Yosif (Joe) Zaki

March 15, 2018

Models of Fear Relapse: Different Animal or Same Beast?
Word Count: 3577
Citation Method: Nature Reviews

Abstract
Fear is a defensive behavior that can be adaptive and promote an animal’s survival;
however, uncontrollable fear can be maladaptive and detrimental to an animal’s health. Fear
conditioning and extinction are laboratory models of fear acquisition and its suppression,
respectively, and are used to elucidate the neural substrates of fear learning. Research has aimed
to understand the neural basis of learned fear, to uncover the etiologies of trauma-related
disorders such as PTSD. However, animals are prone to relapse, and this phenomenon has
largely gone unstudied. This review examines recent studies that have begun to address this
behavior and its neural components.

Introduction
Fear Conditioning
Fear is a defensive behavior that can be adaptive and promote an animal’s survival;
however, uncontrollable levels of fear can be maladaptive and detrimental to an animal’s health.
In the clinic, patients with intractable fear are often diagnosed with anxiety-related disorders or
Post-Traumatic Stress Disorder (PTSD). In the lab, fear conditioning is a behavioral paradigm of
acquired fear that has been studied in rodents for decades1, and serves as a model for trauma-
related disorders. The paradigm consists of co-presentation of an unconditioned stimulus and a
conditioned stimulus, where the unconditioned stimulus represents the innately aversive
experience and the conditioned stimulus is the cue that was initially neutral and, through
association with the unconditioned stimulus, acquired negative valence. The subsequent
conditioned response is freezing behavior. Freezing behavior is characterized by total immobility
of the animal, and it is accompanied by autonomic responses such as increased heart rate2 and
increased levels of stress hormones such as corticosterone3. This behavioral response is a proxy
for “fear,” and this behavioral paradigm has become the dominant model for studying trauma in
rodent models of fear (see Figure 1 for visualization).
For the past few decades, efforts have been aimed at understanding the neural
underpinnings of fear conditioning, in the hopes that they may uncover the etiologies of trauma-
related disorders such as PTSD. Regions of the brain including the hippocampus4 and the
amygdala5 have been implicated in the acquisition, storage, and retrieval of fear memories6. Both
regions have been shown to be necessary7 and sufficient8,9 to drive expression of learned fear,
and thus, these two brain regions have been rendered the major players in the “fear circuit.”
Additionally, several other brain regions such as the bed nucleus of the stria terminalis (BNST)10,
the prefrontal cortex (PFC)11, and the periaqueductal gray (PAG)7 have also been shown to play
roles in modulating fear expression. The fear circuit refers to the collection of brain regions that
collectively process fear-related information (see Figure 2).

Fear Extinction
Alongside the study of fear learning, significant attention has been given to the
behavioral model of suppression of fear—namely, fear extinction learning. Fear extinction refers
to the repeated exposure to the conditioned stimulus in the absence of the unconditioned
stimulus, and the subsequent behavioral response is a reduction in freezing behavior12. This
serves as a laboratory model for exposure therapy, a behavioral treatment aimed to mitigate fear-
related behavior in human patients with excessive fear.
The neural circuitry underlying fear extinction has also been extensively studied, and the
hippocampus13 and amygdala14 have been found to exhibit upregulated activity during fear
extinction learning, implicating them in the behavior. Furthermore, neuronal transmission in the
amygdala has been deemed necessary for extinction learning; that is, inactivation of pyramidal
cell transmission in the amygdala with an NMDA-antagonist abolishes fear extinction learning15.
The prefrontal cortex (PFC) has also been implicated in fear extinction; however, its exact role in
the behavior remains unresolved. For example, several groups have found inactivation of the
PFC to disrupt expression of extinguished fear (lowered freezing)16, while other groups have
found that inactivation of the infralimbic subregion of the PFC (IL) disrupts both fear extinction
learning and expression17. Current evidence points to a potentially dichotomous role that the
prelimbic (PL) and infralimbic (IL) cortices of the PFC play in conditioned fear: heightened PL
activity drives fear behavior whereas heightened IL activity drives suppression of fear18. Indeed,
recent work has demonstrated that projections from the IL to the amygdala are necessary for
extinction learning19.
Functional recordings have also provided evidence that these same brain regions (i.e.
amygdala, hippocampus, PFC) work synergistically to process fear-related information. In fact,
local field potential recordings in the PFC, hippocampus, and amygdala have revealed that
coherence in the theta frequency range arising from the PFC and signaling to the hippocampus
and amygdala correlate strongly with expression of extinction learning20. Thus, a circuit similar
to that which processes fear learning (see Figure 2) may be involved in fear extinction learning,
expression, and retention.

