Download Plasticity-related genes in brain development and amygdala

Genes, Brain and Behavior (2016) 15: 125–143
doi: 10.1111/gbb.12255
Review
Plasticity-related genes in brain development
and amygdala-dependent learning
D. E. Ehrlich†,‡,∗ and S. A. Josselyn§,¶,∗∗,††
† Department of Neuroscience and Physiology, Neuroscience
Institute, NYU Langone Medical Center, ‡ Department of
Otolaryngology, NYU Langone School of Medicine, New York,
NY, USA, § Program in Neurosciences & Mental Health, Hospital
for Sick Children, ¶ Department of Psychology, ∗∗ Institute of
Medical Sciences, and †† Department of Physiology, University
of Toronto, Toronto, ON, Canada
*Corresponding author: D. E. Ehrlich, Department of Neuroscience and Physiology, Neuroscience Institute, NYU
Langone Medical Center, New York, NY, USA. E-mail:
[email protected]
Learning about motivationally important stimuli involves
plasticity in the amygdala, a temporal lobe structure.
Amygdala-dependent learning involves a growing
number of plasticity-related signaling pathways also
implicated in brain development, suggesting that
learning-related signaling in juveniles may simultaneously influence development. Here, we review
the pleiotropic functions in nervous system development and amygdala-dependent learning of a signaling
pathway that includes brain-derived neurotrophic
factor (BDNF), extracellular signaling-related kinases
(ERKs) and cyclic AMP-response element binding protein (CREB). Using these canonical, plasticity-related
genes as an example, we discuss the intersection of
learning-related and developmental plasticity in the
immature amygdala, when aversive and appetitive
learning may influence the developmental trajectory of
amygdala function. We propose that learning-dependent
activation of BDNF, ERK and CREB signaling in the
immature amygdala exaggerates and accelerates neural development, promoting amygdala excitability and
environmental sensitivity later in life.
Keywords: Amygdala, BDNF, CREB, critical period, development, ERK, excitability, GABA, learning and memory,
plasticity
Received 7 July 2015, revised 12 September 2015, accepted
for publication 14 September 2015
Cell signaling molecules involved in brain development have
long been recognized to contribute later in life to learning and
memory (Kandel & O’Dell 1992). Throughout life, neural plasticity is necessary to provide adaptive and enduring refinement of the brain and behavior. Brain structure and function
must be permanently altered in the face of developmental
cues, and comparable long-term alterations are thought to
be the physical substrate of learning. Adaptation on such time
scales is afforded by alterations of neuronal gene expression,
meaning neurons require signal transduction mechanisms to
relay external developmental guidance and learning cues to
the cytosol and nucleus. Classic examples of signal transduction molecules that promote both developmental and
learning-related plasticity include brain-derived neurotrophic
factor (BDNF) and the extracellular signaling-related kinases
(ERKs). Although originally described for their roles in cell
proliferation, maturation and survival (Cohen-Cory et al. 2010;
Lonze et al. 2002; Riccio et al. 1999), these molecules were
subsequently shown to contribute to plasticity underlying
learning and memory in adulthood (Poo 2001; Sweatt 2001).
A wealth of literature has since identified BDNF and ERK
as key mediators of the plasticity necessary for learning in
the amygdala, a brain region important in mediating learning
about motivationally important stimuli (Rattiner et al. 2004b;
Schafe et al. 1999). More recently, additional signal transduction molecules classically implicated in brain development
were found to play roles in amygdala-dependent learning;
these molecules include Wnt (Maguschak & Ressler 2011),
Notch (Dias et al. 2014) and CREB (cyclic AMP response
element binding protein), a transcription factor acting downstream of BDNF and ERK (Josselyn 2010).
Given the pleiotropic function of signal transduction
pathways in both development and learning, an important
question arises: to what extent does learning-induced plasticity influence ongoing development? Early in life, the
amygdala encodes learning about motivational stimuli by
engaging molecules that may also regulate development.
When immature organisms with developing brains learn
about their environments, intracellular signaling pathways
that mediate this learning may also alter developmental
trajectories by virtue of shared molecular pathways. More
specifically, learning-dependent activation of amygdala BDNF,
ERK and CREB may influence amygdala development and
alter subsequent behavioral outcomes.
Here, we review the diverse functions of the BDNF–ERK–
CREB signaling cascade in brain development and
amygdala-dependent learning. First, we describe the physiological conditions that activate these molecules and identify
the pathways that link them. Next, we outline the contributions of BDNF, ERK and CREB to amygdala-dependent
© 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society
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Figure 1: Intracellular signaling pathways linking BDNF, ERK, and CREB. For a detailed description of the signaling pathways linking
these molecules, see text. BDNF from paracrine sources including afferent axon terminals and dendrites in target tissue, as well as
autocrine pools, binds to TrkB receptors and causes receptor dimerization and subsequent downstream signaling. Autophosphorylation
of TrkB at specific tyrosine residues leads to recruitment of adaptor complexes and distinct intracellular cascades. Phosphorylation
of Y515 leads to Ras-ERK and PI3K (phosphatidylinositol-4,5-bisphosphate 3-kinase) signaling, while phosphorylation of Y816 leads to
signaling via PLC𝛾. Through IP3 (inositol trisphosphate) activation and subsequent elevation of cytosolic calcium levels, PLC𝛾 induces
signaling to the nucleus via CaM and CaM-dependent protein kinases. Synapses can also supplement TrkB-dependent signaling by
activating neurotransmitter receptors and ion channels that elevate intracellular calcium. These complementary signaling pathways
are each capable of phosphorylating nuclear CREB and promoting transcription of CREB target genes. AC, adenylyl cyclase; DAG,
diacylglycerol; ECP, extracellular protease; Glu, glutamate; mBDNF, mature BDNF; NMDAR, N-methyl-D-aspartate receptor; PKA,
protein kinase A; Rap1, Ras-related protein 1; RSK, ribosomal S6 kinase; VGCC, voltage-gated calcium channel.
associative learning that occurs early in life while the amygdala is still developing. Based on the canonical roles of BDNF,
ERK and CREB in neural development, we discuss the potential for crosstalk between development and learning-related
plasticity in juveniles, when motivational learning may alter
developmental trajectories of amygdala function. Finally, we
consider the impact of juvenile learning on amygdala function
and speculate on implications for behavioral outcomes and
psychiatric disease.
Intracellular signaling pathways linking BDNF,
ERK and CREB
Signal transduction pathways convey information regarding
extracellular stimuli to the nucleus to regulate gene expression, enabling adaptive plasticity utilized throughout biology.
These signal transduction pathways are not linear or discrete,
but involve many molecules with convergent and divergent
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interactions. The interconnectedness and overlap of signaling pathways not only provides adaptability but also affords
the potential for crosstalk. While distinct extracellular stimuli
give rise to cellular changes underlying neural development
and memory encoding, such stimuli elicit convergent intracellular signaling through BDNF, ERK and CREB. Below, we
describe the major constituents of this signaling pathway and
their interactions (Fig. 1).
Brain-derived neurotrophic factor secretion
and downstream signaling
Brain-derived neurotrophic factor is a secreted molecule
capable of conveying signals to the nucleus to influence gene
expression. It is tonically released from neuron somata via
the ‘constitutive secretion’ pathway to provide a continuous
survival signal, and phasic release from neurites can be triggered via the ‘regulated secretion’ pathway (Brigadski et al.
