PT-630 Neurobiology Exam IV

THE BASAL GANGLIA ARE A COLLECTION OF SUBCORTICAL NUCLEI THAT CONTROL THE EXECUTION OF MOTOR PROGRAMS

BASAL GANGLIA

inputs

-striatum

-STN

outputs

-GPi

-SNr

interneurons

-GPe

modulator

-SNc (dopamine)

STRIATUM: INPUT (INHIBITORY)

The striatum is divided into three nuclei.

caudate and putamen

-separated by internal capsule

-dorsal striatum

-sensorimotor cortex input

nucleus accumbens

-ventral striatum

-reward/motivation

-limbic system input

spiny projection neurons (SPNs)

STRIATUM CELL TYPES

90–95% of striatal neurons

large, spiny dendritic arbors

GABAergic output cell

large aspiny neurons (LANs)

STRIATUM CELL TYPES

pacemaker at ~1–2 Hz

cholinergic interneurons

small & medium aspiny neurons

STRIATUM CELL TYPES

GABAergic interneurons

STN: INPUT (EXCITATORY)

subthalamic nucleus (STN)

input:

-frontal and motor cortices (glutamate)

-GPe (GABA)

output (glutamate):

-pacemake (~20 Hz)

-globus pallidus and substantia nigra pars reticulata.

GPI & SNR: OUTPUT

Globus pallidus internal segment (GPi) and substantia nigra pars reticulata (SNr) input:

-focal GABAergic input from SPNs.

-widespread excitatory input from the STN.

GPi/SNr output:

-pacemake (2–4 Hz)

-GABAergic projections to the thalamus.

-tonic suppression of movement.

GPE: MIDDLE MAN

Globus pallidus external segment (GPe) input:

-SPNs (GABA)

-STN (glutamate)

GPe output:

pacemake (~20 Hz)

-GABAergic projections to:

--striatum (feedback).

--STN (feedback).

--GPi/SNr (feedforward).

SNC: DOPAMINE

SNc neurons release dopamine (DA).

-Promotes movement.

-Plays neuromodulatory roles

in all basal ganglia nuclei.

-Best studied in the striatum.

DA neurons die during normal aging.

-large terminal fields

-pacemake with Ca2+

->50% of DA neurons must die in order to observe any behavioral phenotypes.

THE HYPERDIRECT PATHWAY SUPPRESSES MOVEMENTS

In the hyperdirect pathway, the cortex excites the STN, which directly excites the GPi/SNr within 5–8 ms.

THE HYPERDIRECT PATHWAY SUPPRESSES MOVEMENTS

Global increase in basal ganglia output.

-generally suppresses movement

-greater contrast for direct pathway input

Lesions in the hyperdirect pathway lead to hemiballismus

THE DIRECT PATHWAY SUPPRESSES MOVEMENTS

THE DIRECT PATHWAY PROMOTES MOVEMENT

dSPNs directly inhibit the GPi/ SNr within 15–20 ms, relieving their tonic inhibition of the thalamus and midbrain.

Thalamic activity promotes movements

(the direct pathway is called the “go” pathway).

Decreased activation of the direct pathway slows and prevents voluntary movements (termed bradykinesia and hypokinesia).

THE INDIRECT PATHWAY INHIBITS MOVEMENT

iSPNs indirectly excite the GPi/SNr within 30 ms, suppressing thalamic activity.

THE INDIRECT PATHWAY INHIBITS MOVEMENT

iSPNs inhibit GPe.

GPe disinhibits STN and GPi/

SNr.

STN neurons excite GPi/SNr.

Reducing thalamic activity curbs movement

(the indirect pathway is called the “no go” pathway).

Selective loss of iSPNs leads to persistent, uncontrolled jerky movements (termed chorea).

SPNS IN THE DIRECT (DSPNS) AND INDIRECT PATHWAYS (ISPNS) ARE GENETICALLY DISTINCT

Both dSPNs and iSPNs are GABAergic.

dSPNs express dynorphin, substance P, and D1 dopamine receptors.

iSPNs express enkephalin and D2 dopamine receptors.

