Behavioural Brain Research 416 (2022) 113559

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Behavioural Brain Research

journal homepage: www.elsevier.com/locate/bbr

Spreading depolarization induced by amygdala micro-injury prevents

disruption of fear memory extinction in rats
Maria P. Rysakova *, Irina V. Pavlova, Lyudmila V. Vinogradova **
Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, Moscow, Russia

A R T I C L E I N F O A B S T R A C T

Keywords: Spreading depolarization (SD), a self-propagating wave of near-complete breakdown of the transmembrane ion
Spreading depolarization gradients with water influx, regularly occurs in traumatized human brain. Here, we investigated long-term
Acute brain injury neurobehavioral consequences of injury-triggered SDs. Recently, we revealed that SD is reliably triggered by
Fear conditioning
micro-injury of the amygdala, a key brain structure involved in fear processing. Using the classical Pavlovian fear
Extinction
Amygdala
conditioning paradigm, we investigated effects of the post-retrieval amygdala micro-injury and associated SD on
fear memory in rats. We found that neither SD nor micro-injury alone affect fear response 24 h later but pro­
foundly change it in subsequent extinction phase. If bilateral injury of the amygdala did not induce SD, fear
extinction was severely impaired, while conditioned fear in rats with the identical amygdala injury triggering SD
was successfully extinguished similarly to naïve rats. Our study provides first experimental evidence for
involvement of injury-induced SD in extinction of traumatic fear memory.

1. Introduction amygdala was damaged following fear memory reactivation, when

Spreading depolarization (SD), a self-propagating wave of near-
complete breakdown of the transmembrane ion gradients with water
influx, regularly occurs in traumatized human brain [1]. Recurrent
cortical SDs have been recorded during first weeks after brain injury.
However, a role of SD in neurobehavioral complications of traumatic
brain injury remains elusive. Brain trauma is a major risk factor for
post-traumatic stress disorder (PTSD) characterized by impaired
extinction of maladaptive fear memory [2]. Cortical SD has been shown
to disrupt conditioned fear response acutely [3,4] but has no lasting
effects [5].
The amygdala (Am), the temporal lobe structure highly vulnerable to
brain injury, is a key region for fear memory and pathogenesis of PTSD.
Recently, we have shown that a circumscribed damaging the amygdala
produced by targeted micro-injection procedure frequently induces SD
propagating to the cortex [6]. In the present study we assessed lasting
effects of such amygdala micro-damage and associated SD on fear
memory in the classical Pavlovian fear conditioning paradigm. The
reconsolidation process returns memory to a labile state, and effects of
the amygdala damage on fear reconsolidation and extinction were
evaluated.
2. Materials and methods
2.1. Subjects
Twenty-eight male Wistar rats (350–450 g, Scientific center for
Biomedical Technologies of the Federal Medical and Biological Agency,
Russia) were housed in a temperature-controlled vivarium (22 ◦ C ± 2 ◦ C,
a 12-h light/dark cycle, lights on at 08.00 h) with food and water ad
libitum. Animals were kept 5 per cage before surgery and individually
after surgery. All experimental procedures were conducted in accor­
dance with the ARRIVE guidelines and the Directive 2010/63/EU for
animal experiments. The study protocol was approved by the Ethics
Committee of the IHNA RAS. Every effort was made to minimize animal
suffering and to ensure reliability of the results.

Abbreviations: SD, spreading depolarization; PTSD, post-traumatic stress disorder; Am, amygdala; BLA, basolateral amygdala; AP, anterior-posterior; ML, medial-
lateral; DV, dorsal-ventral; OF, open field; CS, conditioned stimulus; US, unconditioned stimulus; ITI, inter trial interval.
* Corresponding author at: Department of Conditioned Reflexes and Physiology of Emotion, Institute of Higher Nervous Activity and Neurophysiology, Russian
Academy of Sciences, 17485, Butlerova Street 5A, Moscow, Russia.
** Corresponding author at: Department of Molecular Neurobiology, Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences,
17485, Butlerova Street 5A, Moscow, Russia.
E-mail addresses: rymarik@gmail.com (M.P. Rysakova), lvinogradova@gmail.com (L.V. Vinogradova).

