Synaptic Plasticity Lecture 19 PDF | Neuroscience

Synaptic Plasticity I Lecture 19 NRS 401 April 14, 2025 I need 3 volunteers for a demonstration. Volunteers, please see me before class.  Synaptic Plasticity Synapses are constantly changing – this...

Synaptic Plasticity I Lecture 19 NRS 401 April 14, 2025 I need 3 volunteers for a demonstration. Volunteers, please see me before class.  Synaptic Plasticity Synapses are constantly changing – this is the basis of learning. Strengthening & weakening of neurotransmission Changes in structure of pre- and postsynaptic terminals Durations can last as little as a few seconds or years. Different mechanisms are involved in short- vs long-term plasticity Short-term plasticity - changes in neurotransmitter release (axon terminal, Ca2+ and cAMP) Long-term plasticity - changes in gene transcription, protein synthesis, & trafficking of receptors into/out of the membrane  Learning Objectives This lecture should prepare you to…. 1. Describe the distinctions between short-term and long-term synaptic plasticity and how they contribute to learning and memory. 2. Explain how associative and non-associative learning (e.g., sensitization, habituation) are mediated by changes in synaptic strength. 3. Analyze experimental models of synaptic plasticity, including data from Drosophila and Aplysia, to identify cellular and molecular mechanisms underlying memory formation. 4. Evaluate the role of cAMP signaling in short-term memory formation and synaptic facilitation. 5. Relate changes in neuronal excitability and synaptic transmission to behavioral outcomes observed in learning paradigms.  Learning Learning is a change in the structure and/or function of the brain that results from an experience leading to changes in behavior and physiology. Associative learning Non-associative learning Repeated exposure to a Repeated exposure to a stimulus stimulus We learn something new “Meaning” of that stimulus about the meaning of that doesn’t change stimulus Behavior & physiology does Behavior and physiology Habituation – reduction change according to that Sensitization – increase meaning Conditioning Ex. Pavlov’s dogs  Pavlov’s dogs Ivan Pavlov (1849-1936) Digestion physiology researcher Nobel prize 1904 Classical conditioning was a serendipitous finding (1890s) For a historical translation of one of Pavlov’s 1927 experiments click here.  Classical conditioning & Associative learning Classical conditioning helps us understand how environmental cues gain meaning & coordinate behavior. We do this all of the time! Impacted in disease states like addiction & PTSD https://youtu.be/mYHdfDJrwMU?si=tIyI3YC1oo5ri6 Experimental setting: Ef At first, the tone means nothing to the animal. After successive (repeated) pairing of tone with reward/punishment– the tone becomes predictive of the outcome. Animal behavior & physiology changes accordingly  Non-associative learning: Sensitization Exposure to a stimulus results in the progressive amplifications of a response Experimental example: Locomotion in an empty cage 2 groups: saline vs cocaine Treatment is identical across days Comparing behavior during the session on day 1 vs day 8 Cocaine increases locomotor behavior from day 1 to day 8 Behavioral response to the same dose of cocaine has become sensitized Catalfio et al., Biol Sex Diff (2023)  Memory Behavioral and/or physiological expression of learning Sensory Short-term/Working Long-term Memory Stored for a Can be stored for few seconds Stored for hours or years Lasts for the minutes/hours duration of the Decays rapidly over stimulus time Involved in day-to- Declarative Procedural day tasks Semantic: Facts, How to do things Requires attention & data, and events cognitive effort Episodic: Personal stories/events Transition from short-term to long-term memory requires attention, strength of experience, & number of experiences.  Synaptic Plasticity and learning and memory Mode of Effect on Duration Examples Plasticity Synaptic Strength Short-term Sec - min Sensitization, short-term Increase potentiation memory, working memory, Short-term Reduce Habituation depression Long-term Hours - Habituation, acquisition, long- Increase potentiation years term memory Long-term Sensitization, extinction, long- Reduce depression term memory  Brain areas involved in learning and memory Motor Cortex (Procedural memory) Striatum (Modulatory) Recall of order of motor movements Thalamus (Modulatory) Underlies associative learning Regulates activity of cortex Contributes to procedural memory Contributes to attention Cerebellum (Procedural memory) Prefrontal Cortex Trial and error (Modulatory) learning