Hippocampus. Learning and Memory

• The limbic system mediates emotional learning and memory
• It is the region where subcortical structures meet the cerebral cortex, acting as a cortical-subcortical interface

The Limbic System

• There is not one single system mediating emotion
• The limbic system is not what it was originally thought to be
• The concept of the limbic system remains valuable for organizing principles related to medial structures involved in emotional behavior

Cingulate Gyrus

• The cingulate gyrus is part of the cingulate cortex
• It regulates emotions, behavior, and pain
• It also controls autonomic motor function
• It mediates defensive responses

Nucleus Accumbens

• It is a region in the basal forebrain
• It is involved in the cognitive processing of motivation, aversion, and reward
• This includes incentive salience, pleasure, and positive reinforcement
• Functions in reinforcement learning

Ventral Pallidum

• This integrates motivational and emotional information
• It processes reward and incentive salience
• It gates motivated behavior, approach or avoidance
• It acts as a limbic-motor interface translating emotional or motivational signals into action
• The nucleus accumbens (ventral striatum) provides GABAergic input (primary input)
• The amygdala sends emotional and motivational signals
• The prefrontal cortex, via the accumbens, exerts cognitive/motivational control
• The ventral tegmental area (VTA) modulates dopaminergic activity
• The subthalamic nucleus sends glutamatergic input
• The mediodorsal thalamus projects to the prefrontal cortex (motivation → cognition)
• The lateral hypothalamus influences feeding and arousal circuits
• The ventral tegmental area(VTA) sends feedback to the dopamine system
• The lateral habenula (LHb) signals negative valence and aversion
• The pedunculopontine nucleus/brainstem controls motor function and arousal

Hippocampus

• It serves as a memory center
• Episodic memories are formed in the hippocampus, then stored long-term in other parts of the cerebral cortex
• The hippocampus aids in spatial navigation
• Also contributes to learning and emotions
• A location for neurogenesis

Amygdala

• Mediates emotional responses and reactions, such as fight or flight
• Contributes to the formation of new memories
• It determines the appropriate object for memory, while the hippocampus identifies the context
• The amygdala gates memory formation, retaining salient memories and filtering irrelevant ones

Hypothalamus

• Responsible for homeostasis, i.e. maintaining a steady internal state
• This includes autonomic functions like hunger, thirst, body temperature, blood pressure, heart rate, and sexual activity
• It is an interface between the nervous system and the endocrine system
• Serves as the main effector of the stress response

Limbic System Summary

• The limbic system consists of medial areas between sensory-motor areas (stimuli) and the hypothalamus (drives)
• The hypothalamus is responsible for drives like hunger, thirst and sex
• The limbic system helps with the selection of appropriate object for drives

Lesions in the Limbic System

• Cingulate gyrus impairment manifests as inappropriate or lacking emotional response
• Accumbens impairment causes dampened motivation and increased impulsivity
• Ventral pallidum impairment results in addiction, depression, and avoidance
• Hippocampal impairment leads to severe memory impairment and spatial amnesia
• Amygdala impairment can cause Kluver-Bucy Syndrome
• This often results in a loss of fear, fear recognition, increased aggression and irritability
• Hypothalamus impairment causes over-stress, temperature dysregulation, weight gain/loss, and/or impaired libido

Case of S.M.

• The Case of S.M. is about someone whom had congenital amygdala degeneration
• They can learn about an event and also understand the facts. However, they do not have the sweating/increased skin conductance response that correlates with fear

Studies of viewing Fearful Faces

• Amygdala damage impairs recognition of facial fear, indicating a possible connection to autism
• By forcing a patient to look at the eyes of the fear inducing photo helped them identify the emotion
• Fearful faces activate the amygdala

Fear Learning

• Synaptic potentiation is the mechanism that associates elements in memories, e.g. tone with electric shock
• NMDA receptors depend on glutamate release from the afferent axon
• They also depend on the membrane being depolarized by events at another synapse
• Therefore, the NMDA receptor is crucial synaptic element in learning
• PKA and CaMKII phosphorylate AMPA receptors to insert these in the synapse

Memory Strength

• It is easier to remember shocking events, while less important events are forgotten
• Emotional memories are determined by their salience and valence
• Salience is the relevance, biological or perceived, of an experience, correlating with the stress response's intensity
• Valence is the experience's value, which could be positive or negative
• Emotional salience is defined by the emotional arousal (impact) of the experience
• It is valence independent and is mediated by the norepinephrine system in the brain
• Norepinephrine is a neurotransmitter encoding the stress response
• The locus coeruleus is the nucleus transmitting norepinephrine to different parts of the brain during high salience experiences (stress response)
• Norepinephrine promotes AMPA receptors to surface, making it easier for them to relocate to synapses
• Norepinephrine encodes experiences salience
• It prepares synaptic connections for potentiation and thus helps store the memory when a highly relevant event occurs
• Norepinephrine codes for salience, but provides no information about the valence of an experience
• Dopamine encodes valence,
  attributing a "rewarding" or "aversive" label to the memory

