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Amir Mahmoodzadeh
PhD candidate ,shiraz university of medical sciences
Amir.biochem@gmail.com
The Nobel Committee for Physiology
or Medicine
• Is a neural structure in the
medial temporal lobe of the
brain
• likened to the sea hors and
the ram's horns of Amun
• limbic system
• consolidation of information
from short-therm memory to
long-therm memory and
spatial navigation.
• Humans and other mammals
have two hippocampi, one in
each side of the brain.
Forebrain …….Telencephalon
the hippocampus is an elaboration
of the edge of the cerebral cortex
Immediately above the choroidal
fissure, the wall of the hemisphere
thickens, forming the hippocampus
bulges into the lateral ventricle
Temporal lobe
medial temporal lobe
• The dorsal region: spatial
memory, verbal memory, and
learning
• ventral hippocampus
• functions in fear conditioning
and affective processes
Hippocampal formation
• Dentate gyrus
• Cornu Ammonis (CA) fields
• Subiculum
• Presubiculum
• Parasubiculum
• Entorhinal cortex
The Dentate Gyrus (DG)
• 3 layers
• molecular layer
 Superficially,
 250 um
• granule cell layer
 Nero epithelium
 Formation new memory
• polymorphic celllayer
 , which constitutes the third
layer of the dentate gyrus
The granule cell is the only
“principal” cell of the dentate
gyrus; that is, it is the only cell type
that gives rise to axons that
leave the dentate gyrus to
innervate another hippocampal
field (i.e., CA3).
Cornu Ammonis (CA)
• CA1
• CA2
• CA3
• CA4
Also known as: ammon horn, Ammon's horn,
hippocampus, hippocampus major,
hippocampus proper, Cornu ammonis
CA Regions
• Region CA4
– Also called Hilus (when
considered part of the dentate
gyrus)
– Contains mossy cells – receive
inputs from granule cells
– located nearby in the dentate
gyrus
– Receive a small number of
connections from pyramidal
cells
Region CA3
– Receives input from granule
cells in the DG and from
entorhinal cortex
– Pyramidal cells
(approximately 200,000 in
each hemisphere in rats)
send some axons back to the
hilus, but the majority project
to regions CA2 and CA1
– Is considered to be the
“pacemaker”
– memory and learning
hippocampal processes
Pyramidal cell
•The main cell body is within Ammon's horn of
the hypothalamus
•There are usually multiple branching dentrites
to take in information and a single axon to
send it away.
•There are generally 100,000 of these neurons
in a normal human brain
•Neurotransmitter: Glutamate (common
neurotransmitter in mammals)
• Region CA2
– Small region located between CA1 and CA3
– Receive perforant path input entorhinal cortex, but do not from
DG
– Pyramidal cells are more similar to those of CA3 than those of
CA1, so it is grouped as a separate region
• Region CA1
– First region that yields a significant output pathway
– Sends significant output foward to the subiculum
– Like CA3, receives input from superficial entorhinal cortex, but
unlike CA3, contains vey few recurrent connections (in rats, CA1
contains approximately 250,000 pyramidal cells)
Subiculum
• The subiculum the most inferior component of the hippocampal
formation
• It lies between the entorhinal cortex and the CA1
• It receives input from CA1 and entorhinal cortical layer III pyramidal
neurons and is the main output of the hippocampus
• play a role in some cases of human epilepsy and
• working memory
• drug addiction
• hypothalamic-pituitary-adrenal axis
Presubiculum (PrS) and Parasubiculum (PaS)
• located distally from
the HF
• receive numerous
subcortical and cortical
inputs, and sends
major projections to
the superficial layers of
the entorhinal cortex
• Cells fire in relation to
the animal's location in
space, similar to place
cells
The entorhinal cortex
• located in the parahippocampal gyrus
• major gateway between the hippocampal
formation and the neocortex
• The lateral entorhinal cortex, is strongly
connected to the amygdala.
• The medial entorhinal cortex preferentially
connects with the postrhinal cortex, the
presubiculum, visual association (occipital)
cortices.
• Both target the same neurons in the
dentate gyrus and field CA3,
• Alzheimer , epilepsy,
Grid cells
• Grid cells are predominant
in layer II of the entorhinal
cortex, but exist also in
layers III and V
• firing of entorhinal cells
depends on signals from the
head direction cells in the
presubiculum
• Glu
• GABA
Connectivity Is Mostly Uni-Directional
Memory
 memory is simply ways we store and recall
things we have sensed
The major parts of the Limbic System involved
in Memory are
: Amygdala
: Hippocampus
Short-term memory – memory of
events that have just occurred.
