Emotion and Memory

Noradrenergic Activity in BLA and Hippocampus Connects Glucocorticoid Effects and the Memory Retrieval

 

Yumiko Esaki

esakiy@unr.nevada.edu

 

 

This webpage was made for the course BIOL 475, Developmental Biology, Dr. Grant Mastick, University of Nevada Reno.

This is a summary of a research in the effects of stress hormone, g;ucocorticoid, on the memory processes, based on the article “Glucocorticoid effects on memory retrieval require concurrent noradrenergic activity in the hippocampus and basolateral amygdala.”

 

 

Introduction

The memory and emotion seem to be connected as seen in our daily experiences that memories of the emotional events are more vivid or more remembered.  It might also be a familiar experience that the retrieval of memories is hard when we are nervous or stressed out.  Many researches confirmed there actually is the system in the brain that connects the emotion and memory.

Stress hormones secreted from adrenal cortex after an emotionally arousing experience is known to modulate the memory function through influences on the limbic brain structures.

 

Limbic system, a part of the brain, includes the hippocampus and amygdala.

Hippocampus is associated with the formation of new memories, especially spatial and episodic memories.  The lesion results in the difficulties in forming new memories and in retrieving the old memories.  However, it is not the locus of memory storage.

Amygdala is associated with emotion.  The amygdala is connected with other parts of the brain including hippocampus.

Basolateral region of the amygdala (BLA) is thought to mediate the effect of the stress hormones on the memory processes through the connections to the hippocampus and other regions of the brain.

+
 

NE
 

PKA
 

GR
 

+
 

cAMP
 

β
 

Illustration after Roozendaal., Neurobiol Learn Mem. 78(3):578-95.2002

 

Norepinephrine (NE) is a neurotransmitter secreted during an emotionally arousing experience by noradrenergic neurons activated by stress hormones such as epinephrine.

β-adrenoceptor is the membrane bound receptor for norepinephrine found in BLA.  β-adrenoceptor is also found in hippocampus (not shown).  The binding of norepinephrine to β-adrenoceptor activates the adenylyl cyclase (not shown), which starts the cAMP/PKA cascade.

Glucocorticoid is a stress hormone secreted from adrenal cortex during an emotionally arousing experience and known to modulate the memory function through influences on the limbic brain structures.

2 Known Effects of Glucocorticoid

·        Enhance the new memory consolidation of the events at the time of the elevated glucocorticoid → Well studied

·        Temporarily impair the retrieval of the old memories while the level of the glucocorticoid is high → New!

 

How glucocorticoid ENHANCE the new memory FORMATION?

→ Noradrenergic Activity in BLA

Glucocorticoid readily enters the brain and binds to the intracellular glucocorticoid receptor (GR), which is ubiquitously expressed in the brain including both BLA and hippocampus.  The activated GR is known to interact with β-adrenoceptor-cAMP/PKA pathway and increase the noradrenergic activity in BLA, which is sufficient to enhance the memory formation through the connections to other parts of the brain including hippocampus.

Also, GRs in hippocampus is known to be activated only when GRs in BLA are activated.

 

How glucocorticoid IMPAIRS the RETRIEVAL of the old memories?

What we know so far…

·        Noradrenergic activity is involved; but where specifically?

·        GR activation in Hippocampus is required.

·        The lesion of BLA blocks the memory retrieval impairment induced by the forced GR activity in hippocampus.

Is the mechanism underlying the glucocorticoid-induced enhancement of the new memory consolidation related to the mechanism underlying the glucocorticoid-induced impairment of the old memory retrieval or independent of each other?

 

Roozendaal et al (2004) investigated whether the noradrenergic activity in BLA and hippocampus involved in the glucocorticoid-induced impairment of old memories.

 

Why matters?

--Understanding the mechanism how the memory functions are influenced by stress hormones might lead to the therapies for the posttraumatic stress disorder patients and other memory disorder patients.

 

 

Experimental System

The water maze was used as a memory test, which measured the effect of the drugs on the spatial memory retrieval.

Mice were first, trained in the water maze

learned the location of the platform in the water maze

then, treated hippocampus and BLA with drugs at the retention test

Tested the effects of drugs on the memory retention of the platform location by measuring the performance in finding the platform in the water maze.

