Sunday 26 o C sunny. Tuesday -3 o C snow

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1 Sunday 26 o C sunny Tuesday -3 o C snow

2 Maternal regulation of neural development and cognitive function Dong Liu Tim Bredy (Queensland Brain Inst) Danielle Champagne (Lieden) Rose Bagot Tie-Yuan Zhang Ian Hellstrom Marian Joels (Utrecht) Wong Tak Pan (McGill)

3 The development of an individual is a process of adaptation that occurs within a social and economic context:

4 Evolutionary biology - Maternal effects Environmental Parental Developmental signal mediation outcome Nutrient Supply Mate Quality Violence Infection Population density Parental signal Defensive Strategies Foraging/Metabolism Reproductive Strategies Robert Hinde: Evolution has shaped the young to use parental into which they have been born (adaptive function). For most species, there is no single, optimal phenotype.

5 Developmental Origins of Adult Disease Early experience Abuse Family strife Emotional neglect Harsh discipline Health Risks Depression Drug abuse Anxiety Diabetes Heart disease Obesity

6 Early experience Abuse Family strife Emotional neglect Harsh discipline Health Risks Depression Drug abuse Anxiety Diabetes Heart disease Obesity Individual differences in neural and endocrine responses to stress

7 Poverty Parental mediation Early experience Abuse Family strife Emotional neglect Harsh discipline Health Risks Depression Drug abuse Anxiety Diabetes Heart disease Obesity Individual differences in neural and endocrine responses to stress

8 Alternative views: outcomes and improved health status; bad parenting Developmental outcomes must be evaluated within environmental context within which the phenotype * A developmental effect that results in a maladaptive outcome for survival/reproduction regardless of the context.

9 Parental regulation of offspring phenotype the life span?

10 Evolutionary biology - Maternal effects Environmental Parental Developmental signal mediation outcome Nutrient Supply Mate Quality Violence Infection Population density Parental investment Defensive Strategies Foraging/Metabolism Reproductive Strategies Robert Hinde: Evolution has shaped the young to use parental into which they have been born. For most species, there is no single, optimal phenotype.

11 Maternal licking/grooming Source of tactile stimulation/nurturance: Enhances activity of endocrine systems (e.g., GH/IGF) that promote somatic growth, suppresses those (glucocorticoids) that inhibit growth

12 Variations in maternal care Frequency count % Licking/grooming

13 Tactile stimulation (maternal LG) 5-HT 5-HT7 receptor camp PKA CBP Egr1/Sp1 CBP Synaptic plasticity

14 Low LG High LG NGFI-A mrna levels Day * Hippocampal NGFI-A mrna (in situ hybridization) 0.0 Hellstrom et al. (Keystone poster) shows evidence that it is the tactile stimulation associated with pup LG that increases NGFI- A expression & association with NGFI-

15 Energy Neuronal activity Trophic support GluT Insulin receptor Glutamate receptor subunits (NR2B) + + BDNF bfgf = Synaptic development

16 LOW LG HIGH LG Golgi-Cox staining of CA1 pyramidal neurons

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18 density A B 20 * # Spines (per 20 mm) 10 0 Basal Dendrite * 20 Low LG High LG # Spines (per 20 mm) 10 Apical Dendrite 0 Low LG High LG

19 CA 1 - LTP % Potentiation Slope of the EPSP Time (min) High LG Low LG Tetanic stimulation

20 - Slope fepsp (% of baseline) High LG Mid LG Low LG Licking and Grooming (%)

21 Within-litter variation in pup LG frequency predicts mom always ) post-tbs EPSP amplitude ) % LG EPSP amplitude (% baseline) Low LG High LG time (min)

22 Within-litter variation in pup LG frequency predicts hippocampal BDNF expression among littermates 1.4 BDNF exon IX mrna (males) % LG

23 In vivo perforant path LTP % (baseline) pop. spike amp High LG Low LG

24 Maternal care influences hippocampal development Morris water maze N W E S

25 Spatial learning & memory 150 High LG Low LG Latency (sec) Day of Testing Liu et al. Nature Neuroscience 2000

26 Object Recognition Memory Test High LG Low LG Discrimination ratio

27 Low LG litters High LG litters

28 CA 1 - LTP % Potentiation Slope of the EPSP Time (min) High LG Low LG Tetanic stimulation Champagne et al., J. Neuroscience, 2008; Bagot et al., submitted.

