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Neocortex

Primary Cortex

Squire et al. 1989

Association Cortex
Hippocampus

CA1

CA3

“Doughnuts in the brain: periodic boundary conditions on the brain’s spatial coordinate system”
neocortex

Dentate Gyrus

‘Brainbow’ micrograph by Dr. T. Weissman

Neocortex

Bruce L. McNaughton Ph.D. AHFMR Polaris research Chair, Dept. Neuroscience The University of Lethbridge Lethbridge, Alberta, Canada Visiting Professor KUL, NERF bruce.mcnaughton@uleth.ca

CA1

CA3

Dentate Gyrus

‘Brainbow’ micrograph by Dr. T. Weissman

Neocortex

CA1

CA3

Dentate Gyrus

Carol Barnes Bill Skaggs Alexei Samsonovich Matt Wilson Jim Knierim Kati Gothard Min Jung David Redish Alex Terrazas Francesco Battaglia Drew Maurer Zaneta Navratilova May-Britt Moser Edvard Moser Jill Leutgeb Stefan Leutgeb Francesca Sargolini Ole Jensen Laura Colgin

‘Brainbow’ micrograph by Dr. T. Weissman

000 synapses ~1.5-15 G logic operations per second Power consumption ~0.000.000.3 cc Weight ~0.05W Volume 2 cc Weight ~ 2 g .000 neurons 15.5W Volume ~ .9 GB RAM Processor speed ~1.7g Rat brain 150.000.iPad 0.5 GB DDR2 RAM Processor speed 1 GHz Power consumption 1.

5 x 104 neurons 3 x 108 synapses per mm3 Vias ~ 100 nm Fully 3-D interconnects .

and mostly limited to 2-D through-wafer direct die-to-die copper area-array interconnections .Gate pitch ~ 100 nm Connectivity very low compared to brain.

Figure adapted from Pinel. • Hippocampal outputs are widespread throughout the cortex and subcortical regions.Hippocampus is essential for new memory formation • The Hippocampus receives highly processed inputs from a variety of cortical and subcortical areas. 2000 • Hippocampus is part of cortex .

. 1989 .The cortex is arranged as a hierarchical set of vertically and horizontally interacting modules. The Hippocampus is the TOP of the hierarchy hippocampus Felleman & Van Essen '91 hippocampus CONNECTIONS OF THE VISUAL SYSTEM retina Squire et al.

IQ).’s memory capabilities.M.) underwent a bilateral temporal lobectomy (Scoville & Milner. although his cognitive capabilities were relatively intact (e. 1957).g.M. • This procedure had an immediate and devastating impact on H. Hippocampus is essential for new memory formation . an epileptic patient (H.• In 1957.

but disrupts recent memory and new learning: why? Time Consolidated memory Not yet consolidated memory Retrograde amnesia Anterograde amnesia Time of hippocampal damage Present Recall efficiency as a function of the time (before or after hippocampal damage) when the item was experienced .Hippocampal dysfunction leaves old knowledge relatively intact.

WHAT IS MEMORY? Associative memory is the ability to retrieve the whole of an experience from one or more of its parts Seeing the glass fall is typically followed immediately by a .

WHAT IS MEMORY? Associative memory is the ability to retrieve the whole of an experience from one or more of its parts Seeing the glass fall is typically followed immediately by a CRASH .

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the near simultaneous occurrence of two sensory inputs results in the formation of associative synaptic links among the brain cells that ‘represent’ the events .WHAT IS MEMORY? Associative memory is the ability to retrieve the whole of an experience from one or more of its parts Hearing the crash Seeing a glass fall Associative synaptic links form During learning.

WHAT IS MEMORY? Associative memory is the ability to retrieve the whole of an experience from one or more of its parts Remembering the crash Seeing a glass fall Activation spreads via associative synaptic links During recall. We call this “pattern completion” . the occurrence of part of a stored experience causes retrieval of the rest of the experience via associative synaptic links that were formed during learning.

We call this “pattern completion” .WHAT IS MEMORY? Associative memory is the ability to retrieve the whole of an experience from one or more of its parts Remembering the crash Seeing a glass fall Activation spreads via associative synaptic links During recall. the occurrence of part of a stored experience causes retrieval of the rest of the experience via associative synaptic links that were formed during learning.

