior pituitary gland regulates water balance, vasoconstriction, body temperature, blood pressure and memory. AVP expression is sexually dimorphic in the PVN, SON, BST and SCN nuclei of the hypothalamus. The sexual dimorphism in AVP neurons in BST and in their axons in the lateral septum (LS) are testosteronedependent.

6 Assay for partner affiliation Insel & Young, 01

7 AVP regulates male affiliative behavior Prior mating strongly increases the time spent with that partner. This is dependent on AVP. Insel & Young, 01

8 Mating-induced aggression towards strangers

9 Effect of mating on AVP neurons Young et al., 98

10 AVP is required for social memory in mice Normal mice AVPR KO mice injected with AVPR viral vector Presentation of females Time spent investigating another mouse decreases with the number of encounters. This habituation does not occur if a novel mouse is introduced each time. This habituation is based on on olfactory memory, and is blocked by injection of AVP antagonist, and it is not present in the AVPR KO mouse. Social memory is restored in the KO mouse by injection of a viral vector expressing the AVPR. The lower right panel shows that olfactory recognition of scents is intact in the AVPR KO. Presentation of scented cotton Bielsky et al., 2005

11 Altering AVPR expression in a transgenic mouse Young et al., 99

12 AVP behavioral response of transgenic mice Young et al., 99

13 AVP receptor genes in voles and primates The human AVPR gene contains a highly repetitive sequence in the promoter region, and it is highly variable among individuals, suggesting that individual differences in regulatory DNA sequence upstream of the AVPR gene may influence receptor expression and social behavior. [Hammock & Young, 2006]

14 Significant intra-species variation in microsatellite length in the AVPR Because highly repetitive DNA sequences (microsatellites) offer a mechanism for continuous phenotypic variation, it was not surprising that the length of the AVPR microsattelite is variable, as is the behavior of the prairie voles. To test the influence of the microsatellite allele length on behavior, breeding pairs were established based on the longer and shorter length alleles. Hammock & Young, 2005

15 Microsatellite length predicts differences in AVPR distribution ADP, anterior dorsal preoptic nucleus; AOB, accessory olfactory bulb; BLA, basolateral amygdala; BMA, basomedial amygdala; CeA, central amygdala; ChPl, choroid plexus; dbst, dorsal bed nucleus of the stria terminalis; dbstdl, dorsolateral dbst; dls = dorsal lalteral septum; DMH, dorsomedial hypothalamus; dpag, dorsal periaquductal gray; Epl = external plexiform layer of olfactory bulb; Gl, glomerular layer; GrO, granular layer; Ldthal, laterodorsal thalamus; MeA, medial amygdala; MPoA, medial preoptic area; Pcing, posterior cingulate cortex; vbst, ventral BST; VMH, ventromedial hypothalamus; VP = ventral pallidum; vpag, ventral PAG; VTA, ventral tegmental area Hammock & Young, 2005

16 Long allele males have greater social engagement and bonding behavior Hammock & Young, 2005

17 Association between various AVPR alleles and the Partner Bonding Scale in men * Walum et al., 2009

18 Dose-dependence of the 334 allele on marital crisis Walum et al., 2009

19 Conclusions and theorizing about AVP AVPR activation in males is associated with increased rates of pup grooming and partner preference formation. The long AVPR allele males show higher levels of AVPR in the lateral septum, higher rates of pup grooming, and higher levels of partner preference formation. The long allele males also show higher levels of AVPR in the olfactory bulb, and lesions of the OB inhibit partner preference formation and social approach behaviors in prairie voles. Pharmacological manipulation of AVP systems in OB and septum modulate social recognition in rodents. Thus, genotypic differences in AVP binding in these areas are likely candidates for serving as the neural substrates underlying the observed genotypic differences in social behavior. This same locus is conserved between humans and the bonobo, which is known for its socio-sexual reciprocity and bonding, while this locus is not conserved with chimpanzee, which does not exhibit the same level of bonding. There is a modest association of microsatellite alleles at the -3625bp locus with autism, a disorder of profound social deficit.

20 Oxytocin Oxytocin (OT), a uniquely mammalian neuropeptide, released in the posterior pituitary, regulates uterine contraction and milk secretion. OT released by the PVN within 2 hours of partuition decreases aggression and aversion to newborns in sheep and rats (maternal behavior). OT KO mice display a profound social amnesia without other obvious cognitive deficits. Social stimuli that normally induce Fos activation in the medial nucleus of the amygdala and its projection sites, the BST and MPOA, fail to do so in the KO. Injection of OT in the amygdala restores social recognition.

