Lecture 16 - Cellular Learning and Memory (PSYC 211) PDF

Introduction to Behavioral Neuroscience PSYC 211 Lecture 16 of 24 – Cellular learning and memory Professor Jonathan Britt Questions? Concerns? Please write to [email protected]  DISORDERS OF SLEEP Insomnia Insomnia is characterized as diff...

Introduction to Behavioral Neuroscience PSYC 211 Lecture 16 of 24 – Cellular learning and memory Professor Jonathan Britt Questions? Concerns? Please write to [email protected]  DISORDERS OF SLEEP Insomnia Insomnia is characterized as difficulty falling asleep after going to bed or after awakening during the night Insomnia is a problem that affects approximately 25 percent of population occasionally and 9 percent regularly Fatal Familial Insomnia & Sporadic Fatal Insomnia A very rare disease that involves progressively worsening insomnia, which leads to hallucinations, delirium, confusional states, and eventually death (within a few years). It is typically associated with progressive neurodegeneration around the thalamus, hypothalamus, and/or brain stem.  DISORDERS ASSOCIATED WITH NON-REM SLEEP (NON-REM PARASOMNIAS) There are many sleep disorders that occur during non-REM sleep or during transitions out of sleep. They are called non-REM parasomnias. The brain seems to get caught in between a sleeping and waking state. Many people are unaware they exhibit this behaviour. Sleepwalking, Sleep-talking, Sleep-groaning, Sleep-crying, Sleep- eating, Sleep-masturbating, Sleep-teeth grinding – Some of these conditions tend to be more prevalent in children (i.e., people can grow out of it). Episodes can last seconds to minutes or longer. These states can be caused by certain medications or medical conditions. Sleep terrors – Characterized by overwhelming feelings of terror upon waking. May include panic and screaming and bodily harm caused by rash actions. People sometimes have no recollection of these events. Prevalent in people diagnosed with post-traumatic stress disorder (PTSD).  DISORDERS OF REM SLEEP REM sleep behavior disorder Neurological disorder in which the person does not become paralyzed during REM sleep and thus acts out dreams Appears to be a neurodegenerative disorder with at least some genetic component It is often associated with more common neurodegenerative disorders such as Parkinson's disease  LEARNING & MEMORY Learning refers to the process by which experiences change our nervous system and hence our behavior. We refer to these changes as memories (memory traces or memory engrams). Memories can be transient or durable, explicit or implicit, personal or impersonal. Accessing memories is known as memory retrieval. The cellular basis of long-term memory is neuronal plasticity, which refers to the ability of the nervous system to change and adapt.  NEURONAL LEARNING & MEMORY When studying neuronal plasticity, researchers measure… Intrinsic excitability - the number of action potentials a neuron exhibits in response to depolarizing current injections and Synaptic strength - the size of the response in a postsynaptic neuron when a presynaptic neuron has an action potential.  A change in synaptic strength is called synaptic plasticity.  NEURONAL LEARNING & MEMORY Changes in intrinsic excitability and synaptic strength can be measured with brain slice recordings.  MEASUREMENT OF INTRINSIC EXCITABILITY We measure intrinsic excitability by injected depolarizing current into a neuron and counting the number of action potentials it has. Intrinsic excitability is related to the precise composition of ion channels on the membrane (e.g., leak channels and voltage-gated ion channels). Action potentials elicited by a positive current injection This cell is more excitable than the cell above. Neuronal excitability is strongly affected by the number of potassium leak channels on the membrane. Neurons with fewer potassium leak channels are more excitable. Intracellular current injection  SYNAPTIC PLASTICITY Synaptic plasticity refers to changes in the strength of the synaptic connection between two neurons. How big or small is the response in a postsynaptic neuron when a presynaptic neuron has an action potential (regardless of whether the response is depolarization or hyperpolarization)? subthreshold EPSPs If the postsynaptic response is before and after depolarization, we call it an EPSP synaptic strengthening (excitatory postsynaptic potential). Electrical stimulation of nearby afferent axons (presynaptic) Synaptic plasticity can involve pre- and postsynaptic changes. On the presynaptic side, there can be changes in the number of vesicles, the filling of vesicles, or the release of vesicles. On the postsynaptic side, there can be changes in the number of receptors, their sensitivity to neurotransmitter, and their response to neurotransmitter binding. NON-ASSOCIATIVE LEARNING: HABITUATION & SENSITIZATION Aplysia is an invertebrate sea slug with a simple nervous system (20,000 neurons). It has a large gill for breathing, and a siphon through which it expels water and waste. Aplysia reflexively withdraw their gill whenever their siphon is touched. Repeated light touches of the siphon reduce the magnitude of the gill withdrawal reflex to the point where light touches are ignored. This is an example of habituation - reduced physiological or behavioural responding to a repeated stimulus. Another type of non-associative learning is sensitization, when exposure to a strong stimulus (often painful) results in heightened responses to other stimuli. HABITUATION OF THE GILL WITHDRAWAL REFLEX After habituation, is the sensory neuron less sensitive to touch? No, it depolarizes the same amount in response to touch before and after habituation. Is the sensory neuron less excitable in general? No, the same amount of depolarization is needed to elicit an action potential before & after habituation. Is the connection between the neurons weaker? Yes, after habituation, when the sensory neuron spikes, there is a smaller response in the motor neuron.  On the presynaptic side, are there fewer vesicles (yes), less glutamate per vesicle (no), or are vesicles not being released (yes)  On the postsynaptic side, are there fewer glutamate receptors (no) or are these receptors different in some way (no) Is the motor neuron less excitable in general? No, it spikes the same as before when depolarized a set amount. Is the connection between the motor neuron and gill weaker? No, the gill is just as sensitive to an action potential in the motor neuron as before. Enduring, long-term changes in synaptic strength often involve physical changes in the size of pre- and postsynaptic membrane. Typically, when a synaptic connection becomes stronger in an enduring manner, the postsynaptic side grows larger and contains more neurotransmitter receptors. The presynaptic side may also grow larger to accommodate more synaptic vesicles. A large synaptic connection may split into two and keep growing.  SYNAPTIC PLASTICITY Long-term An enduring (long-term) increase in the connection strength between two potentiation neurons (i.e., increased synaptic strength). (LTP) - Can be elicited in reduced preparations (e.g., brain slices) by repeatedly stimulating the inputs to a neuron at a high-frequency. This procedure involves a tetanic stimulation, typically 100 Hz stimulation for 1 second (repeated 4 times). - LTP is often initiated on the postsynaptic side (more receptors). The release of retrograde signaling molecules, such as nitric oxide (NO), from postsynaptic membrane triggers complementary changes on the presynaptic side (e.g., more neurotransmitter released per spike). Long-term Long-term decrease in the strength of the connection between two depression neurons (i.e., decreased synaptic strength). (LTD) - Persistent low-frequency stimulation of the inputs to a quiet neuron often causes LTD. Commonly used is 1 Hz stimulation for 10 minutes. - LTD is often initiated on the postsynaptic side (with less neurotransmitter receptors) but retrograde endocannabinoid signaling can drive presynaptic modifications (e.g., less calcium-influx per action potential).  SYNAPTIC PLASTICITY Long-term An enduring (long-term) increase in the connection strength between two potentiation neurons (i.e., increased synaptic strength). (LTP) - Can be elicited in reduced preparations (e.g., brain slices) by repeatedly stimulating the inputs to a neuron at a high-frequency. This procedure involves a tetanic stimulation, typically 100 Hz stimulation for 1 second (repeated 4 times). - LTP is often initiated on the postsynaptic side (more receptors). The release of retrograde signaling molecules, such as nitric oxide (NO), from postsynaptic membrane triggers complementary changes on the presynaptic side (e.g., more neurotransmitter released per spike). Long-term An enduring (long-term) decrease in the connection strength between two depression neurons (i.e., decreased synaptic strength). (LTD) - Repeated low-frequency stimulation of the inputs to a quiet neuron often causes LTD. Commonly used is 1 Hz stimulation for 10 minutes. - LTD is often initiated on the postsynaptic side (fewer receptors). The release of retrograde signaling molecules, such as endocannabinoids, from postsynaptic membrane triggers complementary changes on the presynaptic side (e.g., less neurotransmitter released per spike).  