Neural Mechanisms of Memory Storage Molecular, synaptic, and cellular events store information in the nervous system. New learning and memory formation can involve new neurons new synapses changes in synapses in response to biochemical signals increased neurotransmitter release changes in neurotransmitter-receptor interactions. Neuroplasticity (or neural plasticity) is the ability of neurons and neural circuits to be remodeled by experience while interacting with the environment.

Synaptic Changes That May Store Memories BP6e-Fig-17-16-0.jpgMolecular, synaptic, and cellular events store information in the nervous system New learning and memory formation can involve new neurons, new synapses, or changes in synapses in response to biochemical signals. Neuroplasticity (or neural plasticity) is the ability of neurons and neural circuits to be remodeled by experience or environment. Physiological changes at synapses may store information. Changes can be presynaptic, or postsynaptic, or both. Changes can include increased neurotransmitter release, or effectiveness of receptors. Synaptic changes can be measured physiologically, and may be presynaptic, postsynaptic, or both. Changes include increased neurotransmitter release and/or a greater effect due to changes in receptors. Changes in the rate of inactivation of transmitter would also increase effects. Inputs from other neurons might increase or decrease neurotransmitter release. Structural changes at the synapse may provide long-term storage. New synapses could form or some could be eliminated with training. Training might also lead to synaptic reorganization.

Memory Storage Requires Neuronal Remodeling Lab animals living in a complex environment demonstrated biochemical and anatomical brain changes from those living in simpler environments. Three housing conditions: Standard condition (SC) Impoverished (or isolated) condition (IC) Enriched condition (EC) Animals housed in EC, compared to those in IC, developed: heavier, thicker cortex; enhanced cholinergic activity; More dendritic branches (especially on basal dendrites near the cell body), with more dendritic spines suggesting more synapses.

Experimental Environments to Test the Effects of Enrichment on Learning and Brain Measures Lab animals living in a complex environment demonstrated biochemical and anatomical brain changes. Three housing conditions: Standard condition (SC) Impoverished (or isolated) condition (IC) Enriched condition (EC) Animals housed in EC developed: Heavier, thicker cortex. Enhanced cholinergic activity. Larger cortical synapses. Altered gene expression. Enhanced recovery from brain damage.

Measurement of Dendritic Branching EC also increases growth in dendrites: More dendritic spines suggesting more synapses. Increased dendritic branching, especially on basal dendrites, nearer the cell body.

Several animal models have been used in the study of memory and cognition Pavlovian olfactory conditioning in Drosophila to understand the molecular genetic basis of learning and memory Cognitive deficits in fly mutants involving genes similar to those related to human intellectual disability. Non-associative “habituation” using the Sea Slug Aplysia Pavlovian Fear conditioning in the mice and rats Isolated hippocampal slice from rats for Long-term potentiation Pavlovian Eye-Blink conditioning in rabbits Fruit flies and intellectual disability. Bolduc FV, Tully T., Fly (Austin). 2009 Jan–Mar; 3(1): 91–104.

The Sea Slug Aplysia

Synaptic Plasticity Underlying Habituation in Aplysia

Simple Systems: Invertebrate Models of Learning Nonassociative Learning in Aplysia (Cont’d) Habituation results from presynaptic modification at L7 Repeated electrical stimulation of a sensory neuron leads to a progressively smaller EPSP in the postsynaptic motor neuron

Dynamics of dendritic spines in the mouse auditory cortex during memory formation and memory recall Memory consolidation in auditory cortex is necessary for experience based responses to sounds from induction of immediate early genes (IEGs) lesions of auditory cortex eliminates the response Using green fluorescent protein (GFP) transgenic mice In a subset of neurons, primarily in layer 5 of cortex Memory formation from auditory-cued fear conditioning paired conditioning: increase in spine formation unpaired conditioning: spine elimination Some new spines persist: a long-lasting trace in the network Memory recall triggered by the reexposure of mice to the sound cue did not lead to changes in spine dynamics.

Synaptic Plasticity Can Be Measured in Simple Hippocampal Circuits Long-term potentiation (LTP)—a stable and enduring increase in the effectiveness of synapses. Synapses in LTP behave like Hebbian synapses: Tetanus drives repeated firing. Postsynaptic targets fire repeatedly due to the stimulation. Synapses are stronger than before LTP can be generated in conscious and freely behaving animals in anesthetized animals in tissue slices LTP is evident in a variety of invertebrate and vertebrate species. LTP can also last for weeks or more. Superficially, LTP appears to have the hallmarks of a cellular mechanism of memory.