WHAT IS MEMORY? Associative memory is the ability to retrieve the whole of an experience from one or more of its parts Remembering the crash Seeing a glass fall Activation spreads via associative synaptic links During recall. the occurrence of part of a stored experience causes retrieval of the rest of the experience via associative synaptic links that were formed during learning. We call this “pattern completion” .

WHAT IS MEMORY? Associative memory is the ability to retrieve the whole of an experience from one or more of its parts Hearing the crash Remembering a glass fall Recall can be bidirectional Activation spreads via associative synaptic links .

First some basics: Brain cells (neurons) and how they communicate with each other. .

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NEURONS and SYNAPSES First some basics: Brain cells (neurons) and how they communicate with each other. dendrite synapse Wij Neuron j cell body (soma) axon S The human cerebral cortex contains more than 10 billion neurons Neuron i .

Each cell sends and recieves about 10,000

synapses
Wij

Wij

S

Usually about 300 400 active synapses are needed to excite a cortical neuron

Classification based on neurotransmitter

Classification based on morphology

Guerra et al 2011

Cortex 2004.14:1310-1327 ©2004 by Oxford University Press . Cereb. Profiles of gene expression and electrical behaviour.Figure 3. Classification based on gene expression and biophysics Toledo-Rodriguez M et al.

Classification based on connectivity Thalamo-cortical and cortico-thalamic circuit http://www.edu/neurobio/mccormick/mccormicknew/Index.html .yale.med.

Cerebellar cortex – basic circuit .

Rev. 2011. Neurosci. Rev. 34:441–66 . 34:441–66 Gerfen & Surmeier Annu. 2011. Neurosci.Synaptic circuits of the striatum Annu.

- + Symbolic neurons and neural networks .

such that reactivation of some members of the group leads to complete retrieval of the active group D.Cells that have fired together form associative groups (assemblies) linked by mutually strengthened synapses. Hebb (1949) provided the key concept underlying the modern theory of neural associative memory A ‘cells that fire together wire together' .O.

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there must be at least a weak connection between the relevant brain cells to begin with.For this to work. .

1970 Simple Memory: A Theory for Archicortex. [from McNaughton & Morris TINS.1971). 1986] .David Marr A Theory for Cerebral Neocortex. 1971 Networks with modifiable recurrent connections could perform autoassociative memory (Marr. The mutual connections among neurons participating in a given “cell assembly” enable the retrieval of a complete pattern from any pattern that is a unique fragment of the original (pattern completion) or that resembles the original closely enough (error correction).

Acad. Natl. Proc. 2554 (1982) neural ‘energy’ landscape model of pattern recognition J. Sci.Hopfield Net ``Neural networks and physical systems with emergent collective computational abilities''. Hopfield .J. USA 79.

Content Addressable Memory (aka autoassociative memory) The current ‘standard models’ assume complete (all-to-all) connectivity

The problem: it won't work. Do the math! Cortical connectivity is much too sparse.
Hypothetical Connection Map of Cortex The typical cortical
1010

i

The synaptic weight matrix Wij
1 1 1010

neuron (j) recieves about 10,000 synapses from other neurons (i); but there are about 10,000,000,000 neurons.

j

On average, each cell recieves input from only one in a million other cells.

Indirect association in a modular, hierarchical network

hierarchical..Modular (“small-world”). 1989 . reciprocal structure may provide a solution to the sparse connectivity problem Primary Cortex Hippocampus Association Cortex Hippocampus Association Cortex Primary Cortex Squire et al.

Recreating the index pattern evokes the corresponding patterns in the lower levels. thus completing the retrieval of the whole memory Compound event encoded over different modules Retrieval cued by external event Spontaneous retrieval .Indirect Association: During the initial encoding of the memory. This provides an index code for each memory. output of the top module may become associated with the patterns in each lower module.

Why does damage to the hippocampus impair new learning? Because there is no index module to enable indirect association .

Modules contain a few thousand neurons. . meaning that there is are groups of cells that are more densly interconnected with each other than with cells in other modules.The cortex is highly modular.