2005; Chen et al. 2005). Brain-derived neurotrophic factor
expression and signaling tend to correlate positively with
Genes, Brain and Behavior (2016) 15: 125–143
Plasticity-related genes in brain development and amygdala-dependent learning
neural activity (Tongiorgi et al. 1997; for review, see West
et al. 2014), affording a useful signal for activity-dependent
synaptic modulation. Brain-derived neurotrophic factor may
be released from either axons or dendrites (Kohara et al.
2001; Kolarow et al. 2007; Matsuda et al. 2009) and act in
both a paracrine and autocrine fashion (Cheng et al. 2011).
In addition to mature protein, immature pro-BDNF may be
released from axons and bind receptors or cleaved by extracellular proteases into the mature peptide (Gottmann et al.
2009; Lu et al. 2005; Yang et al. 2009).
Brain-derived neurotrophic factor dimers bind the extracellular domain of the tropomyosin-related kinase B (TrkB)
receptor, causing receptor dimerization and autophosphorylation. Subsequent binding of intracellular adaptor proteins
leads to the activation of three major signaling cascades:
ERK, phosphatidylinositol 3-kinase (PI3K) and phospholipase
C-𝛾 (PLC𝛾) (Segal & Greenberg 1996). Autophosphorylation of
TrkB receptors at specific tyrosine residues leads to distinct
signaling pathways that include the ERK family of kinases
and CREB (Minichiello et al. 2002). For instance, phosphorylation of TrkB at tyrosine 515 (Y515) provides a docking
site for Shc (Src homology 2 domain-containing adaptor protein), which recruits the adaptor protein, Grb2 (growth factor
receptor-bound protein 2) complexed with Sos (son of sevenless). Sos is an exchange factor for Ras, which sits upstream
of ERK in a canonical mitogen-activated protein kinase cascade (Huang & Reichardt 2003). On the other hand, phosphorylation of TrkB at Y816 leads indirectly to nuclear CREB
signaling via the calcium/calmodulin (CaM) kinase pathway
(Minichiello et al. 2002).
The ERK pathway
Extracellular signaling-related kinases are a family of
effectors for a plasticity-related intracellular signaling cascade, activated not only by BDNF but also by
neurotransmitter-dependent calcium signaling (Sweatt
2001). The ERK pathway consists of three kinases linked in
series via sequential phosphorylation. Ras phosphorylates
a Ras-associated factor (Raf) kinase family member, c-Raf,
which in turn phosphorylates the mitogen-activated protein
kinase kinases, MEK1 and/or MEK2. The MEKs directly
phosphorylate ERK1 and ERK2. Importantly, ERK indirectly
influences transcription via the CREB signaling, and TrkB
phosphorylation may induce translocation of activated ERK
to the nucleus (Pizzorusso et al. 2000; Ying et al. 2002). For
example, ligand-induced endocytosis of neurotrophin receptors drives activation and nuclear translocation of ERK5,
which itself phosphorylates CREB (Watson et al. 2001). In
addition, ERK1, ERK2 and ERK5 phosphorylate the ribosomal
S6 kinase family of protein kinases that can also mediate activation of CREB (Huang & Reichardt 2003; Xing et al. 1996).
Transcriptional regulation by CREB activation
Cyclic AMP-response element binding protein acts as an
effector of multiple signaling cascades to transduce signals
from synapses to the nucleus, regulating transcription of
plasticity-related genes (Deisseroth & Tsien 2002). Cyclic
AMP-response element binding protein is a member of
a family of basic-leucine zipper transcription factors that
Genes, Brain and Behavior (2016) 15: 125–143
bind as dimers to a cAMP-response element (CRE) in the
promoter of numerous genes (Shaywitz & Greenberg 1999;
Sheng et al. 1991). It is canonically sensitive to activation
of the cAMP-dependent protein kinase, protein kinase A
(Gonzalez & Montminy 1989). Cyclic AMP-response element
binding protein also serves as a point of convergence for
the three major pathways activated by BDNF, and CREB
is activated by a variety of extracellular signals including
hormones, growth factors and synaptic activity (Finkbeiner
et al. 1997; Ma et al. 2011), as well as by activity-dependent
calcium influx (Kornhauser et al. 2002). For instance, TrkB
receptor activation can elicit ERK signaling not only via Ras
but also through PLC𝛾, which drives MEK phosphorylation
through diacylglycerol pathway and the Raf kinase, b-Raf
(Schinelli et al. 2001). Complementarily, calcium entry via the
PLC𝛾 pathway can activate the calcium sensor CaM, which
is shuttled to the nucleus by 𝛾-CaM kinase II (𝛾CaMKII) to
phosphorylate the CREB kinase, CaMKIV (Ma et al. 2014).
In addition, CREB is a phosphorylation target of Akt (also
known as protein kinase B), which is activated by BDNF and
TrkB receptors via the PI3K pathway (Du & Montminy 1998;
Yamada et al. 1997). Phosphorylation of CREB at a key serine
residue, Ser133, allows it to interact with transcriptional
coactivators (Mayr & Montminy 2001) to promote transcription of genes enabling structural and functional plasticity
of neurons (Barco et al. 2003; Bourtchuladze et al. 1994;
Josselyn & Nguyen 2005; Martin & Kandel 1996; Silva et al.
1998). Cyclic AMP-response element binding protein can
also activate transcription via a phosphorylation-independent
pathway involving the co-factor CRTC1 (CREB-regulated
transcription coactivator 1) (Sekeres et al. 2012).
The BDNF–ERK–CREB cascade is not unidirectional, as
ERK and CREB also provide feedback regulation of BDNF
expression. Cyclic AMP-response element binding protein
is thought to promote transcription of the Bdnf gene at
promoter IV, which contains a CRE regulatory component
(Zheng & Wang 2009). When applied to neuronal cultures,
for instance, BDNF drives transcription of the Bdnf gene
in a CREB-dependent fashion (Shaywitz & Greenberg 1999;
Tao et al. 1998). Activity-dependent transcription of BDNF
also requires ERK activity (Zheng & Wang 2009). Together,
these findings suggest that BDNF, ERK and CREB work in
concert to adapt neuronal gene expression and function to
developmental and environmental demands. The various
interactions of these signaling molecules creates a point of
convergence in neural function, meaning a variety of extracellular factors can similarly influence signal transduction and
stimulate neuronal plasticity.
Brain-derived neurotrophic factor, ERK
and CREB signaling in amygdala-dependent
learning
Amygdala function in learning and memory
The BDNF signaling pathway has been long recognized as a
regulator of synaptic strength whose experience-dependent
secretion underlies learning (Kang & Schuman 1995; Korte
et al. 1995; Kovalchuk et al. 2002; Minichiello 2009; Pang
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et al. 2004; Patterson et al. 1996), and more recent work has
implicated this pathway specifically in memory encoding in
the amygdala (Andero et al. 2014; Leal et al. 2014; Minichiello
2009). The amygdala is a critical component of the circuit
mediating Pavlovian fear conditioning (Davis & Whalen 2001;
Fanselow & Gale 2003; LeDoux 2007; Maren & Quirk 2004;
Pape & Pare 2010). In this paradigm, a motivationally neutral
cue (such as a tone or light) is paired with a noxious stimulus
(such as a footshock). Subsequent presentation of the tone or
light alone elicits conditioned fear responses (typically measured by freezing behavior or fear-potentiated startle). The
formation of these learned associations regarding threatening stimuli are thought to promote survival by enabling protective behavioral responses.
