Transcript NLM2e Ch13 Lecturex

13
Memory Modulation Systems
Chapter Goals
Arousing experiences are memorable. The goal of this
chapter is to understand why this is the case.
Central idea: Arousing events activate neural and hormonal
processes that influence the cellular–molecular processes
that consolidate memory.
Key Discussion Points
• The memory modulation framework
• The basolateral amygdala
• The Role of Epinephrine
• Epinephrine and and the Blood Brain Barrier
• The Epinephrine Vagus Connection
• The Epinephrine Liver-Glucose Connection
• The Role of Glucocorticoids
Memory Modulation Framework: Assumptions
1. A behavioral experience can have two independent
effects: it can activate specific sets of neurons that
represent and store the content of the experience, and it
can activate hormonal and other neural systems that can
influence the mechanisms that store the memory.
2. These hormonal and other neural systems are called
memory modulators. They are not part of the storage
system, but they can influence the synapses that store the
memory.
3. Memory modulators have a time-limited role and influence
only the storage of very recently acquired memories. They
operate during a period of time shortly after the behavioral
experience when the trace is being consolidated.
4. The neural systems that modulate memory strength are
not necessary for the retrieval of the memory.
Memory Modulation Framework: Assumptions
Experience has two independent effects. It can initiate the
acquisition and storage of the memory trace and it can
activate the release of adrenal hormones that can modulate
the processes that store the memory.
The Great Modulator: The Basolateral Amygdala
The amygdala is anatomically connected to many regions of
the brain that are likely storage sites for different types of
memories. Thus, it is in a position to influence or modulate
storage processes in other regions of the brain.
The Great Modulator: The Basolateral Amygdala
(A) Injecting the stimulant amphetamine into the amygdala following
training on the place-learning version of the Morris water-escape task
improved retention performance. (B) Injecting the amphetamine following
training on the visible-platform task improved retention performance. (Short
latency indicates better retention.) The hippocampus is thought to be a
critical storage site for place learning and the caudate is thought to be
critical for the visible-platform task. (After Packard and Teather, 1998.)
The Great Modulator: The Basolateral Amygdala
(A) An injection of lidocaine into the basolateral amygdala (BLA) following
avoidance training impaired the retention of the inhibitory avoidance
response. (B) Lidocaine had no effect when it was injected into the central
nucleus (CE) of the amygdala. LA = lateral nucleus; BA = basal nucleus.
(After Parent and McGaugh, 1994.)
The Role of Epinephrine
On the training trial, rats received a mild shock when they crossed to the
dark side of the apparatus. Compared to control rats injected with the saline
vehicle, rats that were injected with a dose of epinephrine—calculated to
mimic the level of epinephrine that would naturally be released from the
adrenal gland if the animals had received a strong shock—displayed
enhanced inhibitory avoidance. The enhancing effect of epinephrine,
however, was time dependent. It was more effective when it was given
shortly after the training trial. (After Gold and Van Buskirk, 1975.)
The Blood brain barrier: The Epinephrine Vagus Connection
Epinephrine does not cross the
blood–brain barrier. However,
when it is released from the
adrenal medulla it binds to
adrenergic receptors on the vagal
nerve. In response to activation,
the vagal nerve releases
glutamate on neurons in the
solitary tract nucleus (NTS).
Activated NTS neurons release
glutamate onto neurons in the
locus coeruleus, which in turn
release norepinephrine that binds
to adrenergic receptors in the
basolateral amygdala (BLA).
Disrupting any component of this
neuro-hormonal circuit will prevent
arousal from enhancing memory.
The Role of Epinephrine: Microdialysis
Microdialysis allows
extracellular fluid to be
collected from deep within the
brain. (A) A rat with a specially
designed microdialysis probe
implanted in the brain. (B) A
detail of the microdialysis
probe. (C) A freely moving rat
connected to the
instrumentation designed to
extract a very small quantity of
extracellular fluid. The content
of this fluid can then be
analyzed for its composition.
CSF = cerebral spinal fluid.
Microdialysis: Avoidance Training Causes the Release of
Norepinephrine in the Amygdala
The microdialysis methodology was used to extract norepinephrine from
the extracellular brain fluid. (A) The level of norepinephrine released into
the extracellular fluid in avoidance training is determined by the intensity of
the shock. (After Quirarte et al., 1998.) (B) Just shocking a rat or allowing it
to explore the avoidance training apparatus does not increase the level of
norepinephrine. That requires the rat both to explore the novel apparatus
and to be shocked. (After McIntyre et al., 2002).