21 OT receptor expression in two vole species OTR expression in the nucleus accumbens (NAcc) and the prelimbic cortex (PLC) is different in prairie and montane voles. Insel & Young, 01

22 Effects of AVP and OT on partner preference Young et al., 98

23 Oxytocin KO and social recognition Olfactory investigation by male mouse of same female in repeated trials Olfactory investigation by male mouse of new females in each trial. Ferguson et al., 00

24 Bonding and the dopamine reward system It is interesting that the areas of high OTR (PLC and NAcc) are involved in the mesolimbic dopamine reward pathway. It is possible that prairie vole mating causes OT release in this pathway, which conditions the female to the odor of her mate. Injection of a D2 dopamine receptor antagonist decreases partner preference in females that had cohabitated with a particular male. Conversely, injection of a D2 agonist induces partner preference in the absence of mating. Dopamine plays a key role in the rewarding properties of drugs of abuse and appetitive behaviors. Thus, copulation may be a potent reinforcer in female voles, forming an association between the rewarding or hedonic aspects of mating and the male partner, an association mediated by dopamine. After mating, the male partner is a conditioned stimulus that is measured as partner preference.

25 Circuitry of social bonding Young et al., 2004 Keverne & Curely, 2004

26 Of human bonding In the human brain, OTRs are concentrated in several dopamine-rich areas. While this is consistent with monogamous voles, the receptors are not found in several other relevant areas that are rich in AVP and OT receptors in monogamous voles and monkeys. Intranasal administration of OT to humans increases their level of trust, and increases their ability to infer the mental state of others (empathy). An fmri study of adults looking at pictures of their partners vs. nonromantic friends found activation in areas (Brodmann s areas 14 and 24) distinct from face recognition, sexual arousal or other emotional states. This pattern resembles those seen while a mother listens to infant cries, and during cocaine-induced euphoria.

27 Stress and maternal behavior in rodents Stress in early life can enhance vulnerability to stress-induced illness throughout life. Example: Separation from the mother causes depressive behavior in offspring tested as adults. Even a single period of separation for several hours can have a long-lasting effect. Natural variation in maternal behavior among rats: some mothers spend lots of time licking, grooming and nursing while other mothers that spend little time doing this. As adults, offspring of the former display lower ACTH and corticosteroid responses to stress. Offspring of the latter mothers display increased startle responses, decreased open field exploration and more anxiety near novel objects. BALBc mice are fearful and have elevated responses to stress, but when their offspring are cross-fostered to C57 mothers (which lick and groom their pups more than do BALBc mothers), the cross-fostered BALBc mice grow up to be less fearful and have reduced responses to stress. In contrast, C57 pups cross-fostered to BALBc mothers grow up more fearful than normal. Thus, these differences in adult behaviors are due to epigenetic influences.

28 Maternal effects on glucocorticoid receptor are mediated by 5-HT and transcription factor NGFI-A Meaney & Szyf, 2005

29 Glucocorticoid receptor exon 7 contains NGFI-A binding site, and NGFI-A binding is increased in the offspring of high maternal care mothers Meaney & Szyf, 2005

30 Model for maternal programming of GR epigenetic states Meaney & Szyf, 2005

31 Stress and maternal behavior in non-human primates Monkey mothers maintained under one of 3 foraging conditions: (1) food easily obtainable, (2) food available but required long searches, (3) variable foraging demand in which 1 and 2 conditions varied randomly. Condition 3 is clearly the most stressful and generates increased mother-infant conflict. These infants more timid and fearful, and display signs of depression usually associated with maternal separation. As adults, the condition 3 offspring display altered stress responses, and they tend to display poor maternal behavior as mothers themselves.

32 Zebra finches

33

34 Learning language in humans

35 Audition is critical for song learning

36 Song system circuits the circuits at HVc. Auditory input reaches

37 Sexual dimorphism in the song system Like the behavior, the brain s song system is sexually dimorphic. Many of the song nuclei are larger in males. These areas contain more and larger neurons. The female song system can be permanently masculinized by early treatment with testosterone. (organizational) Singing in adult males is reduced by castration, and providing additional testosterone enhances singing. (activational) Sex hormone receptors are high only in HVc, so hormone actions on other nuclei likely indirect. (neurotrophic factors?)

