Funzioni dei nuclei della base nel controllo posturale e ... · Funzioni dei nuclei della base nel controllo posturale e nella deambulazione Neurons in the ‘‘direct pathway’’

Funzioni dei nuclei della base

nel controllo posturale e nella

deambulazione

Eugenio Scarnati – Marco Paoloni

Funzioni dei nuclei della base nel controllo posturale e nella deambulazione

A major centre in the complex

extrapyramidal motor system.

Are involved in many neuronal

pathways having emotional,

motivational, associative and

cognitive functions as well.

Herrero et al, Functional anatomy of thalamus and basal ganglia, Child’s Nerv Syst 2002

The Basal Ganglia


Putamen

Caudato

Globus Pallidus (GPe,

GPi)

Substantia Nigra

(SNc, SNr)

Subthalamic Nucleus

Striatum


The striatum receive inputs from all cortical

Herrero et al, Functional anatomy of thalamus and basal ganglia, Child’s Nerv Syst 2002

Throughout the thalamus the striatum project principally to frontal

lobe areas (prefrontal, premotor and supplementary motor areas) which are

concerned with motor planning


Schultz et al, 1992


Schultz W, 2003

Discrimination of reward magnitude by striatal neurons. (a) Increasing response in a caudate

neuron to instruction cues predicting increasing magnitudes of reward (0.12, 0.18, 0.24 ml). (b) Decreasing response in a ventral striatum neuron to rewards with increasing volumes.




The dopaminergic system

innervates all BG structures as well

as its projection targets like the

thalamus and brainstem motor

centers


Neurophysiological activations of dopamine neurons following primary rewards and conditioned, reward-predicting stimuli, physically intense stimuli, risk, and primary and conditioned aversive stimuli

Multiple dopamine signals

Schultz W, 2012


Different groups of dopamine neurons convey motivational signals in distinct manners

Multiple dopamine signals

Matsumoto M, Hikosaka O. Nature 2009


The BG and movement: basic concepts

The original model of the BG was concerned with

motor control and based on three main findings:

o Somatotopic Arrangement

o Striato-Pallidal Pathways

o Output of BGObeso et al, Functional Organization of the Basal Ganglia: Therapeutic Implications for Parkinson’s Disease, Mov Disord (2008)


Somatotopic Arrangement

The cortical motor areas (M1, PMA, SMA) and the primary

somatosensory cortex project in a somatotopically organized fashion

to the striatum.

Obeso et al, Functional Organization of the Basal Ganglia: Therapeutic Implications for Parkinson’s Disease, Mov Disord (2008)


Striato-Pallidal Pathways

Striatal efferent neurons, the medium spiny neurons (MSN), are

GABAergic and connect with the GPe and GPi by two different

projections systems, the ‘‘indirect’’ and ‘‘direct’’ pathways



Neurons in the ‘‘direct pathway’’ project directly from putamen to

GPi/SNr. They bear DA D-1 receptors, co-express the peptides

substance-P, and dynorphin and establish a monosynaptic inhibitory

connection with GPi/SNr neurons.

Neurons in the ‘‘indirect pathway’’ contain DA D-2 receptors and

co-express enkephalin. They project to the GPe which in turn influence

the GPi/SNr by a monosynaptic inhibitory connection and indirectly

through the GPe–STN–GPi projection.

DA modulates glutamatergic effects on corticostriatal inputs by exerting a

dual effect on striatal neurons, exciting D1 neurons in the direct

pathway and inhibiting D2 neurons in the indirect circuit.


Striato-Pallidal Pathways


Output of the BG

Reduced BG output leads to movement

facilitation

and increased activity to movement inhibition


Classic model of the organization of the basal ganglia in the normal (A),

parkinsonian (B), and levodopa-induced dyskinetic (C) states.



Current concepts of the BG

The BG are currently seen as a highly organized

network, where different parts are activated depending

on specific functions and circumstances.

The BG are not only involved in movement control, but

also in functions such as learning, planning, working

memory, and emotions



Corticobasal Ganglia Projections

Cortical input accesses the BG through the corticostriatal projection to

medium spiny neurons projecting to the GP and to the STN.

