Modulation of Movements by the Basal Ganglia - VOR is hard

Question 1

What is the Basal Ganglia?

Answer 1

The motor nuclei of the BG are divided into several functionally distinct groups of subcortical nuclei

The Striatum:
*Caudate & Putamen
*Globus Pallidus (internal and external part)
*Substantia Nigra (reticulata and compacta part where dopaminergic cell bodies of the nigro-striatal dopamine system reside)
*Subthalamic Nucleus

Collection of subthalamic nuclei sitting in the heart of the brain and controlling some fundamental functions

Question 2

What is the biggest area of the basal ganglia and what is the primary cell type that it consists of?

Answer 2

The striatum (caudate and putamen)

Consists primarily of medium spiny neurons (85%) -> these are neurons, of which their denditres are densly covered in spines that receive synaptic inputs
They are all projection neurons, so they all project out of the neurostriatum

The axons arising from the medium spiny neurons converge on neurons in the pallidum, projecting to both the globus pallidus and substantia nigra pars reticulata which are the two main outputs from the basal ganglia

Question 3

What are the two main types of receptors in the BG?

Answer 3

*Ones that express D1 type dopamine receptors
*Ones that express D2 type dopamine receptors

D1 type project mainly to the Globus Pallidus internal part and the Substantia Nigra Pars Reticulata

D2 type mainly project to the Globus Pallidus external part

So the biggest area of the BG, the striatum, has basically the same morphological cell type but they express two different kinds of receptors on their cell surface, splitting them into two clear populations of cells

Question 4

What type of receptor are D1 type and D2 type dopamine receptors in the BG?

Answer 4

GABAergic

They are inhibitory, inhibiting the structures that they project to

Question 5

What substance does D1 like release alongside GABA?

Answer 5

Substance P which is a peptide neurotransmitter

Question 6

What substance does D2 like release alongside GABA?

Answer 6

Enkephalin which is a peptide neurotransmitter

Question 7

What two areas of the BG receive the majority of the inputs to the BG?

Answer 7

The Striatum
Subthalamic Nucleus

Question 8

Describe the ‘Go Circuit/Pathway’ in the BG

Answer 8

Cortex sends excitatory projection to the striatum and subthalamic nucleus cells, driving up activitiy in the D1 type cells in the striatum, which are GABAergic

D1 type then projects to the globus pallidus internal part and the substantia nigra pars reticulata (inihbitory GABAergic output)
-> these then inhibit cells that are tonically active, releasing the thalamus which then projects to, and activates, the cortex, facilitating action

Question 9

Describe the ‘Stop Circuit/Pathway’ in the BG

Answer 9

Cortex sends excitatory projections to the subthalamic nucelus and the D2 type striatal neurons, which have inhibitory outputs
D2 neurons have an inhibitory input to the external part of the globus pallidus which releases the subthalamic nucelus and activates the excitatory output from the subthalamuc nucleus (glutaminergic output) to the globus pallidus internal and substantia nigra pars reticulata
This increases the inhibitory tonic stimulation of the thalamus, clamping the thalamus in an off position and inhibiting the cortex

Question 10

How has the idea of two pathways been confirmed?

Answer 10

By optogenetics (getting cells in the brain to express proteins in their cell membranes that make them sensitive to light)

Been confirmed in mouse models which allow us to turn on D1 or D2 cells in the neo-striatum

Freeze et al. (2013)
Direct pathway= on pathway
Indirect pathway = off pathway

Engineered mice to express channel rhodopsin, an oxin which depolarises the membrane when exposed to an appropriate wavelength of light relating to D1 or D2

Exposed mice to a 1s or 100ms pulse of light

When mice exposed to D1 type dopamine activating wavelength (the go pathway), the velocity of the the animal is increased
When the mice are exposed to D2 type dopamine acitivatinf wavelength (the stop pathway, the velocity of the animal is decreased

This is direct evidence of those two pathways which have opposite effects on the animals behaviour

Question 11

What is the hypothesis for BG function?

Answer 11

Redgrave et al. (1999)

Propose that the BG is the central ‘switch’ in the vertebrate brain that enables ‘action’ selection

Selecting some actions via the on pathway and inhibiting others via the off pathway

Question 12

What is action selection about?

Answer 12

Picking an appropriate action within a given context depending on the predisposing conditions, e.g. sensory input (e.g. is there food around), homeostasis (e.g. am i hungry or thirsty), cogntive state (e.g. am i in danger)

Based on these things, one action amy become more salient based on the behaviour that is most adaptive in that particualr context

Question 13

How does the BG mediate competition between actions?

Answer 13

A computational imperative

Central switch has a ‘wiring’ advantage over the distributed alternative

Much nore efficient by way of connectivity - central switch which meadiates actions by which you may want to perform in a particular context

Question 14

What is the action selection hypothesis in the BG?

Answer 14

Basal ganglia circuits are organized to selected desired actions and to inhibit potentially competing unwanted actions. This is accomplished through a complex circuitry that is modified through development and learning.

Question 15

What is the evidence for the action selection hypothesis?