Dopamine

• Dopamine is a neurotransmitter that encodes the valence of events in the brain
• The ventral tegmental area (VTA) transmits dopamine to different brain areas, encoding valence
• Dopamine encodes prediction errors for valence interpretation
• The brain responds to unexpected changes, ignoring what it can predict
• Prediction errors promote learning
• Dopamine reacts when an emotional event violates the prediction
• This can occur when an individual receives unexpected reward or punishment
• VTA dopaminergic neurons are activated by unexpected reward and inhibited by unexpected punishment

Fear

• When a high salience event occurs, norepinephrine primes synaptic connections for potentiation to allow storage for memory
• Dopamine attributes a “rewarding” or “aversive” stamp to memory by encoding prediction errors
• Norepinephrine indicates something important is occurring
• Dopamine indicates whether it is positive or negative

Cortical control of fear

• Pharmacological inactivation of the prelimbic (PL) and infralimbic (IL) regions produce opposite effects on freezing
• PL inactivation decreases fear expression in the case of Muscimol
• Infralimbic (IL) inactivation reduces fear extinction in the case of Muscimol
• Human homologs of rodent PL and IL show that dACC activity correlates with fear conditioning
• vmPFC activity correlates with fear extinction
• PTSD patients fail to recall extinction, and show prefrontal deficits
• The PTSD patients also had a distinct dACC/vmPFC ratio as a biomarker

Ventral Pallidum in Motivation

• Ventral pallidum is a critical hub
• Lesions induce aphagia, adipsia, and anhedonia
• Necessary for drug seeking behavior
• Critical for active avoidance and aversive learning
• Different VP cell types mediate different motivations
• Optogenetics is a tool to manipulate neuronal activity
• Opto-tagged single-unit recordings are used for study
• VP neurons encode salience and valence

Optogenetics

• It is a tool to manipulate neuronal activity
• Different opsins have different purposes
• Opto-tagged single-unit recordings can be utilized

VP Neurons

• VP neurons encode salience and valence
• There are various types including subtypes such as type 1,2,3, and 4
• VP GABAergic neurons mediate reward approach
• VP Glutamatergic neurons mediate avoidance
• Now that we now about circuits that mediate the motivation to approach rewards and avoid threats, we can question how these systems compete in the face of threat/reward conflict?
• Activation of GABAergic VP neurons invigorates reward seeking

Hippocampus

• Hippocampus+ Parahippocampal Gyrus(PHG) = Hippocampal formation
• Hippocampal place cells serve as a neuronal GPS
• These neurons won the Nobel Prize in 2014
• Place Cell Ripples function as memory consolidation
• They thought to stabilize and transfer recent experiences from hippocampus to neocortex
• Planning & learning:
• Ripples may also happen or occur prospectively, helping plan future paths based on experience
• Disruption of SWRs in impairs spatial memory, in rodents disrupting their causal role in learning.

H.M. Patient Notes

• Patient Underwent bilateral resection of medial temporal lobe, to relieve intractable seizures
• Severe anterograde amnesia; Could not form new memories after surgery
• Limited retrograde amnesia: Could only recall pre surgery of 2 years

Amnesia

• Severe anterograde amnesia: could not form new memories after the surgery.
• Limited retrograde amnesia: loss of pre-surgery events back to 2 years.
• Abilities preserved in H.M. (non-hippocampal)
• Short-term memory (0-5 mins)
• Long-term (remote) memory (childhood)
• Learning of skilled movements (e.g. mirror writing)
• Priming
• Conditioning
• IQ

Taxonomy

• Working memory occurs in the prefrontal cortex
• Long-term memory is broken up into Declarative and procedural memory
• Declarative memory has: Remembering events and known facts
• The Hippocampus is nearby cortical areas: Diencephalon
• Procedural memory Consists of : skills, habits, emotional associations and conditioned reflexes
• Striatum, motor areas of Cortex, and cerebellum are what's related to skills
• As far as emotions: It's correlated to the Amygdala
• Lastly:Conditioned reflexes happen in correlation of the cerebellum or also called the "little brain"

Additional Notes

• Electrocunvulsive Treatment (for depression) can interfere with the recent declarative memories (memory consolidation)
• Hippocampus communicates with neocortex through PHG
• There is a Trisynaptic Pathway: Entorhinal→DG→CA3→CA1 →subic
• Ischemia and hippocampal excitotoxicity lead to hypozia
• Results in leadung to NMDARs where there is toxicity in in hipocampis causes cell death
• There is Bilateral memory representation that helps store episodic memories
• This leads to contralateral compensation which a unilateral hippocampal insult
• This phenomenon shows isolated the why and isolated a unilateral damage
• Neurons do not grow back however they create new synapses or remove synapses
• Hebb synapse: when these fire together they wire together.
• In Alzheimer's some people develop tangles and plaques