Basal Ganglia

Basal Ganglia

control mechanism for cognitive, emotional, and motor activity

• components in the telencephalon (cerebrum), midbrain, and diencephalon

• lesion: disorders of movement (PD, hemiballismus, resting tremor, dystonia), OCD, Tourette’s, dementia

Motor control

motor learning- mostly reward-associated

motor program selection

• no direct projections to LMNs

• regulate UMNs mostly in cx

  • cortical UMN- subcortical loop linking most of the cx with UMN motor cortices

  • brainstem and diencephalon- direct projections to the motor center

if the cx makes a wish, the BC decides whether or not to grant it

Input

excitatory mostly

• cerebral cx- excitatory

• substantia nigra pars compacta (dopaminergic)

  • dorsal striatum via nigrostriatal pathway

  • ventral striatum via mesolimbic pathway

  • excitatory and inhibitory

Output

inhibitory

• globus pallidus internus (GPi) and substantia nigra pars reticulata (SNpr)- tonic inhibitory signals to thalamus and BS

Basal Ganglia Anatomy: Cerebrum/Telencephalon

• 3 large subcortical nuclei: caudate, putamen, and globus pallidus

  • striatum = caudate + putamen

  • lentiform nucleus = putamen + globus pallidus

Basal Ganglia Anatomy: subcortical and BS

• subthalamic nucleus (STN) in the diencephalon

• substantia nigra in the midbrain

  • pars reticulata

  • pars compacta

Striatum (caudate + putamen)

function: selection and filtering of incoming/outgoing signals

• rostral: associative and cognitive function

• caudal: sensorimotor function

input section of BG:

• all of cortex, glutamate = excitatory

• thalamus

• SNc = dopamine modulatory input

Histology:

• medium spiny neurons (MSN)

  • projection neurons

  • GABAergic = inhibitory

  • 95% of cells

• interneurons

  • ACh

  • others: GABA, neuropeptides, etc.

Globus Pallidus

GPe:

• input from striatum (GABAergic) = inhibitory

• output- GABAergic projections to STN = inhibitory

GPi: output section og BG

• function: tonically suppresses motor, emotional, and cognitive processes

• input from striatum (GABAergic) = inhibitory

• input from STN = excitatory

Subthalamic Nucleus (in Diencephalon)

Inputs:

• GPe (indirect pathway) = inhibitory

• Cortex (hyperdirect pathway) = excitatory

• Thalamus

Output:

• Glutamatergic = excitatory

  • to GPi, diencephalon, and BS motor centers

Substantia Nigra (in BS)

Pars Reticulata (SNr):

• GABAergic = inhibitory

• output section of BG → thalamus and BS

• role in eye movement and cognition

Para Compacta (SNc):

• Dopaminergic (DA) = excitatory and inhibitory

  • makes dopamine, makes melanin (how it gets its color)

• densely packed, pigmented cells

• projections to striatum

• facilitates movement, reward

• VTA = ventral tegmental area, produces dopamine

Basal Ganglia Input/Output summary

Input section:

• striatum- receives majority of inputs

• subthalamic nucleus (STN)

Output section:

• Globus pallidus internus (GPi)- majority of output

• substantia nigra pars reticulata (SNr)

Basal Ganglia: Limbic System Association

• Ventral Striatum (VS)- nucleus accumbens (largest component) and olfactory tubercle; input

• Ventral Pallidum (VP); ouput

VS and VP are part of the limbic loop

• function- regulate emotional and motivated behavior, mood transition

Ventral Striatum

Input Zone

• analogous (similar to) dorsal striatum

• nucleus accumbens and olfactory tubercle

• input from:

  • limbic cx

  • amygdala and hippocampus

  • basal forebrain

  • medial thalamus

  • midbrain (VTA)

• output:

  • ventral pallidum- analogous to projection pattern of dorsal striatum

  • VTA

function: decision making and reward-related behavior; role in addiction; site of pleasure center (hedonic hotspot)

Ventral Pallidum

Output Zone

• analogous to globus pallidus- output zone of BG

  • GABAergic neurons

  • some cholinergic or glutamatergic neurons

• area ventral to to anterior commissure

Input: ventral striatum and VTA

Output: VTA, STN, Thalamus (MD)

• site of pleasure center (hedonic hotspot)

• function: decision making, goal-directed behaviors, reward prediction, reward-related behaviors, role in addiction

  • critical role in drug self-administration, extinction, and reinstatement in drug-seeking behaviors

Basal Ganglia and Brain Stem Motor Centers

• evolutionary conserved

• Input: Striatum (caudate and putamen)

  • from cortex and thalamus

• Output: SNr and GPi

  • targets: locomotor regions (tectum, mesencephalic, and diencephalic)

  • locomotion, posture, eye movements

• Dopamine- similar actions to those in sub-cortical loops

Striatal Neurons: Caudate and Putamen

medium spiny neurons (MSN)- aka spiny projection

• 95% of cell population

interneurons: ACh, neuropeptides, GABA

Neuronal circuits of striatum

Input from:

