Early Rearing - Maternal Behaviour in the Rat Flashcards
How can stress affect brain structures?
• Mild level of stress, certain neurochemical systems (catecholamines, GCs) might effect learning
• As the level of stress increases, transient and permanent changes are seen in the hippocampus that can potentially influence learning and memory processes.
− Modifications in synaptic plasticity
− Morphological changes
− Suppression of adult neurogenesis
− Neuronal enlargement
What is stress?
• Routinely used as if it were a well-defined psychophysiological measure
• Stress is a nebulous description of diverse behavioural and physiological responses
• No universal definition that can apply equally to rodents and humans because:
− Whether stress occurs is not determined by the environmental stimulation, but by how an organism perceives and reacts to the stimulus eg) some people panic at public speaking, others like it
− There is no unique physiological state associated with stress – elevated GCs is an indicator, but GCs are also elevated during pleasurable activities.
What are the effects of maternal care on the HPA gene expression?
- You have expression of the GC receptor in the hippocampus in regions involved in negative feedback.
- CRH is relatively poorly expressed.
- In pups from naturally high LG mothers, you get high GCR expression, and low CRH expression. There isn’t much difference between the handled and the non-handled pups (mothers are so good at being maternal, they cant really get much more maternal after handling)
- In non-handled pups from naturally low LG mothers, you have diminished GCR expression. You also have massively upregulated CRH, because you don’t have the negative feedback → more stress.
- If you handle the pups form naturally low LG mothers, the mothers will lick them more, and you can reverse the phenotype so they now have high levels of GCR and low CRH → less GC released, so lower stress.
→ brain can be re-wired depending on early rearing experiences!
Are the effects of early rearing long-lasting?
Lasting effects of early rearing:
• Offspring of high LG mothers have lower plasma ACTH levels in response to the stress of restraint in a tube.
• The plasma corticosteroid levels are also lower
• Inverse correlation between amount of licking received as a pup, and plasma corticosteroid levels in response to restraint when tested later as an adult.
Are the effects of early rearing trans-generational?
• Pups that have been induced to be calm from their mothers produce offspring that are also better mothers.
- Adult that had high LG mother and so is high LG itself → offspring pup with low anxiety as adult
- Adult that had low LG mother and so is low LG itself → pup with high anxiety as adult
- Adult that had low LG mother, cross-foster their pups to a high LG mother → pup with low anxiety as adult
− This shows an environmental effect, as pups from naturally poor mothers reared by good mothers end up good mothers themselves with low stress. - Adult that had high LG mother, cross-foster their pups to low LG mother → pup with low anxiety as adult
− This shows a potentially genetic effect, as pups from naturally good mothers are still good mothers even when reared by poor mothers.
Is there a link between early rearing and learning?
Maternal care, hippocampal synaptogenesis and cognitive development in rats:
• Offspring of good mothers are smarter
− Adults reared by high LG mothers performed better in the Morris water maze test → they are better learners
− Spatial learning and memory is associated with hippocampal function and the 1st week of life is a period of intense synaptogenesis
− Synaptogenesis is impaired if you are reared by a less attentive mother.
− There are no obvious differences in hippocampal neuron densities → suggests re-wirings.
So early environment matters in learning:
• Increased number of neurons
• 15% increase in the granular cell layer of the gentate gyrus
• Improved learning in the morris water maze
it also has long-term effects on stress:
• Mediated by patterns of CRH expression and GC receptor, which feedsback to limit stress
• Poor mothers rear offspring with high CRH and low GC receptor expression, who pass this phenotype on to their offspring.
What causes the long-lasting effects of maternal rearing on stress and learning?
Maternal care switches on an epigenetic control circuit:
• High LG mothers have high serotonin tone, leading to activation of cAMP
• This activates transcription of nerve growth factor inducible protein NGFI-A
• NGFI-A switches on GR expression by epigenetic regulation:
− NGF1-A recruits HATs such as CBP
− This initiates transcription as a result of acetylation and demethylation of DNMT
− The stronger the serotonin stimulation, the greater the impact.
So:
• Increased licking leads to increased serotonin tone in the hippocampus, leading to increased NGFI-A
• The GR gene is acetylated and de-methylated, allowing transcription
• This increases GR number in the hypothalamus, leading to a cascade of other endocrine and behavioural factors, and life-long effects
Effects on learning:
• Brain derived growth factor (BDGF) is key to synaptic survival – levels are higher in the hippocampus in high LG mothers
• Activation of NDMA receptors increases BDGF:
− Maternal LG leads to reduced GC production in the young (due to increased GC receptor expression).
− This gives increased NMDA receptor expression
− This leads to increased BDGF expression
− This gives long-term re-structuring of hippocampal function → lasts until old age, old rats have better cognition!
Have these epigenetic changes in GR gene expression in response to early rearing environments been found in humans?
McGowan et al, 2009
• Examined epigenetic differences in a GC receptor promoter (NR3C1) between hippocampus obtaind from suicide victims with a history of childhood abuse, no childhood abuse, or controls.
• No significant different in the methylation between controls and suicides without childhood abuse
• In those that did have childhood abuse, much higher rate of methylation
− Methylation is the switch off mechanism
− Gives low GC receptor expression, takes away negative feedback, increases CRH and GC levels and stress.
− So higher methylation gives higher stress
Describe the link between hippocampus wiring and PTSD?
Gross and Hen, 2004 – Developmental Origins of Anxiety
• Human susceptibility to depression and anxiety can be determined in early life
• Early developmental mechanisms can set the lifelong tendency of an organism to express anxiety in response to threatening stimuli – these mechanisms are under both genetic and environmental control
• PTSD is an example in which environmental risk factors seem to be modulated by genetic factors
• Develops in 15% of people who witness trauma such as rape, murder or military combat
• Characterised by recurrent and intrusive memories of the traumatic event that elicit intense fear
• One of the most consistent findings is a tendency for hippocampal volume to decrease → hippocampus is easily damaged by stress hormones.
− Recent twin studies indicate this is incorrect
− Researches propose that reduced hippocampal volume is a pre-existiing conditions that determines susceptibility to PTSD.
Twin study – Vietnam War
• Of the twins that went to war, 42% developed PTSD
• Their hippocampus volumes were not different to their twins, suggesting reduction of hippocampal volume is not a consequence
• There was however, correlation between hippocampal volume and probability of developing PTSD
- Twins who are not in combat have low risk of PTSD (obviously)
- If the twin in combat has a large hippocampus, they have a low risk for PTSD
- If they twin has a small hippocampus, they have a high risk for PTSD
Describe any other findings to to with the HPA axis in humans
Bick et al, 2010
Childhood adversity and DNA methylation of genes involved in the HPA axis and immune system
• Placement into foster care associated with alterations in the HPA axis that are observed during childhood (when the adversity occurs), adolescence and adulthood
• Alterations in the HPA axis associated with pathogenensis of cellular functioning, impaired neuronal growth and immune system activity, and acceleration of cellular ageing.
• Altered HPA axis thought to be a primary agent in risk for chronic illness and psychiatric disease
• Children experienced neglect been shown to have high immune system activity, signified by increased antibody levels to herpes simplex 1
• Low socioeconomic status and harsh early environment linked with elevated levels of C-reactive protein, a biomarker of inflammatory processes
• Epigenetic changes not limited to brain tissues, they are also seen in the GR gene in leukocytes and have been associated with adults that have had early adverse experiences, adults with borderline personality disorders, and mothers who experienced domestic violence during pregnancy.
