Learning and Memory - Comprehensive Notes

Revision - Brain Regions Involved in Different Kinds of Learning and Memory

  • Long-term memory
    • Declarative (explicit)
      • Episodic: Hippocampus, medial temporal lobe, neocortex
      • Semantic: Lateral and anterior temporal cortex, prefrontal cortex
    • Nondeclarative (implicit)
      • Skill learning (procedural): Striatum, motor cortex, cerebellum
      • Priming: Neocortex
      • Classical conditioning: Amygdala and cerebellum
      • Nonassociative learning: Reflex pathways
      • Spatial memory: Hippocampus and cortex
  • Short-term memory (working memory)
    • Sensorimotor and prefrontal cortex

Definition of Memory & Learning

  • Learning: The process of acquiring new and relatively enduring information, behavioral patterns, or abilities; characterized by modification of behavior as a result of practice, study, or experience.
  • Memory: The ability to store (encode and retain for some interval of time) and retrieve (or reactivate) information.
    • The specific information stored in the brain.
    • A complex dynamic system (change in response to input and to maintain this change for some time).
    • More than stimulus-response reflex.
    • Neural representation.

Memory Storage and Physical Changes in the Brain

  • Memory storage requires physical changes in the brain.
  • Invertebrate nervous systems show plasticity.
  • Some simple learning in mammals relies on circuits in the cerebellum.
  • Synaptic plasticity can be measured in simple hippocampal circuits.
  • In the adult brain, newly born neurons may aid learning.
  • Learning and memory change as we age.

Hebbian Cell Assembly

  • Engram = memory trace
    • Should explain cellular and physiological underpinning of memory
    • Current hypothesis: memory is in the changing of synaptic connections (and their strengths).

Neuroplasticity

  • Neuroplasticity (or neural plasticity) is the ability of neurons and neural circuits to be remodeled in response to experience or the environment.
  • Sherrington
    • Introduced the term: synapse
    • Speculated that alterations in synapses were the basis for learning.
  • Synaptic changes can be physiological or structural (and they can be measured physiologically).
  • Changes may be
    • presynaptic,
    • postsynaptic, or
    • both.

Synaptic Changes

  • Changes include
    • increased neurotransmitter release
    • changes in neurotransmitter-receptor interactions
    • changes in the rate of inactivation of transmitter
    • Greater effect: increased PSP = post-synaptic potential
  • Inputs from other neurons may modulate neurotransmitter release (depolarization or hyperpolarization of axon terminals).

Neuronal Remodeling

  • 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.

Glial Cells and Memory

  • Beyond neural cells – recent findings (Alberini et al, 2017): all types of glial cells (astrocytes, oligodendrocytes, and microglia) make important contributions to the processing of encoded information and storing memories
  • Role of astrocytes: providers of energy for the long-lasting neuronal changes - necessary for long‐term memory formation.
    • Role of glucose metabolism in learning through activity‐dependent metabolic coupling between astrocytes and neurons → long‐term memory formation;
    • Role of astrocytic glucose metabolism in arousal →state that contributes to the formation of very long‐lasting and detailed memories
    • High energy demands of the brain during early development → the possible role of astrocytic and neuronal glucose metabolisms in the formation of early‐life memories

Environmental Complexity

  • Lab animals living in a complex environment demonstrated biochemical and anatomical brain changes different from those living in simpler environments.
  • Three housing conditions:
    • Standard condition (SC)
    • Impoverished condition (IC)
    • Enriched condition (EC)
  • Animals housed in EC, compared to those in IC, developed
    • Heavier, thicker cortex
    • Enhanced cholinergic activity
    • More dendritic branches (esp. basal dendrites), with more dendritic spines, suggesting more synapses
    • Similar findings in other mammals, even in humans (MRI studies)

Aplysia and Synaptic Changes

  • Aplysia (sea slug) is used to study plastic synaptic changes in neural circuits.
  • The advantages of working with Aplysia:
    • Fewer nerve cells
    • Can create detailed circuit maps for particular behaviors
    • Little variation between individuals

Nonassociative Learning

  • Invertebrates demonstrate simplest type of learning: nonassociative learning
    • A single stimulus presented once or repeated alters the strength or probability of a response according to the strength and temporal spacing or the stimulus (stimuli)
    • Three types of nonassociative learning
      • Habituation—a decreased response to repeated presentations of a stimulus (not sensory adaptation or motor fatigue!)
      • Dishabituation—restoration of response amplitude after habituation.
      • Sensitization—prior strong (and/or painful) stimulation increases response to most stimuli.

Aplysia and Habituation

  • Habituation is studied in Aplysia.
  • Squirts of water on its siphon causes it to retract its gill.
  • After repeated squirts, the animal retracts the gills less; it has learned that the water poses no danger.