Fear Relapse
While extinction learning (and analogously, exposure therapy in the clinic) is generally
successful, humans21 and rodents22 are prone to relapse under several different conditions23. The
three most well characterized forms of relapse are termed fear renewal, fear reinstatement, and
spontaneous recovery24. Fear renewal is triggered by a shift in context25; fear reinstatement is
triggered by presentation of the unconditioned stimulus in a novel context22; and spontaneous
recovery describes the unforeseen re-emergence of fear following the passage of time26. These
models are visualized in Figure 3. The fact that fear memories are prone to relapse has led the
learning and memory field to question whether fear extinction is an abolition of the original fear
memory, or a new form of learning that directly inhibits the original fear. Current evidence
points to extinction learning as a suppression of the original fear memory, rather than an erasure
of it27. Indeed, it has been shown that, in the amygdala, cells that seem to store the original fear
memory are directly inhibited by a structural reorganization of inhibitory interneurons after
extinction and this inhibition is necessary for fear extinction expression28. Subsequently, whether
fear relapse is a re-emergence of the original fear memory or the formation of a qualitatively new
memory representation remains to be investigated.
While the behavioral manifestation of fear relapse has been acknowledged in both
humans and rodents—potentially indicating an evolutionarily conserved neural phenomenon—
little work has been done to resolve the neural constituents of fear relapse24. A deeper
understanding of fear relapse may lend to therapeutic treatments that could more robustly combat
 excessive fear and related disorders. This review follows recent work that has been done to
elucidate the neurobiology of fear relapse, and moreover, discusses future directions that may
further our understanding of these behaviors.

Methods
Search Criteria
A literature search was conducted on NCBI PubMed database with the following search
terms: fear reinstatement, fear renewal, fear relapse. Literature was excluded if the paper did not
utilize fear conditioning as a model for the onset of trauma and also if the employed model
organism was not a rodent (excluded papers mainly used human models). Literature was also
excluded if studies involved drug addiction; addiction disorders has been shown to be comorbid
with anxiety- and fear-related disorders, and thus many studies have investigated the relationship
between addiction and fear. That work is outside the scope of this review. The resulting list of
papers is a collection of work studying fear relapse on several levels of complexity—from
neuromodulation, to functional connectivity, to behavioral manipulation. The list was
purposefully made to comprise work from several groups at different institutions; few labs study
fear relapse and so it is easy to fall into evaluating work from one laboratory or institution. A
similar diversity is noted for the journal in which each paper was published.

Research Design Comparison

These studies do not address all models of fear relapse, assess the same brain regions, use
the same behavioral parameters, or use the same manipulation techniques. Thus, a table
comparing these measures across all the papers would help draw connections and potential
disparities between papers (see Table 1).

Author Species Model of Fear Brain Regions Method of Power Tone or

Relapse Neural Contextual Fear
Manipulation Conditioning
1 Goode, 201529 Rat Reinstatement, BNST Intracranial 6-11 rats Tone
Renewal muscimol per group
2 Hitora- Mouse Reinstatement PFC, CeA, Intracranial 4-14 mice Contextual
Imamura, VTA muscimol, per group
201530 SCH23390, or
PBS (Control)
3 Kim, 200731 Rat Reinstatement None None 7-10 rats Tone
per group
4 Marek, 201832 Rat Renewal vHipp, PFC Optogenetics, 1-16 rats Tone
DREADD, per group
intracranial
muscimol or
picrotoxin
5 Yoshii, 201633 Mouse Artificial Whole Brain DREADD 3-12 mice Contextual
Relapse per group
6 Jin, 201534 Rat Renewal vHipp, Histological 26 rats total Tone
Amygdala, PFC quantification
Table 1: Systematic comparison of the evaluated studies, including their model organism, model of fear relapse,
evaluated brain regions (if any), neural manipulations (if any), statistical power, and form of original conditioning.
Brain Region Abbreviations: BNST (Bed Nucleus of the Stria Terminalis), PFC (Prefrontal Cortex), CeA (Central
Amygdala), VTA (Ventral Tegmental Area), vHipp (Ventral Hippocampus)
Methods Comparison
The above studies were all conducted in rodent models—four in rats29,31,32,34 and two in
mice . Two of the studies employed reinstatement as their model of fear relapse30,31, while
30,33

