Memory - hippocampus and prefrontal cortex

Question 1

How many types of memory are there (when discussed temporally?)

Answer 1

• 3
• Short term (seconds)
• Working memory (seconds to minutes)
○ Finding lost keys, remembering if you turned off the stove or not
○ In the frontal lobes where executive function is
○ Pick’s disease will kill frontal lobe and they have problems with working memory AND executive function

Question 2

Where does fMRI evidence suggest long term declarative memories are stored?

Answer 2

• Long term declarative memories are in the neocortex

* Different kinds of memories are stored in different areas of cortex

Question 3

HM, who lost his hippocampal formations bilaterally, did not also lose procedural memory. Why?

Answer 3

• Procedural memory, or the ability to learn new motor skills, is not contingent on the hippocampal formation
  
  • He did not remember that he learned the task, but when pressed to do it he did it well without practice further

Question 4

What is declarative memory?

Answer 4

• The ability to recollect events or facts that have a specific temporal and spatial context
• “I was interviewed in this doctor’s office yesterday”
What is semantic knowledge?
• General knowledge about the world including new word meanings

Question 5

Describe the layout of the hippocampus.

Answer 5

• Jelly roll-like architecture
  
  • One layer of neuron cell bodies arranged in a spiral semicircle (dentate gyrus)
  • Dentate gyrus is surrounded by a larger spiral semicircule of neuronal cell bodies (ammon’s horn)

Question 6

Describe the input pathway into hippocampus

Answer 6

• Input to the hippocampus is from the entorhinal cortex through a bundle of axons called the perforant path
  
  • Perforant path axons make synapses on the neurons in the dentate gyrus and CA3 region of Ammon’s horn
  • The information contained in this input is complex because the entorhinal cortex receives widely distributed input rom many areas of neocortex

Question 7

What is the subarchitecture of ammon’s horn?

Answer 7

• Neurons are diveded into four types

○ Only care about CA3 and CA1 groups

Question 8

What are the two neuronal paths of importance within the hippocampus?

Answer 8

• One bundle is of cells in dendate gyrus that synapse on CA3 neurons
○ Mossy fibers
• Other is Schaeffer collateral axons that originate from the CA3 neurons and synapse onto the CA1 neurons
○ Output is from CA3 and CA1 neurons through axons that form the fornix
• CA1 and CA3 neurons are important because they exhibit LTP

Question 9

What is meant by LTP in the hippocampus?

Answer 9

• Strong repetitive stimulation of the perforant path, mossy fibers or schaeffer collaterals all modify the activity elicited by synaptic transmission of information to the postysynaptic neuron
  
  • Repeated stimulatio nof perforant path on CA3 neurons
  • OR schaeffer collaterals on CA1 neurons

Question 10

Describe the neurophys experiments grossly showing LTP.

Answer 10

• Elicit a stimulus every minute for 15min to establish baseline
  
  • Tetanus stimulus for a bit
  • Go back to every minute stimulus
  • EPSP is stronger after tetanus than before
  • Indicative of increased synaptic efficacy only in the synapses that were stimulated tetanically

Question 11

What two conditions must be met to generate LTP?

Answer 11

• Glutaminergic stimulation
  
  • AND successful EPSP. The neuron has to have glutamate on it AND depolarize.
  • The most important aspect of this is the NMDA receptor

Question 12

Using charades as an example describe how LTP might be the basis of learning?

Answer 12

• Charades, trying to guess “lord of the rings”
  
  • You need lots of stimuli, or clues, to mimic the tetanus stimulation of the experimental model
  • However, after that happens, you need less and less cues to stimulate the association pathway because the synaptic efficacy is better.
  • Soon you need one for two cues to get it down

Question 13

NMDA is a glutamate receptor, but it doesn’t just open when glutamate binds like the AMPA receptor. Why?

Answer 13

• It’s plugged with a Mg ion
  
  • It takes glutamate binding AND a depolarization to pop the Mg ion out of the pore and allow the channel to function ionotropically

Question 14

Calcium is super important for LTP. What’s the reason?

