1. Memory Human Neurobology 217 Jana Vukovic jvukovic@anhb.uwa.edu.au

2. Key points: Famous cases of memory deficit
Brain structures involved – hippocampus
Circuitry of memory – Papez Circuit
synapse strengthening and long-term potentiation (LTP)

3. What is memory?
Memory is defined as the acquisition, storage, and retrieval of information.
All animals learn things from their interaction with the environment
Human brain forms memories more effectively than others
Maximum behavioural flexibility and most efficiently adaptation to environment.

4. Amnesias = memory disorder
time
Brain
damage
occurs
Anterograde amnesia
Cannot later remember
events that occur
after brain damage
Retrograde amnesia
Cannot remember
events prior to
brain damage

5. HM & NA Which brain structures were removed from HM’s brain?
Hippocampus, hippocampal gyrus, amygdala, uncus were removed on both sides
Which brain structures are damaged in NA?
Thalamus and medial temporal lobe, mammilary bodies missing on both sides
Can HM and NA form new long-term memories (declarative)?
NO.
Can HM and NA learn new skills (procedural)?
YES.
What kind of amnesia do HM and NA have?
Sever anterograde amnesia.

6. NA

7. Korsakoff's syndrome:
Found mostly in alcoholics who get most of their calories from alcohol and become vitamin deficient (thiamine deficiency)
Damages mammilary bodies and other nearby parts of the hypothalamus and thalamus
This damage produces an amnesia similar to the type of NA and HM (sever anterograde amnesia)
Altzheimer’s disease:
Loss of neurons in hippocampal and prefrontal cortex produce first signs of memory loss.

8. Long-term memories are biologically different from short-term memories
Long-term memories are stored throughout the brain, but the hippocampus is necessary for the information to reach long-term storage.

9. Memory consolidation
the process by which recent memories are crystallised into long-term memory. The word "consolidation" is used to refer to different levels:
Molecular consolidation: The molecular process by which long-term conductivity of synapses is affected. Memory consolidation occurs after training (e.g. an exposition to a stimulus-response pair). Consolidation increases in strength over time with repetition. Maximum consolidation with minimum time investment is achieved by means of spaced repetition. Molecular consolidation requires protein synthesis.
Network consolidation: Many researchers believe that episodic memories are initially stored in the hippocampus and are slowly moved (or 'consolidated') into the neocortex. This process of consolidation is likely to occur during sleep. Originally it was thought this happens during dreaming (Marr, 1971). However, new research indicates that the NREM phase of sleep is associated with that process (Hobbson, Stickgold, Buzsaki).

10. Long-term memory Declarative Memory (explicit) Procedural Memory
(implicit)
Remembering
events
(episodic m.)
Knowing facts
(semantic m.)
Skills and
habits
Emotional
association
Conditioned
reflexes
Hippocampus
Nearby cortical areas,
diencephalon
Striatum
Motor areas
of cortex
cerebellum
amygdala
cerebellum
Kinds of memory (Fig. 23.1)
Declarative memory = explicit memory - memory for facts or events
Short-term memory - temporary, limited in capacity, requires continual rehearsal
Long-term memory - more permanent, much greater capacity, does not require continual rehearsal
Then there must be a consolidation for the sake of long-term memory which must involve permanent changes like changes in synapses. mRNA and protein MUST mediate change.
Consolidation - transfer from short-term memory to long-term memory
Nondeclarative memory = implicit memory
Procedural memory - memory for skills or behavior
Working memory - temporary information storage that includes several types of information, probably from several sites in the brain
Spatial memory - memory of location
Relational memory - all things that happen at same time get stored together in a manner that ties them together
That there are several different types of memory suggests different strategies/places may be used by the brain for different kinds of memory
Types of Memory
The term memory is a logical construct that subsumes many different processes and requires the
function of many different brain areas. Research in recent years has provided information
necessary to many of the various components of memory and identify associated brain regions.
This section will outline some of the most important types of memory and this same outline of
terms will be later related to brain research identifying specific areas of the brain that are most
important in the proper function of these different types.
Declarative [WHAT]
Memory for facts and events accessible to conscious recollection. Memory for things that one can
recall and declare. Easily formed and forgotten. Sensory -[Encoding]- quickly decreasing sensory
representation of event Episodic -- Memory for past personally experienced events. Semantic --
Memory for facts.
Non-Declarative [How]
Procedural memory - skills and operations not stored regarding time and place. [Non-Declarative].
Recalled without conscious recollection. Longer to form. Priming - skills and operations not stored
regarding time and place. [Non-Declarative]
Perceptual Conceptual
Conditioning - skills and operations not stored regarding time and place. [Non-Declarative]
Simple Delay Conditioning
Trace Conditioning
Short-term Memory -- Temporary storage with limited capacity. Involves multiple sites and continued
rehearsal. Storage without distraction.
Long-term Memory - Memory that has been consolidated or stored so that it is available after distraction.
Working Memory - short term recall & temporary storage of information to complete a task. Thought of
as working with memory - the plan.
Source Memory - most readily lost due to the limitation in associations.
Relational Memory - multi-modality. May have good short-term memory with one modality but not
another.
amnesia in a patient with MR evidence of
mammillary body lesions following a penetrating injury from a snooker cue.

