Master di II Livello in Vestibologia Praticagiovanniralli.it/allegati/127/Sistema vestibolare e...

Master di II Livello in Vestibologia Pratica

Direttore: prof. Giovanni Ralli

Modulo di Anatomia e Fisiologia

Sistema vestibolare e sistema endocrino

Rudi Pecci

Dipartimento neuromuscoloscheletrico e degli Organi di Senso

S.O.D. di Audiologia

Azienda Ospedaliero Universitaria – Careggi

Università degli Studi di Firenze

Walter Cannon

1871 - 1945

DAL CONCETTO DI “OMEOSTASI”…

Nel 1929 Walter Cannon coniò il

termine “omeostasi”:

tendenza dell’organismo a

mantenere lo stato stazionario

Comunicazione, Integrazione, Omeostasi

neuronale (elettrica, tranne il segnale

chimico nelle sinapsi)

endocrina/immunitaria (chimica, tranne

l’eccitabilità elettrica delle cellule)

…AL SISTEMA ENDOCRINO

Ghiandole e ormoni

L’ipotalamo è strettamente connesso all’ipofisi

ATTRAVERSO L’IPOTALAMO…

È il principale centro di controllo del sistema

endocrino.

Utilizza l’ipofisi per comunicare con le altre

ghiandole.

Collega tra loro il sistema nervoso e il sistema

endocrino.

Regione anteriore (area preottica), sopra al chiasma ottico: nucleo soprachiasmatico (pacemaker

circadiano).

Regione media, sopra al peduncolo ipofisario: nuclei dorsomediale, ventromediale, paraventricolare,

sopraottico, arcuato.

Regione posteriore: corpi mammillari, nuclei tuberomammillari.

Nucleo paraventricolare: neuroni magnocellulari (ossitocina e

vasopressina), neuroni parvicellulari (ormoni liberanti e ormoni

inibenti).

Geoffrey Wingfield Harris

1913 - 1971

Geoffrey Wingfield Harris (1913 - 1971) was an

English physiologist and fellow of the Royal

Society, considered by many to be the father of

neuro-endocrinology.

He published the “Neural Control of the Pituitary

Gland” in 1955 which predicted the subsequently

discovered hormone “releasing factors” acting

on the pituitary gland.

L’ipofisi è sotto il controllo dell’ipotalamo:

indiretto sull’ipofisi anteriore e

diretto sull’ipofisi posteriore

…E LA NEURO-ENDOCRINOLOGIA

L’ipotalamo coordina le funzioni

del sistema nervoso autonomo e del sistema endocrino

con il comportamento finalizzato al mantenimento dell’omeostasi

IN UNA VISIONE D’INSIEME

COSA FA

1. Controlla la pressione arteriosa e la

composizione elettrolitica.

2. Regola la temperatura corporea.

3. Controlla il metabolismo energetico.

4. Regola l’attività riproduttiva.

5. Controlla le risposte di emergenza allo stress.

COME LO FA

A. Ha accesso ad informazioni sensitive provenienti praticamente da tutto il corpo.

B. Confronta le informazioni sensitive con valori di riferimento biologici (temperatura, glicemia,

osmolalità, ormoni).

C. Induce la modificazione delle risposte viscerali, endocrine e comportamentali per ristabilire

l’omeostasi.

IN UNA VISIONE “OLISTICA”…

La Pscico-Neuro-Endocrino-Immunologia

(PNEI)

Sisitema di controllo

omeostatico

SISTEMA NERVOSO CENTRALE

SISTEMA NEUROVEGETATIVO

SISTEMA ENDOCRINO

SISTEMA IMMUNITARIO

Il sistema immunitario agisce attraverso i linfociti che producono neurotrasmettitori e hanno

recettori per riceverne gran parte, e possono essere considerati un vero e proprio "sistema

nervoso liquido".