Answer 15

The function of BG and is role in action selection seen in disorders of the BG

Damage to the BG is the cause of:

*Parkinson’s disease
Bradykinesia (slowness of movement), rigidity, tremor

reduce the ability of something to select actions in an appropriate context

*Huntington’s disease
Involuntary movements (chorea)

This leads to disinhibition in terms of movements, the person is making movements they cannot suppress

BG - the way movements are being selected is being affected

Question 16

If the action hypothesis is true then we require what? (separate cards to assess each item)

Answer 16

1. The BG must take input from a wide variety of brain areas that are effectively going to be the command systems that are making action requests
2. There must be some mechanism by which the BG can switch on selected resources
3. There must be evidence of a flow of information between command centres, BG, and associated motor centres
4. The BG must be able to extract the ‘salience’ or ‘urgency’ of each request
5. There must be evidence of neuronal selection mechanisms in BG

Question 17

Does the BG receive information from a variety of brain regions, including cortical and subcortical areas?

Answer 17

BG receives inputs from whole cerebral cortex, with the exception of the primary auditory cortex, and inputs via the thalamus that come from lots of different subcortical structures

It seems to be a hub for receiving information from different areas of the brain, as expected for a central switch model

Question 18

Is there a mechanism for the BG to switch on resources?

Answer 18

Output nuclei of the BG highly active and GABAergic -> inhibit the thalamus by driving GABA into the thalamus

Normal circumstances, with no action request =tonic inhibiting holding the thalamus in inhibited state.

If action request is made to the BG that increases the activity in the striatum, it drives down that tonic activity and releasing the thalamus.

This is a model for how BG MAKES SELECTIONS BY REMOVING TONIC INHIBITION ON THE OUTPUT STRUCTURES
-> if you want an action to take place, you have to remove the inhibition on the circuit that underlies that action to allow that action to take place. This is referred to as disinhibition gating

Question 19

Is there a flow of information between command centres, BG, and associated motor centres and how is this linked to loops?

Answer 19

There are 5 BG main loops to represent discreta actions:

MOTOR (supplementary motor area)
OCULOMOTOR (frontal eye fields)
PREFRONTAL 1 (dorsolateral prefrontal cortex)
PREFRONTAL 2 (lateral orbitofrontal prefrontal cortex)
LIMBIC (anterior cingulate area)

These parallel loops originate in different regions of the cerebral cortex, engage specific subdivisions of the basal ganglia and thalamus, and ultimately affect areas of the frontal lobe outside the primary motor and premotor cortices.

Deterioration of cognitive and emotional function in both Parkinson’s and Huntington’s diseases could be the result of disruption of these non-motor loops

Question 20

How do we know that discrete actions are represented as channels the BG?

flow of information between command centres

Answer 20

Within loops are subloops e.g. primary motor cortex have leg, arm, face, segregations found at every level of the BG right the way up to the thalamus.
So different body parts are represented in the basal ganglia, meaning the basal ganglia has a number of large loops, and within those there are finer loops that allow for finer grain discrimination

Idea is that we may now think in terms of channels instead of loops, so these channels of behaviour run through the BG and are in competition with each other for behavioural expression

Can conclude that BG represents actions in discrete channels

Also sub-cortical BG loops that project directly into the BG via the thalamus

cortical inputs come directly into the BG and subcortical inputs project into the BG via the thalamus

BG at the heart of the brain in terms of activity

Question 21

How does salience/urgency extraction happen in the BG?

Answer 21

Disinhibition gating and channels together

Seems to be set up so that striatal neurons can be sensitive to the strength of the input that is coming in to drive
Salience is determined locally within the neo-striatum, at the level of the BG

We suppose it is encoded in the overall level of activity of the request

Each of these spiny projection neurons have a huge number of synapses, listen carefully to inputs coming in from command centres -> the louder the inputs shout, the more likely that particular action is selected

Question 22

What is the evidence of multiple selection mechanisms in the BG?

Answer 22

Each level of BG seems to suggest an idea of turning some things on and turning some things off

So striatal neurons have 2 states:

When they’re in an up-state they can be activated very easily
When they’re in a down-state they cant be activated very easily

Depending on where the neurons are sitting will make it more easy or more difficult to activate those neurons

~85% of neurons in the neo-striate are GABAergic, they are interconnected, that means that we have local inhibitory circuits, so one medium spiny neuron proejecting to another, so the whole neo-striatum is a network of inhibition
-> a little local exicitation is going to mean that the surrounding area will be inhibited via those local connections-> a little area of excitation compared to a massive area of inhibition

Subthalamic nucelus is excitatory and seems to provide a background level of suppression via the indirect pathway that suppresses other alternative choices, against the selection that the on pathway is making

Question 23

What is the evidence for the disinhibition gating hypothesis?

Answer 23

Alexander et al. (1999)

An injection of glutamate into the striatum
Elecrophysiological recording in the monkey (MUA)
Big increase in local activity recorded in the area next to the injection site

This injection produces an increase in the output from the striatum (inhibitory) and this inhibits the substantia nigra pars reticulata, taking activity there down, that in turn releases the thalamus, you get an excitation in the thalamus as a result of that and also an excitation in any other strcuture that the substantia nigra happens to be talking to on that channel (in this case/study it was the superior colliculus)

This is disinhibition gating actually working and shows it does work