Synaptic Changes in Habituation

  • The habituation is caused by synaptic changes between the sensory cell in the siphon and the motoneuron that retracts the gill.
  • Less transmitter released in the synapse results in less retraction.
  • Over several days, the animal habituates faster, representing long-term habituation.
  • Long-term habituation due to retraction of some synaptic terminals (= number of synapses between the sensory cell and the motoneuron is reduced)

Cerebellum and Classical Conditioning

  • In mammals, neural circuits studied in the eye-blink reflex
  • A circuit in the cerebellum is necessary for some types of classical conditioning.
  • An air puff (US) is preceded by an acoustic tone (CS); conditioned animals will blink (CR) when only the tone is heard.
  • The circuit:
    • Trigeminal (V) pathway carries sensory information from the cornea to its nucleus in the brainstem (inferior olive)
    • Interneurons then send climbing fibers to synapse on cerebellar neurons in the interpositus nucleus

Interpositus Nucleus

  • GABA antagonists reversibly shuts down interpositus nucleus → cause conditioned behaviors to disappear until the drug wears off.

Hebb and Synaptic Connections

  • Hebb proposed that when two neurons are repeatedly activated together, their synaptic connection becomes stronger = „fire together, wire together”
  • Cell assemblies—ensembles of neurons— linked via Hebbian synapses could store memory traces.
  • When researchers applied a tetanus (brief high-frequency burst of electrical stimuli) to the hippocampus, response of postsynaptic neurons changed—larger EPSPs.

Long-Term Potentiation (LTP)

  • Long-term potentiation (LTP)—a stable and enduring increase in the effectiveness of synapses following repeated strong stimulation (tetanus)
  • Weakening of synaptic efficacy—termed long-term depression—can also encode information.

Hippocampal Formation

  • The hippocampal formation consists of two interlocking C-shaped structures
    • Hippocampus
      • CA1
      • CA2
      • CA3
    • Dentate gyrus
  • In CA1, LTP is dependent on NMDA (N-methyl-D-aspartate) receptors that work with AMPA receptors.
  • AMPA=α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acidAMPA = \alpha\text{-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid}

Glutamate and Receptors

  • Glutamate first activates AMPA receptors.
  • NMDA receptors do not respond until enough AMPA receptors are stimulated, and the neuron is partially depolarized.

Calcium Influx and Protein Kinases

  • The large Ca2+Ca^{2+} influx activates certain protein kinases—enzymes that add phosphate groups to protein molecules.
  • One protein kinase, CaMKII (calcium-calmodulin kinase II), affects AMPA receptors in several ways:
    • Causes more AMPA receptors to be produced and inserted in the postsynaptic membrane
    • Moves existing nearby AMPA receptors into the active synapse
    • Increases conductance of Na+Na^+ and K+K^+ ions in membrane-bound AMPA receptors
    • These effects all increase the synaptic sensitivity to glutamate

CREB

  • Protein kinases activate CREB (=cAMP responsive element-binding protein)
  • CREB
    • Transcription factor
      • → binds to DNA promoter regions and changes the transcription rate of genes
  • Genetic deletion leads to impairment in LTM (associated with long-lasting LTP)

Retrograde Messenger

  • Strong stimulation of a postsynaptic cell causes release of a retrograde messenger, that travels across the synapse and alters function in the presynaptic neuron.
  • Ensure that more glutamate released
  • Messenger types: diffusible gas like carbon monoxide (CO) or nitric oxide (NO)
  • Yet, other varied mechanisms of LTP:
    • Mossy fiber pathway (hippocampus): LTP without NMDA receptor activity
    • Drugs with different modes of action can sometimes block LTP (eg: opiate antagonists)

LTP and Memory Formation

  • Evidence indicates LTP may be one part of memory formation
  • Correlational observations
    • time course of LTP is similar to time course of memory formation
    • induced within seconds and lasts days / weeks
  • Somatic intervention experiments—
    • pharmacological treatments that block LTP impair learning
    • Eg: NMDA blocker, CaMKII inhibitor, genetic manipulation of kinase or receptor genes
  • Behavioral intervention experiments
    • training an animal in a memory task can induce LTP
    • Eg: fear conditioning paradigm

LTP and Neuronal Computations

  • Contrary to current conceptual frameworks, we found that hippocampal CA1- region LTP is not required for accurate representations of space in hippocampal neurons, but rather endows these neurons with reward- and novelty-coding properties.
  • Thus, instead of driving formation of cognitive maps and memory engrams, CA1-region LTP incorporates salience information into cognitive representations.