…CHE COINVOLGE ANCHE IL SISTEMA IMMUNITARIO

I linfociti

Recettori

LhRh

GhRh

TRH

Acetilcolina

Noradrenalina

Adrenalina

CRF

VIP

NGF

MIF

GH

Sostanza P

β-endorfine

Somatostatina

ACTH

Citochine

GCSF

IFN-α/γ IL-1…12 TGF-β TNF

Circuito a “feedback negativo”

che regola la secrezione ormonale in un tipico asse

ipotalamo-ipofisi-ghiandola periferica

IL MECCANISMO DI CONTROLLO

Loop Vestibolo-Ipotalamo-Vestibolare

Interazione con l’Asse Ipotalamo-Ipofisi-Surrene (AIIS)

Interazione con l’Asse Ipotalamo-Ipofisi-Tiroide (AIIT)

Interazione tra l’AIIS e l’AIIT

Effetti del Sistema Vestibolare sul Sistema Endocrino

Effetti del Sistema Endocrino sul Sistema Vestibolare

FOCUS ON

LOOP VESTIBOLO-IPOTALAMO-VESTIBOLARE

Vestibular projections to

hypothalamic supraoptic and paraventricular nuclei

Responses of a cell in the SON to electrical

stimulation of the ipsilateral vestibular nerve:

100 stimuli at 1 Hz in A, 4 Hz in B, 6 Hz in C.

Responses of three cells in the PVN to

electrical stimulation of the ipsilateral vestibular

nerve: 100 stimuli at 1 Hz.


Responses of a cell in the PVN to caloric stimulation of the ipsilateral labyrinth with cold (14°C in A) or

warm (46°C in B) water: increase in the discharge rate in A and decrease in the discharge rate in B.




bulbo-pontine reticular ascending projections;

connection between the cerebellar fastigial nucleus and the A1

and A6 cell groups;

neurons dorsal to the lateral reticular nucleus

locus coeruleus

central noradrenergic pathways

area postrema



INDIRECT PROJECTIONS

The labyrinthine input may reach the hypothalamic nuclei through:


Hypothalamic projections to vestibular nuclei

DAI NUCLEI TUBEROMAMMILLARI DELL’IPOTALAMO POSTERIORE…

http://www.google.it/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&docid=qJpfE8nrTD5zXM&tbnid=i5WQlc5q_T4pVM:&ved=0CAUQjRw&url=http://www.ib.cnea.gov.ar/~redneu/2013/BOOKS/Principles of Neural Science - Kandel/gateway.ut.ovid.com/gw2/ovidweb.cgisidnjhkoalgmeho00dbookimagebookdb_7c_2fc~53.htm&ei=J5dXU6quKIndtAb3sICQAQ&bvm=bv.65177938,d.bGQ&psig=AFQjCNFw_EW8rGcPs9QaD6gQSKd6Bdr8IQ&ust=1398335630504941

Biogenous amine of the brain.

Generally considered to be a neuromodulatory

transmitter.

Involved in wakefulness, thermoregulation,

pituitary function and cardiovascular

regulation.

Heterogenous distribution in the brain that

parallels that of the enzyme that synthesises

it, histidine decarboxylase.

In the brain stored in both neuronal (50%)

structures, and non-neuronal (50%) structures

(microvascular endothelium and mast cells).




…AI NUCLEI VESTIBOLARI


HDC mRNA expression in TM nuclei

control

UVN - 3 weeks

UVN - 3 months

UVN - 1 week two-step BVN

one-step BVN

labelled surface

N-α-methylhistamine binding sites

caudal brainstem rostral brainstem

Ipsilateral Ipsilateral Contralateral Contralateral


How to activate the loop

The vestibulo-hypothalamo-vestibular loop may be important in the control of vestibular

functions and in the adaptive response to vestibular lesion and environmental changes.


What is the loop for

http://www.google.it/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&docid=1ppTdBvrhlMZVM&tbnid=tIexmHVJ2aCo9M:&ved=0CAUQjRw&url=http://www.plosone.org/article/info:doi/10.1371/journal.pone.0066684&ei=129fU574DcKkPYz7gOAO&psig=AFQjCNH5p0XOqokv4hUHKwtYksludcAU6w&ust=1398838816607462


What is the loop effect

Head tilting

Limb extending Barrel rolling Circling walk







FOCUS ON

Inhibition

of

stress axis

by

vestibular stimulation

INTERAZIONE CON L’ASSE IPOTALAMO-IPOFISI-SURRENE

Vestibular system acts on the HPA axis in two ways

Activation

of

stress axis

by

vestibular dysfunction

ACTIVATION OF STRESS AXIS BY VESTIBULAR DYSFUNCTION

Stress response is mediated by the HPA axis

Ipotalamo Stress

CRH

Ipofisi

Corteccia surrenalica

ACTH

AVP

Glucocorticoidi

-

-

Vestibular system has connections with the HPA axis


Vestibular dysfunction activates the stress axis

The ocular–motor and postural

syndrome significantly increased the

night salivary cortisol concentration

compared to pre-UL night salivary

cortisol concentrations (p<0.05).