11. Hippocampus Essential for declarative memory Cylindrical structure
Longitudinal axis surround thalamus

13. Entrhinal cortex is affected in Alzheimer’s

14. Out put from hippocampus
fornix
carries signals from the hippocampus to the mammillary bodies and septal nuclei.
the separate left and right side are each called the crus of the fornix.
body of the fornix.
hippocampal commissure. Most fibres stay on their original side.
The body of the fornix travels anteriorly and divides again near the anterior commissure.
continue through the hypothalamus to the mammillary bodies.
mammillary bodies
septal nuclei are structures in the middle anteroventral cerebrum that are composed of medium-size neurons grouped into medial, lateral, and posterior groups. The septal nuclei receive reciprocal connections from the hippocampus, amygdala, hypothalamus, midbrain, habenula, cingulate gyrus, and thalamus.

15. Cingulate Gyrus     Located on medial surface of the brain     Coordinates pleasant memories of previous emotions    
Hippocampus     Located adjacent to olfactory cortex in the temporal lobe     Involved consolidation of short term memory to long-term factual or declarative memory    
Hypothalamus     Controls many aspects of emotional behavior     Deals with the expression of emotion     Programmed response
Anterior Thalamic Nuclei     Gateway to the cerebral cortex     Computes the specific emotional response      modulation of emotional feelings or affect

18. Prefrontal cortex Association Cingulate gyrus Anterior Thalamic nuclei
Mamillary
body
Hypothalamus
Amygdala
Hippocampal
formation
fornix
Mammillo
thalamic
tract
Pathways Added To Circuit     Bi-directional communication between the hippocampus and the association cortex             Allows for comparison of old information and current stimulus                 Input from the hypothalamus to the prefrontal cortex              
Amygdala              Many bi-directional connections to hippocampus, hypothalamus, thalamus, cortex         Projects current status in relation to both surroundings and thoughts                Critical in long term memory         An important component of the learning is the emotion

19. Strengthening of synapses
Long-term potentiation (LTP) is the long-lasting strengthening of the connection between two neurons
can last from hours to days, months, and years.

20. Long-term potentiation of synapses
Hippocampal slice preparation to study LTP
single stimulation to input path
measure hippocampal response baseline
Give train of stimulation to input path
Again give single stimulation to input path
hippocampus response is larger (potentiated)
Give single stimulation a week later
Hippocampus response still potentiated (long term potentiation)

21. Synapses are strengthened
Associativity
Associativity refers to the observation that when weak stimulation of a single pathway is insufficient for the induction of LTP, simultaneous strong stimulation of another pathway will induce LTP at both pathways.
simultaneous delivery of both a strong and weak stimulus makes the response to the weak stimulus stronger
The Nature of Synaptic Change
With repeated stimulation there is an increase in dendrites and thus synapses. l
Also increase in vesicles, post-synaptic membrane, & size of dendritic spines. l
Hebbian theory describes a basic mechanism for synaptic plasticity wherein an increase in synaptic efficacy arises from the presynaptic cell's repeated and persistent stimulation of the postsynaptic cell. It was introduced by Donald Hebb in 1949 and states that:
cells that fire together, wire together, though this is an oversimplification of the nervous system and should not be taken literally.
Not the number of cells but strength of synapse