The amygdala is required for many forms of fear conditioning, and synaptic plasticity in amygdala circuits is thought to
encode these memories (Davis et al. 2003; LeDoux 2007;
Pape & Pare 2010). Through fear conditioning, subsets of
amygdala neurons become necessary (Han et al. 2007, 2009)
and sufficient (Kim et al. 2014; Redondo et al. 2014; Yiu et al.
2014) for recall of memories for fear-inducing experiences,
suggesting that this collection of neurons form a critical
hub in the physical representation of associative fear learning, known as the ‘memory trace’ or ‘engram’. Much of the
learning-related plasticity in the amygdala occurs in its basolateral complex, comprised of the lateral and basolateral (or
basal) nuclei, which acts as a thoroughfare that receives sensory input and projects to amygdala output nuclei (Davis
1992; Fanselow & LeDoux 1999; McDonald 1998). The majority of experiments described below focused specifically on
this subregion.
In addition to its role in mediating fear conditioning, the
amygdala, in particular its basolateral complex, is important for learning about rewarding stimuli (Baxter & Murray 2002; Costafreda et al. 2008; Hennenlotter et al. 2005;
Maren 2003; Namburi et al. 2015). For instance, the amygdala is required for learning in the conditioned place preference paradigm, in which an experimental context becomes
preferred via association with a rewarding drug (Everitt et al.
2003; Fuchs et al. 2002; Heldt et al. 2014; Hiroi & White 1991;
LeDoux 2000). Amygdala neurons become activated during
appetitive Pavlovian conditioning (Cole et al. 2013). By a similar mechanism as that observed for aversive conditioning, a
subset of neurons in the amygdala also constitutes a hub in
a rewarding engram (Hsiang et al. 2014).
The BDNF–TrkB signaling promotes amygdala
plasticity and learning
Amygdala-dependent learning requires BDNF signaling
(Musumeci & Minichiello 2011; for review, see Rattiner et al.
2005). Both BDNF (Conner et al. 1997; Yan et al. 1997a) and
TrkB (Fryer et al. 1996; Yan et al. 1997b) are expressed highly
in the amygdala, and BDNF in the amygdala is activated by
fear conditioning. For instance, presentation of paired neutral
and aversive stimuli, as during Pavlovian fear conditioning,
elicits an increase in BDNF expression and Trk receptor
activation in the amygdala 2 h later. However, unpaired presentation of these stimuli, in a configuration not capable of
producing learning, does not elicit BDNF signaling (Rattiner
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et al. 2004a). Corroborating evidence has since identified
a positive correlation of amygdala BDNF expression and
fear memory (Yee et al. 2007). Fear conditioning involves
selective upregulation in the amygdala of two specific Bdnf
transcripts, with mRNA levels for exons I and III (but not
II, IV or V) showing significant elevation following training
(Rattiner et al. 2004b). Importantly, Exon I of the Bdnf gene is
preferentially transcribed in an activity-dependent fashion by
CREB (Tabuchi et al. 2002). Brain-derived neurotrophic factor
expression in the amygdala is elevated as much as 12 h after
fear conditioning, and TrkB receptor blockade during this
time course interferes with memory at 7 days but not 1 day
after training; these data suggest protracted amygdala BDNF
signaling following learning plays a role in consolidation of
fear memory (Ou et al. 2010).
Manipulation of BDNF expression and function interferes with several forms of amygdala-dependent learning.
Intra-amygdala infusions of nonspecific Trk receptor antagonists or expression of dominant-negative, truncated TrkB
protein interferes with acquisition of Pavlovian fear conditioning (Rattiner et al. 2004a). The contribution of BDNF
to fear learning is likely conserved across species, as the
Bdnf Val66Met single nucleotide polymorphism in humans,
which reduces activity-dependent BDNF release, correlates
with reduced fear learning and episodic memory (Egan et al.
2003; Lonsdorf et al. 2010). In addition, BDNF is required
for the learned suppression of previously acquired fear
associations known as ‘extinction’ (Chhatwal et al. 2006).
Tropomyosin-related kinase B receptor agonists enhance
extinction (Andero et al. 2011), and humans and rodents with
the Val66Met mutation exhibit deficits in extinction learning
that may be instantiated over the course of development,
downstream of BDNF expression (Psotta et al. 2013; Soliman
et al. 2010). Recent research has also shown a role for BDNF
and TrkB activation in the amygdala during appetitive learning
(Heldt et al. 2014).
Brain-derived neurotrophic factor release and TrkB activation are thought to contribute to learning by enhancing
synaptic plasticity in the amygdala. For instance, BDNF is
required for the enduring strengthening of synapses known
as ‘long-term potentiation’ (LTP) of amygdala afferents, and
exogenous BDNF application reduces the stimulation threshold for LTP (Li et al. 2011). Interestingly, LTP of amygdala afferents was also blocked using an inhibitor of extracellular protease activity, suggesting conversion of synaptically released
pro-BDNF to mature BDNF may be a critical step in amygdala LTP (ibid.). Blockade of postsynaptic TrkB receptors in
amygdala neurons was subsequently found to prevent LTP
specifically in thalamic inputs, which are thought to convey
sensory representations of aversive cues (Meis et al. 2012).
Extracellular signaling-related kinase is necessary
for fear learning and amygdala plasticity
Brain-derived neurotrophic factor activation of TrkB receptors promotes learning via activation of the ERK signaling
pathway. The first evidence for a role of ERK signaling in
amygdala-dependent learning was observed after blockade of
fear conditioning by systemic inhibition of MEK (Atkins et al.
1998). Later studies corroborated this effect (Di Benedetto
Genes, Brain and Behavior (2016) 15: 125–143
Plasticity-related genes in brain development and amygdala-dependent learning
(a)
(b)
(c)
Priming Neurons
for Allocation
Priming Requires
Elevated Excitability
LA
Typical Associative
Memory Trace
LA Neuron
CREB or
excitability
Neuron in memory trace
(d)
(e)
Primed Neurons
Sufficient for Fear
CREB &
excitability
(f)
Primed Neurons
Required for Memory
New Learning
Post-Erasure
LA
et al. 2009; Schafe et al. 2000; Tarpley et al. 2009) and
identified an essential role for ERK in fear memory consolidation (Schafe et al. 1999). The ERKs are critical mediators
of the effects of BDNF on fear learning (Ou & Gean 2006)
and synaptic plasticity in the amygdala (Li et al. 2011), and
ERK phosphorylation is increased throughout the amygdala
following Pavlovian fear conditioning (Besnard et al. 2014).
ERK signaling is specifically required for the late phase of
LTP of synapses in the amygdala (Huang et al. 2000), potentially explaining the memory consolidation deficits caused
by TrkB Y515 deletion (Minichiello et al. 2002). In addition,
the ERK pathway is required for extinction of fear learning
(Herry et al. 2006) and reconsolidation following fear memory reactivation (Duvarci et al. 2005). ERK signaling in the
amygdala is not restricted to Pavlovian fear conditioning, as
post-training infusion of an MEK inhibitor into the amygdala
also prevents consolidation of inhibitory avoidance learning
(Walz et al. 2000).
