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 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 I Implant cannula into the BLA II Train Inject drug or vehicle III Test or Sacrifice

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.)