22. More dendritic spines on dendrites where new synapses are made
Soon after Ramon y Cajal first described the dendritic spine, over a hundred years ago, and while there was still a hot debate going on whether the neurons are isolated or are all linked in a continuous cytoplasmic net, Cajal and others had already proposed that the spine is the locus of long term synaptic plasticity associated with storage of memories in the brain (Cajal, 1995). This intuitive dogma, which lasts to this day, stands on two pillars: the observation that spines vary tremendously in shape, size and density even on the same dendrite, and that this variability is correlated with the recent history of the organism; and that spines are formed during development, following the formation of dendrites, when experiences are stamped into the brain, and they disappear in aged animals, when old memories normally fade and new ones do not form. Enriched environment enhances them, and mentally retarded children express immature spines (Purpura, 1974; Scheibel et al., 1975; Greenough et al., 198
Figure 1: Cultured hippocampal neurons express plastic, functional dendritic spines. A 2-week-old cultured neuron loaded with calcein was imaged at 3D in the confocal microscope to show a variety of spine shapes and sizes (A). The cell was exposed to FM4-64 dye that is taken up by active presynaptic terminals, and a section of the dendrite shown in A is magnified to demonstrate that the spines are touched by terminal boutons (B). Formation of a novel spine following a transient (5 minute) exposure of the culture to a conditioning medium that favors activation of the NMDA receptor (C). Images are taken before, left, and at 30-minute intervals after exposure to the conditioning medium. The total length of the spine is 1.5µm  (modified from Goldin et al. 2001).
Dendritic spines from a
cerebellar Purkinje cell, drawn by Cajal (Ramón y Cajal, 1899b).

23. Long-term potentiation
Glutamate Receptor types
Glutamate excitatory neurotransmitter at hippocampal excitatory synapses,
2) AMPA receptor
3) NMDA receptor
NMDA receptor properties
Receptor activated by glutamate, but channel normally blocked by Mg2+, Mg2+ ions repulsed from channel mouth when membrane depolarizes, but if input frequency low, membrane already moving back to resting levels by time that Mg2+ has moved from channels
If there is strong simultaneous input from another source, stronger depolarization causes Mg2+ to move away from mouth of NMDA receptor channel to allow substantial influx of ions
If channel unblocked significant amounts of Ca2+ enter, activate Ca2+/calmodulin dependent protein kinase II, protein kinase C, and Ca2+ dependent proteases
Likely targets of kinases are AMPA and K receptors or associated channels, makes receptor channel complex more sensitive to glutamate, thereby enhancing response to subsequent input
Possible presynaptic mechanisms of LTP
As well as activating protein kinases, influx of Ca2+ caused by opening of NMDA channels induces synthesis of nitric oxide (NO)
NO acts as retrograde messenger, diffuses back to presynaptic cell and affects subsequent transmitter release
At rest, the NMDAR's calcium channel is blocked by magnesium; the blockade is relieved only after strong postsynaptic depolarization[4]. The calcium channel is also ligand-gated, so that it only opens when presynaptically-released glutamate binds the receptor. When the NMDAR opens, calcium floods the postsynaptic cell, triggering associative LTP.
Ca++ will only enter through the NMDA glutamate receptor channel if the postsynaptic membrane has already been depolarized when the glutamate arrives
Only strong stimulus will dislodge Mg2+ from the NMDA receptor