SYNAPTIC PLASTICITY: LTP & LTD High frequency stimulation (~100 Hz) of afferent inputs often produces LTP. Yet the same number of stimulations at a slower rate (1 Hz) often produces LTD. Why??? It turns out that LTP and LTD are a function of the number of times the synapse is activated as well as whether the postsynaptic neuron fired action potentials at those precise times. For LTP to occur, the release of neurotransmitter into the synapse must coincide with a substantial depolarization of the postsynaptic cell (normally associated with an action potential). High frequency stimulation of afferent inputs typically causes postsynaptic neurons to spike (summation of EPSPs brings the neuron across threshold). In contrast, low frequency stimulation is often insufficient to get postsynaptic neurons to spike (since each stimulation elicits a subthreshold response and there is enough time between stimulations for neurons to return to rest). LONG-TERM POTENTIATION  THE GLUTAMATE NMDA RECEPTOR A COINCIDENCE DETECTOR NMDA receptors plays a large role in learning and memory. They are located in almost every glutamatergic synapse in the brain.  THE GLUTAMATE NMDA RECEPTOR A COINCIDENCE DETECTOR The NMDA receptor is a unique type of ionotropic glutamate receptor. It opens when it binds glutamate, but magnesium ions (Mg2+) easily get stuck in the pore of this ion channel and block all current flow. The Mg2+ blockade of the NMDA receptor only occurs when the membrane potential of the cell (where the receptor is) is hyperpolarized (< -40mV), like when the cell is at rest. When the membrane potential of the cell is slightly depolarized (i.e., more positive than -40 mV), then Mg2+ ions generally will not try to pass though the NMDA receptor, and thus they won’t clog the pore. So, current flow through the NMDA channel is gated by both glutamate binding and the membrane potential of the cell. NMDA receptors are permeable to Na+ and Ca2+ ions, but only when glutamate is bound to the receptor and Mg2+ is not clogging the pore.  MECHANISMS OF SYNAPTIC PLASTICITY AMPA The ionotropic glutamate receptor that mediates most of the fast excitatory synaptic currents in the brain. receptor It lets in sodium ions when open, causing EPSPs (excitatory postsynaptic potentials) and membrane depolarization. Most glutamate synapses in the brain contain AMPA and NMDA receptors. NMDA Ionotropic glutamate receptor that passes current only when glutamate is bound AND the membrane potential of the cell is slightly depolarized. receptor If NMDA receptors are activated by glutamate when the cell is at rest or hyperpolarized, the pore of the channel gets clogged by Mg2+. Open, unblocked NMDA receptors are permeable to sodium and calcium ions. CaMKII Type II calcium-calmodulin kinase. It is an enzyme that is activated by calcium influx through NMDA receptors. It participates in the intracellular signaling cascade that establishes long-term potentiation at glutamate synapses, by increasing the number of AMPA glutamate receptors in the postsynaptic membrane.  LONG-TERM POTENTIATION For glutamatergic synapses that form on dendritic spines, the strength of the synaptic connection correlates with the size of the spine and the number of AMPA receptors in it. It is relatively easy to measure changes in the sizes of spines over time. The size of many spines is constantly is fluxed, but some spines are remarkably stable (consistent). CLASSICAL CONDITIONING  SYNAPTIC PLASTICITY: LONG-TERM POTENTIATION Associative The increase in synaptic strength that occurs in weak long-term synapses that happen to be active when stronger inputs potentiation get the postsynaptic neuron to spike. Hebb’s rule Hypothesis proposed by Donald Hebb: The cellular basis of learning involves the strengthening of synaptic connections that happen to be active when the postsynaptic neuron fires an action potential. “Fire together, wire together” more strongly than before. The synaptic connection does have to initially exist. BRAIN SLICE LTP INDUCTION