Rhythms in the brain

Conf. univ. Ana-Maria Zagrean Disciplina Fiziologie si Neurostiinte Fundamentale, UMF Carol Davila Bucuresti azagrean@gmail.com

Premize:

Conexiunile in sistemul nervos sunt la nivel vizibil, morfologic-anatomic si celular, la nivel subtil, subcelular-molecular, biochimic-metabolic, electric… Exista o ordine/coordonare a acestor conexiuni, ca aceea dictata de un dirijor, ordine decisiva pentru coerenta/armonia functionarii sistemului. Fiecare retea neuronala are o oscilatie locala, data de o activitate electrica (spontana sau indusa), coordonata temporal cu oscilatiile celorlalte ansambluri neuronale , precum instrumentele intr-o orchestra “Dirijorul” este cel care initiaza, temporizeaza, impune coordonarea temporala/ timing-ul, insa nu este cel care “ofera” timpul…

BRAIN IS ABOUT TIMING !

A system of brain rhythms Computation in the cerebral cortex of all mammals has two essential features, that require special structural and dynamic organization:

-local-global communication -persistent activity.

Due to the bidirectional and highly branched connectivity of neurons throughout the brain, the results of local computations are broadcast to widespread areas so that multiple structures are informed simultaneously around any given local activity. Also, local circuits are under the continuous control of global brain activity, usually referred to by terms such as “brain state,” “top-down” or “attentional” control. The brains’ persistent activity - ability to maintain a long-lasting trace after the initial input has already vanished.

Dr György Buzsáki

Neuronal networks in the mammalian forebrain support several oscillatory bands (families of oscillations) that span from approximately 0.05 Hz to 500 Hz.

Rhythmically bursting cells in the brain.

-participate in the central circuits that generate rhythmic motor output for behaviors such as locomotion and respiration. -participate to the cardiovascular and metabolic diurnal rhythms. -magnocellular neurons of the hypothalamus secrete peptide neurohormones (arginine vasopressin - ADH, oxytocin), and are also characterized by rhythmic bursting behavior. Rhythmic bursting is a more

effective stimulus for the synaptic release of peptides than are tonic patterns of action potential (bursting patterns and Ca2+ currents drive a relatively high [Ca2+]i necessary to trigger the exocytosis of peptide-containing vesicles).

-rhythmically bursting neurons help drive the synchronous oscillations of neural activity in forebrain circuits (thalamus and cortex) during certain behavioral states, particularly sleep. - electrical properties of neurons are probably adapted to each cell’s particular functions.

Neurons containing serotonin are

located in two groups of raphe nuclei

and project to most of the brain.

Neuronal systems / ensembles

Neurons containing NE are located

in the locus coeruleus and innervate

nearly every part of the CNS

Simultaneity of neuronal activity, brought into existence not by chance but by intrinsic oscillatory electrical activity, resonance and coherence, are at the root of cognition. Indeed, such intrinsic activity forms the very fondation of the notion that there is such a thing called our “selves”.

... understanding the brain-body-mind complex is possible only when these three are considered as a holistic entity and not as discrete structures or functions.

What make neurons spike?

1. An external stimulus 2. Intrinsic - spontaneous electric activity (correlates with

metabolic cellular activity), modulated by external stimuli…

Factors that influence the resting membrane potential

The Na+ /K+ pump contributes to

resting membrane potential in 2 ways:

• Pumping Na+ & K+ ions in a 3:2 ratio

• Maintaining a high K+ concentration

in the cell’s interior

The membrane conductance to K+

far exceeds that to Na+ :

• K+ leakage results in internal

electronegativity

A Motor Neuron

When the neuron is inactive, the

membrane is said to be at rest and

has a resting membrane potential

When the neuron is active, the flow

of information is from soma to axon

terminal action potentials (AP).

Spiny dendrites from hippocampal pyramidal neuron

-The necessary actor in causing both depolarization and repolarization of the

nerve membrane during the action potential is the voltage-gated Na+ channel

-A voltage-gated K+ channel also plays an important role in increasing the

rapidity of repolarization of the membrane.

-These two voltage-gated channels are in addition to the Na+-K+ pump and the K+-

Na+ leak channels.