Norepinephrine Enhances Memories
(A) The injection of norepinephrine into the amygdala following place
learning enhanced the rat’s retention of the platform location, but when
propranolol was injected, retention was impaired. (B) Norepinephrine (NE)
injected into the amygdala following inhibitory avoidance training with a
weak shock enhanced retention performance. Propranolol (Pro) injected
into the amygdala following inhibitory avoidance training with strong shock
impaired retention. (After Hatfield and McGaugh, 1999.)
What Does the Amygdala Signal Do? Arc Translation
Experimental Design
I
Implant cannula
into the BLA
II
Train
III
Test or
Sacrifice
Inject
drug
or
vehicle
• Cannula implanted into the amygdala
• Rats trained on the inhibitory avoidance task
• Rats injected with either a beta-andrenergic agonist
(clenbuterol) or lidocaine, which inactivates the BLA neurons
• Rats either sacrificed or tested on the IA task
• Hippocampus brain tissue was sampled for Arc protein
Norepinephrine Enhances Glutamate Release and Arc Translation
(A) This graph illustrates the effect of injecting lidocaine and clenbuterol
into the BLA on the level of Arc protein in the hippocampus following
inhibitory avoidance learning. (B) This graph illustrates the effect of these
drugs on inhibitory avoidance. Note that lidocaine reduced the level of Arc
protein in the hippocampus and decreased inhibitory avoidance. In
contrast, clenbuterol increased the level of Arc protein and enhanced
inhibitory avoidance. (After McIntyre et al., 2005.) These results suggest
that the BLA might modulate memory by influencing the level of Arc protein
in the hippocampus.
The Norepinephrine Signal in Other Storage Areas
When norepinephrine is
released into the
hippocampus, PKA is
activated and
phosphorylates two sites
(Ser 831 and Ser 845) on
the GluA1 AMPA receptor
subunit. This facilitates the
trafficking of GluA1s into the
dendritic spine and
increases memory strength.
The Epinephrine Liver–Glucose Connection: Bioenergetics and
the Brain
The flow of energy in cells is called bioenergenics, and the
primary source of energy is glucose, which enters the brain
via the cerebral vasculature.
An arousing event activates
the adrenal medulla to
release epinephrine into the
blood system where it binds
to adrenergic receptors in
the liver cell. This results in
the liver secreting glucose
into the blood where it
enters the brain via the
cerebral vasculature
system.
The Epinephrine Liver–Glucose Connection: Glucose Modulates
Memory
This figure illustrates that systemic injections of either
epinephrine or glucose influence memory strength in a
dose-dependent manner. (After Gold and Korol, 2012.)
These data support the view that epinephrine modulates
memory by binding to adrenergic receptors on the liver cells
causing them to release glucose. Sal = saline.00
The Epinephrine Liver–Glucose Connection: Glucose and Aging
(A) In response to an arousing event (footshock), the adrenal gland
releases epinephrine in both young and old rats. (B) Nevertheless, the
liver of only young rats secretes glucose. (After Mabry et al., 1995.) (C) A
systemic injection of glucose prevents forgetting in old rats tested 7 days
after inhibitory avoidance training. (After Morris and Gold, 2013.)
Avoidance training does not lead to CREB phosphorylation (pCREB) in
old rats. However, if glucose is injected following training, phosphorylated
CREB is detected. mA = milliamp; UnT = untrained; Sal = saline; Gluc =
glucose; pg/ml = picograms per milliliter; mg/dl = milligrams per deciliter.
The Epinephrine Liver–Glucose Connection: Glucose and
Transcription
(D) Enduring memories
depend on new genes
targeted by the
transcription factor CREB
(see Chapter 11). (After
Morris and Gold, 2013.)
Avoidance training does
not lead to CREB
phosphorylation (pCREB)
in old rats. However, if
glucose is injected
following training,
phosphorylated CREB is
detected.
Glucocorticoids: The Other Adrenal Hormones
Dexamethazone is a synthetic glucocorticoid. When it is injected
systemically following inhibitory avoidance training, it enhances
retention. However, the effect of dexamethazone also depends on
epinephrine being released in the amygdala, because when injected
into the amygdala, propranolol prevents dexamethazone from
enhancing retention. (After Quirarte et al., 1997.)