X
X
X X X
X X
Cyclic AMP-response element binding protein
shapes memory traces in the amygdala
Similar to BDNF and ERK, CREB is also implicated in learning and synaptic plasticity. The first studies that identified a role for CREB in memory formation were performed
in invertebrates (Dash et al. 1990; Kaang et al. 1993; Yin
et al. 1994, 1995). Cyclic AMP-response element binding
protein was soon after recognized as an essential contributor to synaptic plasticity and long-term memory formation in rodents, including in the amygdala for aversive
learning (Bourtchuladze et al. 1994; Josselyn et al. 2001,
2004; Kogan et al. 1997). Cyclic AMP-response element
binding protein may contribute to memory allocation in
the mouse amygdala by promoting dendritic spine growth
(Sargin et al. 2013).
Cyclic AMP-response element binding protein shapes
memory encoding in the amygdala by regulating competition
among neurons, by virtue of varying expression levels (Fig. 2).
Memory traces encoding Pavlovian fear conditioning include
approximately 15% of pyramidal (excitatory) neurons in the
lateral nucleus of the amygdala (LA). Importantly, LA neurons
can be primed for recruitment to a memory trace through
overexpression of CREB, resulting in their incorporation
into memory traces at much higher rates than neighboring
neurons (Han et al. 2007). During memory recall, this small
subset of LA neurons becomes preferentially re-activated
(ibid.) and was shown to be necessary and sufficient for
recall of conditioned fear; selective ablation of this population causes specific memory erasure without disrupting
other memories or subsequent learning (Han et al. 2009) and
specific reactivation of this population elicits fear responses
(Kim et al. 2014). This mechanism of memory allocation in
the amygdala appears to be employed broadly, as amygdala
neurons expressing higher levels of CREB are selectively
recruited to memory traces for both aversive (Han et al.
2007, 2009; Zhou et al. 2009) and appetitive experiences
(Hsiang et al. 2014).
The contribution of CREB to amygdala-dependent learning
is likely mediated by its actions as a transcription factor,
promoting expression of plasticity-related target genes.
Genes, Brain and Behavior (2016) 15: 125–143
CREB,
then reactivate
CREB,
then ablate
Neuron in
new trace
Figure 2: The role of CREB in memory allocation in the
amygdala. (a) Approximately 15% of neurons in the LA are incorporated into memory traces for aversive and appetitive experiences (Han et al. 2007; Hsiang et al. 2014). (b) LA neurons
overexpressing CREB or with artificially elevated excitability are
preferentially recruited to these memory traces (Han et al. 2007,
2009; Hsiang et al. 2014; Yiu et al. 2014; Zhou et al. 2009). (c)
CREB-mediated increases in amygdala neuron excitability are
required for preferential memory allocation, as reducing excitability by co-expression of a potassium channel blocks the effect
of CREB (Yiu et al. 2014). (d) CREB-primed neurons recruited
to a memory trace are sufficient for fear expression when activated post-learning, as illustrated by co-expressing CREB with an
inhibitory cation channel sensitive to an exogenous ligand (Kim
et al. 2014). (e, f) CREB-overexpressing neurons in a memory
trace are necessary for recall. Ablation of this population erases
memories encoded when CREB levels were high (e) but does not
prevent subsequent learning (f) (Han et al. 2009).
The effects of CREB on memory consolidation may be
mediated by transcription of Bdnf (Suzuki et al. 2011),
but CREB targets also include immediate early genes,
calcium-binding proteins and ion channels (Impey et al.
2004). More recently, a genomic study in the nematode
identified potential memory-promoting targets of CREB
that were upregulated specifically in neurons that mediate learning. These CREB downstream targets include a
wide variety of intracellular signaling molecules, neurotransmitter receptor subunits, synaptic scaffolds, synaptogenic
proteins, axon guidance cues and regulators of neuronal
adhesion and migration (Lakhina et al. 2015). Similar classes
of genes were identified as targets of CREB specifically
in the amygdala, based on a transcriptomic comparison
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from CREB-deficient transgenic and wild-type mice (Ecke
et al. 2011). CREB-dependent transcription is supported by
CRTC1, which also acts in the amygdala and hippocampus
to promote fear memory formation (Nonaka et al. 2014;
Sekeres et al. 2012).
Complementary functions of ERK and CREB
in amygdala-dependent learning
Downstream of BDNF activation of TrkB receptors, ERK and
CREB make divergent contributions to amygdala-dependent
learning. As described above, phosphorylation of TrkB
at distinct tyrosine residues leads to activation of ERK
(Y515) and CREB (Y816) (Minichiello et al. 2002). Knock-in
mice containing single mutations in the ERK signaling
site of TrkB exhibit specific deficits in cued fear consolidation (Musumeci et al. 2009). In contrast, comparable
mutation of the CREB signaling site of TrkB causes a
distinct constellation of effects: deficits in acquisition,
not consolidation, of cued fear, reduced postsynaptic calcium signaling and deficits in intra-amygdalar LTP (ibid.).
Importantly, these data suggest TrkB-dependent ERK and
CREB signaling act somewhat independently and are both
required for proper associative memory formation in the
amygdala.
Amygdala excitability regulates learning
and is sensitive to intracellular signaling
Cyclic AMP-response element binding protein signaling
indirectly contributes to learning by promoting amygdala
excitability. Persistent elevation of neuronal excitability is
long known to contribute to memory encoding (Byrne et al.
1991), and learning classically enhances the excitability of
amygdala neurons. Fear conditioning specifically elevates
the excitability of individual amygdala neurons (Rosenkranz
& Grace 2002; Sehgal et al. 2014), and comparable changes
were recently observed in the amygdala following reward
learning (Motanis et al. 2014). Amygdala neurons more
intrinsically excitable than their neighbors have a competitive
advantage for recruitment to memory traces (Yiu et al. 2014).
Importantly, CREB may promote memory allocation in
the amygdala by enhancing amygdala neuron excitability, as
CREB potently elevates the excitability of amygdala neurons
(Viosca et al. 2009; Yiu et al. 2014; Zhou et al. 2009), and artificially reducing neuronal excitability in CREB-overexpressing
neurons negates their competitive advantage for recruitment
to fear memory traces (Yiu et al. 2014). Therefore, experimentally increasing excitability in a subset of neurons at the time
of training may mimic and amplify endogenous processes
that occur during normal memory encoding. During natural
engram formation, amygdala neurons that happen to be more
excitable at the time of training are preferentially allocated to
the resulting engram (Gouty-Colomer et al. 2015), an effect
predicted by in silico studies (Kim et al. 2013, 2015).
Extracellular signaling-related kinase may also promote
learning via effects on neural excitability. While manipulations
of ERK signaling have no observable effect on cortical neuron
excitability at baseline, when applied after learning, MEK
inhibitors abolish the learning-induced increase in intrinsic
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excitability. ERK signaling is therefore thought to play a
role in maintaining excitability changes following learning
(Cohen-Matsliah et al. 2007). Elevated excitability may in
turn promote CREB-dependent transcription by enhancing depolarization-induced calcium entry via voltage-gated
calcium channels and the N-methyl-D-aspartate glutamate
receptor, which stimulate CaM-dependent signaling pathways that promote CREB phosphorylation (Dolmetsch et al.
2001; Ma et al. 2011).
Amygdala excitability and memory encoding are gated by
the inhibitory neurotransmitter 𝛾-aminobutyric acid (GABA),
which in turn is modulated by BDNF, ERK and CREB.