Na+ permeability

increases 500-5000 x

Action Potential

VARIOUS TYPES OF ION CHANNELS HELP TO REGULATE CELLULAR PROCESSES & EXCITABILITY

CHANNEL TYPE LOCATION FUNCTIONS

Voltage-Gated Channels

Na+ channel Axon, skeletal muscle Upstroke of the AP

K+ channels Axon, skeletal muscle AP repolarization

Ca2+ channels

(many types exist)

Heart, nerve terminals, endocrine

cells

Inject Ca2+ into cells

Ligand-Gated Channels

Nicotinic ACh receptor channel Neuromuscular junction, neurons Synaptic transmission

Glutamate receptor channels Neurons Synaptic transmission

GABA receptor channel Neurons Synaptic transmission

Ca2+-activated K+ channel Almost all excitable cells Regulate burst length

Other Channels

ATP-sensitive K+ channel Pancreas, heart, smooth muscle Glucose sensor in β-cells

NCCa-ATP - a nonselective cation channel, opened by cytoplasmic Ca and ATP depletion in ischemic astrocytes that, when opened, causes cytotoxic edema.

Reactive astrocytes Cytotoxic edema

Inward rectifier K+ channel Heart, brain, skeletal muscle Permit long depolarizations

Store-operated channels Nearly all cells Regulation of [Ca2+]i

Receptor-operated channels Nearly all cells Regulation of [Ca2+]i

Two-pore K+ channel All cells Regulate resting potential

Membrane Ionic Transport System

Ionic channels

Ionic pumps

Ionic exchangers

VOLTAGE-GATED Ca2+CHANNELS CONTRIBUTE TO ELECTRICAL ACTIVITY AND MEDIATE Ca2+ ENTRY INTO CELLS

Ion channels that selectively allow Ca2+ ions to permeate are of vital importance in the normal functioning of nearly all cells. In some cells, voltage-gated Ca2+ channels can generate APs in the absence of Na+ channels. However, in many cells that express both voltage-gated Na+ and Ca2+ channels, Ca2+ channel activity modifies the shape of the AP. Ca2+ channels contribute to the APs generated in the heart, some endocrine cells (e.g., pancreatic β-cells), and specific regions of neurons (e.g., dendrites and nerve terminals).

All excitable cells have Ca2+ channels.

TYPES OF VOLTAGE-GATED Ca2+ CHANNELS: physiological & pharmacological criteria L Type - the major type of Ca2+ channel in muscle cells (cardiac, smooth, and skeletal). L-type Ca2+ current is characterized by a relatively high voltage for activation, fast deactivation, slow voltage-dependent inactivation, a large single-channel conductance, modulation by cAMP-dependent phosphorylation, and inhibition by dihydropyridines, phenylalkylamines, and benzothiazepines. These Ca2+ channels are called L-type channels because of their large conductance and long-lasting single-channel open times. T Type - activate at more negative voltages, have fast voltage-dependent inactivation, have slow deactivation, have a small single-channel conductance and are insensitive to the drugs that block L-type channels. Important for pacemaker currents. They are named T type for their tiny single channel conductance and their transient kinetics. N Type Ca2+ currents were first identified by their intermediate voltage-dependence and intermediate inactivation kinetics. The channels are insensitive to the L-type Ca2+ channel blockers but are blocked selectively by a cone snail peptide toxin, ω-conotoxin. They were called N type because they were neither L-type nor T-type. P/Q Type P-type Ca2+ currents were first recorded in cerebellar Purkinje neurons and are blocked selectively by the spider toxin, ω-agatoxin. Q-type Ca2+ currents were first recorded in cerebellar granule cells and have a lower affinity for ω-agatoxin.

Circuitul Ca2+ si efectul modulator asupra unor functii celulare

Berridge et al. 2003 Nature Reviews 4, 517

PMCA = plasma membrane

calcium/calmodulin-

dependent ATPase (4

isoforms: PMCA1-4)

SERCA = Sarco(endo)plasmic

reticulum (SER) Ca2+ ATPases

NCX = Natrium-calcium exchanger

(3 isoforms: NCX1-3)

Propagarea inductiva a semnalelor de Ca2+ prin stimularea

receptorilor de IP3 (CICR: calcium-induced calcium-release)

CICR: low [Ca2+] stimulates, high [Ca2+] inhibits IP3R

Iacobas A, 2009

Diagram of the wide variety of DEVELOPMENTAL events triggered by spontaneous activity. The blue boxes indicate events that are not linked to the influx of Ca2+ during activity, but rather directly to changes in membrane potential or increases in [Na]i. Red dashed lines and arrows indicate negative-feedback loops. Green dashed lines and arrows indicate positive-feedback loops.