Vestibular nerve section induced a strong increase in the

number of CRF-Ir (up) and AVP-Ir (bottom) neurons.



A possible mechanism

Istamina

NSO

(H1-H2)

NPV

(H1-H2)

+ +

+

Ipotalamo Stress

CRH

Ipofisi

Corteccia surrenalica

ACTH

AVP

Glucocorticoidi

-

-

+

Stress axis activation facilitates vestibular compensation

Effect of ACTH4-10 on vestibular compensation in partially

compensated animals (Rana temporaria). ACTH4-10-

treated group; NaCl-treated control group.

Compensation of spontaneous nystagmus

(SN) for the saline control and ACTH4-10

groups. Injections were given every 4 h for 48

h from the time of the unilateral

labyrinthectomy (UL). For each group, the

mean for each time represents the average

SN for 4 animals.


Excessive stress can impair vestibular compensation

Changes in frequency of spontaneous nystagmus

(SN) with time after UL and effect of stress

application on recovery from SN in each group.

UL

UL + stress

UL + vehicle

UL + stress + vehicle

Running animals had 62–72% higher mean PCNA+

cell counts than the other treatment groups 12 days

after treatment began, a difference that was

statistically significant. The increase in cell

proliferation after 12 days of running was no longer

apparent 19 days after treatment began.


Stress hormones and neurosteroids affect vestibular neurons excitation

A. Effects of prednisolone on spontaneous firing. B

Effects of glutamic acid diethylester (GDEE) and Co2+

on rotation (ROT)-, glutamate (G)- and prednisolone

(P)-induced neuronal discharges of type I medial

vestibular nucleus neurons.

Effects of microiontophoretic application of DHEAS on

GABA-induced inhibition of spontaneous and rotation-

induced firing of type I neuron in the MVN.


The increase in intrinsic excitability in

the rostral MVN cells may be due to a

down-regulation of GABA receptor

efficacy in these cells.


A possible mechanism

In summary: what’s need?


1. Unilateral labyrinthectomy.

2. Unilateral vestibular loss syndrome.

3. Glucocorticoid receptor activation.

A B C D

INHIBITION OF STRESS AXIS BY VESTIBULAR STIMULATION

Vestibular stimulation reduces stress

18 years old college student with height 157 cm,

weight 46 kg, BMI 18.66 kg/m2 .

We have observed steady and significant decrease in

salivary cortisol.

40 vaginally delivered and medically stable infants

between 24 and 48 hours old.

Baseline = Time 1, immediately post-intervention =

Time 2 and 10 minutes post-intervention = Time 3.

Cortisol was significantly different between Groups T

(Tactile) and ATVV (p<.01) and over time among all

three groups (p<.01).

INTERAZIONE CON L’ASSE IPOTALAMO-IPOFISI-TIROIDE

Vestibular stimulation controls the HPT axis by two ways

Indirect dishinibition

of

HPT axis

Direct activation

of

HPT axis

DIRECT ACTIVATION OF HPT AXIS

Ipotalamo Stress

TRH

Ipofisi

Tiroide

TSH T4/T3

-

-

Vestibular system activates the HPT axis

NA NPV

Labirinto

+

+

+

INDIRECT DISHINIBITION OF HPT AXIS

Vestibular system inhibits the HPA axis

Dark line-activation/Light line-inhibition

X

X X

Labirinto -







FOCUS ON

EFFETTI DEL SISTEMA VESTIBOLARE SUL SISTEMA ENDOCRINO

1. Vestibular stimulation modulates melatonin secretion

Melatonin is a produced by the pineal gland (epiphysis) at the base of the brain, it acts

on the hypothalamus and has the function of regulating the sleep-wake cycle.

Vestibular system → intergeniculate leaflet (IGL) →

basal forebrain and visual midbrain →

suprachiasmatic nucleus (SCN) → visuomotor

activity and circadian rhythmicity.

Vestibular system → dorsal raphe nucleus (DRN) and

median raphe nucleus (MRN) → serotonin (5-HT)

release → regulation of mammalian circadian

rhythms.

Medial vestibular nucleus (MVN) → Hypocretin

(Orexin) system → sleep and arousal.


2. Vestibular modulation of thyroid hormones

Vestibular system → DRN and MRN →

neuropeptide Y (NPY) neurons in the arcuate

nucleus (AN) → TRH neurons in the hypothalamic

PVN → TRH release.

