ch18

Learning and Memory: Neural Mechanisms
Chapter 18 Summary

This chapter focuses on answering three main questions:

1. What are the basic biological mechanisms - at the molecular, synaptic, and cellular levels, - for long-term storage of information in the nervous system?
2. At the level of neural circuits, how do the formation and modification of circuits function in memory?
3. What sequence of neurochemical events underlies the storage of long-term memory? (p.553)

Psychologist Donald O. Hebb proposed the idea that the relationship between a presynaptic neuron and a postsynaptic neuron could change if the presynaptic neuron frequently excited the postsynaptic neuron. Investigators have confirmed this hypothesis and the term "Hebbian synapses" has come into use, referring to synapses that grow stronger when the presynaptic terminal repeatedly causes the postsynaptic cell to fire. Hebb also proposed the dual-trace hypothesis which states, "The formation of memory involves first relatively brief transient process: Learning experience sets up activity that tends to reverberate through the activated neural circuits. This activity holds the memory for a short period. If sufficient, the activity helps build up a stable change in the nervous system - a long-lasting memory trace" (p. 556). This hypothesis is supported by findings that show learning experiences having a physical effect on the brain.

The first demonstration of this occurred when an interdisciplinary team discovered the anatomy of the rodent brain changed as a result of formal training or informal experience. Same sex rodents were assigned to a standard condition (SC) cage, an impoverished condition (IC) cage, or an enriched condition (EC) cage. The results showed EC rodents to have greater acetylcholinestesterase (AChE) activity and a heavier cerebral cortex due to thicker cerebral cortices than the IC or SC rodents. This resulted in EC rodents displaying better learning and problem solving in a variety of tests than the IC or SC rodents.

These experiments with rodents also provided evidence that learning can produce new synaptic connections. Psychologist William Greenough found that animals raised in EC conditions had greater dendritic branching than those raised in IC conditions. EC animals also had a greater number of dendritic spines, showing that they develop new synapses and circuits. They have a greater number of filopodia, or extensions from dendrites, and greater postsynaptic thickening in synapses of the occipital lobe. The fact that these changes are found in the cerebral cortex supports the hypothesis that memory is stored in the cortex, but information is processed from memory storage in other brain regions (p. 559).

For Nervous System Plasticity in Aplysia, please refer to Memory-Like Alterations in Aplysia Axons After Nerve Injury or Localized Depolarization

Long-term potential (LTP) is a way in which investigators are attempting to study the vertebrate brain circuit. LTP is a stable and enduring increase in the effectiveness of synapses. In LTP, the axons are stimulated with a brief tetanus, or a flurry of electrical stimulation triggering thousands of action potentials over 1-2 seconds. This causes a group of axons to fire repeatedly. This, in turn, causes the postsynaptic targets to fire repeatedly. The synapses are then stronger than they were prior to the tetanus. "LTP does resemble memory because it can be induced within seconds, can last for days or weeks, and has a consolidation period that lasts for several minutes after induction" (p. 562).

LTP was originally observed to consist of synapses from the perforant path to the dentate gyrus, part of the hippocampal formation. Other pathways, such as CA1 and CA3, have also demonstrated LTP. The synapses use glutamate as a transmitter. "LTP is area CA1 depends on a subclass of glutamate receptors that respond to the synthetic agonist N-methyl-_D-aspartate (NDMA)" (p.563). Blocking the receptors by antagonists of NDMA prevented the induction of LTP in area CA1, but had no affect on the LTP that was already produced.

There are several steps to the induction of LTP in the CA1 region of the hippocampus.

"Steps in the Neurochemical Induction Cascade During the Induction of LTP

1. Strong stimulation of the neuron leads to the rapid increase in the extracellular concentration of the Ca²⁺ ions
2. Increased Ca²⁺ion concentration activates protein kinases, enzymes that catalyze phosphorylation (including Ca²⁺-calmodulin kinase [CaMK], PKA, PKC, etc.), which phosphorylate proteins.