Long-term memory – memory of
events from previous times.
 declarative memory
 Episodic memory
 skill memory
What is amnesia?
– Retrograde amnesia
• the loss of memory events prior to the occurrence of the brain
damage.
– Anterograde amnesia
• the loss of the ability to form new memory after the brain
damage occurred
Injury
Time
Importance of the Hippocampus
• Olfaction
• Inhibition
• Episodic memory
– HM (anterograde amnesia after surgery)
• Navigation
– taxi drivers
Episodic memory is the memory of autobiographical events
(times, places, associated emotions, and other contextual who,
what, when, where, why knowledge) that can be explicitly
stated. It is the collection of past personal experiences that
occurred at a particular time and place.
Hippocampal damage : symptoms
- Amnesia (memory loss)
- Inability to form new explicit memories.
- memories can still be formed
- Poor impulse control
- Hyperactivity
- Alzheimer´s disease
- Disorientation
 Pyramidal cells
 Granule cells
 Cognitive map
Place cells
• A place cell is a type of pyramidal
neuron within the hippocampus
that becomes active when the
animal enters a particular place in
the environment
• Cells in the CA1 and CA3 field of
the hippocampus code for an
environment
• The place where one of these cells
fires is called its "place field".
Zooming into the Rat Brain
• 2g
• 150 million neurons
• 500,000 pyramidal neurons in hippocampus
Unit Recording
• provide a method of measuring the electro-physiological responses of a single
neuron using a microelectrode system.
• suitable wire
• same size or smaller in diameter than the cell bodies being recorded
• stable position nestled up close to the cells bodies of a moving animal
• Multitrode recording technology
• stereotrodes (2 wires; McNaughton, O'Keefe, & Barnes) ,
• tetrode (4 wires; Recce & O'Keefe, Gray et al.).
100th of a mm movement precision for placing electrodes next
to the target cells.
Stereotrode
consists of two teflon-insulated 25 /µm diameter 75% Pt and
25% Ir wires
twisted together and cut transversely with sharp scissors so that
the tips lie at the same level
WE
PI Platinum/Irid
SS Stainless Steel
IR Pure Iridium
Tetrode technology
• constructed from four strands of fine nickel-chromium alloy (nichrome)
wire
• twisted together (overall diameter was 40 µm)
• Each probe could be independently adjusted with a precision of
approximately 10µm.
Place cell recordings
1.
1. Electrode array is inserted to the
brain for simultaneous recording
of several neurons.microdrive
Place cell recordings
1. 2.
1. Electrode array is inserted to the
brain for simultaneous recording
of several neurons.
2. The rat moves around in a
known/unknown environment.
Place cell recordings
1.
3.
2.
1. Electrode array is inserted to the brain for
simultaneous recording of several neurons.
2. The rat moves around in a known/unknown
environment.
3. Voltages recorded on each electrode
are typically passed through
integrated circuits in source-follower
configurations that are mounted near
the animal's head (a headstage).
Walking path and firing activity (cyan
dots).
Results
Results
Sensory input
• Visuospatial cues
 geometric boundaries
 orienting landmarks
 Movement
• Olfactory cues
olfactory information can be used to compensate for a loss of
visual information
Save et al.
Zhang et al.
Abnormalities
• Ethanol
 Place cell firing rate decreases dramatically after ethanol exposure, causing reduced spatial
sensitivity
 GABA and NMDA receptors
• Vestibular lesions
 The vestibular system, part of the labyrinth of the inner ear, plays an important role in spatial
memory
• Diseases
 Alzheimer’s Disease
• Aging
 zif268 mRNA
 Memantine
Grid cells
Grid cells are predominant in layer II of the
entorhinal cortex, but exist also in layers III and
V.
Grid cells in layers III and V intermingle with
cells that code for the direction the animal is
looking, the head-direction cells, as well as
cells with conjunctive grid and head-direction
properties (Sargolini et al., 2006) and border
cells (Savelli et al., 2008; Solstad et al., 2008).
It is quite likely, although not unequivocally
established, that the directional firing of
entorhinal cells depends on signals from the
head direction cells in the presubiculum.
60 degrees ,as
expected if the unit was an equilateral
triangle
The structure of the grid was not confined
by the boundaries of the enclosure.