Top-down projections terminate in NMDAR rich superficial layer of neocortex CA1 CA3 Subiculum Entorhinal Cortex Dentate Gyrus .

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Neurons in the rat hippocampus are very selective. .Listening to a single hippocampal neuron. The traditional question had been: "what do they encode?".

Firing Rate Map Listening to a single hippocampal neuron. . The traditional question had been: "what do they encode?". Neurons in the rat hippocampus are very selective.

1993) “How the hippocampus creates top-down spatiotemporal links for neocortical memory” . (High rate cells are interneurons) (Wilson & McNaughton.Firing Rate Map Firing rate maps for 80 simultaneously recorded hippocampal neurons while rat ran in a square arena.

(High rate cells are interneurons) (Wilson & McNaughton. 1993) How is the spatial code updated as the animal changes its location? What sets the scale? .Firing Rate Map Firing rate maps for 80 simultaneously recorded hippocampal neurons while rat ran in a square arena.

1993) Is the code 'purely' spatial? What kinds of information are actually stored in hippocampus? .Firing Rate Map Firing rate maps for 80 simultaneously recorded hippocampal neurons while rat ran in a square arena. (High rate cells are interneurons) (Wilson & McNaughton.

just from its brain activity.Multi neuron recording enables us to read out the contents of brain’s codes. it allows us to compute in real-time where the rat is and where he is planning to go. Blue: Actual path of rat in a box Red: Path predicted from firing rate maps . For example.

(from Mittlestaedt & Mittelstaedt. To do this they must keep track of changes in direction and distance travelled. 1980) . Without vision or any other external cue."Path integration" in rodents. rats can make a tortuous outward journey from 'home' and then return on a direct route.

.Head direction cells located at input to hippocampal formation and within it 90 120 10 Hz 150 5 Hz 30 60 180 0 210 330 240 270 300 Single HD cell tuning function in polar coordinates Ranck. 1990. Taube et al. 1984. .

” Velocity tuning (McNaughton et al.“…information about distance traversed…. It is unknown where the speed signal comes from! 0 25 Speed (cm/s) Ekstrom et al '01 . but place field size does not seem to change appreciably with speed.. The distance moved by the rat can be accurately gauged by an external observer by integrating the firing rate over time. But integration in the brain means simply updating the position on the map. a constant number of spikes is emitted during each lap through the place field regardless of speed. 1981) There is no evidence for ‘distance cells’ in the hippocampus…you cannot read distance directly from place or grid cells. Roughly. But explicit distance cells are not necessary: the firing rate of most hippocampal pyramidal cells increases linearly with speed (over most of the normal range).

“…information about distance traversed….” Theta power increases linearly with running speed…(there is also a small change in frequency) Raw EEG 7 Hz 150 Hz Spikes (2 sec) Position rat position theta integral Time The distance moved by the rat can be accurately gauged (by an external observer) by integrating the theta power over time Terrazas & McNaughton '03 .

Under conditions of restraint. McNaughton 1989. hippocampal neurons (and head direction cells) become silent Foster. Science 244:1580-1582 . Castro.

J. Neurosci.. place cell firing is independent of direction. 1994 . S Muller et al.The place code is updated by path integration N W Average E During random foraging in two dimensions.

firing locations persist in light! .The place code is maintained in darkness Once initial position is established in light. once initial position is established in dark. firing locations persist in dark. (Each cluster of colored dots represents spikes from different neurons) ALSO.

the cues reset the path integrator. J. McNaughton & Touretzky. the path integrator overrides the effects of the visual landmarks. 94. VanRhoades. but can (sometimes) realign the path-integrator (Fuhs. Neurophysiol. . Casale. 2005. 2603-2616. but in the ‘Same’ orientation condition (S). Skaggs & McNaughton 1995) In the ‘Opposite’ orientation condition (O).External cues do not specify firing fields.

Neurosci.8 0.5 0... J. 2004.9 0.4 The place code is updated by path integration Bin Number along Track 70 60 50 40 30 20 10 Poor 10 20 30 40 50 60 70 Bin Number along Track 80 90 0.7 0.The size of place fields is essentially independent of the rate at which external inputs change 180 cm track CUE-RICH SECTION CUE-POOR SECTION Overlap of Population Vectors along Track Bin Number 1 90 80 Rich 0.3 0.6 0.2 Decorrelation distance is independent of cue density Battaglia et al. 24(19):4541-4550 .

