UCSD COGS 107B - Midterm 2

Lecture 8: Neuromodulators and Drugs of Abuse

Neurotransmitters

Mediates info exchange between neurons through generation of synaptic potentials

3 Basic Types of Neurotransmitters

-Ionotropic Excitatory

-Ionotropic Inhibitory

-Metabotropic/Neuromodulatory

Ionotropic Excitatory

(Glutamate, ACh)

Causes EPSPs

Ionotropic Inhibitory

(GABA, Glycine)

Causes IPSPs

Metabotropic/Neuromodulatory

(NE, 5-HT, DA, HA, Ach)

Causes Biochemical Cascades with ion channel interaction.

What is the difference between ionotropic and metabotropic NTs?

Ionotropic - Directly involved with Ion Channels, Receptors are built into an ion channel. NT Causes ion to bind and cause ion channels to open for ion flow

Metabotropic - Induce cascade of biochemical events that affect functions of voltage-gated ion channels.

How do Metabotropic NTs cause potentials?

NTs cause change in ion channels via voltage gated potentials and change in ion kinetics.

Neuromodulators

- Norepinepherine(NE)

- Serotonin (5-HT)

- Dopamine (DA)

- Histamine (HA)

- Acetylcholine (Ach)

Norepinepherine (NE)

Main Nucleus: "Locus Coerlus" in Pons

Projects to: All parts of the brain

Same as Noradrenaline (NA) analagous to Adrenaline in the Body

Analog in brain. Heightens sensitivity/attention to particular Stimuli

Involved in Stress, and Changes in Normal

Serotonin (5-HT)

Main Nucleus: "Raphe Nuclei" in Brainstem

Projects to: Brainstem Area

Modulates Anxiety and Depression

Dopamine (DA)

Main Nucleus: "Ventral Tegmental Area" and "Substantial Nigra"

Projects To: Nucleus Accumbens and Prefrontal Cortex

Chemically related to NE.

Epinepherine > Norepinepherine > Dopamine

Reward System, if not enough then Parkinsons

Two Types (Type I and Type II) depending on which receptor it is binding on

Histamine (HA)

Main Nucleus: "Posterior Hypothalamus"

Projects to: Cortex

"Forgotten One"

"Antihistamines" - Sleep Aid

Involved in Wakefulness

Acetylcholine (Ach)

Main Nucleus: "Pontine Nuclei" and "Basal Forebrain"

Projects to: Brain Stem

Characteristics Of Brain Modulatory Systems:

1. Small groups of neurons sharing the same NT

2. Projections via unmyelinated fibers to widespread regions of brainstem and forebrain

3. NT Binding to receptors generates through phosphorylation, long lasting (100+ ms) changes in properties of voltage-gated ion channels

4. Firing Activity of neuromodulatory neurons is strongly impacted by sleep/wake state (exception for dopamine)

5. Neuromodulatory Neurons receive input from a number of different sources, but all receive input from prefrontal cortex

6. Low Firing Rates (mean approx. 0-6Hz)

7. Influence the neuronal responses to ionotropic excitatory and inhibitory inputs as opposed to directly mediating excitatory or inhibitory responses ('alter functional anatomy of brain')

What is the main function of Neuromodulators?

They change the ways in which the brain thinks

G-Protein

generated by Neuromodulator interaction. Causes creation of Adenylate Cyclase in order to affect voltage gating ion channels

Adenylate Cyclase

from G-Protien, activates receptor reaction.

ATP > AMP > PKA

Phosphorylation

Phosphate groups attatch to receptor and may or may not cause a membrane potential from Neuromodulator reaction from Metabotropic receptor

How does Neuromodulator affect ion channels?

Alteration of ion channels kinetics and voltage gating through changes in phosphorylation state.

Ach Agonist

when binded to receptor, it acts like Ach

How does Ach affect receptors?

Ach doesn't cause the potentials, it causes the extension of the response

Pyriform Cortex

"Ancient Cortex", only has 3 layers

Dendrites: 1a & 1b

What happens in uneven distribution across dendrites of ion channels?

Leads to alteration of neuronal responses to intrinsic, but not extrinsic inputs in pyriform cortex

Layer 1a inputs to Dendrites of layer II neurons from Olfactory Bulb

Layer 1b inputs to dendrites of layer II neurons arise from other regions from the cortex

Excitatory responses to layer 1a or 1b simulation under different circumstances

How does reading inside from the cell differ from reading outside of the cell?

Due to flow of ions inside and outside of the cell, it changes how the responses look.

Drugs of Abuse Associated with Neuromodulators:

ACh: Nicotine

5-HT: ecstasy, 'magic' mushrooms

NE: yohimbine

DA: heroin, amphetamines, cocaine

HA: ?

Treatment Drugs Associated with Neuromodulators:

ACh: doezepil (Alzheimer's)

5-HT: prozac (depression, OCD, anxiety)

NE: desipramine (depression)

DA: thorazine (schizophrenia), L-DOPA (Parkinsons), Ritalin (ADD)

HA: Antihistamines (Insomnia)

Neurological Disorders Associated with Neuromodulators:

ACh: Alzheimers

5-HT: Depression

DA: Schizophrenia, Parkinson's

Lecture 9: Spatial Cognition

Hippocampus

Important for learning, memory and imagination.