Grids are anchored to external cues
Grid structure persists after cue removal
Positionig system of the brain(noble prize in medicine 2014)
Positionig system of the brain(noble prize in medicine 2014)

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Positionig system of the brain(noble prize in medicine 2014)

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  • 2. Amir Mahmoodzadeh PhD candidate ,shiraz university of medical sciences Amir.biochem@gmail.com
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  • 5. The Nobel Committee for Physiology or Medicine
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  • 7. • Is a neural structure in the medial temporal lobe of the brain • likened to the sea hors and the ram's horns of Amun • limbic system • consolidation of information from short-therm memory to long-therm memory and spatial navigation. • Humans and other mammals have two hippocampi, one in each side of the brain.
  • 8. Forebrain …….Telencephalon the hippocampus is an elaboration of the edge of the cerebral cortex Immediately above the choroidal fissure, the wall of the hemisphere thickens, forming the hippocampus bulges into the lateral ventricle
  • 10. • The dorsal region: spatial memory, verbal memory, and learning • ventral hippocampus • functions in fear conditioning and affective processes
  • 11. Hippocampal formation • Dentate gyrus • Cornu Ammonis (CA) fields • Subiculum • Presubiculum • Parasubiculum • Entorhinal cortex
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  • 13. The Dentate Gyrus (DG) • 3 layers • molecular layer  Superficially,  250 um • granule cell layer  Nero epithelium  Formation new memory • polymorphic celllayer  , which constitutes the third layer of the dentate gyrus
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  • 15. The granule cell is the only “principal” cell of the dentate gyrus; that is, it is the only cell type that gives rise to axons that leave the dentate gyrus to innervate another hippocampal field (i.e., CA3).
  • 16. Cornu Ammonis (CA) • CA1 • CA2 • CA3 • CA4 Also known as: ammon horn, Ammon's horn, hippocampus, hippocampus major, hippocampus proper, Cornu ammonis
  • 17. CA Regions • Region CA4 – Also called Hilus (when considered part of the dentate gyrus) – Contains mossy cells – receive inputs from granule cells – located nearby in the dentate gyrus – Receive a small number of connections from pyramidal cells
  • 18. Region CA3 – Receives input from granule cells in the DG and from entorhinal cortex – Pyramidal cells (approximately 200,000 in each hemisphere in rats) send some axons back to the hilus, but the majority project to regions CA2 and CA1 – Is considered to be the “pacemaker” – memory and learning hippocampal processes
  • 19. Pyramidal cell •The main cell body is within Ammon's horn of the hypothalamus •There are usually multiple branching dentrites to take in information and a single axon to send it away. •There are generally 100,000 of these neurons in a normal human brain •Neurotransmitter: Glutamate (common neurotransmitter in mammals)
  • 20. • Region CA2 – Small region located between CA1 and CA3 – Receive perforant path input entorhinal cortex, but do not from DG – Pyramidal cells are more similar to those of CA3 than those of CA1, so it is grouped as a separate region • Region CA1 – First region that yields a significant output pathway – Sends significant output foward to the subiculum – Like CA3, receives input from superficial entorhinal cortex, but unlike CA3, contains vey few recurrent connections (in rats, CA1 contains approximately 250,000 pyramidal cells)
  • 21. Subiculum • The subiculum the most inferior component of the hippocampal formation • It lies between the entorhinal cortex and the CA1 • It receives input from CA1 and entorhinal cortical layer III pyramidal neurons and is the main output of the hippocampus • play a role in some cases of human epilepsy and • working memory • drug addiction • hypothalamic-pituitary-adrenal axis
  • 22. Presubiculum (PrS) and Parasubiculum (PaS) • located distally from the HF • receive numerous subcortical and cortical inputs, and sends major projections to the superficial layers of the entorhinal cortex • Cells fire in relation to the animal's location in space, similar to place cells
  • 23. The entorhinal cortex • located in the parahippocampal gyrus • major gateway between the hippocampal formation and the neocortex • The lateral entorhinal cortex, is strongly connected to the amygdala. • The medial entorhinal cortex preferentially connects with the postrhinal cortex, the presubiculum, visual association (occipital) cortices. • Both target the same neurons in the dentate gyrus and field CA3, • Alzheimer , epilepsy,
  • 24. Grid cells • Grid cells are predominant in layer II of the entorhinal cortex, but exist also in layers III and V • firing of entorhinal cells depends on signals from the head direction cells in the presubiculum • Glu • GABA
  • 25. Connectivity Is Mostly Uni-Directional
  • 26. Memory  memory is simply ways we store and recall things we have sensed The major parts of the Limbic System involved in Memory are : Amygdala : Hippocampus Short-term memory – memory of events that have just occurred. Long-term memory – memory of events from previous times.  declarative memory  Episodic memory  skill memory
  • 27. What is amnesia? – Retrograde amnesia • the loss of memory events prior to the occurrence of the brain damage. – Anterograde amnesia • the loss of the ability to form new memory after the brain damage occurred Injury Time
  • 28. Importance of the Hippocampus • Olfaction • Inhibition • Episodic memory – HM (anterograde amnesia after surgery) • Navigation – taxi drivers
  • 29. Episodic memory is the memory of autobiographical events (times, places, associated emotions, and other contextual who, what, when, where, why knowledge) that can be explicitly stated. It is the collection of past personal experiences that occurred at a particular time and place.