Vestibular system → vagal stimulation → leptin

secretion → TRH release.

Thyrotrophin releasing hormone (TRH) neurons are located in PVN and the

hypothalamic TRH in tropic fashion turns on thyroid stimulating hormone (TSH)

secretion by anterior pituitary. TSH is the most important physiologic regulator of

thyroid hormone secretion.


3. Vestibular modulation of pancreatic hormones

Vestibular nuclei → nucleus tractus solitarius (NTS)

and dorsal motor nucleus of the vagus nerve (DMX) →

increase in insulin secretion, no significant change

in glucagon secretion, decrease in C-peptide

secretion and pancreatic somatostatin release.

Vagal nerve stimulation in the dog produces

a moderate increase of glucagon secretion

and a marked increase of insulin secretion.


4. Vestibular modulation of adrenal (cortical) hormones

Vestibular system → GABA release in the substantia nigra

→ GABA(A) receptors → regulation of the production of

stress hormones in the HPA axis.

Vestibular system → vagus nerve → reduced cortisol

responses.

Vestibular stimulation modulates hypothalamo-

pitutary-adrenal (HPA) axis (infants who receive

vestibular interventions show a significant

steady decline in cortisol).


4. Vestibular modulation of adrenal (medullary) hormones

Vestibular stimulation promotes GABA release in the

substantia nigra in animals. GABAergic inhibition controls

the activity of the HPA axis.

GABA(A) receptors regulate the production of stress

hormones.

Vestibular stimulation evokes response from the ipsilateral

vagus nerve and vagal stimulation results in reduced

cortisol responses in depressed patients.

Vagal nerve stimulation treatment changes the HPA axis

stress system.

Vestibular afferents → sympathetic nerves → altered firing.

Otolith organs → regulation of autonomic nervous system

(ANS).

Vestibular system → reduced sympathetic activity.

Vestibular system → diencephalon → altered sympathetic

nerve activity.

Vestibular system regulates sympathetic nerve

activity in humans and numerous animal studies

have shown functional interactions between

vestibular and autonomic systems.


5. Vestibular modulation of pituitary (anterior) hormones

Vestibular system → vagus nerve → inhibition and increasing

of somatostatin release in rat and dogs respectively.

Vestibular system → sympathetic nerves → alpha-adrenergic

and beta-adrenergic fibers → inhibition and stimulation of

somatostatin secretion respectively.

Vestibular system → DRN and MRN → AN → activation of

serotonin receptors → secretion of growth hormon (GH).

Vestibular system → GABA release in the substantia nigra →

prolactin (PRL) release from pituitary gland.

Vestibular system → histaminergic neuron system in the

hypothalamus → histamine receptors in the preoptic-anterior

hypothalamic area → PRL release.

The hypothalamic-pituitary-

adrenal axis.



inhibition of luteinizing hormone (LH) release from

pituitary gland.


GABAergic neurons → release of gonadotropin releasing

hormon (GnRH).


increasing endogenous GABA → inhibition of LH releasing

hormone (LHRH) neurons in the preoptic-anterior

hypothalamic area.

Vestibular system → vagal stimulation → leptin secretion →

interaction with the hypothalamic-pituitary-adrenal, the

hypothalamic-pituitary-thyroid and the hypothalamic-

pituitary-gonadal axes.

5. Vestibular modulation of pituitary (anterior) hormones

The hypothalamic-pituitary-

adrenal axis.


Vestibular system → hypothalamic SON and PVN →

increase of vasopressin (VP).

Vestibular system → DRN → 5-HT release →

mediation of VP and oxytocin (OXT) response to

stress.

Vestibular system → vagus nerve → abdominal

vagal afferents and sciatic nerve → secretion of VP

and OXT.

5. Vestibular modulation of pituitary (posterior) hormones

The Human hypothalamic-pituitary-adrenal axis.


6. Vestibular modulation of thymic hormones

Vestibular system → DRN and MRN → AN →

activation of serotonin receptors → secretion of

growth hormon (GH).

The development and aging of the

thymus appear to be dependent on the

serum level of GH which is under the

balance of positive (GHRH) and negative

(GHRIH) signals from the hypothalamus.


7. Vestibular modulation of gastro-intestinal hormones

Vagal stimulation → suppression of somatostatin

release from delta cells.

Activation of the vagal nerves → release of gastrin

and cholecystokinin.

Vestibular stimulation increases vagal

activity.