The cortical projection exerts an opposite (inhibitory/excitatory)

disynaptic effect onto the GPe and Gpi.

Activity of the GPe modulates back the excitability of the striatum and STN by

means of the reciprocal inhibitory connections. The GPe seems as a critically

important nucleus controlling BG output


These five parallel loops are not completely independent; there is a convergence of information:1. At the level of the globus pallidus and substantia nigra pars reticulata2. At the level of the thalamus 3. By axonal collateralisation within the different nuclei

Herrero et al, Functional anatomy of thalamus and basal ganglia, Child’s Nerv Syst (2002)


This anatomical organization sustains functions such as attention, explicit

and implicit learning, reward-related behavior, habit formation, and

time estimation, which depend on the activation of cortical loops through

the caudate nucleus, anterior, and ventral putamen



La via talamo striatale

Le principali origini delle fibre

talamo-striatali sono i nuclei

intralaminari del talamo: centro

mediano (CM) e parafascicolare

(Pf)

Sadikot et al. J. Comp Neurol. 1992

Il CM appare connesso con il

territorio “sensorimotorio” dello

striato, mentre il Pf sembra

innervare predominantemente

il territorio “associativo-

limbico” dello striato.


La via CM- striato sensorimotorio

Calabresi et al. Trends Neurosci 2007; 30: 211-219

Le fibre del CM nello striato fanno sinapsi sulle cellule NADPH-diaforase positive

produttrici di NO.

Considerata la natura glutamatergica della via CM-striato, la attivazione di questa

dovrebbe eccitare le cellule NADPH-diaforase positive ed indurre la liberazione di

NO.

Lo NO è uno degli agenti, assieme alla trasmissione dopaminergica ed a quella

colinergica, in grado nello striato di indurre Log Term Depression (LTD).

La LTD e la Long Term potentiation (LTP) sono i due meccanismi di membrana

attraverso

i quali nello striato si riesce ad evidenziare l’informazione rilevante ai fini della

attività

motoria


La via Pf- striato limbico-associativo

Le fibre talamiche del Pf formano sinapsi asso-dendritiche ed asso-spinose nella

matrix del compartimento “associativo-limbico”.

Per quanto concerne la suddivisione in cellule striatali poste sulla via “diretta” od

“indiretta” le fibre talamiche innervano entrambi i sottotipi cellulari di medium

spiny neurons.

In relazione alla proiezione Pf-striato bisogna notare che queste connessioni tra

parti del

talamo limbico e parti limbiche dello striato ricordano molto da vicino i circuiti

coinvolti

nelle patologia ossessivo compulsive e nei comportamenti da dipendenza.

Tutto ciò suggerisce fortemente che la “motivazione” debba rientrare tra i

meccanismi

alterati nelle patologie dei gangli della base come il Parkinson.


Nuclei ventrale-anteriore (VA) e ventrale-laterale (VL) del talamo

Questi due nuclei sono considerati da tempo i nuclei su cui converge l’output dei

BG proveniente dal GPi nei primati superiori. Tuttavia alcuni dati recenti sono in

grado di far ipotizzare una funzione non solo di mero relay per questi nuclei ma

una qualche funzione integrativa delle attività svolte a monte nei BG.

• Via diretta pallido-VA-corteccia

• Via indiretta pallido-nucleo reticolare-VA-corteccia

Possibili funzioni di feedforward

inhibition in grado probabilmente di

modulare in intensità e durata

l’informazione che fluisce nella

connessione diretta.


Il Nucleo Subtalamico

Di recente la connessione

cortico-sottotalamica diretta è

stata rivalutata ed ipotizzata

essere la terza via dei BG: dopo la

“diretta” ed “indiretta” la via

“iperdiretta”.

La funzione di questa via sembra

essere principalmente quella della

trasmissione della informazione

sensitiva giunta in corteccia che

viene ritraslata ai BG.