Kudrimoti. 1998 Place fields before and after fast or slow rotations of the apparatus with rat . McNaughton.Knierim. J. Neurophysiol.

. Head direction cells and place cells “always” co-rotate as an integrated ensemble.The place code is updated by path integration In uniform cylinder there is random drift of the directional coordinate.

How does the path integrator work? .

It has two principal axes – the longitudinal axis and the transverse axis. but there are important gradients. Transverse slices look very similar anywhere along the longitudinal axis.Hippocampal topology: hippocampus is like a folded sheet of extended cortex. dorsal CA1 CA3 Dentate Gyrus Entorhinal Cortex Subiculum middle ventral .

Left Hemisphere Right Hemisphere .

Basic wiring diagram of hippocampal formation .

Tsodyks) Daniel Amit 1938-2007 neural ‘energy’ landscape for ‘continuous’ functions . 1991 – “continuous attractor” neural networks (with M.1989 .“attractor” neural networks.

“bump”. or “hill” ) Left 0 Right Neurons (conceptually) ordered according to preferred value of parameter .Firing rate Theoretical distribution of firing rates in a population of parietal cortical neurons tuned to different horizontal positions of eye in the orbit Population tuning function (aka activity “packet”.

Local excitatory connections.‘Continuous attractor’ neural network in 1-D) 0 Neurons (conceptually) ordered according to preferred value of parameter. Global feedback inhibition (not shown) limits net activity. Bumps become stable states. .

“Continuous attractor” neural networks in one and two dimensions The effect of local excitatory connections and global inhibitory connections is a single bump of excitation .

Quicktime movie .

.“Continuous attractor” neural networks in one and two dimensions To perform angular or 2-D path integration. you have to make the bump move consistently with the rat’s movement.

. 1989. Key elements are a ring attractor. This is the so-called ‘hidden layer’ of classical neural network theory. Skaggs et al. head-direction cells conjunctive cells 90 120 10 Hz 150 5 Hz 30 60 180 0 210 330 240 270 300 (McNaughton et al.Attractor network model for head direction cells. and a set of cells conjunctive for direction and angular velocity with offset return connections. 1995) ..

head direction (and are linearly sensitive to speed) . 1997) Head direction signal Linear motion signal Conjunctive cells Intermediate layer contains cells that are conjunctive for location.The identical concept in 2-D (Samsonovich & McNaughton.

What happens when the rat gets to the edge of its ‘map’? .? There is a finite number of cells. so the map can’t be infinite.

Samsonovich and McNaughton 1996 .

0 20 40 60 80 100 120 140 160 180 200 0 50 100 150 200 .Samsonovich & McNaughton (1997) implemented the map on a standard torus (periodic boundary condition). which predicts regularly repeating square grid of place fields.

Molden.Microstructure of a spatial map in the entorhinal cortex Hafting. Moser & Moser1 Nature 2005 “Place fields” of layer II medial entorhinal cortical cells have a very regular ‘triangular’ (rhomboidal) grid-like structure . Fyhn.

a b 0 20 40 60 80 100 120 Rhomboidal grid could arise from a simple distortion of a rectangular map with periodic boundaries: a twisted torus 140 160 180 200 0 200 0 50 100 150 200 180 50 160 140 120 100 100 80 150 60 40 20 200 0 .

R O L L .

McNaughton. Hafting. Moser. Fyhn. . there are “head direction” cells and conjunctive “head direction x grid x speed” cells in deeper layers. These are exactly the cells required to implement path integration according to the continuous attractor model. Witter. and Moser (2006) head direction cell Conjunctive grid x head direction cell In addition to “grid cells” in MEC. EC is likely to be the path integrator.Sargolini.

What sets the spatial scale ? .

. 1993) One simple definition of scale is the average size of the place fields.Firing Rate Map Firing rate maps for 80 simultaneously recorded hippocampal neurons while rat ran in a square arena. (High rate cells are interneurons) (Wilson & McNaughton.

