Applied Pharmacology of the Nervous and Endocrine System Presentation

Learning Objectives

• Identify and define the different brain regions and their main functions.
• Identify and define the different cell types found in different brain regions
  and their main neurotransmitter-receptor systems in the central nervous
  system.
• Define the different branches of the autonomic nervous system, and its
  main neurotransmitter-receptor systems.

Brain Regions in Self Reflected

MOTOR CORTEX
(MOVEMENT)
SOMATOSENSORY CORTEX
(SENSATION)
SUBTHALAMIC NUCLEUS
(MOVEMENT)
PARIETAL CORTEX
(INTEGRATING MOVEMENT AND VISION)
FRONTAL CORTEX
(DECISION MAKING, PLANNING,
EXECUTIVE FUNCTIONS)
VISUAL CORTEX
(VISION)
CAUDATE NUCLEUS
(INTIATION OF
MOVEMENT)
SUPERIOR AND
INFERIOR COLLICULI
(VISION AND
HEARING)
GLOBUS PALLIDUS
(MOTOR GATING)
LOCUS COERULEUS
(AROUSAL AND STRESS)
NUCLEUS ACCUMBENS
(REWARD)
RAPHE NUCLEI
(SEROTONIN)
CEREBELLUM
(MOVEMENT AND
PROPRIOCEPTION)
PONS
(MOVEMENT)
OLFACTORY BULB (SMELL)
MAMMILLARY BODIES
(MEMORY)
RETICULAR FORMATION
(MOTOR COORDINATION, EXHALATION,
AWARENES)
RED NUCLEUS
(MOVEMENT)
DENTATE NUCLEUS
(CEREBELLAR OUTPUT)
VENTRAL TEGMENTAL AREA (VTA)
(DOPAMINE/ REWARD)
SUBSTANTIA NIGRA
(LEARNING, ADDICTION)
MISC BRAINSTEM NUCLEI (BREATHING, HUNGER)
INFERIOR OLIVARY NUCLEUS (ERROR CHECKING, MOVEMENT)

WWW.GREGADUNN.COM
THALAMUS
(SENSORY GATING, RELAY,
SIGNAL INTEGRATION)Our brain is a highly complex organ!
Neurons in the brainstem
Pyramidal neurons in mouse cortex
Pyramidal neurons in mouse cortex

Clear Division of Labour Across the Brain

• Cerebral cortex
• Examples of excitatory output in the brain
• Pyramidal neurons with pyramid-shaped
  cell bodies, long axons and apical dendrites
• Basal ganglia (striatum in particular)
• Examples of inhibitory output in the brain
• Voluntary motor responses and fine-
  tuning of motor movement

Lateral View of Right Side of Brain

ANTERIOR
Lateral ventricle
Body of caudate nucleus
Frontal lobe of cerebrum
Thalamus
Putamen
Tail of caudate nucleus
Occipital lobe
of cerebrum
(a) Lateral view of right side of brain

Anterior View of Coronal Section

SUPERIOR
Coronal
plane
Longitudinal
cerebral
fissure
Cerebrum
Corpus callosum
Septum
pellucidum
Lateral ventricle
Internal
capsule
View
Caudate
nucleus
Insula
Putamen
Corpus
straitum
Thalamus
Globus
pallidus
Subthalamic
nucleus
Third ventricle
Hypothalamus
and associated
nuclei
Optic tract
(b) Anterior view of coronal section
Head of caudate nucleus

Functional Areas of the Cerebral Cortex

1
Higher Mental Functions
Concentration
Planning
Judgment
Emotional expression
Creativity
Inhibition - Ability to
control self
9
Somatosensory
Association Area
Understanding of weight,
texture, temperature, etc.
for recognizing and
comprehending an object
6
2
4
10
9
8
Visual Areas
Sight
Ability to recognize
pictures
Awareness of size and
shape
3
1
7
10
5
11
6
Sensory Area
Touching and feeling
7
Auditory Area
Hearing
8
Wernicke's Area
Written and spoken
language understanding
11
Motor Functions
Coordination of movement
Balance
Posture
2
Motor Function Area
Eye movement and
placement of eyes
3
Broca's Area
Ability to talk
Ability to write
4
Motor Function Area
Ability to move
muscles
5
Association Area
Short-term memory
Emotion

Functional Areas of the Cerebellum

Diverse Neuronal Subtypes and Functions of the Brain

• More than 100 billion neurons in the human
  brain
• Diverse subclasses of neurons in the brain
• 7 subclasses of S1 pyramidal neurons
• 2 subclasses of CA1 pyramidal neurons
• 16 subclasses of interneurons in S1 and CA1
• ALL are layer-specific: different functions?

