Physiology of Neuromodulation and neuromodulators. Difference between neuromodulation and synapse. Recent advances in neuromodulation, clinical application of neuromodulation.

1. A.Sankareswari
III year PG
Dept of Physiology
Neuromodulation

2. Discovery of Neurotransmitters
 Otto Loewi, an Austrian scientist,
discovered the first neurotransmitter in
1921.
 He used two frog hearts.
 One heart was still connected to the
vagus nerve.
 Heart #1 was placed in a chamber that
was filled with saline.
 This chamber was connected to a
second chamber that contained heart #2.
 Fluid from chamber #1 was allowed to
flow into chamber #2.

3. Loewi’s Results
 Electrical stimulation of the
vagus nerve attached to heart
#1 caused heart #1 to slow
down.
 After a delay, heart #2 also
slowed down.
 Loewi hypothesized that
electrical stimulation of the
vagus nerve released a
chemical into the fluid of
chamber #1 that flowed into
chamber #2.
 He called this chemical
"Vagusstoff".
 We now know this chemical as
the neurotransmitter
acetylcholine.

4. What is a Neurotransmitter?
 A substance that is released at a synapse by
a neuron and that effects another cell, either a
neuron or an effector organ, in a specialized
manner

5. Neuromodulation
 Neuromodulation is the targeted release of a substance
from a neuron that either alters the efficacy of synaptic
transmission, or the cellular properties of a pre- and/or
postsynaptic neuron (or glial cell) via metabotropic
receptors.
 Neuromodulation is the physiological process by
which a given neuron uses one or
more neurotransmitters to regulate diverse populations
of neurons.

6. Neuromodulation Vs Synaptic
transmission
Neuromodulation Synaptic transmission
 “Neuromodulation occurs when a
substance released from one
neuron alters the cellular or
synaptic properties of another
neuron“.
 The local postsynaptic receptors
are G-protein coupled
receptors(metabotropic)
 Their neurotransmission is slow.
 In classical synaptic
transmission, one presynaptic
neuron directly influences a
single postsynaptic partner.
 The post synaptic receptors are
ligand-gated ion channels.
 Their neurotransmission is fast.

7. Neuromodulators
 Neuromodulators are the
neurotransmitters, neuropeptides,
hormones that have spatially
distributed, temporally extended
effects on the recipient neurons
and circuits.
 Neuromodulators secreted by a
small group of neurons diffuse
through large areas of the nervous
system, affecting multiple neurons.
 Major neuromodulators in the
central nervous system include
dopamine, serotonin, acetylcholine,
histamine, and norepinephrine.

8. Neuromodulators
 Neuromodulators are a subset of
neurotransmitter.
 The release of neuromodulators
occurs in a diffuse manner
(“volume transmission”).
 This means that an entire neural
tissue may be subject to the
neuromodulator’s action due to
exposure. This, in turn, can tune
the neural circuitry of an entire
brain region.

9. Neuromodulatory systems
Ascending neuromodulatory systems
 Cholinergic
 Dopaminergic
 Serotonergic
 Adrenergic
Co-transmitters as neuromodulators
Neuropeptides as neuromodulators
Circulating hormones as Modulators

11. Architecture of the neuromodulatory
systems.

12. Common features among
neuromodulatory systems
1. The origination of these systems is sub-
cortical.
2. Each of these neuromodulatory systems is
the locus of a particular chemical transmitter
that is projected to broad areas of the
brainstem, thalamus, and cortex.
3. All of these neuromodulatory systems are
reciprocally connected with the frontal cortex
and parts of the limbic system.

13. Modes of modulation

14. Types of Neuromodulation
Heterosynaptic
facilitation
Presynaptic
inhibition
Diffusely delivered
modulator can act on
presynaptic
release mechanism
Postsynaptic
receptors

15. Noradrenaline (Noradrenaline
system)
 Noradrenaline regulates the
activity of both neuronal and
non-neuronal cells.
 It participates in the rapid
modulation of cortical circuits
and cellular energy
metabolism, and on a slower
time scale in inflammation and
neuroplasticity.
 Of the multiple sources of NE in
the brain, the locus coeruleus
plays a major role in
noradrenergic signaling.
 It plays a critical role in
modulating plasticity, learning
and memory via the
hippocampus within the brain.

16. Dopamine (Dopamine system)
 Dopamine is centrally
involved in reward,
approach, behavior,
exploration, and
various aspects of
cognition.
 Variations in this
neuromodulator
function appear to be
associated with
variations in
personality.

17. Serotonin (Serotonin system)
 It is well-known for its role
in the brain where it plays
a major part in mood,
anxiety and happiness.
 Over 90% of the body's
serotonin is found in the
gastrointestinal tract
where it has a role in
regulating bowel function
and movements.
 It also plays a part in
reducing the appetite
while consuming a
meal(satiety).

18. Acetylcholine (Cholinergic
system)
 Acetylcholine (Ach) has a role in
the control of autonomic functions
but it is likely that it also modulate
adaptive responses to
environmental and metabolic
conditions.
 Cholinergic signaling can
influence thermoregulation, sleep
patterns, food intake and
endocrine functions including
pancreatic insulin and glucagon
release.
 ACh signaling in a number of
brain areas might also be
important for stress responses as
several studies have shown that
stress increases its release in a
brain.

19. Others
GABA
 Gamma-aminobutyric acid (GABA) has an inhibitory
effect on brain and spinal cord activity.
Neuropeptides
 Opioid peptides - a large family of endogenous
neuropeptides that are widely distributed throughout
the central and peripheral nervous system. Opiate
drugs such as heroin and morphine act at the
receptors of these neurotransmitters.
1.Endorphins
2.Enkephalins
3.Dynorphins
 Substance P

20. Pharmacological applications of
Neuromodulation
 Sympathomimetic and sympatholytic drugs: these
enhance and block at least some of the effects of
noradrenaline released by the sympathetic nervous
system, respectively.
 Dopamine reuptake inhibitors: these prevent
dopamine reuptake by blocking the action of the
dopamine transporter. These drugs are frequently
used in the treatment of conditions including ADHD,
depression and narcolepsy.
 Selective serotonin reuptake inhibitors: these
temporarily prevent the removal of serotonin from
specific synapses, thereby enhancing the effect of
released serotonin. These are used in the treating
depression.
 Cholinesterase inhibitors: these bind to cholinesterase
resulting in increased acetylcholine in the synapses.
These are used to treat dementia in patients with

21. Recent Advances
 Neuromodulation also refers to an emerging class of medical
therapies that target the nervous system for restoration of
function (such as in cochlear implants), relief of pain, or control
of symptoms, such as tremor seen in movement disorders like
Parkinson's disease.
 The therapies consist primarily of targeted electrical
stimulation, or infusion of medications into the cerebrospinal
fluid using intrathecal drug delivery, such as baclofen for
spasticity.
 Electrical stimulation devices include deep brain stimulation
systems (DBS), colloquially referred to as "brain pacemakers",
spinal cord stimulators (SCS), which are implanted using
minimally invasive procedures, or transcutaneous electrical
nerve stimulation devices, which are fully external, among
others.

22. Spinal Cord Stimulation
 This common form of
neuromodulation involves using
a device to deliver electrical
current in therapeutic doses to
the spinal cord to disrupt pain
signals from the spinal cord to
the brain, converting them to a
more pleasant tingling sensation.
 This has been proven a safe and
effective therapeutic approach
for managing chronic pain of the
arms and legs, neck and back
often after spine surgery, or for
other neuropathic conditions.

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