How Evolution Informs the Fate of the Ancient Inhibitory Neurons, in
Relationship to the Cerebrospinal Fluid Contacting Neurons, in the
Human Neocortex
October
23-27, 2016
Kobe, Japan
Alexandra
Kunz, MD
44th ANNUAL MEETING
600Mya
600 million years ago marks an evolutionary milestone, the 1st internal fluid brain
tissue environment, primitive chordate lancelet, earliest vertebrate body plan, its
hindbrain inhibitory neurons (INS) in direct contact with CSF-contacting
(CSF-c) neurons whose cilia transduced diffusible non-synaptic signals
to INS’ progenitor cell bodies;
*
lancelet
lancelet brain vesicle
in CSF-c neurons are identified immunocytochemicals:
glutamate,
GABA,
glycine, dopamine (DA), serotonin (5-HT),
(Tram, 1981; Anadon, 1998; Manaugh, 2013)
acetylcholine (ACh).
In starfish’s nerve cells, dendritic processes face sea water only, not CSF.
Adult lancelet CSF-c neurons directly contact CSF, however their larvae’
directly contact sea water which enters through the neuropore; in the
adult, this closes and sea water becomes modified as CSF,
dependent on brain activity metabolism.
Sea water
neurons of
the starfish
Sea water
CSF
CSF
CSF
neurons of
lancelet larvae’s
brain
CSF-c neurons
of jawless fish
CSF-c neurons
of reptiles
ciliated
neurons of
mammals
(Vigh, 2004)
With evolutionary increases in INS, the more phylogenetically differentiated
vertebrates’ CSF-c neurons migrated from ventricles to internal brain
area, communicating now synaptically, their cilia extending into
the intracellular fluid, preserving their neuromodulatory
function, instructing multiple aspect of neuronal
development, and regulating neurogenesis.
non-synaptic
synaptic
Vertebrate CSF-c
neuronal system:
neurohormonal
sensory, photo
hormonal
mechano, osmo
CSF-c neurons with
inner/outer CSF
and intercellular space
(Vigh, 2004)
Here we explore the modern evolutionary fate of these ancient CSF-c
neuron bathed INS, their significance for functioning in our human
neo-cortex. 3 important aspects are
• energy efficiency
• a bipartite migration mechanism for cortex
development
•
adaptive social acumen
Energy efficiency
Energy metabolism sets humans apart from primates; maintaining neo-cortical
high energy cost is predicted by metabolic demand not size: evolutionary
increase in synaptic signaling, connectivity, quadrupled number of glial
cells, an unexpected 46% greater density in glial:neuron ratio p<0.01.
Human brain efficiency, neuronal signaling and energy production
were up-regulated by positive selection; the human frontal cortex
has the highest level energy metabolism.
human &
primate
cortical
INS
subtypes
mammal
cortical
INS
subtypes
human
0.70
allometric increase
prefrontal gray
matter volume
comparative
laminar
thickness and
neuron density
human/rat/mouse
(de Filipe, 2002; Sherwood, 2005; Batista-Brito, 2009; Raghanti, 2011; Spocter, 2012)
regional variation in
neuropil fraction
in chimps (l)
& humans (r)
Energy efficiency
INS are the real stars of energy efficiency exceeding excitatory neurons, using less
glucose and oxygen, 15% vs 85% respectively; thus INS’ energy cost are often
ignored; both work together ensuring homeostasis through an intricate
relationship; INS provide synchrony, temporally both tonic and
phasic, for excitatory neurons’ spatial-temporal content
through spontaneous intrinsic activity, feed-forward
inhibition, and dendritic inhibition.
spontaneous intrinsic
activity
feed-forward
inhibition
dendritic
inhibition
The relationship between brain energy consumption & physiology is dependent on excitatory neurons/INS
partnership.
(Buzaski, 2007)
Energy efficiency
Excitatory neurons’ recycling of energy consumption uses both glycolytic
and glycogenolytic processes, whereas INS’ synaptic cleft recycling uses only
glycolytic. INS’ action potentials have a shorter firing distance; their resting membrane potential is several mV less negative, thus sustaining firing rates 3xs excitatory
neurons to allow for full control of complex network operations; INS emit more spikes
than all cortex excitatory neurons. INS terminals on cortical neurons are larger for more
efficient transmission, larger ISPS amplitude and less failure, to create a large driving force
for excitatory neurons.
INS’ firing
patterns
increase ISPS & ESPS
frequency with age
(Ascoli , 2008; Cui, 2010)
increase amplitude with
age, ISPS> ESPS
Bipartate migration process
600Mya
450Mya
310Mya
380Mya
210-185Mya
25Mya
40Mya
150K
_____//____________//_____________//_____________//_____________//_________________//_____________//___________//____
gnathostomes
amniotes
*
*
*
*
*
mammals
hominoids
anthropoid primates
Key in INS’ origins is recruitment of other mechanisms
of greater number/diversity for neocortex growth/
development for less stereotypic processing;
the GABA system,
INS’ primary neurotransmitter, is
very ancient coming from a superfamily divergence of inhibitory glutamate/ GABA/ACh/5-HT.
GABA has trophic function in
invertebrates
and is
excitatory in development
(Ben Ari, 2001; Tanaka, 2012)
depolarizing