 

Mice; male adult Sprague Dawley rats were implanted the cannulas in the hippocampus and BLA regions to allow the selective drug manipulation at least a week before the experiment.

 

Water Maze; a circular tank, 1.85 m in diameter and 0.58 m in height with 25 C water filling up to 25 cm of depth.  A platform (20X25) was submerged 2.5 cm below the surface of water and 25 cm away from the edge of the tank, where it could not be seen by the rats.  The maze was placed in a room with a lot of visual cues.

Illustration after Roozendaal., Neurobiol Learn Mem. 78(3):578-95.2002

 

Training and Testing; Rats placed at a starting point were to swim and find the platform.  4 cumulative trials were done on each day for 3 successive days.  The retention of the spatial memory was tested 24 hours after the last training. 

 

Parameters used to measure the retrieval of the spatial memory;

  • Time spent in training quadrant, the quadrant where the platform was located during the training.
  • Time spent in opposite quadrant, the quadrant opposite to the training quadrant.
  • Initial latency for the rats to cross the platform location.
  • Total swim distance. 

The significance of the results was statistically tested. 

 

Drug Treatment; A drug or concurrent two was administered 1 hour before the test.

  • RU 28362 = a specific GR agonist.
  • Atenolol = a selective β1-adrenoceptor antagonist.
  • Xamotenol = a β1-adrenoceptor selective partial agonist A

 

 

Pharmacological Approach; Advantages and Disadvantages

Advantage;

  • Can change the phenotypic behavior only temporarily whereas the genetic engineering changes it permanently
  • Easy to “block it” or “move it” if the molecules involved are known

Disadvantage;

  • Cannot identify the cellular protein status; cannot identify the intracellular cascade unless the molecules involved are known

 

 

 

Results

For selective injections, RU 28362 was used as GR agonist, and atenolol as selective β1-adrenoceptor antagonist.

 

Selective Drug Injections in Hippocampus

The search time in each quadrant and the initial latency to cross the platform are summarized for each treatment in figure 1.

Figure1. after Roozendaal., Neurobiol Learn Mem. 78(3):578-95.2002

 

Control rats (vehicle and saline);

Significantly longer time spent in the training quadrant than in the opposite quadrant 

→ Memory for the platform location learned from the training

GR agonist treatment;

Time spent in the training quadrant lowered to the chance level and more time spent in the opposite quadrant.   Increased initial latency.

→ Impaired memory retrieval

β1-adrenoceptor antagonist treatment;

Significantly longer time spent in the training quadrant than in the opposite quadrant 

→ Memory for the platform location learned from the training

GR agonist and β1-adrenoceptor antagonist;

Significantly longer time spent in the training quadrant than in the opposite quadrant 

→ Memory for the platform location learned from the training

→ Blocked the impairing effect of GR agonist on memory retrieval

 

 

Selective Drug Injections in BLA

The search time in each quadrant and the initial latency to cross the platform are summarized for each treatment in figure 2.

Figure2. after Roozendaal., Neurobiol Learn Mem. 78(3):578-95.2002

 

Control rats (saline and vehicle);

Significantly longer time spent in the training quadrant than in the opposite quadrant 

→ Memory for the platform location learned from the training

GR agonist and saline;

Time spent in the training quadrant lowered to the chance level and more time spent in the opposite quadrant.  Increased initial latency.

→Impaired memory retrieval

β1-adrenoceptor antagonist and vehicle;

Significantly longer time spent in the training quadrant than in the opposite quadrant 

→ Memory for the platform location learned from the training

GR agonist and β1-adrenoceptor antagonist;

Significantly longer time spent in the training quadrant than in the opposite quadrant 

→ Memory for the platform location learned from the training

→Blocked the impairing effect of GR agonist on memory retrieval

 

 

Systemic Injection of β1-adrenoceptor agonist

β1-adrenoceptor agonist, xamotenol, was injected systemically into intact non-operated mice;

A dose dependent reduction in the time spent in the training quadrant and increment in the initial latency

→Impaired memory retrieval in a dose-dependent manner

→ systemic injection of β1-adrenoceptor injection mimics the effect of GR agonist

 

 

 

Conclusions

  • β1-adrenoceptor antagonist blocks the impairment of memory retrieval induced by the GR agonist.