More specifically, episodic memory (order in which something occurs) and Spatial Cognition

What areas of the brain contain the most neurons?

Basal Ganglia, Cerebellum, Hippocampus

LARGE Brain Structures

What brain area is considered the "Little Brain"?

Cerebellum, has 70% of all neurons in the brain

Small Scale Re-entry/Re-entrant Connection

Raw info integrates with processed information

Same stimuli can converge at a point when entering primary cortex

Large Scale Re-Entry/Re-Entrant Connection

Cerebral Cortex > Hippocampus

Hippocampus processes information & Splits it back into the Cerebral Cortex

Output of all regions go into the Hippocampus

Do you get more information from Processed Stimuli or Raw Stimuli?

Processed Stimuli

Damage to the Hippocampus causes:

- Trouble Navigating

- Trouble generating Episodic Memory (Patient H.M.)

Burdois Study with Rats and Spatial Cognition

Rats that have grown up in cages and then thrown out into wild

Able to navigate, create home and social hierarchy

What should we think of when thinking about navigation?

When we think of navigation, we usually think about lines

Lines as pathways, direction, orientation, etc.

Simplifies navigation and understanding of space

Components of the Hippocampus

Dentate Gyrus > CA3 > CA1

CA3 = CA2 (Little Difference)

Where does the Dentate Gyrus receive input from?

Lateral and Medial Entorhinal Cortex

Reentry in the Hippocampus

Certain regions of the brain project into itself

CA1 & CA3 Regions Interconnect Neurons (Small Scale)

CA 1 Projects into Lateral & Medial Entorhinal Cortex (Larger Scale)

All of the Sensory Cortexes project into Structures where the Entorhinal Cortexes Project back into them

Auto-Associative Property

CA3 Region of the Hippocampus: 4% of Neurons are connected to each other

CA1 Region has 1% of Neurons connected with each other

Review the Mapping of the Hippocampus

Remember: intrahippocampal and extrahippocampal connections (with cortex) exhibit patterns of convergence, divergence and reentry at multiple scales.

What does the CA1 Connect?

CA1 Connects information from Entorhinal Cortex with processed information. (Reentry)

Rules for Spatial Cognition

Rule 1: Many different ways to judge spatial relationship (distance)

Rule 2: Different Frames of Reference when talking about Spatial Cognition

Motion Parallax

Depth Perception based off the movement of objects across visual space.

The slower things pass by, the further away you are from that object

Texture Gradient

the tendency for textured surfaces to appear to become smaller and finer as distance from the viewer increases

Occlusion

Object must be further away as it is behind/blocked by things

Retinal Disparity

convergence of eyes yields the focus on closer objects

The further an object is away, the eyes become more straight

Frames of Reference

Senses Musculature

V

Egocentric Frames

V

Arbitrary Frames

Egocentric Frames of Reference

-Retinal Space

-Eye Position

-Hand Space

Arbitrary Frames of Reference

-Allocentric (World-Centered)

-Route-centered

-Object Centered

Allocentric Frame of Reference:

Boundaries of observable environment, any arbitrary space

How do our senses fit into the frames of reference?

All of our senses have to be translated from Egocentric to Arbitrary Frames of reference

Head Direction Cells

Found in multiple areas of the brain

Vestibular Information

Tuned to Animal's Observable Environmental Direction

What cells obey an Allocentric Frame of Reference?

Head Direction Cells

Place Cells

Grid Cells

How does the Head Direction Cell track directional heading?

Firing is tuned to the orientation of animal's two different environments

Directional tuning may differ completely across two different environments that are perceived differently (Can be completely Random)

Universal Mapping

when two particular mappings are similar in that the Head Direction Cells are tuned similarly in two different environments

Grid Cells

Of the Medial Entorhinal Cortex (Universal)

Maps position in the environment by path integration

Not Randomly Placed

How do Grid Cells map your position in the environment?

Neurons of Medial EC exhibit multiple firing fields in any given environment

Such fields are arranged according to nodes of a set tessellated triangles

Grids rotate with boundaries of environment

Place Cells

In the Hippocampus (Specifically in CA1 region, but also in other regions)

Tracking Position in an allocentric frame of reference

Reformable

Firing tuned to the position of the animal in the environment

How do Place Cells track different positions?

There are different neuron maps for the different directions

What happens with Place Cells when the environmental boundaries are rotated?

The Place Cell Fields are Rotated

How are firing rates used in Spatial Cognition?

Firing rates of neurons used to predict animal's position in the environment

Population Firing Rate Vector

Firing rates across full set describe the 'pattern" of activity across full population

All brain regions appear to register information according to such 'population' patterns

Parietal Cortex

Abstract Frame of Reference

Space is defined by the route

Space is also defined by the sequence of behavior changes and spaces spanning them

What do bold signals within the Parietal Cortex and Hippocampus cause?

