Basic neuroanatomy & neurophysiology

Outlines
• Development of brain
• Structural organization
– Cerebral hemispheres
– Brain stem
– Cerebellum
– Meninges
– Blood supply of brain
– Ventricular system and
cerebrospinal fluid

Prefrontal cortexPartsofprefrontalcortex
Dorsolateral prefrontal
cortex (DLPFC)
Orbitofrontal cortex
(OFC)
Medial prefrontal
cortex (MPFC)
Prefrontal motor cortex
Anterior cingulate
cortex (ACC)
Dorsal ACC
Ventral ACC

Neurotransmitters involved
Dopamine
Nor epinephrine
Serotonin
Acetyl choline
Histamine

The CSTC loops
Cortico-Striato-Thalamo-Cortical loop

Prefrontal cortex in psychiatric disorders
Schizophrenia
ADHD
Depression
Mania
Anxiety
Pain
Disorders of sleep and wakefulness

Prefrontal cortex and executive functions

In ADHD
 Dorsolateral prefrontal cortex (DLPFC) –
sustained attention and problem solving
 Orbitofrontal cortex (OFC) – impulsive
symptoms
 Medial prefrontal cortex (MPFC)
 Prefrontal motor cortex – hyperactivity
 Anterior cingulate cortex (ACC)
 Dorsal ACC– selective attention
 Ventral ACC – emotional dysregulation

 Dorsolateral prefrontal cortex (DLPFC)
 Orbitofrontal cortex (OFC)
 Medial prefrontal cortex (MPFC)
 Prefrontal motor cortex
 Anterior cingulate cortex (ACC)

History of limbic system
• Paul Broca – coined Limbic lobe
• James Papez (1937) - Emotional processing
network in limbic structures
• H. Kluver & P Bucy – Supported the concept of
Papez, Kluver Bucy syndrome
• Paul McLean (1952)- coined Limbic System to
the structure earlier called Limbic lobe

Limbic system
(Rhinencephalon) Olfactory bulb, tract and striae
Anterior perforated substance
Uncus
Hippocampus
Dentate gyrus
Indusium griseum
Subcallosal area
Fornix
Thalamus
Mamillary body
Septal area
Amygdala

• Association cortex
• Hippocampal formation – hippocampus,
posterior part of dentate gyrus, indusium
griseum
• Pyriform area – anterior perforated substance,
uncus, anterior end of dentate gyrus medial to
rhinal sulcus

Broadly limbic structure
form two circuits
Medial circuit (Papez circuit) – cognitive
processing
• Mamillary body
• Anterior thalamus
• Cingulate cortex
• Hippocampal formation
Basolateral circuit – emotional / affective
processing
• Amygdala
• Mediodorsal thalamus
• Subcallosal area

Papez Circuit
Cingulate gyrus
Parahippocampal
gyrus
HippocampusMamillary body
Anterior
thalamus
Fornix
Mamillo-
Thalamic
Tract

Memory
processing
Registration
Encoding
Consolidation
Storage
Retrieval
Ecphory

Functional Circuits of limbic system
Association
cortex
Cingulate
cortex
Entorhinal
cortex
Hippocampal
formation
Hypothalamus
and septal
area
Anterior
thalamus
Brainstem &
spinal cord

Prefrontal & temporal
association cortices
Amygdala
Hypothalamus
& septal area
Brainstem &
spinal cord
Medial
dorsal
thalamus

Hippocampal
formation &
amygdala
Ventral
striatum
Venral
pallidum
Medial dorsal
thalamus
Association
cortices

Neurophysiology
&
Neurochemistry

Neurotransmitter
Gamma Amino
Butyric Acid
(GABA)

Positive
Allosteric
Modulation
(PAM)

GABA & Neuropsychiatric disorders
GABA is
involved
in
Epilepsy
Autism
ADHD
Schizophrenia
Mood disorders
Substance use disorder (Alcoholism)
Sleep
Anxiety disorders