D1 dopamine receptors (D1Rs & D5Rs) are Gs GPCRs that excite neurons.

DA RECEPTORS DIFFERENTIALLY REGULATE NEURONAL EXCITABILITY

Gs increases cAMP by activating adenylate cyclase.

cAMP depolarizes the cell via cyclic nucleotide gated (CNG) cation channels.

D2 dopamine receptors (D2Rs, D3Rs & D4Rs) are Gi/o GPCRs that depress neurons.

DA RECEPTORS DIFFERENTIALLY REGULATE NEURONAL EXCITABILITY

Gi/o decreases cAMP by inhibiting adenylate cyclase.

Reduced cAMP levels hyperpolarizes the cell by inhibiting CNG channels.

THE ACTIVITY OF LANS SHIFTS STRIATAL OUTPUT TOWARD THE INDIRECT PATHWAY

dSPNs express M4 receptors (Gi) and are inhibited by ACh.

iSPNs express M1 receptors (Gq) and are activated by ACh.

LAN activity decreases during initiated movements.

-inhibited by DA (D2)

-facilitates direct pathway to complete movements

THE BASAL GANGLIA MAY SELECT SPECIFIC MOTOR PROGRAMS AND INHIBIT COMPETITORS

Within 5–8 ms, the hyperdirect pathway activates the GPi/SNr, which provides general inhibition of motor programs and turns off any potentially competing motor programs.

Within 15–20 ms, the direct pathway inhibits specific GPi/SNr neurons to indirectly activate a desired motor program.

Within 30 ms, the indirect pathway indirectly activates the inhibited GPi/ SNr neurons to cease the execution of the desired motor program.

The basal ganglia promote the swift motor program execution

BASAL GANGLIA FUNCTION IS ILLUSTRATED BY LESIONS

muscimol (GABA agonist) decreases striatal output

contralateral bradykinesia

unaffected movement initiation

The basal ganglia inhibit inappropriate motor programs

BASAL GANGLIA FUNCTION IS ILLUSTRATED BY LESIONS

IEM-1460 (GluA2-free AMPAR antagonist) increases striatal output by inhibiting interneurons

contralateral dyskinesia

ANTIPSYCHOTICS ALTER BASAL GANGLIA FUNCTION

Many antipsychotics are D2 antagonists.

dystonia

acute reaction: increased BG output

abnormal distorted face & limb position

tardive dyskinesia

long-term use: decreased BG output

uncontrolled mouth movements

IN THE RETINA, LIGHT SENSED BY PHOTORECEPTORS IS PROCESSED BY CELLS IN THE INNER NUCLEAR LAYER BEFORE BEING SENT TO RETINAL GANGLION CELLS

Light initially passes through the cornea

LIGHT IS FOCUSED ONTO THE RETINA THROUGH THE VITREOUS FLUID

The iris is a muscular aperture that opens and closes to adjust the amount of light that enters our eyes.

The lens is a lens-shaped meshwork of the crystallin proteins.

Ciliary muscles contract to adjust the shape of the lens.

This changes the plane of focus for light, allowing us to see closer or farther distances

outer nuclear layer: photoreceptors

THE RETINA CONTAINS THREE LAYERS WITH SIX MAIN CLASSES OF CELLS

rods: dim light

cones: wavelength-specific

inner nuclear layer: interneurons

THE RETINA CONTAINS THREE LAYERS WITH SIX MAIN CLASSES OF CELLS

bipolar cells: glutamatergic input to

amacrine and ganglion cells

horizontal cells: GABAergic feedback to photoreceptors

amacrine cells: deliver a variety of different inputs onto ganglion cells

ganglion cell layer: projection neurons

THE RETINA CONTAINS THREE LAYERS WITH SIX MAIN CLASSES OF CELLS

retinal ganglion cells (RGCs): project to midbrain, hypothalamus, and thalamus (LGN)