two others dissected the neural circuitry underlying renewal32,34. One study examined the
difference in BNST inactivation on both reinstatement and renewal behavior29. And one study
utilized a novel tool to mimic re-emergence of fear33—thus, this study does not formally make
use of any of the three commonly used behavioral models. The PFC, CeA (Central Amygdala),
and VTA (Ventral Tegmental Area) were shown to have upregulated activity during
reinstatement30, and the BNST inactivation deemed that brain region necessary for reinstatement
learning29. Additionally, differences in ability to learn reinstatement between young and adult
rats was demonstrated31. Fear renewal, on the other hand, was found to recruit ventral
hippocampal (vHipp) neurons that projected to both the PFC and the amygdala34, and vHipp à
PFC connectivity was necessary for fear renewal to occur32.
Inactivation manipulations included intracranial muscimol infusions29,30,32 and
pharmacogenetic inhibition with DREADDs32. Conversely, stimulation manipulations included
optogenetics32 and pharmacogenetics (i.e. DREADDs)32,33. All of the studies had similar
statistical power, and two of the studies employed a contextual fear conditioning paradigm30,33,
while four of them employed a tone fear conditioning paradigm29,31,32,34.

Results
Behavior
In all the above studies29-34 (which will hereafter be referred to by the name in the
“Author” column of Table 1), the researchers were able to elicit re-emergence of freezing
behavior in their experiments. The one exception to this was in one experiment from Kim, 2007.
They found that, in 16-day old rats, reinstatement could not be induced, whereas in 23-day old
rats it could. They concluded that there must be two different mechanisms by which animals
early in development represent and process fearful memories, compared to animals later in
development. This is in line with previous work demonstrating that amygdala à PFC
connectivity emerges later in development than many other PFC pathways do, and that this
connection seems to be crucial for the modulation of fear states in rodents35. In the other five
studies where relapse was successfully elicited29,30,32-34, adult animals were exclusively used.