Metab Brain Dis. 2014 May 13. [Epub ahead of print]
GABA receptors in brain development, function, and injury.
Wu C, Sun D.
Abstract
This review presents a brief overview of the γ-aminobutyric acid (GABA)
system in the developing and mature central nervous system (CNS) and its
potential connections to pathologies of the CNS. γ-aminobutyric acid
(GABA) is a major neurotransmitter expressed from the embryonic
embryonic stage and throughout life. At an early developmental stage,
stage, GABA acts in an excitatory manner and is implicated in many
many processes of neurogenesis, including neuronal proliferation,
proliferation, migration, differentiation, and preliminary circuit-
building, as well as the development of critical periods. In the mature
mature CNS, GABA acts in an inhibitory manner, a switch mediated by
mediated by chloride/cation transporter expression and summarized in
summarized in this review. GABA also plays a role in the development
development of interstitial neurons of the white matter, as well as in
as in oligodendrocyte development. Although the underlying cellular
cellular mechanisms are not yet well understood, we present current
current findings for the role of GABA in neurological diseases with

GABA in
Epilepsy
Autism
ADHD
Schizophrenia
Mood disorders
Sleep
Anxiety disorders
Nihon Rinsho. 2014 May;72(5):790-5.
[GABA(A) receptor trafficking and epilepsy].
[Article in Japanese]
Maru E, Ura H.
Recent studies clarified a dynamic regulation of the
intracellular trafficking of GABA(A) receptors and its
involvement in the pathophysiology of epilepsy.
GABA(A) synaptic inhibition decreased in the
hippocampal CA1 area of patients with intractable
temporal lobe epilepsy (TLE). The reduction of
GABAergic inhibition was accompanied by a decrease in
decrease in the expression of gephyrin, a scaffolding
scaffolding protein, and GABA(A) receptor gamma2
subunit. These findings indicate that the reduction of
of gephyrin impairs the clustering and fixation of
GABA(A) receptors in postsynaptic membranes, leading
leading to a decrease in number of GABA(A) receptor
receptor subunits and GABA(A) synaptic inhibition. In
In contrast, the GABA(A) synaptic inhibition was
lastingly potentiated in the dentate gyrus of kindled
animals and the expression of GABA(A) receptor
subunits(especially alpha2) was significantly increased in
increased in TLE patients. It is plausible that the

GABA in
Epilepsy
Autism
ADHD
Schizophrenia
Mood disorders
Sleep
Anxiety disorders
Adv Exp Med Biol. 2004;548:92-103.
GABA and its receptors in epilepsy.
Sperk G, Furtinger S, Schwarzer C, Pirker S.
Gamma-aminobutyric acid (GABA) is the principal inhibitory
inhibitory neurotransmitter in the mammalian brain. It acts
acts through 2 classes of receptors, GABAA receptors that are
that are ligand-operated ion channels and the G-protein-
protein-coupled metabotropic GABAB receptors. Impairment
Impairment of GABAergic transmission by genetic mutations
mutations or application of GABA receptor antagonists
induces epileptic seizures, whereas drugs augmenting
GABAergic transmission are used for antiepileptic therapy. In

GABA in
Epilepsy
Autism
ADHD
Schizophrenia
Mood disorders
Sleep
Anxiety disorders
Front Cell Neurosci. 2014 May 22;8:119. eCollection 2014.
Modulation of GABAergic transmission in development and
neurodevelopmental disorders: investigating physiology and
pathology to gain therapeutic perspectives.
Deidda G, Bozarth IF, Cancedda L.
During mammalian ontogenesis, the neurotransmitter GABA is
a fundamental regulator of neuronal networks. In neuronal
development, GABAergic signaling regulates neural
proliferation, migration, differentiation, and neuronal-
network wiring. In the adult, GABA orchestrates the activity
activity of different neuronal cell-types largely
interconnected, by powerfully modulating synaptic activity.
activity. GABA exerts these functions by binding to chloride-
chloride-permeable ionotropic GABAA receptors and
metabotropic GABAB receptors. According to its functional
functional importance during development, GABA is
implicated in a number of neurodevelopmental disorders
disorders such as autism, Fragile X, Rett syndrome, Down
Down syndrome, schizophrenia,Tourette's syndrome and
and neurofibromatosis.The strength and polarity of
GABAergic transmission is continuously modulated during
physiological, but also pathological conditions. For GABAergic
transmission through GABAA receptors, strength regulation is

