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Learning & Memory III and Feeding Behavior - Comprehensive Notes

CA1, Dentate Gyrus, Entorhinal Cortex

  • These brain regions are involved in learning and memory.

London Taxi Cab Drivers and Hippocampal Size

  • London taxi cab drivers have larger hippocampi compared to normal individuals.
  • Research Question: Does learning the complex map of London increase the gray matter volume of the hippocampus?
    • Increased gray matter volume may be associated with neurogenesis and increased dendritic sprouting/synaptic refinement.
  • Study:
    • Adults were studied before and after 4 years of training to become licensed taxi drivers.
    • Those who qualified showed a selective increase in the posterior hippocampi and changes to their memory profile.
    • Trainees who failed or control participants showed no changes.

Morris Water Maze and Neurogenesis

  • Question: In the Morris water maze, will a rat with an intact hippocampus develop a quicker method of finding the platform if the orientation of the room were to change?
  • Answer: Yes
  • Functional importance of neurogenesis:
    • Training on a relational task doubled the number of newborn neurons in the dentate gyrus.
    • Training on a non-relational task had no effect on neurogenesis in the hippocampus.

Outline of Topics

  • Revisiting engrams
  • Cellular basis of memory
  • LTP & LTD (Long-Term Potentiation & Long-Term Depression)
  • Role of NMDAR & AMPAR (N-Methyl-D-Aspartate Receptor & α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid Receptor)
  • Early vs. Late LTP
  • Three properties of artificial LTP similar to theoretical ideas of learning & memory

Engrams

  • Engram: The change in the brain that represents a memory.
  • Introduced by Richard Semon to describe the neural substrate for storing and recalling memories.
  • Semon proposed that an experience activates a population of neurons that undergo persistent chemical and/or physical changes to become an engram that can later be reactivated during recall.
  • Memory Trace:
    • Change in the nervous system following learning.
    • Engram: The ensemble of neurons active during an experience that are somehow important in the memory for that experience.
    • Complication: consolidation vs. storage.
  • Memory Retrieval:
    • The process by which external or internal retrieval cues reactivate the engram to produce memory retrieval.
    • Open questions: Does that include sensory areas, only areas involved in storage, or some combo?

Memory Trace vs. Memory Retrieval in Visual Association Cortices

  • Yang & Maunsell (2004): Recordings show single neurons in extrastriate cortex becoming more sensitive to small differences (firing selectivity changes) as animals learn to detect differences in visual patterns.
  • When monkeys make discriminations, those ensembles are activated.
  • Neurons in area MT are tuned to movement, with cells firing in response to specific direction or type of movement.
  • Novel finding from study: Pictures that imply movement also activate area MT, likely because they require accessing memory of movement (Kourtzi, Z., & Kanwisher, N. 2000).

How Memories Are Stored: Theoretical and Neurobiological Hypotheses

  • Theoretical hypothesis:
    • Memory is a lasting change in the nervous system following learning.
    • Memory is a multi-level process that is supported by various forms of plasticity.
    • Multiple Levels:
      • Systems-level: brain regions, circuits, system.
      • Engram or population level: subpopulation specificity; the ensemble of neurons that support a memory.
      • Synaptic level: ability of synapses to remodel themselves (support stronger or weaker signal transmission).
      • Subcellular neurobiology: gene expression, signaling cascades, etc.
  • Neurobiological hypothesis:
    • Synaptic plasticity supports memory encoding and retrieval.
    • Synaptic plasticity could involve physiological, structural, and/or biochemical changes.
  • Early experimental question: Can we observe changes in synaptic strength as a result of experience?

Synaptic Transmission Basics

  • Action potentials (APs) lead to postsynaptic potentials (PSPs).
  • Stronger excitatory postsynaptic potentials (EPSPs) exceed threshold and lead to action potentials.

Neural Model of Classical Conditioning

  • Pairing of unconditioned stimulus (US - puff of air) with conditioned stimulus (CS - tone) leads to the CS (tone) eliciting the unconditioned response (UR - blink).
  • When the tone is presented just before the puff of air to the eye, the auditory synapse is strengthened.