𝛾-Aminobutyric acid is the primary source of synaptic inhibition in the vertebrate brain, and suppression of GABAergic
inhibition is a common mechanism used throughout the nervous system (Froemke 2015) and specifically in the amygdala
(for review, see Ehrlich et al. 2009) to elevate excitability and promote learning. GABAergic inhibition typically
opposes learning and synaptic plasticity in the amygdala,
and GABAergic agonists suppress the acquisition of both
fear and extinction learning (Ehrlich et al. 2009), although
recent evidence highlights the heterogeneous functions of
GABA in the amygdala (Ryan et al. 2012; Wolff et al. 2014).
Excessive excitability of the amygdala caused by loss of
GABAergic tone is suggested to underlie psychiatric disorders involving excessive amygdala reactivity and memory
encoding (Grace & Rosenkranz 2002; Quirk & Gehlert 2003;
Rainnie et al. 2004).
Indirect effects of BDNF and CREB on neural excitability are mediated by suppression of GABAergic transmission.
For instance, BDNF reduces GABAergic neuron excitability and inhibitory synaptic transmission, providing net disinhibition to neural circuits (Frerking et al. 1998; Holm et al.
2009; Tanaka et al. 1997). In the amygdala, activation of TrkB
receptors by BDNF can elicit GABA receptor internalization,
dampening GABAergic signaling (Mou et al. 2011). In addition,
BDNF knockout mice exhibit increased GABAergic synaptic
transmission in the adult hippocampus. This effect is mimicked by acutely blocking BDNF signaling with scavenger proteins, suggesting BDNF constitutively suppresses GABAergic neuron excitability (Olofsdotter et al. 2000). The effects
of BDNF on the GABA system may rely on CREB signaling, as activity-dependent transcription of Bdnf at promoter
IV, where CREB acts to stimulate BDNF expression, plays
a key role in regulating GABAergic synaptic transmission
and plasticity (Sakata et al. 2009). In contrast, ERK signaling
serves to promote GABA release, and excessive ERK signaling has been linked to GABA-dependent deficits in learning
and synaptic plasticity (Cui et al. 2008).
Temporal overlap of amygdala development
and amygdala-dependent learning
The juvenile amygdala participates in motivational
learning
Given the well-established role of BDNF–ERK–CREB signaling in amygdala-dependent learning, these molecules may
contribute to the effects of early experience on amygdala
Genes, Brain and Behavior (2016) 15: 125–143
Plasticity-related genes in brain development and amygdala-dependent learning
Week
1
2
3
With age...
dendrites
expand;
dendritic
spines
emerge;
excitability
decreases,
firing is more
regular
GABAergic
currents
are larger
and faster.
development. If memory is encoded at early developmental stages when signaling molecules still regulate neuron
maturation, learning-induced signaling may alter ongoing
development. Such an interaction may occur following
amygdala-dependent learning, as Pavlovian conditioning
emerges as early as infancy and maturation of the amygdala
proceeds throughout childhood. Below, we address this
temporal overlap by outlining the ontogeny of fear learning
in relation to the trajectory of amygdala development.
Several recent reviews have thoroughly outlined the
maturation of associative learning, including Pavlovian fear
conditioning, so we provide a brief survey (Callaghan &
Richardson 2013; King et al. 2013; Landers & Sullivan 2012;
Wiedenmayer 2009). In humans, associative fear learning is
observed in childhood and becomes more pronounced with
age (Gao et al. 2010). Infant rodents also exhibit the capacity
for fear conditioning well before puberty, which occurs around
postnatal day 30 (P30) in rats. When presented with an adult
conspecific, infant rats as young as P12 innately respond with
defensive freezing behavior and corresponding amygdala
activation (Moriceau et al. 2004; Takahashi 1992). Rodents
also become capable of associative fear learning at this
stage (Akers et al. 2012; Vogt & Rudy 1984). Pavlovian fear
conditioning elicits the mature phenotype – avoidance of the
originally neutral cue – in infant rats as young as P10. However, before this age, training leads to a paradoxical approach
to the cue (Sullivan et al. 2000). Fear-induced enhancement
of startle responses, known as ‘fear-potentiated startle’,
also emerges at various points in infancy, depending on
the modality of the conditioned stimulus (Barnet & Hunt
2006; Hunt 1999). Developmental regulation of motivational
learning proceeds beyond infancy, as adolescent rodents and
humans exhibit temporary suppression of fear expression
and extinction learning (Pattwell et al. 2011, 2012).
Genes, Brain and Behavior (2016) 15: 125–143
4
Figure 3: A summary of early postnatal development of amygdala
neurons. Amygdala development progresses throughout infancy and into
early adolescence, with pronounced
maturation of neuron structure and
function. Across the first postnatal
month, changes include (from top
to bottom): expansion of dendritic
arbors, illustrated with representative
dendrite reconstructions; dendritic
spine emergence from relatively
aspinous dendrites at 1 week of age;
reduced intrinsic excitability, with
more depolarizing input required to
drive action potential production, and
a concurrent increase in maximal
action potential frequency; more
regularity of firing, with a loss of
calcium-dependent burst discharges
and increased synaptic strength,
depicted with currents elicited by
application of GABA (adapted with
permission from Ehrlich et al. 2012,
2013; Ryan et al. 2014).
Childhood development of amygdala structure,
function and connectivity
The emergence and refinement of fear learning in infancy
parallels the structural and functional maturation of the
amygdala. In children, the amygdala already contributes to
motivationally relevant behavior, as this region is specifically
activated in response to viewing faces that depict emotional
states (Baird et al. 1999; Thomas et al. 2001). The amygdala
is also activated during fear conditioning in human children
(Monk et al. 2003). Studies on humans and nonhuman primates have shown protracted structural development of
the amygdala well into childhood (Giedd et al. 1996; Payne
et al. 2010). In rodents, the age at which Pavlovian avoidance
emerges directly corresponds with training-induced activation of the amygdala, further suggesting that the amygdala
begins to contribute to learning in infancy (Sullivan et al.
2000).
Rodent research has identified maturation of amygdala
neurons throughout infancy and into adolescence (Fig. 3).
The amygdala emerges during gestation in rats (Berdel et al.
1997a) and undergoes volumetric changes soon after birth
(Berdel et al. 1997b; Chareyron et al. 2012). As the region
grows individual amygdala neurons mature, exhibiting pronounced dendritic expansion and emergence of dendritic
spines between birth and adolescence (Ryan et al. 2014).
Concomitant with structural maturation are pronounced electrophysiological changes in the amygdala. During infancy,
amygdala neurons become an order of magnitude less
excitable and lose their propensity to fire bursts of action
potentials (Ehrlich et al. 2012). Synaptic transmission in the
amygdala is also refined during this period (Bosch & Ehrlich
2015; Ehrlich et al. 2013), and adult-like LTP of amygdala afferents emerges during infancy when the amygdala begins to
contribute to fear learning (Thompson et al. 2008).
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Ehrlich and Josselyn
Infant amygdala development also includes refinement of
GABAergic function. Individual GABAergic neurons develop
more widespread connectivity, as GABAergic axons increasingly collateralize with age while cell bodies decrease in
density (Brummelte et al. 2007). Early in infancy, GABA
in the amygdala is not inhibitory, but rather elicits excitatory responses in amygdala projection neurons (Ehrlich et al.