GABA in
Epilepsy
Autism
ADHD
Schizophrenia
Mood disorders
Sleep
Anxiety disorders
Front Psychiatry. 2012 May 31;3:51.
GABAergic circuit dysfunctions in
neurodevelopmental disorders.
Chattopadhyaya B, Cristo GD.
GABAergic interneurons control neuronal
excitability, integration, and plasticity. Further,
Further, they regulate the generation of temporal
temporal synchrony and oscillatory behavior
among networks of pyramidal neurons. Such
oscillations within and across neural systems are
are believed to serve various complex functions,
functions, such as perception, movement
initiation, and memory. Alterations in the
development of GABAergic circuits have been
implicated in various brain diseases with
neurodevelopmental origin. Here, we highlight
highlight recent studies suggesting a role for
alterations of GABA transmission in the
pathophysiology of two neurodevelopmental

GABA in
Epilepsy
Autism
ADHD
Schizophrenia
Mood disorders
Sleep
Anxiety disorders
Neuropsychopharmacology. 2014 May 2
[Epub ahead of print]
Prefrontal Cortical GABA Transmission
Modulates Discrimination and Latent
Inhibition of Conditioned Fear: Relevance for
Schizophrenia.
Piantadosi PT, Floresco SB.
Inhibitory gamma-aminobutyric acid
transmission within the prefrontal cortex
(PFC) regulates numerous functions, and
perturbations in GABAergic transmission
within this region have been proposed to
contribute to some of the cognitive and
behavioral abnormalities associated with
disorders such as schizophrenia. These
abnormalities include deficits in emotional
regulation and aberrant attributions of
affective salience.
• Data suggest that normal PFC GABA
transmission is critical for regulating and

GABA in
Epilepsy
Autism
ADHD
Schizophrenia
Mood disorders
Sleep
Anxiety disorders
Psychopharmacology (Berl). 2005 Jul;180(2):191-205. Epub
2005 Apr 28.
GABAergic dysfunction in schizophrenia: new treatment
strategies on the horizon.
Guidotti A1, Auta J, Davis JM, Dong E, Grayson DR,Veldic M,
Zhang X, Costa E.
Cortical gamma-aminobutyric acid (GABA)ergic neurons
contribute to the orchestration of pyramidal neuron
population firing as follows: (1) by
releasing GABA on GABA(A) and GABA(B) receptors, (2) by
by releasing reelin in the proximity of integrin receptors
receptors located on cortical pyramidal neuron dendritic
dendritic spines, and (3) through reelin contributing to the
the regulation of dendritic spine plasticity by modulating
modulating dendritic resident mRNA translation.
In schizophrenia (SZ) and bipolar (BP) postmortem brains,
brains, the downregulation of mRNAs encoding
glutamic aciddecarboxylase 67 (GAD(67)) and reelin
decreases the cognate proteins coexpressed in prefrontal
prefrontal cortex (PFC) GABAergic neurons.
• In mice that model SZ symptoms, imidazenil increases
increases signal transduction at GABA(A) receptors

GABA in
Epilepsy
Autism
ADHD
Schizophrenia
Mood disorders
Sleep
Anxiety disorders
Neuropsychopharmacology. 2014 Apr 24. doi:
10.1038/npp.2014.95. [Epub ahead of print]
Neurodevelopment, GABA System Dysfunction, and
Schizophrenia.
Schmidt MJ, Mirnics K.
The origins of schizophrenia have eluded
clinicians and researchers since Kraepelin and
and Bleuler began documenting their
findings. However, large clinical research
efforts in recent decades have identified
numerous genetic and environmental risk
factors for schizophrenia.The combined data
data strongly support the
neurodevelopmental hypothesis of
schizophrenia and underscore the
importance of the common converging
effects of diverse insults. In this review, we
we discuss the evidence that genetic and