• Cerebral cx/Thalamus- principal input

• Substantia Nigra pars compacta (SNpc)- dopaminerginic input, excitatory or inhibitory depending on receptor type on MSN

• corpus striatum- local circuit neurons

MSP- hyperpolarized (takes more stimuli for AP)→ decreases likelihood of depolarization and AP

• little spontaneous activity, requires summation of inputs from SNpc and Cx to be activated

• THIS IS WHY DOPAMINE IS IMPORTANT

Take Home: the striatum (input nuclei) receives a lot of input but it is difficult to get the signal to continue to the output nuclei (GPi/SNr) without input from the BS and cortex as well

• Striatum is a filter

Substantia Nigra Reticulata (SNr) and Globus Pallidus Internus (GPi): Output

• high level of tonic activity

• use GABA as NT

• inhibits motor cx indirectly via thalamus

• inhibits brainstem motor centers directly

• If action is needed, striatum inhibits SNr and GPi

  • → disinhibits cortex and brainstem centers —> movement, behavior, and cognitive processes

Inhibition and Disinhibition

inhibition: neuron releases (usually) GABA

disinhibition: usually glutamate

Tripartite Hypothesis

describes anatomical separation of sensorimotor, limbic, and associative pathways

• now we recognize that the division of labor may not be so distinct and there may be overlapping boundaries

Rate Model (Go/NoGo)

described anatomical and neurochemical connections between nuclei

• postulate: imbalanced electrical activity or abnormal rates of firing in BG nuclei → human movement disorders

• model is too simple to account for all observed phenomena (tremors), but accurate enough to be retaiend

Direct Go Pathways

• motor cx sends a Go command

• inhibitory firing of striatum increases

• inhibitory firing in GPi decreases

• motor thalamus disinhibited

• movement

Indirect NoGo Pathway

• motor cx sends a stop command

• inhibitory firing of striatum increases

• inhibitory firing of GPe decreases

• excitatory firing of STN increases

• inhibitory firing of GPi increases

• motor thalamus is inhibited

• movement stopped/inhibited (stopping a movement, inhibiting a competing movement)

Direct vs Indirect (Go/NoGo

Take Home: indirect = inhibitory and direct = excitatory

• probably more complex than this

Direct: Striatum → GPi

• releases thalamic neurons from tonic inhibition; disinhibition of excitatory thalamic neurons

Indirect: Striatum → GPe → STN → GPi

• increases level of tonic inhibition by GPi; increases tonic inhibition of thalamus

• producing motion is dependnt on the balance of activity in direct and indirect pathways

• both pathways are activated before and during movement

• both pathways are quiet during inactivity

Hyperdirect Pathway

• motor cortex sends a stop command

• excitatory firing of STN increases

• inhibitory firing of GPi increases

• motor thalamus inhibited

• movement stopped/inhibited

Take Home: the motor cortex has direct/rapid control over output nuclei

• part of global stopping network

Why do we have 2 competing circuits?

standard view: pathways work together to open/shut physiological gates that initiate and terminate movement

new view: BG circuits also work to suppress competing motor programs → focused selection

• hyperdirect and indirect pathways used to suppress competing motor programs

• center-surround organization of direct and indirect pathways: activation of indirect pathways → neurons in a “surround” region of GPi are driven by excitatory input from STN → suppresses large number of competing motor programs → focus the disinhibition of the thalamus by GPi

Why do we need a hyperdirect pathway?

• still researching but we think…

• gives the motor cx direct control over output nuclei

  • allows for more specific top down control

• inhibits premature responses (batter waiting to swing)

• is a brake during decision conflict

• brake during surprising events

• resets or suppresses cortical activity related to ongoing movement and prepares for forthcoming movement

  • stops irrelevant movement before movement initiation

• prey and predator response (freeze)

Dopamine Producing Areas

Nigrostriatal pathway: SNpc → Striatum

• enables us to take action toward or away from stimulus

Mesolimbic pathway: Midbrain (meso) to ventral striatum (nucleus accumbens) via medial forebrain bundle

• ventral tegmental area (VTA) produces dopamine (DA)

• projects to other limbic areas

• reward pathway

“DA nigrostriatal circuit allows us to open doors, and DA in mesolimbic circuit allows us to appreciate being able to open doors”

Dopamine (DA) and Aging

decrease in DA with age → contributes to a decrease in eagerness ot explore new things

DA and Parkinson’s Disease

decrease in DA levels with disease progression

• deficits in memory, attention, learning and solving visuospatial tasks

• need large mental effort to perform simple tasks

DA circuits: Movement

dopaminergic cells in substantia nigra pars compacta (SNpc)

• relatively small amount of neurons, but profound effect on cortical input to striatum

• DA input to striatum can be excitatory or inhibitory

  • dependent on receptors on postsynaptic striatal cells

  • D1 receptors: enhances input from cx

  • D2 receptors: dampens input from cx

• overall DA has an excitatory effect on the generation of movement

  • D1 + D2 activation needed for disinhibition

  • DA excites the Direct (Go) pathway and depresses the Indirect (NoGo) pathway

    • in reality D1 and D2 receptors have a more mixed effect

Cholinergic Circuits

Acetylcholine (ACh) is a NT in striatal interneurons

• ACh excites GABAergic fibers

• normally ACh’s GABAergic excitation is balanced by DA inhibition of GABAergic fibers, via D2 receptors

