Hippocampus & Disease, Functional Synthesis of Episodic Memory PDF

1 LECTURE 7: SYNAPTIC ORGANIZATION OF THE HIPPOCAMPUS PROF. JUNIOR STEININGER THE HIPPOCAMPUS One of the most intensively studied structure in the brain Together with the amygdala, the hippocampus is the central component of the Limbic system. 3 CORONAL PLAN...

1 LECTURE 7: SYNAPTIC ORGANIZATION OF THE HIPPOCAMPUS PROF. JUNIOR STEININGER THE HIPPOCAMPUS One of the most intensively studied structure in the brain Together with the amygdala, the hippocampus is the central component of the Limbic system. 3 CORONAL PLANE OF THE HIPPOCAMPU S 4 HIPPOCAMPUS AND CORTICO-STRIATAL LOOPS The hippocampus is a major component of the “affective” cortico-striatal loop, providing limbic information to both the ventral striatum and medial prefrontal cortex. WHAT WE LEARNED FROM PATIENT H.M. The most famous case of amnesia Case details: Seizures started at 10 years old Generalized (whole body) seizures started at 16 Medication was not controlling seizures At 27: Surgically removed his medial temporal lobe bilaterally 6 PATIENT H.M. - SYMPTOMS Result of this surgery: Global amnesia Anterograde amnesia: unable to form new declarative long-term memories (episodic & semantic) Retrograde amnesia: unable to retrieve any declarative memories from the 11 years before his surgery Other aspects of memory & cognition were preserved Short-term/working memory Procedural memory Language Visuospatial perception Attention 7 FUNCTION: SPATIAL LEARNING AND MEMORY/NAVIGATION Length of time spent as taxi driver correlates with increased volume of right posterior hippocampus (Maguire et al., 2000) “Place cells” in the hippocampus of rodents (O’Keefe & Dostrovsky, 1971) - > preferential firing for certain locations of the environment 8 FUNCTION: CONTEXT LEARNING AND RETRIEVAL Rats without a hippocampus do not show freezing to a context that has been previously paired with shock (Kim & Fanselow, 1992) PET study - context anxiety in humans is associated with activation in the right hippocampus and ventral pallidum (Hasler et al., 1997) 9 FUNCTION: WORKING MEMORY fMRI study - hippocampal activation during the maintenance phase of working memory task (Ranganath & D’Esposito 2001) Hippocampal lesions in rats impairs spatial working memory task using radial maze (Olton et al., 1979) 10 AND MANY OTHER THEORIES! Higher order perception of spatial information (rodents and humans) Novelty detection (rodents and humans) Processing timing Anxiety (rodents) Behavioural inhibition / control of impulsivity (rodents)  11 MEDIAL TEMPORAL LOBE CIRCUITRY PLEASE WATCH: https://www.youtube.com/watch?v=lkegFMnGY74 12 HIPPOCAMPUS PROPER Well-defined laminar structure with clear rows of pyramidal cells Transverse brain slices maintain main circuitry with easily defined lamina EC->DG->CA3->CA1- >Sub 13 HIPPOCAMPA L NETWORK: TRANSVERSE PATHWAYS 14 TWO TYPES OF PRINCIPAL NEURONS: 15 DENDRITIC LENGTH & ORIENTATION OF PRINCIPAL NEURONS 16 SUMMARY NOTES: LAYER/CELL TYPES Dentate Gyrus (DG) is composed of 3 layers; shaped like a “V” or “U” in rodents 1. Principal (i.e. granule) cell layer – only about 4-6 cells thick 2. An acellular molecular layer above the granule cell layer 3. A polymorphic cell layer below the granule cell layer Dendrites of granule cells extend perpendicular to the layer Cells are monopolar (dendrites only extend up) Mossy fibers = axons of the granule cells, enters stratum lucidum of CA3 Hippocampus is composed of principal cell layer, and the regions above and below this layer are divided into a number of “strata” The principal pyramidal cell layer can be divided into 3 regions based on size and appearance: CA1, CA2, CA3 Typically divided into large-celled region (CA3 and CA2) and the smaller-celled distal region (CA1) Only CA3 receives mossy fibers from DG Pyramidal layer is only 3-6 cells thick; all neurons arranged orderly in same direction Pyramidal cells have elaborate dendritic tress covered in spines that extend perpendicular to layer, and in both directions (i.e. multipolar) The Apical dendrites extend longer than basal dendrites Basal dendrites go into stratum oriens Apical dendrites go into stratum radiatum (technically the apical dendrites travel through 2 other strata, stratum lucidum and stratum lacunosum-molecular, but you aren’t responsible for knowing that)  17 TRANSVERSE AND SEPTOTEMPORAL PATHWAYS 18 SYNAPTIC INPUTS TO PYRAMIDAL NEURONS MAIN INPUT 19 INTRACELLULAR RESPONSE TO STIMULATION The EPSP is followed by a prolonged IPSP mediated by feed- forward inhibition from interneurons (acting on postsynaptic GABAA and GABAB receptors) Feed-forward inhibition serves: to dampen effect of afferent excitation, narrows time window that presynaptic activity can trigger AP This enables the CA1 neuron to be a coincidence indicator and allow high fidelity transfer of timing information between brain regions. 20 INTRINSIC ELECTROPHYSIOLOGICA L PROPERTIES OF HIPPOCAMPAL NEURONS 21 EXTRACELLULAR RESPONSES IN THE HIPPOCAMPUS 22 EXTRACELLULAR RESPONSES IN THE HIPPOCAMPUS Local field potentials: summed electrical activity from a large number of cells. Relatively large and reliable population EPSPs (pEPSP) can be recorded from the hippocampus due to the fact that the neurons are arranged in the same orientation and receive synaptic inputs in the same area Time course of field potentials often matches the underlying synaptic currents 23 EXTRACELLULAR RESPONSES IN THE HIPPOCAMPUS Local field potentials: summed electrical activity from a large number of cells Relatively large and reliable population EPSPs (pEPSP) can be recorded from the hippocampus due to the fact that the neurons are arranged in the same orientation and receive synaptic inputs in the same area Time course of field potentials often matches the underlying synaptic currents 24 EXTRACELLULAR RESPONSES IN THE HIPPOCAMPUS 25 SUMMARY NOTES: FIELD POTENTIALS IN THE HIPPOCAMPUS Because of the orderly arrangement of pyramidal neurons and their dendrites, the electrical fields generated by active neurons has a symmetry that makes field potentials very informative Time course of field potential is approximately equal to the time course of the underlying synaptic current During excitatory synaptic activity current flows into the dendrites, down toward the soma, and then down the axon if an AP is triggered. The amplitude of the fiber-volley is proportional to the number of presynaptic axons being activated by the electrical stimulus applied If a field electrode is positioned near the dendrites where the synaptic input is going to come in (i.e. stratum radiatum), then depolarizing input will be flowing away from the electrode down the dendrites towards the soma of the cell, hence a negative going potential (#2). The slope of this deflection indicates the amount/intensity of postsynaptic depolarization coming in to the neuronal population. If a field electrode is positioned near the cell body layer instead (i.e. stratum pyramidale), then first you will see a positive going deflection as current moves from the synaptic site towards your electrode. If the depolarization is sufficient to trigger action potentials in the population of cells, as it is here, then you will see a population spike. This is a negative going deflection because the current is now moving down the axon, away from your electrode. The size of the population spike indicates the number of cells and the synchrony with which the recorded population of neurons reached threshold for firing an action potential. 26 PERFORANT PATHWAYS Perforant path (PP) axons bifurcate and synapse repeatedly on granule cell dendrites within the dentate gyrus (DG) Can be split into two groups: medial and lateral perforant path (MPP, LPP) Terminate on distinct regions within the dendritic field MPP terminates more proximal to the cell soma Distinct populations of CA3 and CA1 also receive LPP and MPP inputs Functional dissociations (spatial vs object representations), but depends on the region 27 DENTATE GYRUS – MOSSY FIBER AND MOSSY CELLS 28 DENTATE GYRUS – MICROCIRCUIT S 29 MOSSY FIBER SYNAPTIC CONTACTS 30 SUMMARY NOTES: DG MICROCIRCUITS DG has 3 main types of GABAergic interneurons: 1. Basket Cells: Most prominent class of interneuron in DG Located at the border of granule cell layer and polymorphic layer Terminate on cell bodies and proximal dendrites 1 basket