Answer 14

• Calcium influx increases calmodulin activation
• Calmodulin activation increases CaMKII activation, which autophosphorylates and is active for edays
• CAMKII will elicit several changes that lead to longer EPSP
○ Incorporation of AMPA into postsynaptic membrane
○ Phosphorylation and tuning of AMPA response

Question 15

Use alzheimers as an example of memory storage physiology

Answer 15

• Early on, pure impariment of cognitive funciton
• Affects synaptci transmission in limbic and association cortices
• Loss of ability to encode new declarative memories in an individual with otherwise normal intelligence, motor an sensory functions
• Caused by the NFTs and amyoloid build-up
*lose the ability for LTP at the neuronal level too

Question 16

How are emotions expressed in the brain?

Answer 16

• Autonomic visceral and somatic motor actions corrdinated by the hypothalamus and midbrain reticular formation in the brainstem
• Autonomic - hypothalamus
• Somatic motor - brainstem reticular formation
• The emotional limbic system involves the amygdala, the cingulate gyrus, the mediodorsal nucleus of thalamus, ventral basal ganglia and insular cortex and hypothalamus
○ Fear and reward, sadness and elation

Question 17

Experimental messing with the amygdala created what changes?

Answer 17

• Modification of circuits in the amygdala mediate changes in development of emotion to specific stimuli
• Example - fear conditioning in rats - fear develops to a previously neutral stimulus through fear conditioning
• Fear develops when this neutral stimulus is paired with an inherently aversive one such as an electric foot shock
*eventually the normal, non-averse stimulus creates the conditioned response after the amygdala attributes the valance of “fear” to that stimulus

Question 18

Describe the importance of the amygdala in the conditioned fear response

Answer 18

(discussing the experiments of conditioned fear in mice, which causes thermal differences and the behavior of freezing)
• This conditioned fear is mediated by changes in the neuronal circuits in the lateral and central nuclei of the amygdala
• These nuclei receive input from both the auditory system and from the somatosensory system and they send output to the midbrain reticular formation that is key for the freezing behavior in mice, and to the hypothalamus that controls the rise in blood pressure

Question 19

In conditioned food avoidance, an unfortunate co-morbidity of cancer and chemotherapy, what is the stimulus profile and why is it different than the fear conditioning experiment in mice?

Answer 19

• Fear conditioning in mice involves simultaneous stimuli (sound and shock) which is still processed through the amygdala and made into “fear”
  
  • In CFA though, the stimuli have temporal separation (1/2 hour after having the food they get sick)
  • The fear response is pretty robust and long-lasting, up to years in duration
  • Thus the major difference is the temporal separation and the potency of the memory/fear response

Question 20

Describe the neurocircuitry of CFA using experiments in rats as a model system

Answer 20

• When the rat is exposed to a novel food, cholinergic neurons in the basal forebrain are stimulated to release ach throughout the brain
• One area where ach is released is insular cortex, the area of the brain that is important in taste responses (taste cortex)
• If muscarinic receptor antagonists are perfused into insular cortex the rats do not acquire CFA when food is paired with malaise
○ Indicating that muscarinic receptors in the insular cortex are essential for acquisition of CFA
• Muscarninic stimulation of neurons in the insular cortex leads to phosphorylation of the NMDA receptor, modulating receptor activity for about 1/2 hour
• If, during that period, malaise afferent information comes in from the vagus, then there can be neuronal association of taste with malaise

Question 21

Depression can be treated how? (think invasive, non-pharm)

Answer 21

DBS of the limbic system. Thus, the limbic system is involved in depression. (big picture and general)

Question 22

How can the frontal lobes be divided (general)?

Answer 22

• Primary motor cortex (Broadmann’s area 4)
• Premotor cortex (BA 6)
• Prefrontal cortex
○ Those parts of the frontal lobe that receive input from the mediodorsal nucleus of the thalamus
• anterior cingulated cortex is also often included
○ This receives input from the anterior nucleus of the thalamus

Question 23

Describe “executive function”, which is often attributed to the PFC in physiological terms

Answer 23

• PFC operations can directly enhance certain networks and inhibit others
  
  • motor function - where certain motor and premotor networks can be enhanced and others inhibited, in what amounts to motor planning
  • Also true for sensory function, where enhancement of some sensory processing and inhibition of others produces selective attention to stimuli that relate to current goals
  • PFC operations also act to enhance and inhibit certain interoceptive stimuli and internal states producing what amounts to emotional control

Question 24

One widely used scheme to subdivide the PFC spits it into 3 sub-parts. What are these?