(High rate cells are interneurons) (Wilson & McNaughton. .Firing Rate Map Firing rate maps for 80 simultaneously recorded hippocampal neurons while rat ran in a square arena. 1993) Another definition of scale is the rate at which the population activity changes as position changes.

PV Cell # 1 2 3 . . . N Population vector for a one dimensional space .

N Nearby vectors are correlated . . .PVPV Cell # 1 2 3 .

. .PV PV Cell # 1 2 3 . N Correlation decreases with distance .

correlation decreases more slowly with distance . . .PV PV Cell # 1 2 3 . N For bigger place fields.

8 1 0.6 0.9 0.8 Bin Number along Track 70 50 40 30 20 0.4 0. vector corr.7 0.4 0. One dimensional case: Overlap of Population Vectors along Track Bin Number 1 90 80 0.3 pop.2 10 0.2 10 20 30 40 50 60 70 Bin Number along Track 80 90 0 -0. 60 0.Spatial scale can be defined as the distance over which successive population vectors become decorrelated.5 0.6 0. 2004 .2 -50 0 distance on track (cm) 50 Population vector correlation matrix Battaglia et al.

Dorsal Place fields get bigger. and fewer cells are active at a given location as recording location move ventrally dorsal middle Middle ventral Jung. Wiener. . J. 14(12): 73477356. Neurosci. McNaughton (1994).

Weiner. McNaughton. Lipa. McNaughton 1994 Maurer. 2005 .dorsal middle ventral Spatial scale increases systematically along the dorso-ventral axis of the hippocampal formation Jung. VanRhoades. Sutherland.

Grid orientation is constant.Hafting et al. 2005 Grid scale also increases systematically along the septotemporal axis.. .

"Fourier Synthesis" of Place Fields Combining ‘grid’ fields at different spatial scales could lead to nonrecurring ‘place fields’ such as observed downstream of the entorhinal cortex in hippocampus (McNaughton. Solstad et al. Battaglia. 2006). Moser and Moser. Jensen. Nature Rev. Neurosci. (2006) .

Head direction signal Linear motion signal Conjunctive cells Reducing the gain of the motion signal would make the bump move slower – grid scale would look bigger .

0 20 40 60 80 100 120 140 0 20 40 60 80 100 0 50 100 150 200 160 180 200 120 140 160 180 200 0 50 100 150 Bump speed sets the spatial scale 20 .

Barnes (J. Gothard. McNaughton. Neurosci 2005) Deletion of self-motion signals makes the hippocampal code change more slowly with position: place fields get bigger . Krause.Terrazas.

Place field expansion after degradation of movement signal is as predicted by slower bump movement: overlap distribution preserved. Like this Not like this Also. in-field peak rates decrease . population sparsity is preserved.

This prediction was recently confirmed Ventral MEC large scale = low speed Speed signal . One ‘bump’ can’t move simultaneously at different speeds.Grid Scale Quantization A prediction of the Dorsal MEC small scale = high speed toroidal attractor model (but not the interference model): independent modules from dorsal to ventral MEC. so each module can have a different movement speed gain.

consistent with a network mechanism . Moser. grid cells are organized into modules with similar spacing and orientation. Moser. Stensola.tetrodes were moved tangentially along layer II of MEC This showed discrete steps in grid spacing Stensola. unpublished (slide courtesy May-Britt Moser) Thus. Solstad. Frøland.

Is the code 'purely' spatial? What kinds of information are actually stored in hippocampus? .

8 0.5 Cells ordered by location parameter relative to current rat location .6 0.5 -0.1 0 0.4 0.2 -0.3 -0.4 0.2 0.3 0.2 0 -0.1 0.“Classical” view of ‘activity bump’ is a smooth distribution with rate falling off as a function of distance Firing rate 1 0.4 -0.

Constant Place . Leutgeb. This implies that external inputs affect how much cells fire.Variable Place In Samsonovich & McNaughton attractor map model. to enable correction of the PI by landmarks. Moser.Variable Cues Independent Codes for Spatial and Episodic Memory in Hippocampal Neuronal Ensembles Leutgeb. Science. external (cortical) inputs (V) become Hebbian associated with bump locations. Barnes. Moser. but not where they fire! . McNaughton. 2005 Constant Cues .