Maintain internal Coordination of representation of tasks movements Focus attention Amygdala (Modulatory) Hippocampus (Declarative memory) Provides emotional context Ability to recall events in sequential order How do brain regions modulate memory? Perforant path: Dentate gyrus (DG) → CA3 → CA1 → Subiculum (S) Glutamatergic neurons Baslolateral amygdala (BLA) is the major output region of the amygdala Projects to S, CA1-CA3 Concurrent activation of BLA with hippocampus ↑ activity in S, CA1, and CA3 Memory Engrams Memories are not stored in a single location in the brain. Rather distinct networks and neuronal populations are active during learning and recall Engrams Ideas in learning theory - the more we know the easier it is to learn new things. Neuronal activity determines recruitment to memory engram Neurons differ in their intrinsic properties. Differ in their: Excitability Firing rate Connections When presented with an environmental cue/stimulus, some neurons will be preferentially recruited. Activity of individual neurons in short- term learning First shown in 1982 by Fuster and Jervey. Study in monkeys Delayed matching-to sample (DMS) task Measured activity of individual neurons in inferotemporal cortex (used for image recognition) Short-term/working memory is encoded by sustained spiking patterns of localized neurons.  Cellular basis of Short-term memory Tested Drosophila mutants in an odor avoidance task Training: Avoidance odor + Of Odor Testing: Avoidance odor Of Odor  Cellular basis of Short-term memory: Training Learning index – is the proportion of flies that avoid the odor paired chamber Index increases with ↑ in # of shocks & ↑ shock intensity Cellular basis of Short-term memory: Training Tested using 4 strains of drosophila cs – wild type amn – amnesiac rut – rutabaga dnc – dunce Mutants had lower levels of retention at the first trial and declined more rapidly Mutants all have disruptions in cAMP  Let’s review: cAMP and neuronal excitability In 1995 Wright & Zhong stumbled across effects of cAMP on ion channels Mushroom body cells (MBCs) in Drosophila olfactory cortex Applied 8-B.cAMP & measured K+ current using electrophysiology & found cAMP delays opening of K+ channels Reduces amount of K+ that effluxes cAMP prolongs depolarization. Wright & Zhong, Jneurosci (1995) Glomerulus experiment Glomeruli is where olfactory information is segregated & relayed to deeper brain structures (MBC) Glomeruli neurons express olfactory receptors (Golf paired GPCRs) Signal via cAMP Measure activity in response to odorants Alone or with shocks  cAMP in short-term learning Used GH146-GAL4 to target a fluorescent virus that marks active neurons Exposed flies to 3-octanol (OCT; earthy, mushroom, nutty, “herbaceous”) and methylcyclohexanol (MCH; coconut oil + methanol)  Shocks (# or intensity) drive Odorants recruit avoidance specific neurons Lessons learning from Drosophila Shock recruits broader Learning & population of memory is neurons & impaired by produces cAMP stronger activation Aplysia as a model to study synaptic plasticity Favorable model for studying learning and memory Measurable and modifiable behaviors Siphon-gill reflex Simple but accessible nervous system https://www.youtube.com/watch?v=cvCXFp-jCDs  Siphon-Gill reflex Touch siphon & gill withdraws (defensive behavior). Repeated tactile stimulations with no consequence results in habituation Pairing light tail shock with siphon touch reinstates gill withdrawal Tail shocks sensitize Gill withdrawal Shock regimen determines the intensity of the behavior & duration of learning. # of experiences increase magnitude of response Increases the duration of learning Neuronal circuit in Aplysia Sensory neurons & motor neurons are glutamatergic. Interneuron – inhibitory GABAergic Modulatory (Faciliatory) Interneurons – serotonergic (5-HT)  Neuronal activity during habituation & sensitization Sensory neuron of siphon doesn’t change. Activity of motor neuron changes Reductions during habituation Increased after shock Neuronal basis of habituation Neurotransmitter & vesicle release is reduced during habituation Voltage-gated Ca2+ channels inactivate Neurotransmitters become temporarily depleted Transmission returns to normal once Ca2+ channels reset & vesicle pools replenish  cAMP increases neurotransmitter release 1. 5-HT is released 2. G⍺s active to ↑ cAMP 3. cAMP activates PKA 4. PKA phosphorylates K+ channel prolonging depolarization 5. Ca2+ channels stay open longer 6. More vesicles fuse Touch of the siphon must be paired with the tail shock In CS/US paired condition, aplysia has associated touch of siphon with “danger” of tail shock.