Synaptic Plasticity

  • The ability of synapses to remodel themselves (support stronger or weaker signal transmission).
  • This can involve presynaptic changes, postsynaptic changes, or both.
  • Different physiological, structural, and biochemical changes have been observed in different areas of the brain.

LTP and LTD: Artificial Models of Synaptic Plasticity

  • Slices of the hippocampus were used to study synaptic mechanisms.
  • Experimental Set-up:
    • Stimulating electrode
    • Recording electrode
  • Experimental question: Can we model changes in synaptic strength following experiences by exposing cells to artificial experiences?
  • Two opposing processes were identified to reflect the strengthening and weakening of synapses:
    • Long-term potentiation (LTP): enduring increase of synaptic transmission.
    • Long-term depression (LTD): enduring decrease of synaptic transmission.

Artificially Inducing LTP and LTD

  • Long-term potentiation (LTP) and long-term depression (LTD) can be artificially induced with high and low frequency stimulation protocols, respectively.

LTP/LTD as Evidence of Synaptic Change

  • LTP/LTD are NOT a mechanism. Rather, they are evidence that synaptic strength CAN be changed by experience.
  • Mechanisms are the actual neurobiological changes (structural & biochemical) that support synaptic plasticity.
  • They can involve presynaptic changes, postsynaptic changes, or both.
  • They differ based on the area being studied.
  • LTP is better studied than LTD.
  • It involves the glutamatergic NMDA and AMPA receptors, as well as pre- and postsynaptic changes in the synapses of hippocampal cells (and cells in other regions as well).

Glutamate Receptors

  • AMPA: Na permeable
  • NMDA: Na & Ca permeable

LTP: Role of NMDA Receptors

  • NMDA receptors are normally blocked by Magnesium ions (Mg^{++}) at resting membrane potentials (-70 mV).
  • NMDA receptors do not respond unless glutamate binds to the receptor and the neuron is already partially depolarized (which repels Mg^{++}).
  • Ca^{2+} does not flow into the cell unless both conditions are met. Ca^{2+} influx may activate protein kinases that induce changes necessary for LTP.

LTP: Role of AMPA Receptor Trafficking

  • Ca^{+2} enters NMDARs
  • Ca^{+2} activates enzymes that cause AMPARs to move into spine
  • Increased number of AMPARs increases synaptic strength

Pre- and Postsynaptic Mechanisms of LTP

  • Postsynaptic Changes: Insertion of glutamate receptors in postsynaptic membrane.
  • Presynaptic Changes: Increase of glutamate release in presynaptic neuron.
  • Both: LTP begins in the postsynaptic neuron, which provides feed-back signals to the presynaptic neuron through soluble gases such as Nitric Oxide or via endocannabinoids.

Early and Late Phases of LTP

  • This process represents an early phase (1-3h) of LTP.
  • A late phase (days) involves protein synthesis.
  • Injecting anisomycin (a protein synthesis inhibitor) blocks continued persistence of LTP beyond 3 hours.
  • Early LTP (1-3hr): NMDA receptors are needed for induction of LTP, but not its maintenance.
  • Late phase LTP (days or longer): requires changes in gene expression and protein synthesis.
  • Can involve the formation of new synapses (spine growth), synapse rearrangement, etc.
  • Carlson Textbook also talks about PKM -zeta

Growth of Dendritic Spines After LTP

  • Two-photon microscopic images show a segment of a dendrite of a CA1 pyramidal neuron before and after electrical stimulation that established long-term potentiation.

LTD Mechanisms

  • A mechanism involving postsynaptic NMDA receptors and AMPA receptors was also identified in the hippocampus.
  • LTP: High frequency stimulation; AMPAR activation à Ca^{+2} entering through NMDAR à Molecular activation à AMPAR trafficking and insertion = increased AMPAR & increased EPSPs.
  • LTD: Low frequency stimulation; AMPAR activation à Modest Ca^{+2} entering through NMDAR à Molecular activation à AMPAR internalization = decreased AMPAR & decreased EPSPs.

NMDA Receptor Dependence

  • The NMDA receptor is unusual in that it is BOTH voltage-dependent and neurotransmitter-dependent.