lamprey

lancelet
hyperpolarizing
humans
Bipartate migration process
600Mya
450Mya
380Mya
310Mya
210-185Mya
40Mya
25Mya
150K
_____//____________//_____________//__________//_____________//____________________//_____________//___________//____
lancelet
lamprey
gnathostomes
amniotes
600Mya
mammals
anthropoid primates
hominoids
humans
450Mya
Lancelet: GABA in central/peripheral nervous system
histology
lancelet
GABA immunoreative
(Ir) cells
Lamprey: primitive vertebrate, robust INS but rudimentary sense organ/pallium/geniculate eminence
(GE); laminar brain and continuous periventricular striatum with little cellular migration; many
GABA-ergic cells as part of CSF-c neurons.
lamprey
GABA Ir cells
(Anadon, 1998; Barreiro-Iglesia, 2009 ; Mahmood, 2009; Candiani, 2102; Manaugh, 2013)
Bipartate migration process
600Mya
450Mya
380Mya
310Mya
210-185Mya
40Mya
25Mya
150K
_____//____________//_____________//_____________//_____________//______________//________________//___________//____
lancelet
lamprey
gnathostomes
amniotes
380Mya
mammals
anthropoid primates
hominoids
humans
310Mya
Gnathostomes: jawed fish vertebrates with GE; INS migrate tangentially from GE to new pallium
highly conserved; basic plan for INS in new parts of brain.
shark
GABA Ir cells
Amniotes: INS are competent to enter neo-cortex primordium, the sub-ventricular zone (SVZ) from
GE; GABA is local.
turtle
GABA Ir cells
(Metin, 2007; Rodriguez-Moldes, 2011; Manaugh, 2013)
Bipartate migration process
600Mya
450Mya
380Mya
310Mya
210-185Mya
40Mya
25Mya
150K
_____//____________//_____________//_____________//___________//________________//________________//___________//____
lancelet
lamprey
gnathostomes
amniotes
mammals
anthropoid primates
hominoids
humans
210-185Mya
Mammals: SVZ well established, also intermediate zone (IZ) and cortical plate (CP) layers II-VI in
dorsal pallium; INS originating in GE tangentially migrate to SVZ/VZ change trajectory to enter CP
and marginal zone (MZ); complex boundary pallium and sub-pallium controls tangential migration;
increase in GABA INS parallels increase in structural complexity of INS differing in geometry/distribution
patterns among species:
bat/rat 1%
INS
migration
pathways
from GE
to cortex
GABA
migration
with
age: rat