cell can influence a large number of granule cells 2. Chandelier Cells: A type of axo-axonic interneuron in DG Found in the molecular layer Terminates on axon initial segments of granule cells 3. Somatostatin-containing interneurons: found in the polymorphic layer and tends to project up to molecular layer Feedback Loops: mossy cells in polymorphic layer will send projections back up to proximal dendrites of granule cells in molecular layer Excitatory; targets granule cells that fall within a different septotemporal plane than the mossy cell An associational/commissural projection targets molecular layer Excitatory; information is arriving from both sides of the brain Excitatory terminals from EC (mostly layer 2) are confined to synaptic sites on distal dendrites 31 DENTATE GYRUS AND PATTERN SEPARATION 32 DENTATE GYRUS AND PATTERN SEPARATION 33 CA3 – MICROCIRCUITS 5 major interneurons that can target perisomatic or distal dendritic sites (or both) Dendritic gap junctions allow interneurons to synchronize their activity, and thereby also provide a synchronous inhibition of the pyramidal cells.  34 CA3 PYRAMIDAL CELLS – MUTUAL EXCITATION CA3 neurons within the same septo-temporal level have reciprocal glutamatergic connections, exerting mutual excitation associational projections CA3 neurons also send reciprocal projections to CA3 neurons in the contralateral hemisphere commissural projections Mutual excitation creates a positive-feedback cycle, prone to hyperexcitability (could lead to seizure activity) CA3 collaterals also project back to the DG to make monosynaptic contact with dendrites of mossy cells 35 SUMMARY NOTES: CA3 MICROCIRCUITS CA3 has 5 main types of GABAergic interneurons: Basket (BC), Axo-Axonic (AAC), and Bistratified (BS) interneurons target perisomatic sites Oriens-lacunosum moleculare (O–LM) cells target distal dendritic sites Trilaminar Cells (TC) target both perisomatic and distal dendritic sites Some interneurons are coupled through dendritic gap junctions that synchronize their activity, and thereby also provide a synchronous inhibition of the pyramidal cells. An associational/commissural projection targets Stratum Radiatum Excitatory terminals from EC (mostly layer 2) are confined to synaptic sites on distal dendrites 36 PATTERN COMPLETION AND RECURRENT COLLATERALS  37 SCHAFFER COLLATERAL PATHWAY (CA3 ->CA1) The axons of CA3 pyramidal neurons project to CA1 neurons via the Schaffer collateral (SC) pathway. CA3 to CA1 synapses are by far the most thoroughly studied synapses in the mammalian CNS, owing to their highly plasticity nature. 38 SEPTOTEMPORA L PATHWAYS  39 HIPPOCAMPUS & DISEASE, FUNCTIONAL SYNTHESIS OF EPISODIC MEMORY 40 HIPPOCAMPUS AND DISEASE The hippocampus is highly prone to disease Epilepsy, Alzheimer’s Disease, Schizophrenia The hippocampus is highly excitable Overexcitation can result in uncontrolled excitation that synchronizes and spreads to other areas (epilepsy) Recurrent collateral circuitry and propensity of CA3 neurons to fire in bursts of APs make the CA3 region the most vulnerable to overexcitation Over-stimulation of NMDA receptors causes pathological increases in intracellular calcium that can trigger necrosis and apoptosis (cell death) The price you must pay for being able to rapidly encode new information? 41 EPILEPSY & THE Two hallmarks of seizures: - Hyperexcitability refers to the reduced threshold for HIPPOCAMPUS neuronal firing - Hypersynchrony is defined by neurons in a given area firing together. The hippocampus is the most epilepsy-prone region of the brain Glutamatergic neurons become hyperexcitable, firing prolonged bursts of action potentials that synchronize with neighboring neurons Seizure activity can remain focal (complex partial seizure) or spread from its origin, to other areas such as the motor cortex, causing muscles to contract uncontrollably (tonic-clonic seizure). 