Introduction to Hippocampal Anatomy and Function PDF

# Lecture # 29 ## Date: 11/13/2024 ### Dr. Brandon ## INTRODUCTION TO HIPPOCAMPAL ANATOMY AND FUNCTION ### The Hippocampal Memory System - Patient HM and declarative memory - Hippocampal anatomy - Hippocampus and spatial memory - Methods for recording neural activity in freely behaving animals -...

# Lecture # 29 ## Date: 11/13/2024 ### Dr. Brandon ## INTRODUCTION TO HIPPOCAMPAL ANATOMY AND FUNCTION ### The Hippocampal Memory System - Patient HM and declarative memory - Hippocampal anatomy - Hippocampus and spatial memory - Methods for recording neural activity in freely behaving animals - Modern techniques for establishing the role of the hippocampus in spatial memory ## History - Schizophrenia, bipolar disorder, and psychosis are very prevalent in society - In the late 1800s and early 1900s, state governments around North America and Europe created psychiatric hospitals. - Psychiatric hospitals are psych wards in which people who are unable to take care of themselves and who are often abandoned can be treated. - Example: Verdun - Protestant Centre for the Clinically Insane, now Douglas Center - "Treatment": Intervention. Performed brutal experiments. - Lobotomy = Psychosurgery - At the time, schizophrenia was known to be a disease of the brain. As such, the frontal lobotomy was developed. - Frontal lobes (such as prefrontal cortex) were damaged, and patients would become muted, seemingly happier. - Patients were now "easier to care for" and "controlled" but lost all cognitive function. - Walter Freeman, a pioneer in lobotomy who won a Nobel Prize. - Developed **Ice Pick Lobotomy**. - Crude lobotomy where ice pick goes through the orbital frontal bone and placed on the back of the eye. It would scramble part of the prefrontal cortex via blunt force trauma. - William Scoville, a neurosurgeon at Hartford Hospital - Developed a more methodical way drilling a hole in the temple and making precision cuts in the prefrontal cortex. - Goal: To minimize damage while alleviating positive symptoms. - Noticed that upon lifting the prefrontal cortex, he could see the uncus, a bulb in the innermost part of the temporal lobe. - The anterior segment overlies the amygdala and belongs to the Para hippocampal gyrus. - The posterior segment of the uncus belongs to the hippocampal formation. ### Patient HM - At the age of seven, he was hit by a car, suffered a traumatic brain injury and developed epilepsy. - As a teen, he developed epilepsy that kept on getting worse. - Up to 20 grand mal seizures a day which are complete seizures of the body. - By his twenties, he had trouble doing daily tasks due to his epileptic seizures. - In the late 1940s and early 1950s, patient HM went through psychotic surgery performed by neurosurgeon Dr. William Scoville. - Scoville performed a primitive EEG to see which part of HM's brain caused seizures. - Conclusion: The uncus (the hippocampus) may be the cause of the seizures. - A bilateral removal of the uncus (entire hippocampal and entorhinal cortex). - Result: Seizures reduced. - However, he had a memory span of ~45 seconds. - E.g., He got lost in the hospital. He would never remember the people he met post-surgery. - Continued to have procedural memories (*e.g. learn new motor patterns*). - Lost the ability to create new declarative memories (aka episodic memories). - He had the surgery at 27 years of age and lived until he was 84. Thus, he did not have a new memory since the age of 27. ### Interpretation: The hippocampus is critical in creating NEW memories. Led us to understand where memory is processed. Led us to understand the different types of memories (declarative and nondeclarative). ### Summary: Hippocampus is involved in declarative memory AND the formation of new memories. ## Memory - Multiple types of memory streams and systems. - **Short-term memory** - Originate and sustained in the cortex. - Includes sensory memory, short term/working memory. - **Long-term memory** - Split into declarative memory (*explicit*) and nondeclarative (*implicit*). - **Declarative memory (explicit memory)** - *Events (episodic memory)* - *Facts (semantic memory)* - **Nondeclarative memory (implicit memory)** - *Procedural memory (e.g., bike riding, simple motor coordination, etc.)