→  the glucocorticoid effects on the memory retrieval require the concurrent noradrenergic activity

→  Comparable to the noradrenergic requirement of glucocorticoid effect on memory consolidation

 

  • The effect of glucocorticoid activity in hippocampus on memory retrieval requires the concurrent noradrenergic activity in both hippocampus and BLA.

→  the memory retrieval involves in not only hippocampus but also BLA.  The input from BLA enables the hippocampal glucocorticoid to impart the effect on memory retention.  Consistent with the hypothesis that emotion-activated BLA modulates the memory processes through connections to other parts of the brain.

 

  • The systemic injection of β1-adrenoceptor agonist mimics the effect of GR agonist on memory retrieval

→  Noradrenergic activity is sufficient to induce the glucocorticoid effect on memory retention

→  Glucocorticoid induced retention impairment involves facilitation of noradrenergic activity in hippocampus

 

đ       Mechanism underlying the glucocorticoid-induced enhancement of memory consolidation is comparable to the mechanism underlying the glucocorticoid-induced impairment of memory retrieval

đ      May be regulated by the same cellular mechanism that involves in the noradrenergic activity

đ      The formation of new memory at the time of  stressful event is enhanced, while the retrieval of old memory is temporarily impaired by the stress hormone-norepinephrine system

 

 

 

Significance

  • Another evidence for the involvement of BLA in memory processes
  • Demonstrated that the involvement of noradrenergic activity in BLA and hippocampus

→ Implication that the glucocorticoid effects on the memory retrieval and memory formation are coordinated by the same cellular mechanism

  • Consistent with our experiences that during an emotionally arousing experience such as an exam, it is hard to remember the memory from studying, but the memory of taking the exam might last a lifetime
  • Implication that a long time exposure to stress might contribute to the impairment of memory retrieval; may involved in some of the symptoms of Alzheimer’s disease?

 

 

 

Future Directions

What is the cellular mechanism that coordinates the stress effects on the memory formation and retrieval?

  • The cellular protein status in BLA and hippocampus would need to be understood to clarify how the elevated noradrenergic activity and the subsequent elevated production of cAMP/PKA influence the memory consolidation and retrieval.
  • cDNA library, in situ hybridization, and yeast 2 hybrid might be useful methods to figure out this…

 

 

 

References

Primary Research Article: 

Roozendaal, B., E.L. Hahn, S.V. Nathan, D.J. de Quervain, and J.L. McGaugh.  “Glucocorticoid Effects on Memory Retrieval Require Concurrent Noradrenergic Activity in the Hippocampus and Basolateral Amygdala.”  Journal of Neuroscience 2004, 24(37):8161-8169.

-The selective pharmacological treatment in the hippocampus and BLA of mice revealed that the glucocorticoid-induced impairing effect on the memory retrieval requires the concurrent noradrenergic activity in both BLA and hippocampus.  It also demonstrated that the forced noradrenergic activity is sufficient to mimic the glucocorticoid effect.  These findings suggest that the glucocorticoid effects on the memory retrieval might share the common pathway or neurobiological substrate with the well-studied another effect of glucocorticoid on the memory consolidation.

 

Review Article:

McGaugh, J.L.  “The amygdala modulates the consolidation of memories of emotionally arousing experiences.”  Annual Review of Neuroscience 2004, 78(3):578-95.

- Summary of BLA functions in modulating the effects of stress hormones on the memory consolidation.  Introduces the different stress hormones that can affect the memory consolidation.

 

Roozendaal, B.  “Stress and memory: opposing effects of glucocorticoids on memory consolidation and memory retrieval.”    Neurobiology of Learning and Science 2002, 78(3):578-95.

- Summary of known glucocorticoid effects on the memory consolidation and memory retrieval.  Roozendaal suggested the integrated hypothesis that the mechanisms underlying the glucocorticoid effects on the two cognitive phases interrelate and share the same substrate.

 

 

This page was constructed by:

Yumiko Esaki

esakiy@unr.nevada.edu

11/16/04