EFFETTI DEL SISTEMA ENDOCRINO SUL SISTEMA VESTIBOLARE

Although most steroid hormones have free access to the

brains, other types of hormones can access only those

areas in the brain that lack an effective blood-brain barrier

(the circumventricular organs), or areas that effect specific

active transport mechanisms across the blood-brain

barrier.

Therefore, whereas plasma steroid hormones can access

both central vestibular pathways and the peripheral

vestibular apparatus, other plasma hormones can freely

access only the latter.

Hormones: activity in and accessibility to the brain


Hormonal influence on peripheral vestibular apparatus

Circulating hormones, including glucocorticoids, mineralocorticoids, vasopressin

and catecholamines, may potentially modulate the activity of the vestibular end

organ via:

1. alteration of the homeostatic control of the endolymph or

2. alteration of neurotransmitter function in the vestibular end organ.

Vasopressina → diminuzione della traslocazione

delle acquaporine del sacco endolinfatico mediata

dai recettori della vasopressina → idrope

endolinfatico.


Hormonal influence on peripheral vestibular apparatus

Blood

Catecolamine → recettori β1 → aumento della secrezione di K+ delle

dark cells.

Antagonisti dei recettori dei glucocorticoidi → diminuzione

dell’attività della Na+/k+ ATPasi delle dark cells mediata dai recettori

dei mineralcorticoidi / aumento della secrezione di K+ delle dark cells

mediata dai recettori del GABA → aumento della eccitabilità delle

cellule ciliate.


Steroid modulation of GABAA receptor in central vestibular pathways

Antagonisti dei recettori GABAA (deidroepiandrosterone solfato e pregnenolone solfato) →

aumento dell’attività dei neuroni del nucleo vestibolare mediale.

Agonisti dei recettori GABAA (20-idrossiecdisone) → diminuzione dell’attività dei neuroni del nucleo

vestibolare mediale.


Steroid modulation of ionotropic glutamate receptors in

central vestibular pathways

Pregnenolone solfato → eccitazione dei neuroni del nucleo vestibolare mediale mediata dai recettori

NMDA.


Modulation of steroidogenic activity and vestibular function

Inibitori della 3β-idrossisteroidodeidrogenasi (trilostano) → diminuzione del progesterone e dei

suoi metaboliti (allopregnenolone, glucocorticoidi e mineralcorticoidi) e aumento del pregnenolone, del

deidroepiandrosterone, dei loro solfati e dell’androstenediolo → attenuazione degli effetti negativi dello

stress sul compenso vestibolare (GABA antagonisti e NMDA agonisti).


Stress → aumento dei livelli di cortisolo → saturazione dell’attività dell’11β-idrossisteroido

ossidoriduttasi di tipo 2 → conversione del cortisolo in cortisone → aumento dei livelli di glucocorticoidi

→ modificazione dell’attività del nucleo vestibolare mediale dopo deficit vestibolare monolaterale →

compenso vestibolare.

Modulation of steroidogenic activity and vestibular function


Steroids and vestibular compensation

Glucocorticoidi → diminuzione dell’efficacia

dei recettori GABAergici nel nucleo vestibolare

mediale → aumento dell’eccitabilità intrinseca

dei neuroni del nucleo vestibolare mediale →

compenso vestibolare.

Deidroepiandrosterone solfato e

pregnenolone → attivazione dei recettori

NMDA nel nucleo vestibolare mediale →

aumento dell’eccitabilità intrinseca dei neuroni

del nucleo vestibolare mediale → compenso

vestibolare.


Steroids and vestibular compensation

Deafferentazione vestibolare acuta → stress

adeguato → aumento dei glucocorticoidi →

facilitazione del compenso vestibolare.

Immobilizzazione post-deafferentazione →

stress eccessivo → attivazione del sistema

limbico coinvolto nella reazione di difesa e

paura → rallentamento del compenso

vestibolare.

SISTEMA VESTIBOLARE E SISTEMA ENDOCRINO

Sistema vestibolare

Sistema endocrino


Asse Ipotalamo-Ipofisi-Surrene Asse Ipotalamo-Ipofisi-Tiroide

Melatonina

Tiroide

Pancreas

Ipofisi

Surrenale

Timo

Gastro-intestinale

Adrenergici

Glucocorticoidi Vasopressina

GABA

Glutammato

Take home message

Master di II Livello in Vestibologia Praticagiovanniralli.it/allegati/127/Sistema vestibolare e...

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