They implicate hippocampal and Parietal Cortex Novel Space Construction

Recall: 'What' and 'Where" Pathways of the Brain

IT (TE + TEO) = Visual Object identification

MT/MST (Parietal Cortex) = Detection of Movement Direction

V4 = First Site for Figure/Ground Separation

Recall: Area MST of 'Where' Pathway

Integrates Optic and Vestibular 'Flow'

Recall: Area VIP of Parietal Cortex:

Brings together personal spaces of somatosensory and visual areas

Lecture 10: Basal Ganglia and Cerebellum

Reentry

Brain isn't strictly a feed-forward system

Brain is a combo of feed-forward and feed-back (reentrant) points / inputs

Pattern Completion

a process assumed to be supported by the hippocampus by which a subset or portion of an experience that originally established a memory trace can activate or replay the entire experience

Functions of the Larger Brain Systems

Hippocampus = Spatial Cognition, Episodic Memory

Basal Ganglia = Actions/Planned actions and Expected Reward (Motivation)

Cerebellum = Refining Motor & Perceptual Control

Shared Properties of the Hippocampus, Basal Ganglia, and Cerebellum

1) Each system receives input from widespread regions of cortex

2) Each system outputs back into cortex (reenters)

3) Composed of subregions in which informational input from cortex converges and output diverges

4) Each is implicated in learning & exhibits unique form of learning at cerebellar level (unique forms of learning)

5) Neurons exhibit firing patterns related to 'contextual info' (activity not related to single sensory or motor variable)

Flow of Input:

Sensory Input ->

Cerebral Cortex ->

Basal Ganglia

Hippocampus

Cerebellum

Motor Output

Cerebellum

Role in timing and adjustment of motor patterns

In charge of Fine motor Control

The Cortex-Cerebellum-Cortex Loop

Cerebral Cortex >

Pontine Nuclei (Mossy Fibers) >

Granule Cells >

Purkinje Cells >

Cerebellar Nuclei (Base of Cerebellum, each contains homunculus) >

Ventrolateral Thalamus (and brainstem/spinal cord) >

Motor/Prefrontal Cortex

Where is the only Inhibitory Projection on the Cortex-Cerebellum-Cortex Loop?

The Convergence of the Purkinje Cells onto the Cerebellar Nuclei

Every other projection is excitatory

Learning Occurs when:

Neurons of the Superior Olive fire in response to some kind of error (Something doesn't go as expected)

Internal models can or cannot connect

Spikes in Inferior Olive cause Depolarization which causes Depotentiation of Synapses that were active at the time

How does the Cerebellum Learn?

The Cerebellum creates fine adjustments within everything we do, monitoring errors and learning from them.

Folia

Folds of the cerebellum

Contains Purkinje Cells, also where Dendritic Trees are Stacked and Spread

Parallel fibers run through these trees and synapse on dendrites

Cerebellar Nuclei

High Baseline rates modulated by Purkinje cell inhibition

Fastigial Nucleus

Neuronal Activity: Eye Movements/Walking

Localized Inactivation: Posture and Gait Instability

Function: Postural Adjustments

Interpositus Nucleus

Neuronal Activity: Perturbation of Limb/Body from holding position

Localized Inactivation: Tremor

Function: Balance of Agonist/Antagonist Muscles

Dentate Nucleus

Neuronal activity: Auditory and Vision Triggered Movements

Localized Inactivation: Reaction Time Delays, Poor Endpoint Control

Function: Timing/Cross Muscle Coordination

Tremor

Constant registration of error causing agonist and antagonist adjustments of muscles (uncontrollable shaking)

Basal Ganglia

structures in the forebrain that help to control movement

What diseases is the Basal Gangia Involved in?

Parkinson's

Tourettes

Huntington's Chorea

OCD

ADD

Drug Addiction

What does the Basal Ganglia Consist Of?

Striatum:

- Caudate

- Putamen

Globus Pallidus

- External Segment = GPe

- Internal Segment = GPi

Substantia Nigra:

- Pars Compacta = DA Neurons

- Pars Reticulata = GABA Neurons

Ventrolateral Thalamus(Basal Ganglia Output)

Superautobiographical Memory

Accurate memory for very specific things.

Head of Caudate was almost double in size for people that have this

Transition of Memory

Movement from one side of the caudate to another

Spiny Gabaergic Neurons then project into the Globus Pallidus

What is the main Neuromodulator in the Basal Ganglia

Dopamine

Information Flow within Basal Ganglia

Cortex > Basal Ganglia > Cortex

Direct, Indirect, and Hyperdirect Pathways to the Brainstem

Review the Flow Chart

Indirect Pathway

Spiny Gabaergic Neurons Project into the GPe first before Projecting into the GPi

Direct Pathway

Spiny Gabaergic Neurons Project directly into the GPi

Hyperdirect Pathway

cortex to subthalamic nucleus into the GPi

How are the Indirect and Direct Pathways modulated differently by DA?

Direct Path: DA input to D1 receptors enhances Glutamate Effect

Indirect Path: DA input to D2 receptors supresses Glutamate Effect

(All Cortex Input is Glutamate Excitatory)

How is DA Neuron Activity driven?

Driven by positive errors in reward expectation

Getting more value than the expected in a given situation

Lecture 11: Sleep and its Function