2013). This switch to mature GABAergic inhibition in the
amygdala coincides with the emergence of LTP of amygdala
synapses and the expression of fear conditioning (Sullivan
et al. 2000; Thompson et al. 2008). There is a concurrent shift
in the complement of GABA receptor expression in the amygdala, influencing the kinetics of GABA receptor-mediated
responses (Ehrlich et al. 2013; Zhang et al. 1992).
As intrinsic connectivity of the amygdala is refined, its
neurons also become better integrated with distant brain
regions. For instance, relative to adults, children have less
functional connectivity of the amygdala with cerebral cortex,
including prefrontal and association cortices (Qin et al. 2012).
Prefrontal cortical and thalamic afferents in the amygdala
undergo growth and subsequent pruning during infancy
and adolescence (Bouwmeester et al. 2002a; Cressman
et al. 2010). One indication of synapse number suggests
that synaptic density increases in the amygdala threefold
from infancy to adolescence (Morys et al. 1998). Amygdala
projections to distant target regions also mature during this
developmental window, as efferents to the prefrontal cortex
become refined during infancy (Bouwmeester et al. 2002b;
Verwer et al. 1996).
Brain-derived neurotrophic factor, ERK
and CREB regulation of neural development
We propose that learning-induced BDNF–ERK–CREB signaling in juveniles alters amygdala development by exaggerating and accelerating the developmental functions of these
molecules. Below, we describe the contributions of BDNF,
ERK and CREB to neural development, which include promoting proliferation and survival, enhancing neurite growth,
stimulating synapse and dendritic spine formation and regulating developmental synaptic plasticity. Given the breadth
of developmental functions and stages under regulation of
BDNF–ERK–CREB signaling, identifying specific processes
and temporal windows of potential regulation will be key for
determining mechanisms of crosstalk between development
and learning.
Signal transduction pathways for cell proliferation,
differentiation and survival
Early in development, BDNF, ERK and CREB promote neuron
proliferation and survival. For instance, BDNF signaling at
the TrkB receptor opposes apoptosis and promotes survival
of developing neurons via an ERK-dependent mechanism
(Hetman et al. 1999). Similarly, ERKs 1 and 2 were first
identified as regulators of cell division and differentiation
that are sensitive to mitogens (for review, see Sweatt 2001).
Deletion of ERK early in development limits neural progenitor
populations and causes precocious neurogenesis, altering
132
developmental trajectories and outcomes for neuron number
(Pucilowska et al. 2012). It is now known that neurotrophin
signaling activates ERK5 in axons and stimulates its translocation to the nucleus, where it acts to promote survival
(Watson et al. 2001).
Similar to ERK5, CREB provides an axonally-derived signal for survival, being trafficked to the soma following local
translation in developing axons (Cox et al. 2008). Nearly every
dividing neural cell, in neurogenic brain regions in both the
embryonic and adult brain, contains activated CREB (Dworkin
et al. 2007; Nakagawa et al. 2002), and loss of CREB in neural
progenitor cells reduces BDNF expression and limits neuron
survival and growth (Dworkin et al. 2009). CREB regulation
of neural proliferation is bidirectional; while overexpression
of dominant negative CREB limits neuronal proliferation, constitutively active mutant CREB causes excessive proliferation
(Dworkin et al. 2007).
Signal transduction pathways for neurite growth
and synapse formation
Brain-derived neurotrophic factor, ERK and CREB also regulate wiring of developing brain circuits. Consistent with its
membership in the neurotrophin family, BDNF acts as a guidance cue for growth cones (Song et al. 1998) and potentiates
transmitter release from developing axons (Zhang & Poo
2002). Axon guidance also relies on ERK signaling, as ERK1
and ERK2 mediate responses of developing axons to the
guidance cue, Netrin (Forcet et al. 2002). Complementarily,
BDNF helps provide sites of synaptic contact by promoting outgrowth of dendrites in developing cortical neurons
(McAllister et al. 1995). The effects of BDNF on dendritogenesis may act via CREB signaling, as targeted ablation of
CREB restricts dendrite growth (Herold et al. 2011). Cyclic
AMP-response element binding protein may also support
nascent communication by promoting proliferation and differentiation of oligodendrocytes, the myelinating glia of the
central nervous system (Afshari et al. 2001; Sato-Bigbee
et al. 1999).
Brain-derived neurotrophic factor, ERK and CREB also
regulate neuron morphogenesis, shaping dendrite patterning and the growth of dendritic spines. For instance,
BDNF application to developing neurons in culture promotes spinogenesis in a neural activity- and TrkB-dependent
manner (Shimada et al. 1998; Tyler & Pozzo-Miller 2003).
Brain-derived neurotrophic factor acts via TrkB to enable
structural plasticity, destabilizing dendrites and dendritic
spines of cortical neurons (Horch et al. 1999) and elevating
spine density of dendrites (Sanchez et al. 2006). Consistent with its role in signal transduction, BDNF promotes
robust dendritic outgrowth from developing cortical neurons in a neural activity-dependent manner (McAllister et al.
1996), and BDNF is required for dendritic spine enlargement
following paired pre- and post-synaptic stimulation at individual synapses (Tanaka et al. 2008). Such BDNF-mediated
increases in dendritic spine density also require ERK signaling
(Alonso et al. 2004).
Genes, Brain and Behavior (2016) 15: 125–143
Plasticity-related genes in brain development and amygdala-dependent learning
Brain-derived neurotrophic factor, ERK and CREB
regulation of developmental ‘critical periods’
Brain-derived neurotrophic factor and CREB play key roles
in coordinating ‘critical periods’ of plasticity in development,
when re-wiring exclusively occurs during specific developmental stages. Critical periods have been observed for
several amygdala-dependent behaviors, with critical period
timing likely determined by amygdala plasticity. For example,
amygdala development is thought to trigger critical period
closure for the paradoxical appetitive conditioning to aversive
stimuli observed in infancy (Sullivan et al. 2000; Thompson
et al. 2008). In addition, although extinction training typically
suppresses the original association and permits recovery of
fear, extinction learning in infancy occurs by a distinct mechanism that causes memory erasure (Kim & Richardson 2007,
2008). Despite the robustness and stereotyped timing of
these transitions, a major knowledge gap remains regarding
the contribution of signal transduction pathways to critical
period plasticity in the amygdala. Insight on the potential role
of BDNF, ERK and CREB in amygdala critical period plasticity
must therefore proceed from evidence gleaned from other
developing neural circuits.
Molecular regulation of critical period plasticity has been
elucidated largely through work focused on the critical period
for ocular dominance (OD) plasticity in the visual cortex.
Selectively during this developmental critical period, visual
experience can shift the balance of visual cortical sensitivity
to sensory input from each eye. Early in life, blockade of
input from one eye, termed ‘monocular deprivation’, leads
to synaptic remodeling that affords heightened sensitivity
to visual input from the unaffected eye at the expense of
sensitivity to the deprived eye (for review, see Hensch 2005).