BG: Learning and Memory

incorporates limbic, sensory, and executive info from higher-order brain nuclei to influence motor behavior → generates behavioral strategies for gaining favorable outcomes

• non-declarative memory: procedural or habit learning; gradual learning of stimulus-response association over many trials; compute probability of outcomes → “gut feeling”

• reward-based learning: reward prediction and feedback processing

• motor sequence chunking: learning a piece of music

Movement Disorders

Hyperkinetic- too much movement

Hypokinetic- not enough movement

Huntington’s Disease (HD)

hyperkinetic disorder; progressive, autosomal dominant neurodegenereative disorder

• decreased tonic inhibition of thalamus; increased disinhibition of thalamus

• etiology: inherited; loss of projections to GPe, reduced size of caudate and putamen, loss of MSN in striatum

• motor symptoms: chorea (brief involuntary movements that flit from one body part to another randomly; can be graceful or dancelike)

• non-motor symptoms: cognitive disturbances, reduced memory, verbal fluency, judgement, reasoning, poor concentration, difficulty planning, apathy, depression, irritability/temper, withdrawal, anxiety

Parkinson’s Disease

Hypokinetic disorder; most common BG disease

• increased tonic inhibition of thalamus by BG; decreased disinhibition to thalamus —> overactivity og GPi

• etiology: loss of dopaminergic neurons in SNpc, decreases the drive to the striatum

• motor symptoms: bradykinesia, resting and pill-rolling tremor, cogwheel rigidity (freezing, falling, postural instability)

• non-motor symptoms: dementia, depression

• Tx: levodopa, DA agonists, Anti-cholinergics, deep brain stimulation

Tremor

neurological disorder that causes shaking movements in one or more body parts, most often hands

• can occur in arms, legs, head, vocal chords, and torso

• rhythmic pattern caused by unintentional muscle contractions

postural tremor- most prominent when limbs are actively held in a position

resting tremor- most prominent when limbs are at rest

intention (ataxic) tremor- occurs as patients attempt to move their limb towards a target

Dystonia

hyperkinetic: repetitive, stereotypes involuntary movements that can be twisting, writhing, jerking; can also be fixed abnormal postures

• co-contraction of agonist and antagonist muscles

• associated with lesions in the putamen; presumed reduction in GPi output

Hemiballismus

large amplitude, forceful, flinging movments involving mostly the proximal musculature

• muscles of shoulder and pelvic girdle; kicking or throwing movements

• lesions of the contralateral subthalamic nucleus; usually from stroke

• usually leads to choreoathetotic movements within days or weeks

• tx: dopamine antagonists

Newer Perspective

Antagonist pathways: structurally and functionally intertwined, not anatomically segregated

• co-expression of D1 and D2 receptors on medium spiny neurons

• co-activated during movement, both silent during inactivity

abnormally synchronized oscillatory activity observed in PD patients

• suggest it may not be so much change in overall firing rate but change in oscillatory activity that is responsible for PD symptoms

Motor Loop (Cortico-basal ganglia-thalamic loop)

Motor Cx → Striatum → GPi → thalamus (VA, VL) → cortex

• nuclei are in a feedback circuit with UMN in cerebral cx, brain, and diencephalon

• initiating and terminating movement

• determining selection of motor programs

Eye Movement Loop (oculomotor circuit)

• FEF → Caudate (body) → GPi, SNr → thalamus (VA, MD) → cortex

Goal-directed behavior loop (dorsolateral prefrontal circuit)

diPFC → head of caudate → GPi, SNr → thalamus (VA, MD) → Cx

• important in initiating and terminating cognitive processes

  • planning, decision making, working memory, attention

Social Behavior loop (lateral orbitofrontal circuit)

orbitofrontal/anterior cingulate cx (limbic) → head of caudate → GPi, SNr → thalamus (MD) → Cx

• important for recognizing social cues, impulse restrait, separating relevant/non-relevant info

Emotion loop ( medial prefrontal/anterior cingulate circuit [ACC])

medial pre-frontal, anterior cingulate cx → ventral striatum → ventral pallidum → GPi, SNr → Thalamus (MD) → Cx

• important for regulating emotional and motivated behavior, determining reward, mood transition

• hyjacked in addiction

Emotion (limbic) and Motor Loop

motor loop: Motor Cx → Dorsal Striatum → GPi, SNr → thalamus (VA, VL)

limbic loop: pre-frontal + anterior cingulate cx → ventral striatum (nucleus accumbens + olfactory tubercle) → ventral pallidum → thalamus (MD)

BG: Summary

• Basal nuclei in feedback circuit with UMN in cerebral cx

• direct connection with BS and motor centers

• facilitates desired movement by disinhibition of thalamus or BS motor centers

• direct, indirect, and hyperdirect pathways work together to suppress unwanted/competing movement/cognitive/emotional processes and facilitate desired movement/cognition

• important for determining the selection of motor program

• role in motor learning- reward-associated