29 What about long-term synaptic depression (LTD)? LTD occurs at synapses stimulated repeatedly over time (10-15 minutes) at a low frequency (approximately 1 Hz) resulting in depressed excitatory postsynaptic potentials (EPSPs). The Ca ++ signaal in the postsynaptic cell determines whether LTD or LTP occurs. + LTP - LTD Low High Range of post-synaptic activity

30 Does maternal care affect bidirectional synaptic plasticity? LTP + High LG Low LG Hypothesis 1 Greater capacity for synaptic plasticity - LTD + LTP High LG Low LG Hypothesis 2 for synaptic plasticity - LTD

31 Threshold hypothesis The Bienenstock, Cooper, Munro (BMC) model propose a neuronal threshold: a)postsynaptic responses below the threshold leads to LTD; b)responses above the threshold leads to LTP.

32 LTD is enhanced in low LG rats LFS 300 x 1Hz (NMDAR-dependent) % Baseline * low LG high LG Low LG 200pA 20ms High LG Time (mins)

33 Maternal care shifts the modification threshold of synaptic plasticity % Baseline Time (mins) LFS low LG high LG TBS + LTP LFS High LG TBS Low LG - LTD

34 Evolutionary biology - Maternal effects Environmental Parental Developmental signal mediation outcome Nutrient Supply Mate Quality Violence Infection Population density Parental signal Defensive Strategies Foraging/Metabolism Reproductive Strategies What about synaptic plasticity under stressful conditions?

35 A 300 p< 0.01 High LG + VEH High LG + CORT B Saline Slope of the fepsp (% Baseline) Slope of the fepsp (% Baseline) ** High LG-VEH High LG-CORT Groups Time (Min) C Low LG+ VEH Low LG+ CORT D 100 nm CORT Slope of the fepsp (% Baseline) p< Slope of the fepsp (% Baseline) ** Low LG-VEH Low LG-CORT Groups Time (Min)

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38 Effect of corticosterone on hippocampal LTP Slope fepsp (% Baseline) Vehicle Corticosterone * * Low LG High LG

39 Low LG offspring show facilitation of LTP with high CORT Slope fepsp (% Baseline) Vehicle Cort Low LG Mid LG Licking and Grooming (%) High LG

40 CORT: Effect on LTP in dentate gyrus Saline 100 nm CORT

41 So it is NOT the case that the capacity for synaptic plasticity is necessarily greater in the offspring of High LG mothers, but rather that maternal care influences the conditions under which synaptic plasticity is most likely to occur as well as the nature of synaptic plasticity. Does this also apply to learning/memory?

42 Contextual fear-conditioning: Hippocampalmediated learning under stressful conditions 100 % Freezing * Low LG High LG 25 0

43 Farrington & Tremblay studies crime environments is behavioural inhibition (fear, timidity) which are also endophenotypes for affective illness.

44 Farrington & Tremblay studies crime environments is behavioural inhibition (fear, timidity) which are also endophenotypes for affective illness. What does this imply for public health policy that is based exclusively on health outcomes?

45 Maternal care affects ratio of AMPAR/NMDAR current NMDAR +40mV +DNQX 0 AMPAR -60mV ratio (AMPAR/NMDAR) * Low LG 100pA 40ms High LG low LG high LG

46 Increased expression of mglur1 in high LG rat hippocampus mglur1/actin (ROD) * mglur5/actin (ROD) mglur1 High LG Low LG 0 mglur5 High LG Low LG actin actin

47 mglur-ltd is enhanced in dentate gyrus of high LG rats * low LG % Baseline DHPG low LG high LG.5 mv high LG 20ms Time (mins)

48 CORT eliminates effect of maternal care on AMPAR/NMDAR current 0 Low LG low LG High LG high LG ratio (AMPAR/NMDAR) control CORT