Structural and Functional Connectivity

The structural and functional connectivity between brain regions involved in the
conditioning and suppression of fear have been well characterized (see Figure 2). Gaining a
similar functional map for the brain regions responsible for different models of fear relapse could
provide valuable insight into the etiologies of such behaviors. Moreover, relationships between
the etiologies of different models of relapse may become accessible through such work, and this
may lead to a deeper understanding of the common processes underlying all models of fear
relapse. Yoshii, 2016 demonstrated that brain-wide stimulation of fear-processing cells was
sufficient to induce re-emergence of fear. They employed a recent technique whereby neurons
active during a discrete experience are genetically modified and thereafter liable to artificial
manipulation. They refer to this label an “engram,” or, physical representation of a memory trace
in the brain, and they use this technique to label cells active during fear conditioning. After
extinction learning, they artificially activate the brain-wide fear engram to see whether this set of
cells is sufficient to drive a re-emergence of fear in rodents. Indeed, this is what they found;
however, how this relates to one of the established models of fear relapse is unclear. Moreover, it
cannot be resolved what elements of this network hold exceptional importance in this
phenomenon; it is likely that some portion of this network is crucial for this behavioral outcome
while other regions play no role at all.
Marek, 2018 and Jin, 2015 took a much more targeted approach, observing and
manipulating activity in brain regions known to be involved in fear conditioning and extinction
(i.e. the hippocampus, PFC, and amygdala). Jin, 2015 found that neurons in the vHipp that send
dual projections to the amygdala and the PFC are preferentially active after fear renewal34.
Similar patterns of activity were not observed in vHipp neurons that sent projections to just one
of those targets. Marek, 2018 subsequently found that the connectivity between the vHipp and
the PFC is crucial for fear renewal; that is, vHipp neurons that innervate the PFC provide feed-
forward inhibition to the PFC, and inhibition of this pathway reduced the likelihood of a rat to
exhibit fear renewal32. The exact contribution of the amygdala to fear renewal remains untested.
Goode, 2015 took a similarly targeted approach, but was the only study to assess the role of the
BNST in fear relapse broadly29. They demonstrated that pharmacological inactivation of the
BNST does not prevent fear renewal, indicating that perhaps the BNST is not a crucial node that
regulates fear renewal. Of course, the dynamics of pharmacological inactivation is dissimilar
from optogenetic inactivation. It is possible that a different mode of manipulation would lead to a
different behavioral outcome. Goode, 2015 was also the only study to employ multiple models of
fear relapse and attempt to connect a neural component to both renewal and reinstatement,
although the BNST was deemed necessary for only reinstatement.
Hitora-Imamura, 2015 found a role for the PFC in fear reinstatement, whereby neurons in
the PFC receive dopaminergic inputs from the VTA and then the PFC send projections to the
CeA, and this circuit is necessary for fear reinstatement; that is, inactivation of dopaminergic
signaling in the PFC using a D1R antagonist led to a restoration of PFC activity, a decrease in
CeA activity, and a disruption of fear reinstatement behavior.30. Whether the same PFC circuit
found in Jin, 2015 and Marek, 2018 that regulate renewal also receive modulatory dopaminergic
input from the VTA, or whether that circuit is also involved in reinstatement, remain to be
investigated. Furthermore, whether the VTA, CeA, PFC, vHipp, and amygdala share functional
connectivity with the BNST is an open question. Collectively, the above studies provide
preliminary insights into the circuits driving these phenomena.

Similarities
Few studies have systematically assessed the potentially differential consequences of
neural manipulations in different models of fear relapse. It is possible that while different sorts of
manipulations (e.g. pharmacological vs optogenetic) do not agree across studies of different
models of relapse (e.g. renewal vs reinstatement), similar manipulations across relapse models
may lead to similar outcomes.
Furthermore, there is initial evidence that similar brain regions and potentially similar
mechanisms may be regulating both fear reinstatement and fear renewal. For instance,
dysregulation of inhibitory signaling in the PFC may be at the heart of both fear renewal32 and
fear reinstatement30, since inhibitory signaling in the PFC has been implicated in both relapse
phenomena separately. While the approach used in Yoshii, 2016 was insufficient to tease out the
differential contributions that different brain regions may be playing in this behavior, it is
possible that the pharmacogenetic stimulation that they administered provided the appropriate
dysregulation of signaling in the PFC that is necessary to elicit re-emergence of fear behavior. It
is also possible that other key brain regions are sufficient to drive fear relapse, or that it is not
necessarily the brain regions that are crucial as is the nature of the stimulation (e.g. optogenetic
and transient, pharmacogenetic and sustained). These, of course, are questions open for
neuroscientists to answer.