Answer 24

• Dorsolateral prefrontal cortex
		○ DLPFC
	• Ventromedial prefrontal cortex
		○ VMPFC or orbitofrontal or orbitomedial
	• Anterior cingulate cortex
		○ ACC

Question 25

Lesions to the DLPFC will cause perseveration and environmental dependency. Does this make sense given the inputs and outputs?

Answer 25

• Overall inability to employ intention (goals) to modulate attention (task at hand)
• Perseveration - failure to switch attention
• Environmental dependency - lack of internally generated goals will render the patient dependent on external cues to perform certain tasks/goals
• Inputs -
○ Predominantly from somatosensory, visual and auditory cortical association areas in the parietal, occipital and temporal lobes
○ Strongly included in re-entrant basal ganglia-thalamocortical circuits that involve parts of the basal ganglia which are projected upon by parietal, occipital and temporal association corticies
• Outputs -
○ Directed towards the promotor cortex
○ Also the somatosensory association cortices (those areas it receives input from)
○ Also sends information to the brainstem structures like deep superior colliculus, midbrain tegmentum and PAG

Question 26

What are the outputs of the DLPFC?

Answer 26

• Outputs -
○ Directed towards the promotor cortex
○ Also the somatosensory association cortices (those areas it receives input from)
○ Also sends information to the brainstem structures like deep superior colliculus, midbrain tegmentum and PAG

Question 27

What are the inputs of the DLPFC?

Answer 27

• Inputs -
○ Predominantly from somatosensory, visual and auditory cortical association areas in the parietal, occipital and temporal lobes
○ Strongly included in re-entrant basal ganglia-thalamocortical circuits that involve parts of the basal ganglia which are projected upon by parietal, occipital and temporal association corticies

Question 28

The Iowa Gambling Task is used to measure the severity of lesions to which part of the PFC?

Answer 28

• Ventromedial prefrontal cortex
  
  • VMPFC
  • Lesions will produce characteristic performance

Question 29

What goes on in the Iowa Gambling Task?

Answer 29

• 4 decks of cards, and participatnts win money each time they choose a card
  
  • There are randomly distributed penalty cards in the deck
  • Good decks and bad decks.
  • VMPFC damage will continue to draw from bad decks even though they know cognitively they are losing
  • Healthy people will show stress responses to bad decks but VMPFC damage will never develop this physiological reaction
  • Can’t recognize impending punishment

Question 30

All told, what do the behavioral changes associated with VMPFC damage tell us about it’s function?

Answer 30

• Mediates the ability to estimate the risk/reward associated with certain behaviors
  
  • Gut feeling about the implications of a given behavior and it implies VMPFC has a role in suppression of behaviors felt to be excessively risky
  • Especially control over risky behaviors in a social situation

Question 31

Besides the specific Iowa Gambling task results, what other behavioral problems does VMPFC result in?

Answer 31

• Inadequate inhibition of aggression, sexual behavior, anxiety, and appetitive functions
  
  • Fail to correctly employ these behaviors in APPROPRIATE circumstances

Question 32

What are the inputs of the VMPFC?

Answer 32

INPUTS
• Somatosensory, visual and auditory association areas just like DLPFC, though to a much lesser extent
• Inputs from olfactory, gustatory and visceral sources are much more prominent and widespread in VMPFC than DLPFC
• Strong inputs from basal amygdaloid complex and the parahippocampal cortices
○ Inputs from hippocampus proper reach predominantly the medial wall of the PFC
• Involved in re-entrant basal ganglia-thalamocortical circuits that involve the BG that are innervated by the hippocampus and amygdala as well as by limbic associational cortices

Question 33

There is a reciprocal relationship between the VMPFC and the cholinergic cell groups in the basal forebrain and the monoaminergic cell groups in the brainstem and hypothalamus

Answer 33

• Through these projections the VMPFC may influence the cholinergic and monoaminergic innervation of widespread cortical and subcortical regions fo the forebrain
• VMPFC further projects to the lateral and posterior hypothalamus where it interconnects with stress and autonomic centers in the brain
• Also projects direct to periaqueductal grey, nucleus tractus solitarius and dorsal motor nucleus of vagus
○ All these are involved in autonomic functions

Question 34

The anterior cingulate cortex is what BA?

Answer 34

• Broadmann area - 24

* ACC = anterior cingulate cortex

Question 35

In primates, what is the result of general electrical stimulation of the primate ACC?