Synapses and Memory

  • Our understanding of the processes underlying learning and memory has been dominated by the view that synapses are the principal site of information storage in the brain.
  • This view has received substantial support from research in several model systems, with the vast majority of studies on the topic corroborating a role for synapses in memory storage.
  • Yet, despite the neuroscience community’s best efforts, we are still without conclusive proof that memories reside at synapses.
  • Furthermore, an increasing number of non-synaptic mechanisms have emerged that are also capable of acting as memory substrates.

Forgetting

  • Main reasons behind forgetting:
    • Erasure / storage failure (true loss of memory content
    • Retrieval failure
    • Memory disruption
  • Theory of disuse (Bjork and Bjork 1992):
    • Two types of memory strength:
      • Storage strength (how well a memory was learnt)
      • Retrieval strength ( how well a memory can be accessed – currently!)
    • Storage strength not reduced only retrieval strength changes over time
    • Possible reason behind: increased adaptability – less need for older information?
    • Other idea: generalization of memories?

Molecular Mechanisms of Forgetting

  • Removal of GluA2/AMPAR?
    • If peptide used to interfere with GluA2/AMPAR function: forgetting prevented Migues et al 2016
    • Activity dependent synaptic removal of GluA2/AMPAR Forgetting – active process !

METAPLASTIC REGULATION OF FORGETTING AND MEMORY PERSISTENCE

  • Molecular Mechanisms:
    • BRAG2 degradation
    • PKMT/BRAG2
    • PKMζ/BRAG2
    • PICK1 degradation
  • Glutamate
  • Ca2+Ca^{2+}
  • GluN2A/NMDAR
  • GluN2B/NMDAR
  • GluA2/AMPAR

Adult Neurogenesis

  • Adult neurogenesis in the brain occurs primarily in the dentate gyrus.
    • More plastic
    • Show enhanced LTP
  • Using conditional knockout studies, turning off neurogenesis in adult brains reduced spatial learning—minimal effect on other behaviors.
  • Adult neurogenesis is also seen in the olfactory bulb.

Learning, Memory, and Aging

  • Healthy elderly
    • Some impairments in conscious recollection (presence of structure or cue will increase performance)
    • Working memory impairments
    • Decline in formation of new episodic and declarative memory
    • Some decline in spatial memory and navigational skills
    • Autobiographical memory stable
    • Semantic knowledge stable
    • Vocabulary: even outperform younger participants
  • Pathological aging
    • More severe impairments & steeper decline
    • Eg: Alzheimer’s disease

Age-Related Memory Impairments

  • Impairments of coding and retrieval
    • less frontal and temporal cortical activation in some tasks like in learning new faces
    • However recognition is comparable to younger participants
  • Loss of neurons and/or neural connections
    • some parts of the brain lose a larger proportion of volume (especially the frontal cortex)
  • Deterioration of cholinergic pathways
    • the septal complex and the nucleus basalis of Meynert provide cholinergic input to the hippocampus and cortex.
    • Cholinergic pathways to the cortex are lost in Alzheimer’s disease.

Nootropics and Lifestyle

  • Nootropics are a class of drugs that enhance cognitive function.
  • Cholinesterase inhibitors can have a positive effect on memory and cognition.
  • Ampakines, which act via glutamate receptors, improve LTP in the hippocampus.
  • Protein kinases, such as PKMζ (ζ is zeta) may contribute to long-term maintenance memory traces.
  • Lifestyle factors can help reduce cognitive decline:
    • Living in a favorable environment
    • Involvement in complex and intellectually stimulating activities
    • Having a partner of high cognitive status

Artificial Activation of an Engram

  • Mice were genetically modified so that when neurons in the dentate gyrus (DG) were active, they would produce channelrhodopsin
    • optogenetic protein that excite those cells (and only those cells) when exposed to blue light.
  • Fiber optics were implanted that could be made to shine on the DG neurons.
  • The mice were subjected to two contexts:
    • Context A—A box with a white plastic floor, in a dimly lit room with black walls, and a faint smell of almonds; exploring the chamber triggered no signs of fear.
    • Context B—A box with a wire grid floor, in a bright room, white walls and the smell of vinegar; exploration was accompanied by a tone and electrical shock, resulting in fear conditioning.

Conditioning Experiment

  • Conditioning, while active neurons were able to produce channelrhodopsin, caused mice to find context B frightening—freeze response.
  • Reactivating those neurons using blue light while in context A caused the mice to freeze in fear, even when they were in a completely different context.
  • Turning the light off again caused the animals to resume activity, indicating that they remained unafraid of context A.
  • It wasn’t just that light- induced activation of a random set of DG neurons induced fear, because when blue light reactivated DG neurons that had been active in a third (nonfearful) context (C), the animals did not freeze.