42 EPILEPTIFORM ACTIVITY IN PYRAMIDAL CELL The intracellular correlate of the interictal EEG spike is the paroxysmal depolarization shift (PDS) If the normal post-PDS hyperpolarization fails, ictal discharge can occur (i.e. seizure) 43 POTENTIAL MECHANISM FOR EPILEPSY 44 HIPPOCAMPUS AND ALZHEIMER’S DISEASE Inability to form new memories, old memories weaken and fail Evidence that entorhinal cortex may be one of the first brain regions in which Alzheimer’s pathology becomes apparent 45 HIPPOCAMPUS AND SCHIZOPHRENIA Hippocampal and amygdala volumes are also reduced in schizophrenics During a memory retrieval (words) task, schizophrenics show abnormal baseline levels of activity in the hippocampus, and a failure to recruit the hippocampus during memory retrieval 46 FUNCTIONAL SYNTHESIS: ENCODING EPISODIC MEMORY One time when little Jenny was at the zoo, she dropped her cotton candy on the ground and a monkey in the cage nearby stole it! This made Jenny very sad. How does the hippocampus help encode this memory? 47 CONTEXTUAL MEMORY: “AT THE ZOO” Animal sounds and smells Outdoors / Forest smell Animals in cages Balloons Smell of cotton candy 48 CONTEXTUAL MEMORY: “AT THE ZOO” Animal sounds and smells Outdoors / Forest smell Animals in cages Balloons Smell of cotton candy 49 CONTEXTUAL MEMORY: “AT THE ZOO” Animal sounds and smells Outdoors / Forest smell Animals in cages Balloons Smell of cotton candy 50 CONTEXTUA L MEMORY: “AT THE ZOO” 51 CONTEXTUA L MEMORY: “AT THE ZOO” 52 CONTEXTUA L MEMORY: “AT THE ZOO” 53 ENCODING EPISODIC MEMORY One time when little Jenny was at the zoo, she dropped her cotton candy on the ground and a monkey in the cage nearby stole it! This made Jenny very sad. How does the hippocampus help encode this memory? Early view: information flows serially through hippocampal regions, with CA3 being most critical region because of its recurrent network. Autoassociative Mechanism -> The CA3 recurrent network would allow synaptic links to be strengthened symmetrically between cells that represent different components of the same memory. Example: “Jenny” cells, “candy” cells, “drop” cells all get strengthened. These strengthened links then allow a complete memory to be recalled when only a few components are presented 54 BUT, LATER RESEARCH SHOWED… Instead, CA3 appears to function according to heteroassociation mechanism -> critical for encoding temporal sequencing of events; asymmetrically links memories that occurred at different times. Example: “Jenny” cells, “candy” cells, “drop” cells all get strengthened. “Jenny dropped candy” cells get linked to “monkey reached through cage and stole it” cells (directional) We also know now that DG has its own recurrent network between the granule cells and mossy cells that could allow for autoassociation There are reciprocal connections between the DG and CA3 networks – why would we need this?? 55 2 RECURRENT NETWORKS WORKING TOGETHER If CA3 follows heteroassociation and functions alone -> Problem is that this type of encoding is susceptible to passing on degraded representations (due to intrinsic and synaptic noise), which would progressively get worse at each link. But, if DG is autoassociative (and reciprocal communication is allowed), then DG can help 56 2 RECURRENT NETWORKS WORKING TOGETHER If CA3 follows heteroassociation and functions alone -> Problem is that this type of encoding is susceptible to passing on degraded representations (due to intrinsic and synaptic noise), which would progressively get worse at each link. But, if DG is autoassociative (and reciprocal communication is allowed), then DG can help correct any degraded memories for CA3 along the way 57 ENTORHINAL CORTEX AND “CONTEXT” Entorhinal Cortex input doesn’t just go into DG, it can also go directly into CA3 and CA1 Direct perforant path input may provide the context signal (Example: “at the zoo”) PP targets distally, so not super effective. But, could produce a depolarizing bias in target cells that would then allow axonal input from DG to reach threshold in CA3 cells. 58 FUNCTION OF CA1 AND HIPPOCAMPAL OUTPUT CA1 region receives input from CA3 and provides output back to the Entorhinal Cortex CA1 acts as a “decoder” -> conveys information derived from hippocampal computations back to the cortex CA1 may also have a role in making a “match/mismatch” computation in which sensory “reality” arriving directly from the EC is compared with predictions of reality made by the DG–CA3 networks. 59 FUNCTIONA L SYNTHESIS SUMMARY