I.     Main ideas:

A.       Mild to moderate short term stressors enhance cognition

B.        Severe or very prolonged stressors impair it.

II.    How memory works

       A.    Different types of memory

1.        Short term  vs. long term (including remote)

2.        Declarative vs. implicit (procedural)

a.         Transfer from declarative to implicit

b.         Difficult to mix the two

B.    Brain areas

1.        Cortex & hippocampus (declarative)

2.        Cerebellum (implicit)

C.       Networks, not single neurons

D.       The role of glutamate

a.         Nonlinear (threshold):  due to Mg++ ions blocking a Ca++ channel associated with an NMDA-type of glutamate receptor..  You need enough activation of AMPA-type glutamate receptors to open Na+ channels to depolarize the neuron enough to make the neuron interior unattractive to the Mg++ ion, which then leaves in disgust.  Therefore Ca++ can flow in and activate a number of intracellular processes that produce long-term changes.

b.        Long-term potentiation (LTP) and long-term depression (LTD)

III.   Improving your memory during stress

       A.    James McGaugh:  story re. Mother and son walking through town

1.        Experimental subjects remembered only the exciting part.

2.        Beta-blocker (propranolol):  Experimental and control subjects similar

a.         Propranolol disrupted only the stress-related enhancement—not memory per se.

b.         Symp. NS à increased oxygen and glucose available to brain

B.        Paul Gold:  Glucose is important for both memory formation and retrieval.

C.       Glucocorticoids act directly in hippocampus to increase LTP in vitro.

D.       Sensory receptors are more sensitive under moderate stress.

IV.  When stress goes on for too long

A.       “Big-time stress” levels of glucocorticoids or sustained sympathetic activation impairs memory.

B.        Major stressors also increase LTD à forgetting.

C.       Glucose utilization is back down to normal by 30 min, and declines further after that, esp. in hipp.

1.        Possible rationale:  you’re running on automatic (reflexive and motoric)

2.        But there’s no evidence whether the “saved” glucose is sent to brain areas that control those fns.

V.    The plot thickens

       A.    Neuronal damage

               1.    Bruce McEwen: a few weeks of stress or exposure to glucocorticoids à axons atrophy and retract.

a.         They can regrow after stress has ended.

b.         Meanwhile, you need more associative cues to remember something.

2.    Cushing’s dementia:  MRI scans:  hippocampi had shrunk; rest of brain was normal.

a.         Correlation between severity of disease and amount of shrinkage.

b.         After removal of tumor: atrophy normalized.

B.    Neuroendangerment

1.        Glucocorticoids inhibit glucose storage by about 25% in hippocampal neurons. 

2.        This decreases their ability to survive an epileptic seizure, cardiac arrest, stroke, or concussion.

3.        Also impairs survival after exposure to beta-amyloid (similar to Alzheimer’s) or gp120 (AIDS)

4.        However, glucocorticoids also decrease inflammation, which is another component of Alzheimer’s disease; therefore, it’s not clear whether glucocorticoids worsen the disease.

5.        Humans with stroke:  the higher the glucocorticoids when the person enters the ER, the more damage and memory problems.

C.    Implications for glucocorticoid therapy

1.        Glucocorticoids block edema due to tumors and other kinds of trauma, but don’t help after stroke.  Since they impair neuron survival in hippocampus, they shouldn’t be used in stroke patients.

2.        Glucocorticoids, given to AIDS patients for other reasons, may endanger hippocampus.

3.        Stress-induced glucocorticoids also impair hippocampus.  Rats adrenalectomized or given a drug to shut down adrenal cortex have less hipp. damage after stroke or seizure.

D.       How did this mechanism evolve?  No evolutionary pressure to produce a more adaptive response, since no one survived such neurological insults until about 50 years ago.

VI.  Glucorticoid neurotoxicity

A.       Prolonged stress or glucocorticoids kill hippocampal neurons.

1.        Hipp. is loaded with glucocort. receptors, as part of the negative feedback control. 

2.        Extent of glucocorticoid exposure over rat’s lifetime predicted hippocampal degeneration and memory problems.

3.        PTSD:  major and selective atrophy of hippocampus, even decades after the original trauma.

4.        Yvette Sheline: Long-term depression does the same thing, also including years later.

5.        However, only half of depressives secrete excess glucorticoids.

6.        Also, PTSD victims actually have lower than normal        at the time of the measurement. 

a.       However, they probably had very high levels at the time of the trauma. 

b.      Also, only 10-20% of people exposed to combat trauma develop PTSD.

c.       People with smaller hippocampi may be more likely to succumb to PTSD. (?)

7.        People taking glucocorticoids for autoimmune disorders (lupus, multiple sclerosis, rheumatoid arthritis) often have memory problems.

VII. Recent discovery:  Monkeys and humans produce new neurons in the hippocampus in adulthood.