Somatosensory Cortex Cell Capture

A
Somatosensory
Cell capture
Biclustering
cortex (S1)
Whole tissue
cell suspension
O
Single-cell
RNA-seq
3,005 cells
9 classes
47 subclasses
Hippocampus
CA1
A
S1PyrL23
S1PyrL4
S1PyrL5a
S1PyrL5
S1PyrL6
S1PyrL6b
S1PyrDL
ClauPyr
Tbr1
Rasgrf2
Pvrl3
Cux2
Rorb
Plcxd2
Thsd7a
Kcnk2
Cplx3
Sulf2
Foxp2
Pde1a
Lphn2
Kcnip2
Rgs10
Synpr
Pcp4
Rasgrf2.
Crh
Plcxd2
Kcnk2
Sulf2
Rprm
Cplx3
DL
II/III IVVa V VI VIb
C
5HT3aEGFP PAX6 ALDOC
I
-
250ms
=
PAX6Biotin
IV
V
VI
0
B
Interneuron subclasses
Int
Int16
Gad1
Pvalb
Sst
T
Htr3a
Vip
Rein
Cck
Npy
Lhx6
Calb2
Syt6
Rprm
Nr4a2
Nov
Cpne5 I
Slc5a7 __
Pax6
Cxcl14
H
Gda_
Sema3e
S1
CA1
FACS S1
Pia
D
60mV
25 um
PAX6 neurons by layer (%)g
T
T

Diverse Neuronal Subtypes and Functions of the Brain (Continued)

• Distinct gene expression in each subclass of
  neurons
• Express distinct patterns of
  neurotransmitter-receptors in different
  neuronal subtypes across different brain regions
• Unique biochemical and functional properties
• Unique firing pattern

Somatosensory Cortex Cell Capture and Analysis

A
Somatosensory
Cell capture
Biclustering
cortex (S1)
Whole tissue
cell suspension
O
Single-cell
RNA-seq
3,005 cells
9 classes
47 subclasses
Hippocampus
CA1
A
S1PyrL23
S1PyrL4
S1PyrL5a
S1PyrL5
S1PyrL6
S1PyrL6b
S1PyrDL
ClauPyr
Tbr1
Rasgrf2
Pvrl3
Cux2
Rorb
Plcxd2
Thsd7a
Kcnk2
Cplx3
Sulf2
Foxp2
Pde1a
Lphn2
Kcnip2
Rgs10
Synpr
Pcp4
Slc5a7 __
Rasgrf2.
Crh
Plcxd2
Kcnk2
Sulf2
Rprm
Cplx3
DL
II/III IVVa V VI VIb
C
5HT3aEGFP PAX6 ALDOC
I
-
250ms
=
PAX6 Biotin
IV
25 um
V
VI
0
B
Interneuron subclasses
Int
Int16
Gad1
Pvalb
Sst
T
Htr3a
T
Vip
Rein
Cck
Npy
Lhx6
Calb2
Syt6
Rprm
Nr4a2
Nov
Cpne5 I
Pax6
Cxcl14
H
Gda_
Sema3e
S1
CA1
FACS S1
PAX6 neurons by layer (%)g
Pia
D
60mV
T

Diverse Neuronal Subtypes and Functions of the Brain (Continued)

• Unique connections formed between these functionally
  and chemically diverse neurons
• Each neuron can form thousands of synapses with other
  neurons
• Purkinje cell in cerebellum or monoamine-containing
  neuron in brainstem forms more than 100,000 synapses!
• More than 100 trillion synapses
• Form diverse circuitry - small local neuronal groups to
  long-distance projections
• Specific brain circuit - specific brain function

Drawings of Typical Neurons in the CNS

A
A
A
2-3
Drawings of typical neurons in the CNS. 'A' marks the axons of some of these neurons.

How Neurons are Interconnected

Fig. 38.2 Simplified scheme of neuronal
interconnections in the central nervous system.
Neurons 1, 2 and 3 are shown releasing transmitters a, b
and c, respectively, which may be excitatory or inhibitory.
Boutons of neuron 1 terminate on neuron 2, but also on
neuron 1 itself, and on presynaptic terminals of other
neurons that make synaptic connections with neuron 1.
Neuron 2 also feeds back on neuron 1 via interneuron 3.
Transmitters (x and y) released by other neurons are also
shown impinging on neuron 1. Even with such a simple
network, the effects of drug-induced interference with
specific transmitter systems can be difficult to predict.
b
3
a
C
X
a
y
1
2
a
b
a

• Principal cells (cell #1): process information within their brain region, and project their
  axons to other brain regions, thereby innervating and regulating other brain regions
• Interneurons (cell #2): process information within their brain region, and project their axons
  to local neurons only, thereby regulating activity of neighbouring principal cells