Nambu A. Prog Brain Res. 2004; 143: 461-66


La via Talamo-sottotalamica

Possibile importanza dal momento che i nuclei talamici si trovano a

controllare con il loro input sia “l’inizio” del circuito dei BG che quello che

viene giustamente considerato un nucleo chiave per la sua valenza

eccitatoria: il STN.

Nambu A. Prog Brain Res. 2004; 143: 461-66


Anatomy, Physiology, and Pathophysiology of the Pedunculopontine Nucleus. Jenkinson et al, Mov Disord, 2009

The Pedunculopontine Nucleus (PPN)

Is formed by an ensemble of cholinergic

(the majority cells express Ach) and

noncholinergic neurones (many cells

utilize other neurotransmitters, Glutamate,

Gaba, Dopamine)

Two parts: the pars compacta (PPNc) and

the pars dissipatus (PPNd).

Its rostral end begins just below the red nucleus, dorsal to the SN,

continuing caudally to the level of the locus coeruleus



The anatomical connections and physiological properties of the PPN

suggest that the nucleus is in a position to influence the control of

movement





Connections

Nuclei of the thalamus: a role in

producing the fast cortical oscillatory

activity associated with arousal and REM

sleep.

Direct cortical afferents, with fibers

arising in the M1, SMA, pre-SMA, PMC,

frontal eye fields.

A much smaller unilateral projection

from the ipsilateral PPN to the

same areas of cortex originating from


PPN

Brainstem Spinal Cord

Thalamus

ST

N

SNc

Cerebell

um

Red Nucleus

Pivotal role in the control of arousal and the sleep-wake cycle

StriatumGP

i

Thus the PPNs major targets in the basal

ganglia are the SN

and STN, with a

relatively smaller projection to the

pallidum

Motor

Cortex

PPN

SN

r

The major efferent and afferent pathways of the PPN to the basal ganglia and other motor

structures


Takakusaki et al, 2008

The basal ganglia are involved in the visuomotor coordination of cognitive

processes and the emotional expression of locomotor behaviors

Basal Ganglia and Locomotion


Locomotor behaviors require the activation of the following three

processes:

i) Locomotion initiation processes

ii) Locomotion regulation processes

iii) Basic locomotion execution process

Framework of the neuronal mechanisms of locomotor behaviors



i) Midbrain locomotor

region

ii) Muscle tone inhibitory

region

Locomotor rhythm generating system






Initiation of locomotion

Limbic-hypothalamic systems for evoking emotional locomotor behaviors

The MLR has been established as a functional region

involved

in the initiation of locomotion on the basis of its

connections with limbic structures and the basal ganglia

Contribut ion of the cerebral cortex to volit ional and cognit ive behaviors



Regulation of locomotion

The current understanding is that the basal ganglia and cerebellar loops

with the motor areas of the cerebral cortex are involved in the control of

voluntary movements and automatic execution of learned motor plans and

programs, while loops of the prefrontal cortex with the caudate nucleus

and the lateral zone of the cerebellar hemisphere are involved in the

regulation of complex, visually guided limb movements and the planning

and programming of those movements.

Loops of the motor cortical areas with the putamen and the intermediate

zone of the cerebellum may contribute to the regulation of voluntary,

discrete, ipsilateral limb movements.



Hypothetical model for the control of movements by the

BG


� Have an important regulatory influence on cortex , providing

information for both automatic and voluntary motor responses to the

pyramidal system

� likely act as an intermediary betw een the cerebral cortex and

brainstem for automating the selection and execution of a context

specific postural response

� is responsible for pre-select ing and opt imizing postural

responses based on current context

� Play a role in predict ing future events, reinforcing wanted

behaviour and suppressing unwanted behaviour

� Are involved in shifting attentional sets and in both high order

processes of movement init iat ion and spat ial w orking Herrero et al, Functional anatomy of thalamus and basal ganglia, Child’s Nerv Syst 2002

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Funzioni dei nuclei della base nel controllo posturale e ... · Funzioni dei nuclei della base nel controllo posturale e nella deambulazione Neurons in the ‘‘direct pathway’’