The axons from ganglion cells have to pierce through the retina (at the optic disc) in order to exit through the back of the eye and migrate toward the LGN.

photopigments

retinal: small molecule that absorbs

370 nm light

opsin: GPCR

Δ wavelength sensitivity

creates intracellular signal

RODS AND CONES EXPRESS PHOTOPIGMENTS, WHICH ABSORB LIGHT

Cones express color-sensitive opsins:

L-opsins: red/yellow

M-opsins: green/yellow

S-opsins: violet/blue

Rods express a relatively color-insensitive opsin called rhodopsin

Opsin activates the G protein transducin

activates phosphodiesterase •

hydrolyzes cGMP

cyclic nucleotide-gated cation channel

↓cGMP,↓pNa,↓Vm

reduced glutamate release

fovea: high acuity & color

corresponds to center of our

visual field

highest concentration of cones

1:1 mapping to RGCs

foveola: greatest acuity

only outer nuclear layer

midget cones

periphery: high sensitivity

mostly rods

15-30:1 mapping to RGCs

off bipolar cells

BIPOLAR CELLS CAN BE HYPERPOLARIZED OR DEPOLARIZED BY LIGHT

iGluRs (kainate and AMPA type)

hyperpolarized by loss of glutamate

only used with cones

(color-opponent processing)

on bipolar cells

BIPOLAR CELLS CAN BE HYPERPOLARIZED OR DEPOLARIZED BY LIGHT

mGluRs (Gi)

depolarized by the loss of glutamate

used with rods & cones

Bipolar cells release glutamate onto amacrine and ganglion cells.

Light hyperpolarizes photoreceptors, reducing their excitatory input onto horizontal cells.

As a result, horizontal cells are less active, reducing GABA release to nearby photoreceptors.

Nearby photoreceptors that are not activated by light will thus be depolarized, increasing their amount of glutamate release.

This increases the contrast at borders of light and dark.

In center-surround organization, the center and periphery of the RGCs receptive field respond differently to light.

on-center RGCs: activated by light in the center; inhibited by light in the periphery

off-center RGCs: inhibited by light in the center; activated by light in the periphery

Center-surround is created by horizontal cells

THE OPTIC NERVES AND TRACTS PROJECT FROM THE RETINA TO THE LGN

optic nerve: myelinated RGC axons

optic chiasm: convergence

optic tracts:

-medial root:

--superior colliculus

--pretectal nucleus

--reticular formation

-lateral root: LGN

M cells are RGCs that project to the magnocellular layers (1–2).

THE LGN SEPARATES CHROMATIC & ACHROMATIC CELLS

fast AP conduction

rapid desensitization

responsive to dim light

(large dendritic arbors)

P cells are RGCs that project to the parvocellular layers (3–6)

THE LGN SEPARATES CHROMATIC & ACHROMATIC CELLS

smaller receptive fields

sensitive to red & green light

K cells are RGCs that project between layers and respond to blue light.

THE LGN SEPARATES CHROMATIC & ACHROMATIC CELLS

larger receptive fields

only center, no surround

OPTIC RADIATIONS

PROJECT FROM LGN TO V1

primary visual cortex (V1)

-calcarine sulcus

-ocular dominance columns

-retinotopic map

-respond to very specific visual stimuli

Higher-level information is extracted in visual association cortices.

RGCs, LGN, & V1: color-opponent cells

COLOR VISION IS BUILT AT MULTIPLE LEVEL

“Red” neurons are excited by L- cones inhibited by M-cones.

“Green” neurons are excited by M-cones and inhibited by L-cones.

“Yellow” neurons are excited by L- and M-cones and inhibited by S- cones.

“Blue” neurons are excited by S- cones and inhibited by L- and M- cones.