* - No involvement of the hippocampus. - In patient HM, remained intact (i.e., he still knew how to bike). - However, he could learn new skills (nondeclarative) but had no recollection of learning the skills (declarative). - *Perceptual representation system* - *Classical conditioning* - *Skills (motor and cognitive)* - *Perceptual priming* - *Nonassociative learning* - *Conditioned responses between two stimuli* - *Habituation* - *Sensitization* - **Declarative: Anything that can be stated as a fact or event. Involvement of hippocampus.** - **There is a transfer from episodic memory to semantic memory.** - Once a memory turns to fact, it's no longer hippocampal-dependent. - However, not every episodic memory turns into a fact (e.g., we don't remember what we had for dinner 13 days ago). Mainly the salient things turn into semantic facts. - In patient HM, episodic memory lost in patient HM; semantic memory remained intact. - However, he could not make any new declarative memories. ## Cajal's Early Drawing of the Hippocampus - Clear, discrete densely packed cell bodies and pyramidal cells. - Hippocampus receives inputs from the cortex and provides outputs back to the cortex. Mainly through the entorhinal cortex. - **Dentate gyrus** - First structure of the hippocampus. Organized into C shape. Inputs enter through here. Feeds into CA3 via mossy fibre connections. - **CA3:** Second processing stage. Synapses to CA1 via Schaffer collaterals. - **CA1:** Output of the hippocampus. Projects to the subiculum. ## Hippocampus and Entorhinal cortex in the rat vs human brain - Comparing the hippocampus and entorhinal cortex in the rat and human brain: - The human hippocampus lies flat, whereas the rat hippocampus is positioned more vertically. Both hippocampi have a C-like curvature. - The entorhinal cortex sits right behind the hippocampus. ## Components Of Hippocampal Formation - The "hippocampus" contains CA1, CA2, CA3. - Main structures discussed: CA1, CA3, DG. - CA = Cornu Ammonis (Ammon's horn). - The "hippocampal formation" includes CA, dentate gyrus ("toothlike bump"/double-bladed structure), entorhinal cortex, subiculum, pre- and para-subiculum. ## Rat Hippocampus (Left) And Monkey Hippocampus (Right) - **Hilus:** sandwiched in between dentate bleeds, reciprocally connected to dentate gyrus. ## Human Hippocampus - In Latin, hippocampus = "sea horse." Due to its resemblance. - Structure and circuitry are very similar to the rat hippocampus. - The volume of the human hippocampus is about 100 times that of the rat, and 10 times that of the monkey. ## Some Numbers For The Rat - **Dentate gyrus** - 1.2 million granule cells - 4 thousand basket cells: inhibitory interneurons - 32 thousand hilar interneurons (20k mossy cells) - **CA3/CA1** - 330k/ 420k pyramidal cells - Various interneurons - **Entorhinal cortex layer II** - Around 200k cells (20% interneurons?) - Layer 2 and 3 are most important layers cause provide input to entorhinal cortex. - **Subiculum** - Around 180k cells - Computation issue: there are many more neurons in DG than in CA3/ CA1). - Important in pattern separation. ## Basic Circuitry of the Entorhinal-Hippocampal System - The mossy fiber synapse is one of the largest and most powerful synapses in the brain. - EC = entorhinal cortex. - EC is the main gateway into the hippocampus. - Layer II perforant path goes from EC and projects onto DG and CA3 - Layer III perforant path goes from EC and projects directly onto CA1 - CA1 and subiculum project back to EC layer V - DG = dentate gyrus - DG projects directly onto CA3 via mossy fibers (feed-forward projection). - Thus, CA3 has two sources of input: DG and layer II performant path of EC - Layers II and III are the output structures of the EC projecting into the hippocampal structure. - The output of the hippocampal structure comes from layers V and VI, the input structures of the EC (i.e., CA1 and Subiculum project back to EC layers V and VI). - **CA3** - Schaffer collaterals from CA3 to CA1. - **CA3 recurrent collaterals are critical for systems designed to store memory - pattern completion.