49 AMPAR mediated transmission is not affected by brief CORT exposure fepsp slope low- CORT low- vehicle Fibre Volley Amplitude (mv) fepsp slope high- CORT high- vehicle Fibre Volley Amplitude (mv)

50 NMDAR mediated transmission in DG of low LG is not affected by brief CORT exposure fepsp slope low- CORT low- vehicle Fibre Volley Amplitude (mv)

51 NMDAR mediated transmission in DG of high LG is increased by brief CORT exposure fepsp slope * * * * * * * hi gh- CORT high- vehicle Fibre Volley Amplitude (mv)

52 Ovalbumin Synaptophysin H-H H-L L-L H-L Optical density unit High/High High/Low Low/Low Low/High Liu et al. Nature Neuroscience 2000

53 Threshold hypothesis The Bienenstock, Cooper, Munro (BMC) model propose a neuronal threshold: a)postsynaptic responses below the threshold leads to LTD; b)responses above the threshold leads to LTP.

54 How does maternal care affect bidirectional synaptic plasticity? LTP + High LG Low LG Hypothesis 1 Greater capacity for synaptic plasticity - LTD + LTP High LG Low LG Hypothesis 2 for synaptic plasticity - LTD

55 LTP is greater in dentate gyrus of High LG rats TBS 100Hz

56 A High LG + VEH High LG + CORT B Slope of the fepsp (% Baseline) p< Slope of the fepsp (% Baseline) ** High LG-VEH High LG-CORT Groups Time (Min) C Low LG+ VEH Low LG+ CORT D Slope of the fepsp (% Baseline) p< Slope of the fepsp (% Baseline) ** Low LG-VEH Low LG-CORT Groups Time (Min)

57 Evolutionary Biology: Maternal Effects Environmental Parental Developmental signal mediation outcome Nutrient Supply Mate Quality Violence Infection Population density Parental signal Defensive Strategies Foraging/Metabolism Reproductive Strategies

58 Gestational stress/maternal behaviour High/Stress % Licking/grooming High/Ctl Low/Stress Low/Ctl Day

59 Does maternal care affect the mechanism of LTP induction? LTP is induced by NMDAR activation and expressed by increased efficacy of AMPAR (Nicoll, 2003) Does maternal care affect NMDAR or AMPAR function?

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61 Summary Low LG is associated with impaired LTP however NMDAR current is enhanced. LTP requires optimal NMDAR activity and overactivity of NMDAR impairs LTP (Coan & Collingridge, 1989; Zajackowski 1997; Katagiri, 2001) Brief CORT facilitates LTP in low LG while suppressing LTP in high LG rats and may do so by altering NMDAR function NMDAR function can be rapidly modulated by the acute environment (e.g. CORT), interacting with the effect of maternal care

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63 Developmental Origins of Adult Disease Early experience Abuse Family strife Emotional neglect Harsh discipline Health Risks Depression Drug abuse Anxiety Diabetes Heart disease Obesity

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65 survive & reproduce successfully in a variety of ecological settings. capacity for phenotypic plasticity. The human genome can support a wide range of phenotypes.

66 survive & reproduce successfully in a variety of ecological settings. capacity for phenotypic plasticity. The human genome can support a wide range of phenotypes. derives from gene x environment interactions, whereby environmental variations are associated with variation at the level of cellular signals that, in turn, differentially activate the genome.

67 Summary brain that regulate responses to stress and thus forms the basis for individual differences in vulnerability for illness.

68 The development of an individual is a process of adaptation that occurs within a social and economic context:

69 The development of an individual is a process of adaptation that occurs within a social and economic context: Adaptation to adversity forms the developmental origins of vulnerability for chronic disease

70 Developmental Origins of Adult Disease Early experience Abuse Family strife Emotional neglect Harsh discipline Health Risks Depression Drug abuse Anxiety Diabetes Heart disease Obesity

71 Early experience Abuse Family strife Emotional neglect Harsh discipline Health Risks Depression Drug abuse Anxiety Diabetes Heart disease Obesity Individual differences in neural and endocrine responses to stress

72 Poverty Early experience Abuse Family strife Emotional neglect Harsh discipline Health Risks Depression Drug abuse Anxiety Diabetes Heart disease Obesity Individual differences in neural and endocrine responses to stress