GABA in
Epilepsy
Autism
ADHD
Schizophrenia
Mood disorders
Sleep
Anxiety disorders
Hashimoto K. Abnormalities
of the glutamine-
glutamate-GABA cycle in
the schizophrenia brain.
Schizophr Res. 2014
Jul;156(2-3):281-2. Epub
2014 May 5.

GABA in
Epilepsy
Autism
ADHD
Schizophrenia
Mood disorders
Substance use disorder
(Alcoholism)
Sleep
Anxiety disorders
Korpi ER, Debus F, Linden
AM, Malécot C, Leppä E,
Vekovischeva O, Rabe H,
Böhme I, Aller MI, Wisden
W, Lüddens H. Does ethanol
act preferentially via
selected brain GABAA
receptor subtypes? the
current evidence is
ambiguous. Alcohol. 2007

GABA in
Epilepsy
Autism
ADHD
Schizophrenia
Mood disorders
(Alcoholism)
Sleep
Anxiety disorders
Arch Gen Psychiatry. 2006 Sep;63(9):957-68.
Gamma-aminobutyric acid type A receptors and
alcoholism: intoxication, dependence, vulnerability,
and treatment.
Krystal JH1, Staley J, Mason G, Petrakis IL, Kaufman J,
Harris RA, Gelernter J, Lappalainen J.
Alcohol facilitates gamma-aminobutyric acid
function, and GABA type A (GABA(A)) receptor-
facilitating agents suppress alcohol withdrawal
symptoms. Alcohol increases GABA release, raises
neurosteroid levels, and may potently enhance the
function of a GABA(A) receptor subclass that
high affinity for GABA and neurosteroids, relative
insensitivity to benzodiazepines, low chloride
conductance, and an extrasynaptic location.
in GABA(A) receptor subunit genes may contribute
the vulnerability to alcoholism, particularly in the
context of environmental risk factors. Alcohol
dependence is associated with time-dependent
changes in brain GABA(A) receptor density and
gene expression levels that contribute to a
withdrawal-related deficit in GABA(A) receptor
function. However, cortical GABA levels are not
reduced during acute withdrawal. Benzodiazepine-

GABA & Neuropsychiatric disorders
GABA in
Epilepsy
Autism
ADHD
Schizophrenia
Mood disorders
Sleep
Anxiety disorders

GABA in
Epilepsy
Autism
ADHD
Schizophrenia
Mood disorders
Sleep
Anxiety disorders
Sleep. 2014 May 1;37(5):893-900
Cortical gamma-aminobutyric acid and glutamate in
posttraumatic stress disorder and their relationships
to self-reported sleep quality.
Meyerhoff DJ, Mon A, Metzler T, Neylan TC.
STUDY OBJECTIVES:
To test if posttraumatic stress disorder
is associated with low brain gamma-
aminobutyric acid (GABA) levels and if
reduced GABA is mediated by poor
quality.
CONCLUSIONS:
Low brain gamma-aminobutyric acid
(GABA) concentration in
stress disorder (PTSD) is consistent
most findings in panic and social
disorders. Low GABA associated with
poor sleep quality is consistent with