3. Phosphorylated CREB protein binds to cyclicAMP response elements in the promoter regions of many gense. CREB binding regulates the transcription of many different genes.
4. Changes in gene transcription lead to changes in proteins, including enzymes and structural proteins. Some of these proteins are necessary to induce LTP.
5. Many of the proteins synthesized are transported down the axon and into dendrites to alter the response of the neuron to further stimuli" (p. 566).

There is evidence to support LTP as being similar to certain forms of learning and memory. Similarities in synaptic strength have been found between the two processes. Also, in Kandel's "knock-out mice", four different kinases were disrupted in four different groups of mice. The results showed that hippocampal LTP was reduced only in mice missing a specific gene, fyn. Also, these mice were the only ones to show a deficit in maze learning, showing the same protein to be important in both LTP and in maze learning.

While much focus was on the neural circuit of invertebrates and the phenomenon of LTP, Psychologist Richard F. Thompson and his colleagues focused on studying the neural circuitry of eye-blink conditioning in rabbits. The basic circuit was found to be simple. "Sensory fibers from the cornea run along cranial nerve V (the trigeminal nerve) to its nucleus in the brainstem. From there, some interneurons send axons to synapse upon other cranial nerve nuclei (VI and VII) in the brainstem. Motor fibers in the cranial nerves then activate the muscle fibers that cause the eyelids to close" (p. 571). Thompson and his colleagues also found that the hippocampus is not required for conditioning. Rather, an increase in neural activity was found in the cerebellum and certain nuclei in the pons. It was concluded that "the cerebellum is part of a superordinate circuit, and that training (the repeated pairing of CS and US) modifies synaptic strength within this superordinate circuit until the CS alone can elicit an eyeblink" (p. 572). Studies involving humans have shown similar results on eyeblink conditioning.

Drugs are another commonly used method to test memory formation since they can produce brief, accurately timed effects that are reversible. Different drugs affect different stages of memory. Psychologists Marie Gibbs and Kim Ng found that short-term (STM), intermediate-term (ITM), and long-term memory (LTM) in chicks are sequentially linked neurochemical processes. This was studied by using a single-trial peck avoidance. Potassium chloride prevented the formation of STM and therefore ITM and LTM as well, Ouabain prevented the formation of ITM and therefore LTM as well, and protein synthesis inhibitors, such as anisomycin, prevented the formation of LTM. This confirms at least three distinct stages of memory formation. With advances in research using drugs, it was found that repeated administration of anisomycin could overcome relatively strong training to cause amnesia. This suggests that protein synthesis is needed for the formation of LTM.

Memory formation can be affected by many things other than drugs, such as emotions, certain neurotransmitters, opioid peptides, hormones, and sensory stimulation. Research has shown that emotions enhance memory. The hormone epinephrine also enhances memory by influencing the amygdala to release norepinephrine.Propranolol and opioid peptides, on the other hand, block the release of norepinephrine into the amygdala therefore inhibiting memory-formation effects. Based on these findings, James L. McGaugh proposed "The amygdala influences memory formation in certain brain regions to which it sends axons, including the hippocampus and the caudate nucleus. The amygdala integrates the influence of several neuromodulatory systems that act on it, including adrenergic, opioid, GABA-ergic, and cholinergic" (p.576).

Memory loss is associated with an increase in age. In humans, aging results in a loss of neurons and/or neural connections, as seen in Alzheimer's patients. Also, the brain as a whole decreases in weight, with some parts of the brain losing more than others. A shrinkage in the hippocampus can result in impaired memory. Other studies focus on the septal complex, which provides input from subcortical structures to the hippocampus. These neurons use acetylcholine (ACh) as their neurotransmitter. In a study done on rates by Michela Gallagher, it was found that older rates that had significantly low levels of acetyltransferace (ChAT), the enzyme that catalyzes ACh, performed more poorly in the water maze when compared to younger rats with higher levels of ChAT. Finally, longitudinal research on humans has shown that enriched experience throughout life can help lower the risk of cognitive decline in old age.

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