** ## Rat Connectivity - **Perforant path projection to DG** - Around 4,500 spines per granule cell (75% from EC). - One EC cell makes about 18,000 synapses with granule cells. - **CA3: three distinct inputs** - 50-80 mossy fibers from DG - 3,500 perforant path synapses from EC II - 12,000 recurrent collaterals from other CA3 cells - 8,000 to basilar dendrites (stratum oriens) - 4,000 to apical dendrites (stratum radiatum) - Most of the input comes from neighboring cells -- a big contrast to CA1. - In CA1, the cells are not connected to each other. - In CA3, the cells are heavily connected to each other. - If there are 100 neurons that code for what we ate for breakfast, around 10 of them are activated when asked what we ate for breakfast, and the other 90 are activated from the initial 10 neurons, since they are heavily connected to each other. - **CA1: inputs form CA3 and EC** - From CA3 Schaffer collaterals: 4,500 basilar, 6.500 apical synapses - From EC layer III: 2,500 synapses - **Structures Projections: EC Layer II Vs. III** - LEA (dark gray) and MEA (light gray) both project into the hippocampus. - Can see from the diagram that these dark and light colors alternate their projection onto the hippocampus. - In the dentate gyrus, the LEA comes into the distal dendrite and the MEA comes into the more proximal dendrite. - In CA1, there is a segregation of input based on the distance from CA3. - Proximal: the portion of CA1 closer to CA3 - Receive almost all its inputs from MEA - Distal: the portion of CA1 further from CA3 - Receive inputs from LEA. - The opposite is true for the subiculum. - This anatomical segregation underlies memory processing. - **Medial entorhinal cortex:** where - **Lateral entorhinal cortex:** what and when ## Three Major Fiber Systems - **Angular bundle from EC: performant path (and more)** - Input from the EC to the hippocampus. - **Fimbria/ fornix to subcortical areas.** - Subcortical projection from the medial septum to the hippocampus. - Fimbria shown in red - Fornix shown in yellow - **Dorsal and ventral commissures link hippocampi (bilateral connectivity)** - Dorsal shown in purple - Ventral shown in green ## Memory Impaired During Inactivation Of The Medial Septum + Hippocampal lesions in rats disrupt memory performance - **Morris Water Maze:** Water is opaque. Hidden black platform inside the maze. - When the animal is put into the water maze, it wants to get out. - It swims randomly until it hits the platform and climbs onto it. - Good assay of hippocampal memory (i.e., spatial memory). - With repeated trials, the animal will get better at finding the platform. - It uses distal visual cues in the environment to remember the location of the platform and associates the environment of the platform in relation to the platform itself. - If the medial septum is inactivated (or HC is damaged), the animal will not learn this task. - Medial septum is the origin of the fimbria/ fornix projection to the hippocampus. - Train animals with hippocampus wait for some time (e.g., 30, 40, 100 days) take the hippocampus out achieve the task fine. - Train animals with hippocampus do not wait some time take hippocampus out do not achieve the task fine. - Delay in episodic memory is transferred to semantic memory. - **Hippocampal lesions in rats disrupt memory performance.** - With "probe trials" the rat has the lesion performed, then the platform is removed to see where the rat will be swimming. - If the ventral HC is lesioned, the animal can still do the task. - If the dorsal HC is lesioned, the animal swims around randomly. - **Conclusion:** The dorsal part of the HC is important in this water maze task. ## The Hippocampus Encodes Recent Memory: - Task is to know how long the memory moves from hippocampus to become semantically contextualized and become from episodic to fact. - **Context fear conditioning task.