GABA in
Epilepsy
Autism
ADHD
Schizophrenia
Mood disorders
Sleep
Anxiety disorders
Mol Brain. 2014 May 29;7(1):39. [Epub ahead of print]
ExtrasynapticGABAA receptors in mediodorsal thalamic
nucleus modulate fear extinction learning.
PaydarA, Lee B, GangadharanG, Lee S, Hwang EM, Shin
HS.
The gamma-amino-butyric acid (GABA)
system is a critical mediator of fear extinction
extinction process. GABA can induce "phasic"
"phasic" or "tonic" inhibition in neurons through
synaptic or extrasynaptic GABAA receptors,
respectively. However, role of the thalamic
"tonic GABA inhibition" in cognition has not
been explored.We addressed this issue in
extinction of conditioned fear in mice.
CONCLUSIONS:
Our results suggest that "tonic GABA inhibition"
mediated by extrasynaptic GABAA receptors in
MD neurons, suppresses fear extinction

GABA in
Epilepsy
Autism
ADHD
Schizophrenia
Mood disorders
Sleep
Anxiety disorders
Palotai M, Telegdy G, Jászberényi M. Orexin A-induced
anxiety-like behavior is mediated through GABA-ergic,
α- and β-adrenergic neurotransmissions in mice.
Peptides. 2014 May 27. pii: S0196-9781(14)00149-1.
Orexins are hypothalamic neuropeptides,
are involved in several physiological functions
the central nervous system, including anxiety
stress. Several studies provide biochemical and
behavioral evidence about the anxiogenic action of
However, we have little evidence about the underlying
neuromodulation. Therefore, the aim of the present study
investigate the involvement of neurotransmitters in the orexin
induced anxiety-like behavior in elevated plus maze (EPM)
Accordingly, mice were pretreated with a non-selective
cholinergic antagonist, atropine; a γ-aminobutyric acid
(GABA-A) receptor antagonist, bicuculline; a D2, D3, D4
receptor antagonist, haloperidol; a non-specific nitric oxide
(NOS) inhibitor, nitro-l-arginine; a nonselective α-adrenergic
antagonist, phenoxybenzamine and a β-adrenergic receptor
propranolol 30min prior to the intracerebroventricular
orexin A. The EPM test started 30min after the i.c.v. injection
neuropeptide. Our results show that orexin A decreases
time spent in the arms (open/open+closed) and this action is
bicuculline, phenoxybenzamine and propranolol, but not by

GABA in
Epilepsy
Autism
ADHD
Schizophrenia
Mood disorders
Sleep
Anxiety disorders
J Clin Psychiatry. 2003;64 Suppl 3:21-7.
The role of GABA in anxiety disorders.
Lydiard RB.
Anxiety stems from and perpetuates
dysregulation of neurobiological systems, but
but the exact mechanisms of anxiety
disorders are still only partially understood.
understood. Gamma-aminobutyric acid
(GABA) is the primary inhibitory
neurotransmitter known to counterbalance
counterbalance the action of the excitatory
excitatory neurotransmitter glutamate. Several
Several pharmacologic agents target the GABA system
and modulate the overall effect of GABA. This article
highlights multiple neurobiological interactions that play
a role in anxiety and reviews selected studies of plasma
neurosteroid levels, plasma GABA levels, and
benzodiazepine binding site sensitivity and density in

GABA in
Epilepsy
Autism
ADHD
Schizophrenia
Mood disorders
Sleep
Anxiety disorders
J Altern Complement Med. 2010 Nov;16(11):1145-52. doi:
10.1089/acm.2010.0007. Epub 2010 Aug 19.
Effects of yoga versus walking on mood, anxiety, and brain
GABA levels: a randomized controlled MRS study.
Streeter CC,WhitfieldTH, Owen L, ReinT, Karri SK,Yakhkind A,
Perlmutter R, Prescot A, Renshaw PF, Ciraulo DA, Jensen JE.
Yoga and exercise have beneficial effects on mood and
anxiety. γ-Aminobutyric acid (GABA)-ergic activity is reduced
reduced in mood and anxiety disorders. The practice of yoga
yoga postures is associated with increased brain GABA levels.
levels. This study addresses the question of whether changes in
changes in mood, anxiety, and GABA levels are specific to yoga
or related to physical activity.
CONCLUSIONS:
The 12-week yoga intervention was associated with greater
improvements in mood and anxiety than a metabolically
matched walking exercise. This is the first study to demonstrate
that increased thalamic GABA levels are associated with
improved mood and decreased anxiety. It is also the first time
time that a behavioral intervention (i.e., yoga postures) has
been associated with a positive correlation between acute
acute increases in thalamic GABA levels and improvements in
improvements in mood and anxiety scales. Given that