Answer 35

• Corresponding to broadman area BA 24
• Variety of autonomic and limbic responses
• Heart rate changes
• Blood pressure changes
• Respiration rate changes
• Vocalizations, facial expressions and likely emotions
○ Thus the ACC should be considered in the context of its extensive reciprocal relationships with limbic and autonomic structures

Question 36

The ACC is involved in attention how?

Answer 36

• EEG signal in ACC increases as attentional demands for a task increase
• If a subject has mastered a task then there is no activity in the ACC
• Essentially it’s involved in focus and attention, associated with task difficulty
• Also, lesions to this area cause abulia or lack of will
○ Can be as severe as akinetic and mute in some cases

Question 37

What is meant by “the PFC is modulatory rather than transmissive”?

Answer 37

• The pathway from input to output does not run through the PFC in the traditional sense
  
  • Instead, the PFC guids activity flow along task-relevant pathways in more posterior and/or subcortical areas
  • Liken the function to a switch operator in a system of railroad tracks. The brain is a set of tracks connecting various origins to destinations
  • The goal is to get the trains (activity carrying information) at each origin to their proper destination as efficiently as possible, avoiding collisions
  • When a track is clear than no modulatory intervention is needed (PFC is not needed to carry out that behavior)
  • However, if two trains must cross the same bit of track, then some coordination is needed to guide them safely to their destinations
  • The PFC just decides which train will go first and which will wait

Question 38

In summary, what are the tasks performed by the VMPFC and DLPFC?

Answer 38

• DLPFC - contributes to the representation, planning, and selection of goal-directed behaviors
• VMPFC - central role in assessing the positive and negative valence of stimuli and (with help from the limbic system) computes the potential gains and losses of potential actions
○ Receives input from the amygdala, which itself tasks in external and internal sensors and modulates the intensity of aversion and fear
• ACC promotes action towards goal/motivation and will lead to apathy or lack of will if ablated

Question 39

The hippocampus can be thought of as a search engine. Why?

Answer 39

• Allows a fast and efficient search among the deposited memories in the neocortex
○ Where the long term memory consolidation is
• This is essential for planning the future and generating creative ideas

Question 40

Besides short term, declarative memory and searching through stored memory, what else is the hippocampus important for?

Answer 40

• It can be thought of as the GPS of the brain
  
  • Most physiological studies on the hippocampus have been performed during spatial navigation
  • The neural algorithms, perhaps evolved initially for computing locations and distances in the physical world, are likely the same as those used for the navigation in cognitive space during recall and planning
  • Everything the hippocampus does is strongly associated with the entorhinal cortex

Question 41

Where are grid cells located?

Answer 41

• These grid cells are related to place cells
  
  • Place cells are hipoocampus and grid cells are in the entorhinal cortex
  • The entorhinal cortex is the principle input structure to the hippocampus
  • Both systems work together to give a cognitive representation of euclidean space
  • Also, it provides a theory as to how the brain structures human position relative to the stored map of the brain and the memory association of the senses

Question 42

Where do granule cells and pyramidal cells live?

Answer 42

• Granule cells are the major cell type of the dentate gyrus
  
  • Pyramidal cells are the major cell type of the hippocampus
  • Interneurons are found within each leary and are mostly GABAergic

Question 43

What are the two major inputs to the hippocampal formation?

Answer 43

• Entorhinal cortex and septal nuclei
• Entorhinal input is considered more important. Also called trisynaptic circuit because of it’s course through the hippocampal formation
Trace the flow of information through the hippocampus
• Entorhinal cortex, neuronas send axons to dentate gyrus (with smaller direct input to hippocampus)
• From dentate gyrus, granule cells send axons to the CA3 field of hippocampus
• From CA3 feld, pyramidal cells send a major projection to CA1 field
○ Some fibers go directly from CA3 to hypothalamus through fornix
• Much of the CA1 input is sent on to subiculum
• From subiculum information can be conveyed to entorhinal cortex which then projects to cortical association areas

Question 44

Summarize the pathway through the hippocampal formation using the important terms like mossy fiber and perforant path

Answer 44

• Entorhinal cortex sends projections via the perforant path to the dentate gyrus
○ Some projections to CA3 and CA1 directly, but minor
• Dentate granule cells send axons called MOSSY FIBERS to CA3 field
• Axon collaterals from CA3 neurons which form autoassociations with the same and other CA3 neurons and with CA1 via the shaffer collaterals
• From the CA1 field, information is conveyed to subiculum and entorhinal cortex