38 Sexual dimorphism of neurons in RA

39 Development of BDNF expression Akutagawa & Konishi, 98

40 BDNF expression in LMAN Akutagawa & Konishi, 98

41 Testosterone control of BDNF expression Rasika et al., 99

42 BDNF control of neuronal number Rasika et al., 99

43 FoxP2 and language Mutations in the FoxP2 transcription factor cause developmental verbal dyspraxia, a speech and language disorder that compromises the fluent production of words and the correct use and comprehension of grammar. FoxP2 patients have structural and functional abnormalities in the striatum, which also expresses high levels of FoxP2. The sequence of FoxP2 is strongly conserved from reptiles to humans, including birds. FoxP2 expression in songbirds increases in Area X during the time of vocal learning. RNAi knockdown of FoxP2 in Area X causes an incomplete and inaccurate imitation of tutor song. Suggests that auditory-guided motor learning requires FoxP2.

44 Incomplete tutor song imitation by FoxP2 KD pupils Haesler et al., 2007

45 FoxP2 mutant mice have altered vocalizations whistles clicks Shu et al., 2005

46 Changes in Foxp2 during evolution Foxp2 is among the most highly conserved 5% of proteins, indicating a fundamental role in mammals. Moreover, different human populations show essentially no variations in aa sequence, indicating that this sequence is fixed in humans. Since mice and humans diverged 70M years ago, only 3 aa s have changed in Foxp2. Two of these changes are present in humans but not in chimps, gorillas or orangutans. Hence, these substitutions arose and became fixed 4-6M years ago. This rate of change is greater than expected. These 2 aa changes represent a selective sweep in which this putatively advantageous genotype spread rapidly in all human populations. It is estimated that this spread was completed within K years ago.

47 Changes in Foxp2 for humanization Foxp2 in chimps differs from Foxp2 in mice by one conservative aa substitution (D80E). Thus, the WT mouse protein can be regarded as a model for the ancestral version of the human FOXP2 protein, and compared to a partly humanized version in which the 2 aa replacements have been introduced. In the KE family, only one copy of FOXP2 is mutated and nonfunctional. Since heterozygous Foxp2 wt/ko mice show intermediate levels of Foxp2 protein, they can be used to assess the consequences of reduced Foxp2 expression.

48 Screen for changes in the FOXP2 hum/hum mutant mice Enard et al., 2009

49 Dopamine concentrations in FOXP2 hum/hum and Foxp2 WT/KO Enard et al., 2009

50 FOXP2 hum/hum increases long term depression in medium spiny neurons Enard et al., 2009

51 FOXP2 hum/hum affects the structure of pup isolation calls (A) Examples of acoustic parameters analyzed illustrated for typical call. (B) Plots of acoustic parameters differing between genotypes. Measurements are averaged across days and individuals (±SEM). The peak frequency (PF) refers to the frequency with the maximum amplitude in each analyzed time window of 0.21 ms. Asterisks indicate significant differences between genotypes (**: < 0.01; ***: < 0.001). Enard et al., 2009

52 Background PARENTAL BEHAVIOR & PAIR BONDING * Insel TR (2010) The challenge of translation in social neuroscience: A review of oxytocin, vasopressin, and affiliative behavior. Neuron 65: Fisher HE, Aron A, Brown LL (2006) Romantic love: a mammalian brain system for mate choice. Phil Trans R Soc 361: Meaney MJ, Szyf M, Seckl JR (2007) Epigenetic mechanisms of perinatal programming of hypothalamic-pituitary-adrenal function and health. Trends Molec Med 13: Student presentations * Walum H, Westberg L, Henningsson S, et al. (2008) Genetic variation in the vasopressin receptor 1a gene associates with pair-bonding behavior in humans. Proc Natl Acad Sci USA 105: * Chang SWC, Barter JW, Ebitz RB, Watson KK, Platt ML (2012) Inhaled oxytocin amplifies both vicarious reinforcement and self reinforcement in rhesus macaques. Proc Natl Acad Sci USA 109: Background BIRDSONG * Bolhuis JJ, Okanoya K, Scharff C (2010) Twitter evolution: converging mechanisms in birdsong and human speech. Nature Rev Neurosci 11: Student presentations References * Wissman AM, Brenowitz EA (2009) The role of neurotrophins in the seasonal-like growth of the avian song control system. J Neurosci 29:

53 AVP receptor gene expression

54 Association between 334 allele in men and their wive s reports of marital qualities Walum et al., 2009

55 Making FOXP2 hum/hum mutant mice Enard et al., 2009

56 FOXP2 hum/hum increases dendrite length Enard et al., 2009