GABA in
Epilepsy
Autism
ADHD
Schizophrenia
Mood disorders
Sleep
Anxiety disorders
Liu ZP, Song C,Wang M, HeY, Xu
XB, Pan HQ, ChenWB, PengWJ,
Pan BX.
Chronic stress impairs GABAergic
control of amygdala through
suppressing the tonic GABAA
receptor currents. Mol Brain. 2014
Apr 24;7(1):32. doi: 10.1186/1756-
6606-7-32.

Neurotransmitter
Acetylcholine
(Ach)

Ach in
ANS
• ANS
– Sympathetic – NA, Adr, DA
– Parasympathetic – Ach

Action of Ach
• Central
• Peripheral
Distribution of
Ach receptors
Central
Peripheral
Metabolism
of Ach
• AchE
• BchE

Parkinsonism & Parkinson’s disease

Faure P,Tolu S,Valverde S, Naudé J. Role of nicotinic acetylcholine receptors
in regulating dopamine neuron activity. Neuroscience. 2014 Jun 2. [Epub
ahead of print]
Midbrain dopamine (DA) neurons play a central role in a
wide range of behaviors, from attention and motivation to
motor control and reinforcement. The release of DA is
modulated by a number of factors, and its deregulation has
been implicated in multiple psychiatric disorders, such as
addiction. In particular, nicotinic acetylcholine receptors
(nAChRs) are key modulators of DA cells. Nicotine, the main
addictive component in tobacco, strongly interacts with these
receptors in the midbrain DA systems, resulting in reinforcing
effects that are at the core of tobacco addiction. nAChRs are
virtually expressed on every cell of the DA system, both at pre-,
post- and extra-synaptic locations. The complex issue of
interpreting the role of the large portfolio of different nAChR

Neurotransmitter
Noradrenaline
or
norepinephrine
(NA or NE)

Norepinephrine
Dopamine
DOPA
Tyrosine

•Important location of NE
neurons in brain are
–Primary somatosensory cortex
–Locus ceruleus

• NE neurons project to
– Cerebral cortex (widespread projections)
– Spinal cord
– Pons
– Cerebellum

• NE neurons from Locus ceruleus
project to dorsal raphe nucleus
containing serotonergic neurons
and regulate serotonergic activity

• Locus ceruleus (LC) is turned offDuring sleep
• Locus ceruleus (LC) fires at a slower rateDuring awake state
• LC fires in faster rateIn the presence of a novel
stimulus
• LC stops firing
Repetition of the stimulus
(little significance to
individual)
• LC fires slowlyAnimal – grooming or eating
• LC fires in faster ratePredator / Threat comes

Norepinephrine
Synthesis
3 enzymes (Tyrosine hydroxylase,
DOPA decarboxylase, Dopamine β
hydroxylase)
Metabolism
MAO – A & B
COMT

Receptors
α β
All NE receptors are metabotropic receptors
α2 receptor is the only receptor present pre-synaptically (AUTORECEPTOR)

• Serotonin regulates NE release through 5HT2C
and 5HT3 receptors
• NE regulates 5HT neurons by alpha- 1 & 2
receptors
α1 -
accelerator
α2 -
decelerator

Norepinephrine and psychiatric disorders
Mood disorder – Depression
Enuresis
Anxiety disorders
ADHD

• Norepinephrine and stress response
• Norepinephrine and memory
• Norepinephrine and cardiac co-morbidity
• Norepinephrine and emotional excitement

Basic neuroanatomy & neurophysiology

Basic neuroanatomy & neurophysiology

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