Future Directions
Here, six recent studies were reviewed regarding several different models of fear relapse
and the implications they may have for uncovering the neural bases for these behavioral
phenomena.
While these studies have begun to tie structural connectivity in the brain with function of
their studied brain regions, there are still many crucial questions that can be tackled based on the
knowledge that these studies have introduced. For example, Marek, 2018 and Hitora-Imamura,
2015 both exemplified a role that the PFC may have in regulating renewal and reinstatement,
respectively. However, it is striking that there is a convergence point in the inhibitory PFC
networks addressed in both papers. A next logical question would be whether these two
behaviors share functional connectivity, or if the involved brain regions compute similar
algorithms to drive these behaviors.
The BNST is another region of the brain that has, until recently, gone largely unstudied.
In fact, attention has more recently been drawn to the BNST as a potential regulator of stress-
related behaviors10. It is an exciting time for research in fear learning, since tools such as
optogenetics, genetic manipulations (i.e. CRISPR-Cas9), and in vivo imaging tools such as 1-
and 2-photon calcium imaging have provided us with unprecedented spatiotemporal and genetic
control over observation and manipulation in the brain.
The developmental disparity in the ability to induce reinstatement in young versus adult
rats may provide novel insights into how aberrant fear circuitry develops in organisms with early
life trauma. Perhaps even more interesting is that a separate group found that female juvenile rats
were prone to all three models of fear relapse whereas male juvenile rats were prone to none of
them36, which is in line with Kim, 2007. This speaks to a broader issue in neuroscience research
which is that sex differences are rarely acknowledged; that is, most neuroscience research is
conducted in solely male organisms, despite the overwhelming understanding that there are
major differences between male and female rodent brains, in characteristics as fundamental as
distribution of inhibitory networks throughout the brain37.
It is important to note that this review has largely focused on fear renewal and
reinstatement because literature on spontaneous recovery is scarce. This is likely due to the
technical limitation that spontaneous recovery generally takes several weeks to wait for in
rodents, whereas renewal and reinstatement can be triggered by the experimenter directly after
extinction learning. Despite this limitation, spontaneous recovery of fear should be actively
explored to discern the similarities and differences between this and other models of relapse—
especially since spontaneous recovery is not triggered by a salient external stimulus and thus
may work through un-overlapping mechanisms to renewal and reinstatement.
In the past few decades, an abundance of research has been aimed at discovering how the
brain processes, stores, and expresses fear and the subsequent suppression of fear. While strides
have been made in answering these questions, the question of why fear relapse continues to
plague both rodents and humans remains largely enigmatic. We have the tools and conceptual
basis to begin to answer these questions on many levels of complexity, and these recent papers
have begun to pave the way to a deeper understanding of rodent models of fear relapse.

Acknowledgements
I would like to acknowledge Jake Campolo and Katie Kerr for always listening to me
ramble on about my science. I would like to thank Dr. Leon Reijmers for introducing me to the
field of learning and memory, and Dr. Patrick Davis for continuing to be an invaluable mentor
for me through the years. Additionally, I thank Dr. Steve Ramirez for supporting me as I
navigate through the trenches of science research, both financially and—much more
importantly—morally. I thank Dr. Cecelia Musselman, for providing thoughtful feedback on my
first draft with such a quick turnaround. And I thank my peer reviewers—Madison Micou and
Kyle Darrow—for their valuable feedback on my first draft.
Figures

Figure 1: (A) Schematic of contextual fear conditioning paradigm. CS-US pairing (fear conditioning; first
box) leads to expression of fear expression (fear retrieval; second box). Sequential placement in the
conditioned context leads to reduced fear expression (fear extinction; third box). The level of fear
expression can be assessed by placing the subject back in the conditioned context after fear extinction
(second fear retrieval; fourth box). (B) Schematic for cued fear conditioning paradigm. The steps are the
same as they are above; however, an additional cue for the expression of fear in this case is an auditory tone
played during fear conditioning38.
Figure 2: Schematic for the fear circuit, the brain regions involved, their structural connectivity, and their
putative functional properties of information processing
Abbreviations: AC, auditory cortex; BA, basal nuclei of the amygdala; BNST, bed nuclei of the stria
terminalis; CEl, lateral division of central nucleus of the amygdala; CEm, medial division of the central
nucleus of the amygdala; HIP, hippocampus; IC, inferior colliculus; IL, infralimbic division of the medial
prefrontal cortex; ITC, intercalated cells of the amygdala; LA, lateral nucleus of the amygdala; LH, lateral
hypothalamus; MGdv, dorsal and ventral divisions of the thalamic medial geniculate nucleus; MGm,
medial division of the thalamic medial geniculate nucleus; NAcc, nucleus accumbens, dlPAG, dorsolateral
division of the periaqueductal gray; vPAG, ventral division of the periaqueductal gray; PIN, posterior
intralaminar nucleus of the thalamus; PL, prelimbic division of the medial prefrontal cortex; PRh,
perirhinal cortex; PVN, paraventricular nucleus of the hypothalamus39.
Figure 3: Behavioral paradigms for relapse of fear memory expression; these manipulations all lead to a
relapse in freezing behavior in rodents40.
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