73 Structural Gene Parental care changes in Phenotype expression the DNA (The chemistry of the DNA)

74 Maternal licking/grooming Source of tactile stimulation/nurturance: Enhances activity of endocrine systems (e.g., GH/IGF) that promote somatic growth, suppresses those (glucocorticoids) that inhibit growth

75 Variations in maternal care Frequency count % Licking/grooming

76 NR3C1 (GR) gene locus (Chromosome 18) CpG Islands H3K9ac DNA Me mrna EXP Genes PCDH clusters

77 NGFI-A Overexpression Effect of NGFI-A overexpression vector on NGFI-A mrna Total GR expression in NGFI-A overexpression cells Normalized NGFI-A NT EV OE Normalized Total GR NT EV OE Normalized exon GR Exon 1 7 expression in NGFI-A overexpression cells NT EV OE Normalized exon GR Exon 1 11 expression in NGFI-A overexpression cells NT EV OE

78 NGFI-A Overexpression Normalized exon GR Exon 1 10 expression in NGFI-A overexpression cells NT EV OE Normalized GAD GAD1 expression in NGFI-A overexpression cells NT EV OE GR total GR exon 1_7 exon 1_10 exon 1_11 GAD1 promoter contains a CpG island with consensu sequence sites for NGFI-A and for SP NGFI-A

79 CpG Islands H3K9ac CpGme mrna Genes McGowan et al. submitted PCDH clusters NR3C1 (GR) Within protein-coding exons, High LG animals showed significantly higher gene expression overall across the locus profiled (P = 2x10-25

80 LOW LG HIGH LG Golgi-Cox staining of CA1 pyramidal neurons

81 MeCP2 binding to the exon IV BDNF promoter 1.2 Antibody/input (ROD) * HIGH LOW MeCP2 binding is mediated by CpG methylation

82 CA 1 - LTP Slope of the EPSP % Potentiation Time (min) High Low Tetanic stimulation

83 Spatial learning & memory 150 High LG Low LG Latency (sec) Day of Testing Liu et al. Nature Neuroscience 2000

84 Miller & Gauthier Neuron 2007

85 Gliogenesis: CT-1 LIF CNTF Ectopic CNTF expression induces premature astrocyte formation (Barnabé-Heider et al Neuron 2005) BMP Ncor2 Ncor -/- show premature gliogenesis; Ncor2 Inhibits gliogenic effect of BMP NF I/A Proastrocytic transcription factor (gfap) EGF/FBG modulators: Emr1 Miller & Gauthier Neuron 2007

86 Neurogenesis: Ngn related protein Sox2/GFAP (marks early phase (type CNTF Ectopic CNTF expression induces premature astrocyte formation (Barnabé-Heider et al Neuron 2005) BMP Shank2, tubulin. LIM homeobox 2 Associates with dendritic ourgrowth NF I/A Proastrocytic transcription factor (gfap)

87 Prenatal Maternal adversity Nutrition Maternal depression/anxiety Maternal endocrine state MAVAN Project Tobacco/alcohol Environmental factors Low SES High SES Partner relationship Violence Social Support Relationship to mother Community Workplace Individual Resources Self-Esteem Optimism Fetal growth Adaptations Vulnerability Neural development Postnatal Maternal adversity Nutrition Maternal depression/anxiety Family life Tobacco/alcohol Outcomes Cognition function Emotional function

88 Transmission of individual differences in maternal care Mothers Offspring Low LG Mean - 1SD High LG Mean + 1SD 15 Frequency count Licking/Grooming High/LG Low/LG % Licking/grooming Maternal Origin

89 Hippocampal (DG) LTP Basal (low CORT) Stress (High CORT) Bagot et al (Submitted)

90 1st litter 2nd litter Characterize High and Low Mothers One-half of each group are exposed to stress during gestation. Prediction: If the quality of the environment regulates maternal care, then High mothers/gestational stress should resemble Low mothers.

91 Phenotype of the offspring 20 High Low 0.3 % Licking/grooming 10 Optical Density Units No-Stress Stress 0.0 No-Stress Stress Maternal behaviour Hippocampal GR levels

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