LTP as Evidence of Neural Changes During Learning and Memory

  • LTP effects are greatest in brain areas involved in learning and memory.
  • Elicited by high-frequency electrical stimulation of the presynaptic neuron; mimics normal neural activity.
  • Learning can produce LTP-like changes.
  • Blocking LTP interferes with learning.
  • Mice with abnormal NMDA receptors did not have LTP and could not learn a spatial task.
  • NMDA receptors are needed for inducing LTP, but not for maintaining it.

Properties of Artificial LTP Similar to Learning & Memory

  • Cooperativity: If only a weak input (relatively few fibers) is stimulated, LTP does not develop. It is only when a relatively large number of inputs are stimulated that there is induction of LTP. There is a threshold for induction of LTP that depends on coincident activation of pre and post synaptic cell. Stim many axons at a time.
  • Specificity: When LTP is induced by activation of one synapse, it does not occur at other inactive synapses on the same neuron.
  • Associativity: If one pathway is weakly activated at the same time as a neighboring pathway is strongly activated, both will undergo LTP.

Blocking LTP Induction

  • The induction of early long-term potentiation in the hippocampus would be blocked by a drug such as AP5 that blocks NMDA receptors.
  • If the question asked about late LTP, the answer would be a drug that blocks protein synthesis.

Revisiting LTP Induction Protocols

  • LTP: high-frequency stimulation (100Hz for 1s) = increased synaptic strength
  • LTD: low frequency stimulation (1-10Hz for 10 min) = decreased synaptic strength

Issues/Disorders Due to Inability to Form/Grow Dendritic Spines

  • YES
  • Developmental Disorder:
    • Fetal alcohol syndrome: Dendrites tend to be short, with few branches (toxin).
    • Rett Syndrome: Associated with lack of dendritic development (genetic mutation).

Feeding Behavior Outline

  • Homeostatic feeding
  • Set-point theory
  • Hormones
  • Dual-center hypothesis
  • Arcuate nucleus control of feeding
  • Hedonic feeding
  • Positive inceptive perspective
  • Factors that influence what, when, and how much we eat
  • Cognition, reward, emotion
  • Intersection of Homeostatic and Hedonic Feeding

Homeostatic vs. Hedonic Feeding

  • Homeostatic Feeding:
    • Obtain enough energy for survival.
    • Food intake is driven by the need to maintain energy balance, body weight, and metabolic function.
  • Hedonic Feeding:
    • Gain pleasure through eating.
    • Food intake is driven by sensory perception or pleasure, i.e., eating to satisfy reward or alleviate punishment.

Energy Utilization and Storage

  • During digestion, food is broken down and absorbed.
  • Food is turned into nutrients & energy for our bodies to function.
  • Energy is stored as fat, protein, and carbohydrates.

Energy Homeostasis and Set Point Theory

  • Set point theory suggests that the optimal weight (set point) is regulated at a predetermined level by feedback mechanisms.
  • The body acts like a thermostat: monitors energy levels (glucose or fat) and adjusts intake to achieve caloric balance:
    • Caloric expenditure = caloric intake + stored calories
  • According to theory, hunger is a signal of energy deficit.

Problems with Set-Point Theories of Hunger and Eating

  • Reductions in blood glucose or body fat do not reliably induce eating.
  • Early ancestors needed to store body fat.
  • Do not account for the influence of external factors on eating and hunger.
  • Epidemic of obesity and eating disorders (anorexia, binge eating).

Control of Feeding Behavior

  • Centrally controlled by the brain: initiation of food seeking and consumption triggered within the brain.
  • Input from the periphery: peripheral signals convey nutrient and energy information via circulating factors.

Hunger and Satiety Signals

  • Hunger signals: Ghrelin (from stomach)
  • Satiety signals: CCK (from intestines), GLP1 (from intestines)
  • Conveyed via afferent nerves and the blood stream (endocrine system)
  • Injection of each of those substances stimulates or inhibits food intake, respectively

Ob/ob Mouse

  • Ob mouse strain has low metabolism, overeats, obese, diabetes in adulthood.
  • Cannot produce Leptin – satiety signal secreted by adipose tissue!