** - Method: Tone-Shock Pairing Memory - Pair a tone with a shock on the floor to condition fear into the animal. - If the animal remembers the unpleasant experience, then its natural response is to freeze when put back in the same shocking environment. - We can use this response to assess how much the animal remembers the context. - Graph: - X-axis: time (days) after training is the HC removed. - Y-axis: freezing response (in %). - HC removal - After 1 day of training: no freezing, the animal does not remember being shocked. - After 7 days: freezes a little. - After 28 days: starts to show more memory. - After 100 days (Maren): freezes as much as the control. - Memory has moved out of the hippocampus and into other parts of the brain. The memory is rewritten in the cortex. - Episodic memories have turned into semantic memories. - **Conclusion:** The hippocampus encodes recent memory. Hippocampus is involved in learning, no longer required for memory remembering. Takes episodic memory out of hippocampus to make a semantic memory in cortex. ## Single Neuron Recordings of AP in Awake, Behaving Rodents - Dr. John O'Keefe - **Extracellular recording of action potentials in awake, behaving rodents (unit recording)** - Four microwires twisted into a bundle (tetrode) to pick up voltage changes in neurons (four electrodes can triangulate the location). - Detects the extracellular action potentials from these cells. - Different neurons will have different amplitudes on the four wires. - When tetrode is inserted into a dense cell region such as the hippocampus, it will pick up activity from 5 or 6 neurons simultaneously. - Can change the depth of tetrode. - Can record the activity for months as the animal is awake/ sleeping while doing memory tasks. - Tetrodes implanted onto the surface of the brain, pass tetrode tracks through the brain into the most dorsal tip of the hippocampus, recording from CA1. - **Raw data from tetrodes** - See individual extracellular spiking activity. - Looks like EEG recordings without filtering. - Filtering produces higher frequency components. ## Microelectrodes Implanted In The Hippocampus - Place the animal in a pit. Monitor animals from the top with a camera. Monitor neuronal activity. - Can assign spikes to the location the animal was in compared to its cell activity. - **Interpretations:** neurons in the CA1 cell layer were firing at a particular location. - Take the animal out and put it back in, the neurons still fired at the same location. - A representation of space was created within the animal. - All the neurons firing at the same time create a map in the HC. - Can retrieve memory of a location from specific neurons (place cells). ## Hippocampal Place Cells - Place cells are evenly distributed throughout the environment. - Hippocampus generates maps of the environment. - A sequence of place cells is created upon novel stimuli. - Biggest cue for memory recall is location. - Where you were. - Cells firing in diagram--interneurons. - Creates a cognitive map in environment - **Neurons in the medial temporal lobe encoding the location of the animal. - **Grid cells** - **Place cells** - **Head Direction Cells: only fire when animal is facing a certain direction** ## Explicit Memory Creating During Sleep Demonstrates A Causal Role Of Place Cells In Navigation - Place cells guide behavior. - During sleep, HC is spontaneously active. - Record CA1 place cells in an open field environment with an electrode inserted into the medial forebrain bundle (MFB). - Every time active neurons are detected or spikes, use an electrode to deliver an electric pulse to the medial forebrain bundle. - A pathway mostly composed of dopaminergic cells (reinforcing stimulation). - **Pair medial forebrain bundle stimulation whenever place cell fires: when animal goes back to field → it will go to wear pairing happens : this is when awake.** - Firing the place cell at a certain location with stimulation of the MFB produces an association. - In another test, the animal was taken out of the room, and fell asleep; the experimenters stimulated the MFB, and caused a place cell to fire so that when the animal walked back into the original room, it ran directly to that location associated with the place cell. - Stimulation of the place cell guided the behavior of the animal. - **Finding: Upon stimulating the MFB at a particular place cell that is spontaneously active during sleep will induce the animal to run directly to the location that the place cell codes for.** - **Spiking of place cells coincides with rewarding events→ can drive behavior of animal.** - **Conclusion: the firing of the place cell is meaningful and is influenced by rewards** - Not only drives fear, but also drives reward seeking behavior. - Place cells code specific memories. - You can associate a location with your place cell map -- if the location is associated with positive or negative outcomes it will guide your behavior.