It is now known that BDNF and CREB play a key role in
establishing the critical period for OD plasticity. For instance,
overexpression of BDNF in transgenic mice leads to precocious closure of the critical period, suggesting BDNF–TrkB
signaling promotes maturation in these circuits (Hanover
et al. 1999; Huang et al. 1999). In support of this notion, while
sensory deprivation typically delays visual cortical development and critical period onset, overexpression of BDNF
blocks such effects (Gianfranceschi et al. 2003). Trk receptor activation is reduced in visual cortex by sensory deprivation, which may thereby suppress BDNF-dependent maturation (Viegi et al. 2002). As a potential mechanism for
BDNF-induced critical period closure, BDNF prevents synaptic plasticity typically observed in immature visual cortical
neurons in response to low-frequency electrical stimulation
(Kinoshita et al. 1999). On the other hand, infusion of either
BDNF or a TrkB antagonist into primary visual cortex of
developing cats blocks OD plasticity near the infusion site,
suggesting optimal levels of BDNF are necessary to enable
critical period plasticity (Cabelli et al. 1995, 1997). Optimal
expression of plasticity-related genes may not simply promote brain development but may actively oppose critical
period plasticity in adulthood, as expression of constitutively
active CREB can reintroduce OD plasticity to the adult visual
cortex (Pham et al. 2004).
Brain-derived neurotrophic factor, ERK and CREB effects
on critical period timing may occur indirectly via effects
on neuronal excitability, allowing for potential interaction
Genes, Brain and Behavior (2016) 15: 125–143
with learning-induced changes to excitability. Extracellular
signaling-related kinase and CREB are thought to promote
learning by elevating neuron excitability (Cohen-Matsliah
et al. 2007; Yiu et al. 2014), and increasing neuronal excitability accelerates critical period closure. Changes in visual cortical representation during the critical period for OD plasticity
are mediated by changes to intrinsic neuronal excitability
(Lambo & Turrigiano 2013; Nataraj et al. 2010), and intrinsic
excitability typically increases during closure of the critical
period for sensory map formation in barrel cortex. Importantly, sensory deprivation delays the maturation of neuronal
excitability and prolongs critical period plasticity for sensory
map formation (Maravall et al. 2004). Elevating intrinsic
excitability may promote critical period closure by negatively
regulating signal transduction pathways; in immature hippocampal neurons, BDNF–TrkB–ERK signaling typically promotes synapse maturation, but elevating the excitability of
cultured hippocampal cells blocks the capacity of BDNF and
ERK to stimulate synapse development (Suzuki et al. 2005).
Brain-derived neurotrophic factor, ERK and CREB
accelerate GABAergic development
Brain-derived neurotrophic factor, ERK and CREB indirectly
regulate development, including critical period timing, by
affecting GABAergic function and maturation. 𝛾-Aminobutyric
acid is implicated in a variety of developmental processes
including cell proliferation, migration and differentiation,
synapse maturation and stabilization and the wiring of neural
networks (Huang & Scheiffele 2008; Le Magueresse &
Monyer 2013; Owens & Kriegstein 2002). 𝛾-Aminobutyric
acid receptor activation is necessary and sufficient to close
critical period plasticity (for review, see Hensch 2005), and
transplantation of immature GABAergic neurons reopens
critical period plasticity in adulthood, suggesting immature
GABAergic neurons imbue circuits with plasticity during
development (Southwell et al. 2010). Furthermore, GABAergic transmission is typically modulated at critical period onset,
and appropriate levels of inhibition are required to enable
critical period plasticity (Katagiri et al. 2007; Toyoizumi et al.
2013); given that levels of excitatory synaptic transmission
are largely stable during development, GABAergic synaptic
structure and strength must undergo experience-dependent
regulation to balance excitation and inhibition (Dorrn et al.
2010; Zhang et al. 2011).
While adult BDNF–ERK–CREB signaling directly influences GABAergic transmission, during development this
pathway accelerates GABA circuit maturation (Huang et al.
1999). Chronic BDNF application to immature hippocampal
cultures facilitates GABA release and increases expression
of GABA receptors and the GABA-synthesizing enzyme, glutamic acid decarboxylase (Yamada et al. 2002). Brain-derived
neurotrophic factor is required for dendritic expansion of
GABAergic neurons as they develop in culture (Kohara
et al. 2003; Jin et al. 2003). Furthermore, BDNF application
to developing cultures elevates expression of parvalbumin, a marker for a subtype of GABAergic interneurons
that emerges during critical period closure, in a TrkB- and
ERK-dependent manner (Patz et al. 2004). In isolated cultures of parvalbumin-expressing GABAergic neurons, BDNF
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Ehrlich and Josselyn
application promotes cellular growth and mature spike patterning while elevating expression of markers for GABAergic
synapses (Berghuis et al. 2004).
Cyclic AMP-response element binding protein promotes
GABAergic circuit development indirectly via Bdnf transcription. Interfering with Bdnf expression by manipulating promoter IV, one of the two sites at which CREB acts to increase
transcription, or directly influencing CREB binding to this
promoter, reduces the density of GABAergic interneurons
and the number, strength and release rates for GABAergic synapses (Hong et al. 2008; Sakata et al. 2009). Cyclic
AMP-response element binding protein activity at Bdnf promoter IV is also required for reorganization of GABAergic circuitry in the developing cortex following sensory deprivation
(Jiao et al. 2011).
Interestingly, while BDNF–ERK–CREB signaling promotes
GABAergic maturation, neurotransmission provides positive
feedback for this signal transduction pathway. Specifically, in
immature neurons when GABA is excitatory, GABA release
promotes ERK activation, downstream CREB phosphorylation, and Bdnf transcription (Fukuchi et al. 2014; Obrietan
et al. 2002). Excitatory GABA in the immature brain is also
capable of stimulating release of BDNF protein (Fiorentino
et al. 2009). In turn, BDNF can provide further feedback,
promoting GABA release by increasing the excitability of
GABAergic neurons and preventing GABA receptor endocytosis (Obrietan et al. 2002; Porcher et al. 2011).
Effects of learning-dependent intracellular
signaling on amygdala development
and behavioral outcomes
Given the myriad contributions of BDNF, ERK and CREB
to neural development, dysregulation of their activity during development may influence brain function later in life.
A wealth of studies described above have shown that
BDNF–ERK–CREB signaling during development influences structural and functional outcomes including cell
density, neuron morphology, synaptic connectivity, neuron
excitability and GABAergic neurotransmission. Based on
this complement of developmental functions, we predict
how learning-induced activation of BDNF, ERK and CREB in
the juvenile amygdala may influence the maturation of its
neurons. Furthermore, we relate these proposed effects to
clinical and preclinical observations of adverse consequences
of early motivational learning.
Proposed effects of excessive BDNF–ERK–CREB
signaling in the developing amygdala
We hypothesize that learning-related activation of BDNF, ERK
and CREB in the immature amygdala exaggerates and accelerates amygdala development (Fig. 4). Intracellular signaling
typically promotes development and wiring of the immature
amygdala, and motivationally relevant experiences that elicit
amygdala-dependent learning may cause excessive signaling.
Specific predictions about the consequences of excessive
signaling follow from the typical function of these molecules
in development.
134
Brain-derived neurotrophic factor, ERK and CREB promote neuron proliferation and survival (Cohen-Cory et al.
2010; Riccio et al. 1999), and excessive signaling in the
developing amygdala may increase amygdala volume and
neuron density. Amygdala volume and neuron density continue to increase into childhood (Giedd et al. 1996; Morys
et al. 1999; Payne et al. 2010), suggesting that the proliferative and pro-survival effects of the BDNF–ERK–CREB
pathway could act in childhood to enlarge amygdala volume. Increased volume of the amygdala may result in
greater amygdala activation and downstream signaling,
potentially yielding exaggerated motivational learning. In
support of this notion, stress exposure in juveniles, which
likely stimulates BDNF–ERK–CREB signaling, results in
greater amygdala volume and emotional dysfunction in
humans and non-human primates (Howell et al. 2014;
Tottenham et al. 2010).