8 0.5 .1 0 0.4 0.6 0.1 0. Barnes. Leutgeb.1 0. Independent Codes for Spatial and Episodic Memory in Hippocampal Neuronal Ensembles Leutgeb.2 0.2. but not which cells can fire. The potentially active population is determined by the path integrator. Moser. 2005 1 0.3 0.3.5 Fluctuations in the “activity bump” are not all noise but reflect the influence of external cues on the cells encoding a given location 1 0.5 -0.Constant Place .2.4 -0.2 -0.2 0.4 -0.2 0 1.……………………………………………………………n -0.2 -0.Variable Cues .4 0.RATE REMAPPING Variations in cues affect how strongly cells fire.6 0. Science.……………………………………………………………n Cell # / location -0.2 0 1.1 0 0. Moser.8 0.4 0.5 -0.3 0.4 0.3 -0.3 -0.3. McNaughton.

GLOBAL REMAPPING Variations in cues affect how strongly cells fire.8 0. Barnes.……………………………………………………………n Cell # / location -0.3 -0.4 0.2.2 -0.4 0.6 0.2. 2005 1 0.1 0 0. Moser.2 0 1.3.Constant Cues .Variable Place .4 -0.5 -0. The potentially active population is determined by the path integrator.1 0.4 -0.4 0.1 0. but not which cells can fire.……………………………………………………………n -0.3 -0.5 Fluctuations in the “activity bump” are not all noise but reflect the influence of external cues on the cells encoding a given location 1 0.4 0.6 0.2 -0.3 0. Moser.2 0.5 .1 0 0.3 0.3.5 -0.2 0 1. Leutgeb. Science.2 0.8 0. McNaughton. Independent Codes for Spatial and Episodic Memory in Hippocampal Neuronal Ensembles Leutgeb.

Inbound Outbound .

Independent codes for places and events Constant Place – Variable Cue Constant Cue – Variable Place Place 1 Place 2 r>0 r~0 The population vectors of active neurons on two visits to the same place span statistically correlated subspaces. even if the cues are different. Cue 1 Cue 2 Place 1 Place 2 . The population vectors of active neurons in two different places span statistically independent subspaces. even if the cues are similar.

spatial context sensitive context insensitive Hippocampal recipient layers are modality AND context sensitive .

How could a toroidal synaptic matrix be wired up by self-organization? .

What if inhibition is not global? Range of excitatory connections Range of inhibitory connections ‘Mexican hat’ function or ‘DOG’ (difference of Gaussians) .

What if inhibition is not global? Range of excitatory connections Range of inhibitory connections Network forms multiple bumps at closest packing density allowed by range of inhibition .

What if inhibition is not global? Range of excitatory connections Range of inhibitory connections Network forms multiple bumps at closest packing density allowed by range of inhibition 0 20 40 60 80 100 120 .

Spontaneous symmetry breaking in a topographically structureless ‘Turing’ layer with short range excitatory connections and longer range inhibitory connections .McNaughton. Rev. Moser & Moser (Nat. 2006)¶ The effect of local excitatory connections and local inhibitory connections can be multiple bumps of excitation in one or two dimensions This phenomenon was first The ‘mexican hat’ function: Short range described theoretically by excitation & long range inhibition the mathematician Alan Turing (but in a different context). Battaglia. Jensen. Neurosci.

2006)¶ Can a topographically structureless cortical sheet that gives rise to a grid of activity in brain space be used to organize connections in a network that will give rise to The ‘mexican hat’ function: Short range excitation & long range inhibition cells that fire topographically in a grid like fashion in physical space? In other words. Neurosci. can a toroidal synaptic matrix be self-organized during early development? . Moser & Moser (Nat. Battaglia. Rev. Jensen.McNaughton.

Battaglia. Rev. Jensen. 2006)¶ “Turing” layer ‘Mexican hat’ connections Impose random drift of grid phases random top down connections (competitive learning) developing grid cell layer random connections (‘Hebbian” learning) .McNaughton. Neurosci. Moser & Moser (Nat.

2006)¶ Output layer self-organizes as a toroidal synaptic matrix . Neurosci.McNaughton. Rev. Battaglia. Jensen. Moser & Moser (Nat.