Light in center = increase in RGC's

Light in surround = decrease in RGC's

All Primary Visual Cortex sees is lines & angles

Shaped & colors are determined in higher structures later on

Chorea

“dance”

continuous

fluid or jerky

Ballismus

large amplitude

flinging

involuntary movements: chorea + ballismus potential sites

iSPNs & STN

GPi, SNr

decreased movement

brady- = slowed

hypo- = decreased

a- = absence

brady-, hypo-, and akinesia: potential sites

SNc (DA)

dStr (dSPNs)

GPe

rigidity: potential sites

dStr

SNr (head)

GPi (body)

Tremor

resting tremor

-decreases during movement

-seen in PD

-due to oscillations in basal ganglia?

intention tremor

-present during targeting

-cerebellar sign

Rigidity

resistance to passive movement

clasp-knife = CST

lead pipe = basal ganglia

cogwheel = lead pipe + tremor

Parkinsonian signs

resting tremor

bradykinesia

cogwheel rigidity

unsteady gait

Parkinson’s disease is caused by

SNc degeneration and improves with levodopa.

Drug-induced parkinsonism is caused by

D2 antagonists

Long-term use of antipsychotics leads to tardive dyskinesia.

Multisystem atrophy

caused by marked basal ganglia degeneration,

does not improve with levodopa,

Progressive supranuclear palsy

includes vertical gaze palsy.

Dementia with Lewy bodies

is a form of dementia that includes parkinsonian signs.

HD is caused by decrease in ISPN's (Dorsal Striatum)

4 nuclei of thalamus

Non-specific

Motor

Sensory

-association

Cognitive

projection neurons

THE THALAMUS AND CORTEX HAVE RECIPROCAL CONNECTIONS

core: layer 4, focal

matrix: layer 1, diffuse

thalamic peduncles

THE THALAMUS AND CORTEX HAVE RECIPROCAL CONNECTIONS

anterior: PFC & cingulate

posterior: occipital & parietotemporal

superior: premotor, motor, and somatosensory

inferior: anterior temporal & orbital

Motor nuclei of thalamus

VAN: motor planning

VLN: motor output

Sensory nuclei of thalamus

VPN: somatosensation

LGN: vision

MGN: audition

PL/PuN: multimodal

association

DMN: olfaction & pain

THE INTRALAMINAR NUCLEI HAVE DIFFUSE CORTICAL PROJECTIONS

subcortical inputs:

-spinothalamic tract

-ascending arousal system

outputs:

-cortex (arousal)

-striatum (action)

function:

-synchronize activity

-facilitates communication

THE THALAMIC RETICULAR NUCLEUS IS AN INHIBITORY FILTER

input:

-all thalamocortical and

-corticothalamic fibers

ascending arousal system

-α2ARs

-M2 AChRs

TRN neurons (gap junctions)

output (GABA):

-other thalamic nuclei

function:

-noise reduction

-selective attention

TRN NEURONS FILTER THALAMIC ACTIVITY

filter out noise (weak activity)

-thalamic nuclei stimulate TRN

-diffuse GABAergic feedback

select which thalamic neurons impact cortical activity

-visTRN target LGN

-less active when attending to

that sensory modality

-more active when attending to other sensory modalities

sleep spindles

TRN NEURONS CONTRIBUTE TO SLEEP

bursts of TRN activity

observed during stage 2

function unclear (memory?)

inhibits sensory nuclei

TRN NEURONS CONTRIBUTE TO SLEEP

Spindles only occur in TRN neurons that target sensory nuclei.

TRN neurons that target limbic nuclei don’t exhibit spindles.