Hypothalamus

  • A subcortical structure.
  • Controls autonomic nervous system and the endocrine system (hormone system).
  • Regulates the body and organizes behaviors related to the survival of the species - the so-called four F’s - fighting, fleeing, feeding, and mating.

Hypothalamic Nuclei and Intake

  • Lesions of lateral hypothalamus à anorexia
  • Lesions of ventromedial hypothalamus à overeating
  • “Feeding center” vs. “Satiety center” - Dual-center hypothesis (1954)

More Complex Hypothalamic Regulation

  • Hypothalamic regulation of intake involves more than just two nuclei.
  • To maintain energy homeostasis, appetite-inducing (orexigenic) and appetite suppressing (anorexigenic) neurons and peptides functionally interact to regulate food intake.
  • An important nucleus that can interface with the peripheral signals is the Arcuate nucleus.

Arcuate Nucleus Anatomy

  • Contains several different cell types, two of which are thought to work together to bidirectionally regulate intake.
  • Cell types are named according to the neuropeptides they release:
    • NPY/AgRP: promote intake/hunger.
      • Releases Neuropeptide Y & Agouti-related protein.
    • POMC/CART: inhibit intake/promote satiety.
      • (Proopiomelanocortin, cocaine- and amphetamine-regulated transcript).
      • Releases α-MSH, CART, β-enkephalin (an opioid).
  • Both project to the lateral hypothalamus (LH) and release their neuropeptides onto neurons that release orexin or MCH (melanin-concentrating hormone).
  • Neurons in this region (and the PVN, etc.) also have MC4 receptors.

Hunger Signals

  • Ghrelin binds to ghrelin receptors in the arcuate nucleus.
  • Activates NPY/AGRP neurons, which release neuropeptides into the LH.
  • Activates MCH and orexin neurons in LH, which stimulate hunger and decrease metabolic rate to preserve energy stores.
  • Insulin & leptin can also inhibit NPY/AgRP neurons.

Satiety Signals

  • Insulin & leptin binds to insulin receptors in arcuate nucleus
  • Activates POMC/CART neurons, which release neuropeptides into the LH.
  • Inhibits MCH and orexin neurons in LH, which reduces hunger/stimulates satiety.
  • Again, insulin & leptin also inhibits NPY/AGRP neurons.

Arcuate Nucleus - MC4 Receptors

  • NPY/AgRP: promote intake/hunger.
    • Releases Neuropeptide Y & Agouti-related protein.
    • AGRP is an antagonist of the MC4R receptor.
  • POMC/CART: inhibit intake/promote satiety.
    • Releases α-MSH, CART, β-enkephalin (an opioid).
    • α-MSH is an agonist of the MC4R receptor.

Optogenetics

  • Light-gated ionotropic receptor is inserted into the brain.
  • Experimenter shines different wavelengths of light to either excite (depolarize) or inhibit (hyperpolarize) cells by opening channels.
  • Advantages: genetic specificity (can activate or inhibit specific cell types).

Stimulation of AgRP Neurons

  • Stimulation of channelrhodopsin-expressing AgRP neurons leads to food intake (Aponte et al. 2011).

Positive-Incentive Perspective

  • Developed to overcome shortcomings of set-point theory.
  • Emphasizes the anticipated pleasure of eating.
  • Humans have evolved to crave food.
  • What and how much animals eat is influenced by factors other than energy deficit.

Factors Influencing What Is Eaten

  • Tastes preferred:
    • Sweet and fatty foods – very palatable & energy-rich.
    • Salty – sodium-rich.
  • Tastes avoided:
    • Bitter tastes – often associated with toxins.
  • Learned preferences:
    • Food tried and enjoyed.
    • Socially/culturally appreciated foods.
    • Advertisements.
  • Learned taste aversions:
    • Ingestion followed by illness (often one-trial learning).

Factors Influencing How Much Is Eaten

  • Energetic need: Humans need ~ 2000-2500 kcal/day.
  • Physical constraints: Stomach distension inhibits eating.
  • Incentivizing stimuli: Preferred or palatable foods are overeaten; more is eaten when with others.
  • Sensory-specific satiety: Satiety is largely taste-specific; intake increases with a varied diet.
  • Health knowledge/goals.