Adolescent development, hypothalamic-pituitary-adrenal function, and programming of adult
learning and memory
Chronic exposure to stress is known to affect learning and memory in adults through the release
of glucocorticoid hormones by the hypothalamic-pituitary-adrenal (HPA) axis.
Biological transitions are times of increased vulnerability that may be related to change in the
reactivity of the stress systems, notably the hypothalamic-pituitary-adrenal (HPA) axis
o Immediate energy demands of stressor: The HPA axis is involved in “allostasis”, which means
that the axis is a mechanism by which adaptive changes are initiated to maintain
physiological stability, influencing diverse actions such as energy metabolism, immune and
cardiovascular function through actions of glucocorticoids on almost every cell type of the
body
o Long term effects: By altering synaptic structure and function in pathways mediating goaldirected behaviour (dopamine pathway from the ventral tegmental area to the nucleus
accumbens) and learning and memory (mPFC, amygdala, and hippocampus), glucocorticoids
influence the behavioural and physiological responses to subsequent encounters
o The extra-hypothalamic limbic structures that are important for regulating HPA function,
notably the hippocampus, prefrontal cortex, and amygdala, have long-established roles in
learning and memory. Their roles also involve the dopaminergic projections from the ventral
tegmental area to the nucleus accumbens, a pathway that is important for motivation, and
the function of which is regulated by glucocorticoids (
Exposure to high levels of glucocorticoids:
Adulthood:
relatively transient effects of stress on cognitive function
Glucocorticoids alter synaptic structure and function in brain regions that express high levels of
glucocorticoid receptors and that mediate goal-directed behaviour and learning and memory.
Early life:
can produce enduring changes through substantial remodeling of the developing nervous
system.
Adolescence is another time of significant brain development and maturation of the HPA axis,
thereby providing another opportunity for glucocorticoids to exert programming effects on
neurocircuitry involved in learning and memory. Stress-related plasticity that may be unique to
adolescence due to qualitatively different changes than in childhood and adulthood
Stress
Intrinsic stress (i.e. stress related to the cognitive task) generally enhances the consolidation of
memory through actions of norepinephrine and glucocorticoids on the neural circuits activated
by the learning experience
Long-term potentiation (LTP) and long-term depression (LTD) are considered to be the
neurophysiological correlates of the plasticity associated with learning and memory, and are
highly sensitive to extrinsic stressors (stress derives from conditions other than the cognitive
task)
Exposure to recurring or chronic stress impairs:
o medial prefrontal cortical-dependent tasks such as the recall of extinction of
conditioned fear
o attentional set-shifting
o hippocampal-dependent performance in spatial tasks such as the spatial Y-maze and
radial arm maze
o Numerous markers of neuroplasticity are altered by chronic stress and may contribute
to the changes in learning and memory
o Chronic stress and chronic elevation of glucocorticoids result in retraction of dendrites
in the hippocampus, the medial prefrontal cortex and, depending on the type of
stressor, enhancement or retraction of dendrites in the basolateral amygdale. Chronic
stress and/or chronic elevation of glucocorticoids decrease neurogenesis in the dentate
gyrus.
Experience
Environmental experiences in adolescence influence later performance on spatial cognition.
o enriched environments over adolescence, but not later in life: improved Morris water
maze performance in and Morris water maze performance and radial arm maze
performance in rats.
o exposure to stressors eg exposure to variable physical stressors (forced swim, restraint,
cold, noise, ether) and not variable social stressors (litter shifting, subordination,
crowding, isolation, novel environment) daily from P28 to P56 in male rats led to
decreased performance in a Morris water maze test and decreased hippocampal volume
several weeks later. Also had reduced long-term potentiation in the CA1 pyramidal layer
and reduced expression of several hippocampal proteins associated with learning and
memory compared to controls.
Lasting effects of stress in adolescence have also been observed for fear conditioning
drug-related plasticity. Drugs of abuse produce structural changes in the nucleus accumbens,
hippocampus, and PFC, and the molecular mechanisms underlying the plasticity are thought to
be the same as those underlying learning and memory. Thus, any adolescent stress-induced
alteration in learning and memory may be accompanied by altered behavioural and structural
responses to drugs of abuse. Stress exposures in adolescence alter sensitization to drugs of
abuse
Issues with tests:
many of the learning and memory tests that have been used are inherently stressful (e.g., Morris
water maze, fear conditioning)  performance may be affected by the extent to which an
adolescent stress procedure alters HPA responses to a new stressor
extent to which the enduring effects of stressors in adolescence are mediated or moderated by
changes in the HPG axis. There are widespread activational effects of gonadal hormones on
learning and memory, and like glucocorticoids, gonadal hormones influence the underlying
neuroplasticity. There is increasing evidence that gonadal hormones exert relatively permanent
organizational effects on ongoing brain development over adolescence, and exposure to gonadal
hormones in adolescence influences gonadal actions in the brain in adulthood