"Cells that fire together, wire together"

GABA is inhibitory in normal mature nervous system, but it’s excitatory during fetal life or post-lesion in adult brain

Computation in the brain relies on dynamic interactions between excitatory and inhibitory circuits. Appropriately timed inhibition exerted on specific somatodendritic compartments of principal cells is needed not only to balance excitation, but also for the selective filtering of synaptic excitation, timing of spike output, gain control, governing burst firing and synaptic plasticity, and, at the network level, coordination of cell assemblies through maintenance of oscillations and synchrony.

Control of timing, rate and bursts of hippocampal place cells by dendritic and somatic inhibition, Sébastien Royer, 2012

You can dissolve an embryonic heart into its individual cell types with

trypsin, an enzyme that destroys the protein glue between the cells. Plate

these cells in a dish and you will see some cells - called myocytes - that

beat independently, some faster, some slower, as long as they do not touch

one another. The cells shown here are from the chick embryo.

http://www.cellsalive.com/myocyte.htm

Autorhythmic cells exhibit PACEMAKER POTENTIALS

Cell automatism in a dish…

After two or three days in vitro, the myocytes form interconnected sheets of

cells (monolayers) that beat in unison. Pores (gap junctions) open between

adjacent touching cells, making their cytoplasm's’ interconnected. These gap

junctions ensure the synchronous activity of the connected cells.

Neural oscillation - rhythmic / repetitive neural activity in the CNS

- triggered by mechanisms localized within individual neurons or by interactions between neurons. - in individual neurons - oscillations in membrane potential or - rhythmic patterns of action potentials, which then produce oscillatory activation of post-synaptic neurons. - in neural networks, synchronized activity of large numbers of neurons can give rise to macroscopic oscillations (which can be observed in the EEG, e.g. alpha activity). Oscillatory activity in groups of neurons generally arises from feedback connections between the neurons that result in the synchronization of their firing patterns. The interaction between neurons can give rise to oscillations at a different frequency than the firing frequency of individual neurons.

The possible roles of neural oscillations: -processing and transfer of neural information, -generation of rhythmic motor output, -feature binding: Sensory and other information is represented in the brain by networks of neurons. Neural oscillations have been suggested as the mechanism of neural binding: -neurons within neuronal assemblies fire in synchrony to link different features of neuronal representations together (e.g. shape, motion, colour, depth, and other aspects of perception).

The local field potential reflecting the summed activity of individual neurons.

Simulation of neural oscillations at 10 Hz.

Spiking of individual neurons (with each dot representing an individual action potential within the population of neurons.

Figure illustrates how synchronized patterns of action potentials may result in macroscopic oscillations that can be measured outside the scalp (EEG).

Intrinsic cellular mechanisms of thalamic delta oscillation. (A) Voltage dependency of delta oscillation in a lateroposterior thalamocortical neuron recorded in vivo. The cell oscillates spontaneously at 1.7 Hz. This oscillation is blocked by current depolarization (between arrows) and resumes at removal of the current. The 3 cycles marked by the horizontal line are expanded below. (B) Spontaneous rhythmic burst firing in a neuron recorded in vitro before and after block of voltage-dependent Na+ conductances with tetrodotoxin (TTX). (Steriade, 1993.)

Thalamocortical feedback loop and the generation of sleep spindles

(Steriade, 1993) Recordings from individual neurons

Provide the basis for sleep spindle generation

Oscillatory activity - levels of organization: 1) the micro-scale (activity of a single neuron), 2) the meso-scale (activity of a local group of neurons) 3) the macro-scale (activity of different brain regions)

http://cercor.oxfordjournals.org/content/14/8/933.long

Amzica, 2000

http://www.antanitus.com/hypothesis/

Expression of neurotransmitter receptors in astrocytes in different brain regions is highly heterogeneous and is likely to be regulated by local neurotransmitter environment and often the assortment of receptors expressed by astroglia matches that present in the their neuronal neighbors (Verkhratsky, 2011).

Acta Neuropathol (2010) 119:7–35