GE
cat/monkey 25%
(Winer, 1996; Wonders, 2006; Petanjek, 2008; Manaugh, 2013)
Bipartate migration process
600Mya
450Mya
380Mya
310Mya
210-185Mya
40Mya
25Mya
150K
_____//____________//_____________//_____________//_____________//_________________//_____________//___________//____
lancelet
lamprey
gnathostomes
amniotes
mammals
anthropoid primates
hominoids
humans
40Mya
Anthropoid primates: a folding neo-cortex increased migration distances GE to SVZ, so direct generation
now of intrinsically derived SVZ/VZ INS, a boosting for large dorsal production, a bipartite process
where INS migrate radially in addition to tangential migration; INS’ number/diversity increased more
than excitatory neurons; + selection for calcium binding proteins, CB/CR/PV, specifying differentiation
of INS overlaid on conserved architecture.
GABA migration
with age:
primates
CB
CR
PV
Petanjek, 2008; Sherwood, 2010; Manaugh, 2013)

Bipartate migration process
600Mya
380Mya
450Mya
310Mya
210-185Mya
40Mya
25Mya
150K
_____//____________//_____________//_____________//_____________//______________//________________//___________//____
lancelet
lamprey
gnathostomes
25Mya
amniotes
mammals
anthropoid primates
hominoids
humans
150Kya
Hominoids: local INS circuits crucial role; neo-cortex INS relatively invariant across species; increased
INS innervation to layers III and V for oral/facial expression.
Humans:18-34 weeks prenatal transient “ganglio-thalamo body” streams in INS to thalamic neurons;
significant changes INS organization, regions now connected to each other anatomically and functionally,
co-evolve; increase adhesion and axonal guidance molecules.
GABA migration with
age: humans
(Petanjek, 2008; Manaugh, 2 013)

Adaptive social acumen
Relaxed phylogenetic brain/body constraints, an evolutionary shift in behavioral inhibition was the
adaptive force/selective advantage for anthropoid primates’ social acumen to enhance attention
to gaze/self-awareness capabilities/diffusion of social learning; an extrinsic supply of neuromodulators specifying behavioral flexibility, DA/5-HT/ACh, natural selection’s
candidate substrates, reorganizing slower longer modulation of spatial
differences, thus altered INS’ terminal axon patterns; these
neuromodulators’ key role conferred advantage over
GABA by synchronizing multiple neurons for speed/
precision/feedback control/symbolic logic.
*
primate clade
honoring
social
acumen
DA
(Tram, 1981; Udin, 2007)
5-HT
ACh
Adaptive social acumen
9
9
human
4
32
homnoid
4
32
32
9
macs
4
These neuromodulators were regional (areas 9, 32 and 4) and layer specific, new innervation patterns
differing among species; the phylogenetic shift of anthropoid primates increased DA/5HT/ACh to
prefrontal cortex’s infragranular layers due to an accelerated rate gene coding sequences in
receptor domains; hominoid’s axon densities to the neo-cortex increased again as
“coils/clusters” for increasing plasticity, and a subtle human evolutionary shift
favored V/VI layers’ increased innervation, species x area x layer, p<0.05.
Prefrontal cortex areas:
DA:
9
32
4
layers V/VI
human >hominoids >macs
Alv/Nv:
true measure of
neuromodulator
density
5-HT
layers V/VI
human & hominoids >macs
layers V/VI
ACh:
(Raghanti 2007, 2008a, 2008b)
human >hominoids >macs
Conclusion
The evolutionary ancient CSF-c neurons were vitally important to
INS’ brain function 600 Mya, and leave a legacy for today for
neo-cortical INS functioning in helping define our
preeminent human identity.
starfish
44th
lancelet
starfish
ANNUAL MEETING
lancelet
jawless
fish
jawless
fish
reptiles
reptiles
mammals
mammals
44th ANNUAL MEETING ISPN
Thank you
Thank you
Alexandra Kunz, MD
Harvard University, Extension
Cambridge, MA, USA
[email protected]