Pyramidal Neurons

• Principal cells in the cerebral cortex are
  called 'pyramidal neurons', which have
  pyramid-shaped cells
• Major excitatory neurons (70-85% of all
  neurons) in the mammalian cortex)
• Receive input from different brain regions
• Project to different brain regions and their
  targets

Examples of CNS Neurons

FIGURE 12.4
Two examples of CNS neurons. Arrows indicate
the direction of information flow.
The dendritic branching pattern often is distinctive for a
particular type of neuron.
Dendrites
Cell body
1
Axon
Axon
terminal
(a) Purkinje cell
(b) Pyramidal cell

Organization of Cerebral Cortex Neurons

1
I
=
Ch
Il
III
Sp
Asp
Py
IV
V
V
Py
VI
·VI
Bas
mPy
4Thalamocortical
terminals
Thalamus
Cortex
Claustrum
Spinal cord
Thalamus
Striatum
Cortex
Brainstem
Cortex
(callosal)
Corticocortical terminals
IV

Types of Interneurons in the Cerebral Cortex

A
Layer 1 has no pyramidal neurons and very few somas.
II
Layer II and III pyramidal neuron somas are grouped
together. Layer II contains the smallest somas in this group.
III
Layer III contains pyramidal neurons whose somas are
largest at the lower surface of the layer and then
gradually decrease in size moving towards Layer II.
Layer IV contains pyramidal neurons as well as spiny
stellate neurons (though spiny stellates are absent in
the motor cortex). This is the densest of the layers in terms
of cell body occupancy.
V
Layer V contains the largest pyramidal neuron somas. Similarly to
layer III, the larger somas are located in the lower half of the layer.
Compared with Layer VI, this layer has sparsely packed somas.
VI
Layer VI, similarly to Layer IV, has densely packed somas.

• Diverse neuronal subtypes based on: . Allows for highly
• Morphology
• Physiology
• Neurochemistry
  complex patterns of
  regulating pyramidal
  neuronal activity

Interneuron Types

VI
Interneurons
Excitatory
Spiny Neurons
Inhibitory
Aspiny Neurons
neuroglial cell
-
double bouquet
cell
chandelier
cell
Vasointestinal Peptide
(VIP, CR, 5HT3aR)
Somatostatin-
Calretinin
(SST-CR)
Calretinin
(CR)
Parvalbumin
(PV)
multipolar
cell
bipolar
cell
IV
RorB, MDGA1, Eag1/2,
Parvalbumin
(PV)
Reelin
(RLN, 5HT3aR)
Parvalbumin
(PV)
Somatostatin
(SST)
chandelier
cell
small
basket cell
nest basket
cell
FIRST
Reelin
(RLN, 5Ht3aR)
I
Martinotti
cell
large
basket cell
small
basket cell
V
Martinotti
cell
neuroglial
cell
large
basket cell
Somatostatin-
Calretinin
(SST-CR)

Neurotransmitter-Receptors in Pyramidal Neurons

• Pyramidal neurons are excitatory in nature
• Primarily release glutamate from their axons
• Main source of neuronal excitation in the
  brain
• Diverse synaptic inputs onto different dendritic
  and somatic regions
• Excitatory: glutamate receptors (NMDA,
  AMPA, kainate), acetylcholine (M1, nicotinic
  ACh), dopamine (D1 and D5), noradrenaline
  (a1, B1, B2), serotonin (5-HT2A)
• Inhibitory: GABAA receptors (mainly on cell
  bodies and dendritic shafts)

Dendritic Spines and Inhibitory Synapses

A
Dendritic Spines
B
Inhibitory Synapses

Basal Ganglia

• A group of interconnected nuclei located in the
  subcortical brain region
• Caudate nucleus and putamen form the dorsal
  striatum (MOST important integrating centre)
• initiating and controlling movements of the body,
  limbs, and eyes
• The ventral striatum consists of the nucleus
  accumbens and the olfactory tubercle.
• motivation, reward, reinforcement, and
  aversion

Major Pathways of the Basal Ganglia

GLU
GLU
Cerebral
cortex
Brainstem and
spinal cord
GLU
GLU
DA
GLU
Thalamus
Caudate nucleus
Putamen
ACh
GABA/SP
Pars
compacta
Pars
reticulata
Substantia
nigra
GABA/SP
GABA/ENK
GLU
Subthalamic
nucleus
A
Globus
pallidus
GABA
GABA
GABA
Figure 12.19 . Major pathways of the basal ganglia and their
neurotransmitters. ACh, acetylcholine; DA, dopamine; ENK, enkephalin;
GABA, gamma aminobutyric acid; GLU, glutamate and/or aspartate;
SP, substance P. (Modified from Fix, JD (1995) Neuroanatomy, 2nd edn.
Williams & Wilkins, Baltimore; fig. 21.4.)