THALAMIC DAMAGE

loss of function

-damaged relay neurons

synesthesia

-loss of thalamic output to TRN (i.e., disinhibition)

-strengthening of weak synapses

thalamic pain

-present in ~25% of people with thalamic strokes

-mechanism may be similar to synesthesia

THE OLFACTORY SYSTEM PROVIDES DIRECT INPUT TO THE LIMBIC CORTEX

nasal cavity

lined with respiratory (not sensory) and olfactory epithelia

olfactory epithelium

contains olfactory sensory neurons

olfactory nerve

formed by olfactory sensory neurons (1° afferents)

olfactory bulbs

connects olfactory nerve to olfactory tracts (2° afferents)

OLFACTORY SENSORY NEURONS (OSNS)

project olfactory cilia (or hairs) into nasal cavity

-increases surface area

-express one type of

-odorant receptor

form CN1

-axons pierce cribriform plate

-synapse in olfactory bulbs

replaced every 1–12 months

-basal cell = stem cell

-air damages plasmalemma

Odorant Receptors

GPCRs (Gs)

-bind one or a few odorants

cAMP-gated cation channels

-depolarize OSNs

glomeruli

OLFACTORY BULBS

collections of OSN axons & mitral cell dendrites

correspond to one specific odorant receptor

lateral inhibition

OLFACTORY BULBS

periglomerular cells stimulated by OSNs

granule cells stimulated by mitral cells and feedback from piriform cortex

OLFACTION PATHWAYS

2° afferents project to piriform lobe (connected to limbic system)

-amygdala(emotion)

-entorhinal cortex (memory)

3° afferents project to:

orbitofrontal cortex (conscious perception)

-hippocampus(memory)

-hypothalamus(autonomic

response)

-olfactory bulbs (modify sensitivity via granule cells

ENTORHINAL CORTEX

located in anterior PHG

main input/output of the hippocampus

reciprocal connections with:

-association cortices

-hippocampal complex

memory functions

-encoding: input to hippocampus alters circuits

-consolidation: output to cortex alters circuits

HIPPOCAMPAL STRUCTURE

Hippocampal structure

allocortex (3 layers)

medial temporal lobes

three general areas:

-dentate gyrus (DG): input

-hippocampus(CA1–4): relay

-subiculum: output

general circuit:

-DG→CA→sub

entorhinal cortex

Hippocampal connections

-perforant path (DG)

-alvear path (CA3 & CA1)

-subiculum→EC

Papez Circuit

Hippocampal connections

-linked to other limbic

structures by fornix

-involved in memory function

Hebbian plasticity

LONG-TERM POTENTIATION

fire together, wire together

Co-activation of pre- and postsynaptic neurons strengthens synapses

long-term potentiation (LTP)

NMDA receptors

-Mg2+ block (voltage)

-glutamate (ligand)

Ca2+ influx stimulates:

-CaMKII, PKA, & CREB

-↑AMPAR conductance & abundance

POTENTIATING LTP

fast excitatory input synchronizes

neuron activity

-amygdala

-septum

neuromodulators provided via fornix

-ACh (septum): M1AChRs (Gq)

-NE (LC): βARs (Gs) N N O

-5-HT (raphe): 5-HT4 (Gs) cAMP ATP

-DA (VTA): D1Rs (Gs)

HIPPOCAMPAL LESIONS PRODUCE PROFOUND AMNESIA

patient HM

-epileptic

-bilateral medial

-temporal lobe removal

-complete anterograde amnesia

THE ANTERIOR CINGULATE CORTEX HAS DIVERSE FUNCTIONS

emotional area

-active during positive emotions

-silent during negative emotions

other areas:

-motor planning

-pain

-bladder

-vocalization

-autonomic

THE AMYGDALA DETERMINES EMOTIONAL SALIENCE

limbic areas:

hippocampus: links emotion & memory

insula: links pain & emotion

nucleus accumbens: links positive & negative emotion

association cortices (perceptions & memories)

autonomic responses:

arousal (locus coeruleus)

heart rate (medulla)

stress (hypothalamus)

THE AMYGDALA RECOGNIZES AND PRODUCES FEAR & ANGER

activated when viewing fearful faces

damage produces fearlessness

-patient SM: bilateral damage

animal studies

hyperactivity is associated with anxiety