  • 30. Hippocampal damage : symptoms - Amnesia (memory loss) - Inability to form new explicit memories. - memories can still be formed - Poor impulse control - Hyperactivity - Alzheimer´s disease - Disorientation
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  • 32.  Pyramidal cells  Granule cells  Cognitive map
  • 33. Place cells • A place cell is a type of pyramidal neuron within the hippocampus that becomes active when the animal enters a particular place in the environment • Cells in the CA1 and CA3 field of the hippocampus code for an environment • The place where one of these cells fires is called its "place field".
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  • 35. Zooming into the Rat Brain • 2g • 150 million neurons • 500,000 pyramidal neurons in hippocampus
  • 36. Unit Recording • provide a method of measuring the electro-physiological responses of a single neuron using a microelectrode system. • suitable wire • same size or smaller in diameter than the cell bodies being recorded • stable position nestled up close to the cells bodies of a moving animal • Multitrode recording technology • stereotrodes (2 wires; McNaughton, O'Keefe, & Barnes) , • tetrode (4 wires; Recce & O'Keefe, Gray et al.). 100th of a mm movement precision for placing electrodes next to the target cells.
  • 37. Stereotrode consists of two teflon-insulated 25 /µm diameter 75% Pt and 25% Ir wires twisted together and cut transversely with sharp scissors so that the tips lie at the same level WE PI Platinum/Irid SS Stainless Steel IR Pure Iridium
  • 38. Tetrode technology • constructed from four strands of fine nickel-chromium alloy (nichrome) wire • twisted together (overall diameter was 40 µm) • Each probe could be independently adjusted with a precision of approximately 10µm.
  • 39. Place cell recordings 1. 1. Electrode array is inserted to the brain for simultaneous recording of several neurons.microdrive
  • 40. Place cell recordings 1. 2. 1. Electrode array is inserted to the brain for simultaneous recording of several neurons. 2. The rat moves around in a known/unknown environment.
  • 41. Place cell recordings 1. 3. 2. 1. Electrode array is inserted to the brain for simultaneous recording of several neurons. 2. The rat moves around in a known/unknown environment. 3. Voltages recorded on each electrode are typically passed through integrated circuits in source-follower configurations that are mounted near the animal's head (a headstage). Walking path and firing activity (cyan dots).
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  • 51. Sensory input • Visuospatial cues  geometric boundaries  orienting landmarks  Movement • Olfactory cues olfactory information can be used to compensate for a loss of visual information Save et al. Zhang et al.
  • 52. Abnormalities • Ethanol  Place cell firing rate decreases dramatically after ethanol exposure, causing reduced spatial sensitivity  GABA and NMDA receptors • Vestibular lesions  The vestibular system, part of the labyrinth of the inner ear, plays an important role in spatial memory • Diseases  Alzheimer’s Disease • Aging  zif268 mRNA  Memantine
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  • 55. Grid cells are predominant in layer II of the entorhinal cortex, but exist also in layers III and V. Grid cells in layers III and V intermingle with cells that code for the direction the animal is looking, the head-direction cells, as well as cells with conjunctive grid and head-direction properties (Sargolini et al., 2006) and border cells (Savelli et al., 2008; Solstad et al., 2008). It is quite likely, although not unequivocally established, that the directional firing of entorhinal cells depends on signals from the head direction cells in the presubiculum.
  • 56. 60 degrees ,as expected if the unit was an equilateral triangle The structure of the grid was not confined by the boundaries of the enclosure.
  • 57. Grids are anchored to external cues
  • 58. Grid structure persists after cue removal