Brain-derived neurotrophic factor, ERK and CREB promote
dendrite expansion and spinogenesis (Alonso et al. 2004;
Herold et al. 2011; McAllister et al. 1995), and excessive
activation of this pathway may alter amygdala neuron morphology. Dendrite growth and spine emergence proceed into
early adolescence in the amygdala (Ryan et al. 2014). In juveniles, amygdala-dependent learning and BDNF–ERK–CREB
signaling may cause enlarged or more spine-dense dendrites
later in life. As dendrites constitute the major site for synaptic input onto amygdala neurons, dendritic expansion may
result in greater synaptic input to amygdala neurons and
more capacity for learning related to motivationally relevant
stimuli. Interestingly, stress exposure during adolescence
causes enlargement of amygdala neuron dendritic arbors
(Eiland et al. 2012), which has been suggested to mediate
some adverse behavioral effects of chronic stress (McEwen
& Chattarji 2004).
Signal transduction by BDNF, ERK and CREB promotes
neural circuit maturation and triggers critical period closure, and learning-dependent activation of this pathway
may restrict the formation of new synaptic connections in
the amygdala. Brain-derived neurotrophic factor signaling is
directly linked to critical period closure (Hanover et al. 1999;
Huang et al. 1999), and BDNF–ERK–CREB effects to elevate
neural excitability and stimulate GABAergic circuit development may indirectly promote critical period closure (Hensch 2005; Huang et al. 1999). In the cortex, critical period
plasticity enables drastic remodeling of connectivity; amygdala remodeling also occurs in adolescence, as afferent and
efferent synapses with neurons in the prefrontal cortex are
formed (Bouwmeester et al. 2002a, 2002b; Cressman et al.
2010; Verwer et al. 1996). If critical period plasticity were prematurely closed in the amygdala before the establishment
of connections with the prefrontal cortex, amygdala neurons
may be less sensitive to arriving cortical axons and form
fewer synapses. Given that the prefrontal cortex provides
top–down inhibition of the amygdala, excessive amygdala
activation and behavioral reactivity may result from deficits
in amygdala–prefrontal cortical connectivity (Callaghan et al.
2014; Casey et al. 2008; Correll et al. 2005).
Genes, Brain and Behavior (2016) 15: 125–143
Plasticity-related genes in brain development and amygdala-dependent learning
Developing
Amygdala
F
proliferation
& survival
BDN
motivationally
relevant
experience
dendritogenesis
ERK
greater
amygdala
volume
synaptogenesis
GABA
circuit
maturation
CREB
elevated
excitability
memory encoding
enlarged
dendritic
arbors
Key:
preferential
connection
with early synaptic
w
partners
enhanced
motivational
learning
diminished
top-down
regulation of
emotion
critical
period
closure
developmental
function
amygdala
outcome
behavioral
impact
Figure 4: Predicted effects of learning-induced BDNF–ERK–CREB signaling on amygdala development. Learning about motivationally relevant experience is encoded in the amygdala via BDNF–ERK–CREB signaling. Given the additional contributions of BDNF,
ERK and CREB to neural development, learning-induced signaling in juveniles may exaggerate or accelerate typical development of the
amygdala. The BDNF–ERK–CREB pathway promotes neuron proliferation and survival, so learning-dependent signaling may promote
larger amygdala volume later in life. This pathway also promotes dendritic arborization, so learning-dependent signaling may cause
excessive expansion of dendritic arbors. In addition, by promoting synaptogenesis and premature closure of critical period plasticity,
juvenile BDNF–ERK–CREB signaling may bias amygdala connectivity toward early over late-developing synaptic partners.
Motivational learning and intracellular signaling
in juveniles promote risk for psychiatric disease
Given the prominent role for BDNF, ERK and CREB in brain
development, early associative learning that activates this
pathway in the amygdala may perturb trajectories of development and behavioral outcomes. A wealth of literature has
identified effects of motivational learning during infancy on
amygdala development. For instance, cued fear conditioning
in infant rat pups at P8 causes deficits in fear learning and
amygdala activation later in life (Moriceau et al. 2009). On
the other hand, contextual fear conditioning later in infancy,
at P17, causes subsequent lifelong enhancement of fear
learning (Quinn et al. 2014). In addition, when an expected
reward is withheld from pups at P10, the amygdala is acutely
activated and those same subjects in adulthood exhibit
enhanced fear learning (Stamatakis et al. 2013). Models of
early-life stress have also identified long-term changes to
amygdala structure and function (Ehrlich & Rainnie 2015;
Ehrlich et al. 2015; for review, see Tottenham & Sheridan
2009) that may emerge because of the altered critical period
timing (Callaghan et al. 2013, 2014). However, no study to
date has established BDNF, ERK or CREB as a mediator of
the effects of early experience on amygdala development or
emotional outcomes.
Genes, Brain and Behavior (2016) 15: 125–143
Intracellular signaling pathways may provide a means of
direct interaction between genetic and environmental risk
for psychiatric illness. Owing to its breadth of function, this
signaling pathway constitutes a point of vulnerability to insult
for the developing brain. Aberrant expression of BDNF, ERK
and CREB has been linked to numerous psychiatric disorders,
including autism spectrum disorders (Almeida et al. 2014;
Castren & Castren 2014; Correia et al. 2010; Kalkman 2012;
Yin et al. 2014), mood disorders (Geller et al. 2004; Kerner
et al. 2013; Strauss et al. 2004) and schizophrenia (Chiaruttini et al. 2009; Green et al. 2011; Ho et al. 2007; Kawanishi
et al. 1999; however, see Crisafulli et al. 2012). Given the sensitivity of BDNF–ERK–CREB signaling to environmental factors, this signaling pathway may provide a substrate through
which gene-by-environment interactions can act on genetic
predisposition for illness. Defining the consequences of motivational learning on intracellular signaling in the developing
amygdala therefore holds promise for identifying the sequelae underlying psychiatric disorder pathogenesis.
Conclusions
Brain-derived neurotrophic factor, ERK and CREB work in concert to promote plasticity by transducing extracellular signals
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Ehrlich and Josselyn
to the nucleus to regulate gene expression. This intracellular signaling pathway underlies plasticity essential not only
for neural development but also for learning. Infants learn
associations regarding motivationally relevant stimuli utilizing
the amygdala, suggesting that learning-related signaling by
the BDNF–ERK–CREB pathway may perturb ongoing amygdala development. We suggest that amygdala-dependent
learning may exaggerate and accelerate amygdala development, negatively affecting later amygdala function and motivational behavior. More specifically, we suggest that accelerated closure of critical period plasticity in the amygdala may
diminish connectivity with late-developing inputs that inhibit
amygdala reactivity. If adverse behavioral consequences of
early life experience are instantiated throughout development
as amygdala connections form, promoting critical period
plasticity in the precocious amygdala may provide a novel
avenue for intervention. However, several key knowledge
gaps remain; a critical next step in this line of inquiry will
be to determine the contribution of intracellular signaling cascades to learning-related plasticity in the immature amygdala.
Given the potency of early life experience in regulating behavioral outcomes, we predict that BDNF–ERK–CREB signaling
in the immature amygdala is sensitive to experiential factors,
but this notion remains largely unexplored.
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Acknowledgments
The authors declare no conflicts of interest. This work was
supported by Canadian Institutes of Health Research grant
MOP-74650 to SAJ.
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