25. A ‘‘Vicious Circle’’ model of obesity
Fig. 6 depicts what might be termed a ‘‘Vicious Circle’’
model of obesity. This model starts with the conventional
assumption that an ‘‘unhealthy diet’’ is one that includes too
many highly palatable foods that are rich in saturated fat and
refined sugar. However, in the Vicious Circle model, this diet is
not considered to be unhealthy for the conventional reasons
(e.g., increased risk of cardiovascular disease, hypertension,
etc.). This diet is considered unhealthy to the extent that
consuming it interferes with or degrades a critical hippocampal
Diet
This function involves the ability to inhibit the
activation of the memories of food or of the rewarding
consequences of eating. If this inhibitory function is disturbed,
these memories and the environmental cues that retrieve them
will have increased power to evoke appetitive responses that
are instrumental to obtaining and consuming food. Based on
the assumption that the inhibition of these memories and the
responses they trigger is normally strongest under conditions of
positive energy balance, weakening of this type of control
would result in energy intake in excess of energy needs (i.e.,
overeating).
The types of foods that are most likely to be approached and
over-consumed are those that are associated with the most
numerous and salient environmental retrieval cues (e.g., are
widely available, highly advertised), that excite memories of
highly rewarding oral (i.e., are highly palatable) and postingestive
(e.g., produce quick corrections of mild negative
energy balance) sensory consequences. Within the Vicious
Circle model, these foods may be the same widely available,
highly marketed, highly palatable, energy-dense products that
give rise to hippocampal dysfunction in the first place. This set
of circumstances could provide the basis for a potential
‘‘vicious circle’’ of intake leading to reduced inhibitory control
producing increased intake, resulting in greater failure of
inhibitory control, etc., all of which are antecedent to the
gradual fattening of population.
The Vicious Circle model outlines a mechanism whereby
changes in the food environment that began many years ago
could gradually alter brain functioning to weaken the regulatory
control of energy intake. A number of important details of
this model have already been mentioned. For example, recent
reports show that diets high in fat and processed sugar reduce
hippocampal BDNF and that reduced hippocampal BDNF
alters at least some hippocampal-dependent cognitive processes.
In addition, receptors for important short-term (CCK) and
longer term (leptin, insulin) intake inhibiting neuropeptides are
not only abundant in the hippocampus, but have also been
shown to influence memory functions that are thought to rely
on hippocampus. Impaired hippocampal sensitivity to the
intake suppressive effects of one or more of these signals
could promote food intake. Furthermore, a variety of research
findings and several current theoretical formulations have
already suggested that one of these hippocampal-dependent
memory functions is to inhibit activation of highly salient or
prepotent memories, thereby contributing to the inhibition of
the behavioral responses they evoke. Thus, links between the
hippocampus and behavioral inhibition have already been
identified. Moreover, there is substantial evidence from human
and animal studies that disrupting hippocampal function
reduces the ability to inhibit eating and appetitive behavior
and to regulate body weight.
6. Conclusions
It is often said that people who overeat and become
overweight or obese lack the ability or will-power to control
their eating behavior. Many attribute this lack of control to an
environment where food is abundantly available and where
people are constantly reminded about the pleasures of eating it.
These cues may be too much to resist. There is good reason to
believe that learning about environmental cues that have been
associated with the rewarding consequences of eating is an
important contributor to caloric intake in excess of regulatory
needs. Research reported in this issue (Balleine; Holland and
Petrovich; Kelley) provides important new findings about the
brain substrates that underlie the potential incentive value,
reward, and habit mechanisms which contribute to the
excitatory control of conditioned feeding behaviors.
In the present paper, we attempted to expand on this basic
conceptualization in several ways. We proposed that: (1)
regulatory control of food intake depends not only on
excitatory, but also on concurrent inhibitory learning about
the relationship between environmental food cues and rewarding
postingestive events; (2) the presence and absence of
physiological satiety signals modulate whether food cues excite
or inhibit the memory of these rewards; (3) the modulatory
power of satiety signals emerges as a result of their being
embedded in a ‘‘natural’’ Pavlovian conditional discrimination
or negative occasion setting problem; (4) the hippocampus is at
least part of the neural substrate for the type of inhibitory
learning on which occasion setting is based.
Finally some researchers attribute the continuing trends
toward increased eating, body weight, and obesity to a
biological system of intake control that has been contraprepared
by evolution to meet the regulatory challenges posed
by the current food environment. The rapid increase in
overweight and obese people in the general population has
led others to question whether or not caloric intake is even a
regulated parameter, at least in environments where food is
readily available (e.g., Mattes, this issue). The present paper
retains the idea that caloric intake is under regulatory control
(also see Woods, this issue). But rather than attribute the
current weakness in energy regulation solely to genetic factors,
we offer the alternative possibility that recent changes in the
food environment have diminished the ability of the hippocampus,
and perhaps other brain areas, to perform higher order
cognitive inhibitory control functions.
It may be that our obesigenic environment also interferes
with these inhibitory control functions in other ways. For
example, intake regulation may depend in part on the ability to
use orosensory stimuli to predict nutritive or caloric outcomes
(see Swithers and Davidson, this issue [140–142]). Degrading
this predictive relationship by intermittent exposure to food
cues that are not good predictors of calories or nutrients would
presumably make it more difficult for animals to use their
satiety signals to set the occasion for when a given food cue
will or will not be followed by rewarding postingestive
stimulation. This could interfere with the ability of satiety
cues to function as negative occasion setters. The possibility
that exposure to aspects of the current food environment might
impair energy regulation by interfering with the neural
substrates that underlie negative occasion setting or by
disrupting negative occasion setting itself may provide a useful
alternative framework for approaching the continuing problem
T.L. Davidson et al. / Physiology & Behavior 86 (2005) 731–
of excess food intake and body weight gain in the human
population

26. Exercise and trophic factor production in the adult brain

27. Describe Papez circuit?

28. Amygdala
The amygdala is involved directly in agression and agressive response to situations. When damaged in primates, it will generally cause a creature to fall to the boddom of the pecking order.
Cingulate Cortex
A large area of neocortex. The anterior region is responsible for emotional reaction to pain.
Network consolidation: Many researchers believe that episodic memories are initially stored in the hippocampus and are slowly moved (or 'consolidated') into the neocortex. This process of consolidation is likely to occur during sleep. Originally it was thought this happens during dreaming (Marr, 1971). However, new research indicates that the NREM phase of sleep is associated with that process (Hobbson, Stickgold, Buzsaki).
Last Slide