Long-Term Potentiation Occurs in the Hippocampus Long-term potentiation (LTP)–a stable and enduring increase in the effectiveness of synapses. Tetanus–a brief increase of electrical stimulation that triggers thousands of axon potentials. Synapses in LTP behave like Hebbian synapses: Tetanus drives repeated firing. Postsynaptic targets fire repeatedly due to the stimulation. Synapses are stronger than before. LTP occurs at several sites in the hippocampal formation–formed by the hippocampus, the dentate gyrus and the subiculum. Regions CA1 and CA3 are most often studied.

Synaptic Plasticity Can Be Measured in Simple Hippocampal Circuits LTP occurs at several sites in the hippocampal formation—formed by the hippocampus, the dentate gyrus and the subiculum (also called subicular complex or hippocampal gyrus). The hippocampus has regions called CA1, CA2, and CA3 (CA=Cornus Ammon which means Ammon’s Horn). The CA1 region has two kinds of glutamate receptors: NMDA receptors (after its selective ligand, N-methyl-D-aspartate) AMPA receptors (which bind the glutamate agonist AMPA) Glutamate first activates AMPA receptors. NMDA receptors do not respond until enough AMPA receptors are stimulated, and the neuron is partially depolarized.

Hippocampal slice preparation

Hippocampal slice preparation

Hippocampal slice preparation

Hippocampal slice preparation

Hippocampal slice preparation

Roles of the NMDA and AMPA Receptors in the Induction of LTP in the CA1 Region The CA1 region has both NMDA and AMPA receptors. Glutamate first activates AMPA receptors. NMDA receptors do not respond until enough AMPA receptors are stimulated and the neuron is partially depolarized. NMDA receptors at rest have a magnesium ion (Mg2+) block on their calcium (Ca2+) channels. After partial depolarization, the block is removed and the NMDA receptor allows Ca2+ to enter in response to glutamate. The large Ca2+ influx activates certain protein kinases–enzymes that add phosphate groups to protein molecules. One protein kinase is CaMKII–it affects AMPA receptors in several ways: Causes more AMPA receptors to be produced and inserted in the postsynaptic membrane. CaMKII: Moves existing nearby AMPA receptors into the active synapse. Increases conductance of Na+ and K+ ions in membrane-bound receptors. These effects all increase the synaptic sensitivity to glutamate. The activated protein kinases also trigger protein synthesis. Kinases activate CREB–cAMP responsive element-binding protein.

Steps in the Neurochemical Cascade during the Induction of LTP CREB binds to cAMP responsive elements in DNA promoter regions. CREB changes the transcription rate of genes. The regulated genes then produce proteins that affect synaptic function and contribute to LTP. Strong stimulation of a postsynaptic cell releases a retrograde messenger that travels across the synapse and alters function in the presynaptic neuron. More glutamate is released and the synapse is strengthened. There is evidence that LTP may be one part of learning and memory formation: Correlational observations–time course of LTP is similar to that of memory formation. Somatic intervention experiments–pharmacological treatments that block LTP impair learning. Behavioral intervention experiments–show that training an animal in a memory task can induce LTP.

Common Mechanisms of Synaptic Plasticity Minireview in Vertebrates and Invertebrates. David L. Glanzman (2010) Current Biology 20, R31–R36, Figure 3. General model for learning-related enhancement of excitatory glutamatergic synapses.

In the Adult Brain, Newly Born Neurons May Aid Learning Neurogenesis, or birth of new neurons, occurs mainly in the dentate gyrus in adult mammals. Neurogenesis and neuronal survival can be enhanced by Exercise environmental enrichment memory tasks. neurogenesis occurs in hippocampus-dependent learning. Conditional knockout mice, with neurogenesis selectively turned off in specific tissues in adults, showed impaired spatial learning but were otherwise normal. Genetic manipulations can increase the survival of newly generated neurons in the dentate, resulting in improved performance. These animals showed enhanced hippocampal LTP, which was expected since younger neurons display greater synaptic plasticity.

Neurogenesis in the Dentate Gyrus Neurogenesis, or birth of new neurons, occurs mainly in the dentate gyrus in adult mammals. Neurogenesis and neuronal survival can be enhanced by exercise, environmental enrichment, and memory tasks. Reproductive hormones and experience are also an influence. In some studies, neurogenesis has been implicated in hippocampus-dependent learning. Conditional knockout mice, with neurogenesis turned off in adults, showed impaired spatial learning but were otherwise normal.