https://doi.org/10.1016/j.bbr.2021.113559
Received 26 May 2021; Received in revised form 14 August 2021; Accepted 23 August 2021
Available online 25 August 2021
0166-4328/© 2021 Elsevier B.V. All rights reserved.
M.P. Rysakova et al.
2.2. Stereotaxic surgery
Under chloral hydrate anesthesia (400 mg/kg, i.p. AppliChem, Ger­
many), rats were implanted with the bilateral stainless steel guide
cannulas (23 gauge) aimed at the basolateral amygdala (AP: -2.76, ML: -
4.8 mm DV: - 7.5 mm) [7]. Recording nichrome electrodes were
implanted in the frontal and occipital cortices (AP: +1.2, ML: ± 2.3 mm,
DV: - 1.8 and AP: -5.88, ML: ± 3.5 mm, DV: - 1.5 mm, respectively). The
guide cannulas and electrodes were fixed on the skull with acrylic dental
plastic. A 30-gauge stylus of the same length as guide cannula was
inserted into it to prevent clogging. Rats were given antibiotic Amoxi­
cillin (15 %, 0.2 mL, intramuscular) and the mixture of glucose (5%)
with NaCl mixture (2 mL, subcutaneously) after surgery. Experiments
started 10–14 days post-surgery.
2.3. Behavioral procedures
Fear acquisition, testing and extinction were performed in Startle
and Fear Combined System (PanLab, Harvard Apparatus, Spain) con­
sisted of a conditioning chamber (28 × 28 × 28 cm) enclosed in a sound
attenuating box, equipped with a movement-sensitive platform, a
loudspeaker and a grid floor consisted of stainless steel rods (3 mm
diameter, 10 mm apart). Shock was delivered to the floor by a computer
controlled shock source. Illumination was provided by a light bulb (30
lx) located on the wall of the chamber. The chamber was cleaned with
water between subjects.
Freezing was defined as a cessation of movement (at least 2 s) apart
from respiration and converted to a percentage [(freezing time/total
duration of a period) ×100] for the baseline period (effect of context)
and tone presentations (cue effect).
The open-field (OF) test was run in a wood circular arena measuring
100 cm in diameter and 30 cm high. The arena was lit with 180 lx. Rats
were placed individually in a center of the arena and behavior was
recorded for 5 min using EthoVision 3.0 video tracking software (Noldus
Information Technology b.v., 2003). The distance traveled (cm), ve­
locity (cm/s) and time spent in OF border region (17 cm wide, thig­
motaxis) were recorded and automatically calculated.
The researcher analyzing the behavioral data was blinded to the
experimental groups.
2.4. Micro-injury of the amygdala and SD recording
Awake freely moving rats were individually placed in a shielded
experimental chamber (60 × 40 × 40 cm) and the implanted connector
was attached to the recording cable. After a 5-min habituation period
and a 10-min baseline recording of wideband cortical activity (0− 30 Hz,
1 kHz sampling rate), a small bilateral amygdala injury was induced. An
awake rat was gently handled, the stylus was removed from the guide
Fig. 1. Scheme of the experiment.
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Behavioural Brain Research 416 (2022) 113559
cannula and the 30-gauge needle extending 1.0 mm from the tip of the
guide cannula, was inserted. No substance was infused. Cortical activity
was recorded for 15 min post-injury using a four-channel, high-input
impedance (1 gΩ) dc amplifier and a/d converter (E14-440, L-Card,
Russia) with simultaneous video-monitoring of behavior. Our pre­
liminary experiments using the recording system showed that chroni­
cally implanted nichrome electrodes, which are used for long-term
intracranial AC recording in animal experiments, allow to detect cortical
SD in freely moving rats, although of smaller amplitude compared to
carbon electrodes that we used for SD monitoring in our previous studies
[6,8]: 3.0 ± 0.2 mV for nichrome-recorded SD versus 3.9 ± 0.4 mV for
carbon-recorded SD (p = 0.017). Close association between
nichrome-recorded negative potential shifts and depression of cortical
activity, the reliable electrographic hallmark of SD, confirmed that the
field potentials reflect SD occurrence. Histological data showed
non-toxicity of chronically implanted nichrome electrodes.
2.5. Experimental design
Three-four days before the start of experiment, all animals were pre-
handled and habituated to the stylus removal daily. Scheme of experi­
ment is presented in Fig.1. On day one, rats were placed individually
into the conditioning chamber and allowed free exploration for 2 min in
the house light (30 lx) before the delivery of the auditory conditioned
stimuli (CS; 30 s, 80 dB, 2000 Hz). The freezing response to the first tone
during training was used as baseline (Test 0). The last 2 s of tone
exposure co-terminated with a foot-shock unconditioned stimulus (US; 2
s, 0.8 mA) through a grid floor. A total of 3 pairs of CS-US with a 50 s
inter trial interval (ITI) were presented to each animal in the training
stage. The rat was removed from the chamber 1 min after the last foot-
shock and placed back in its home cage.
Twenty-four hours after fear acquisition, the memory was reac­
tivated (Test1, T1). The rat was placed in the same chamber and a two-
minute tone (80 dB, 2000 Hz) without the foot-shock was presented
after 2 min free exploration. The rat was removed from the chamber 2
min after CS presentation. Freezing responses to the environmental
context and tone were recorded. One hour after T1, implanted rats
received bilateral amygdala injury and naïve rats were exposed to sham
manipulations without injury. Implanted rats were assigned to three
groups after amygdala injury: Am injury/no SD – without SD, Am
injury/uni SD – with unilateral SD, Am injury/bi SD – with bilateral SD
after micro-injury. Only the animals without postoperative complica­
tions, with stable recording of cortical activity and the damage locali­
zation within the amygdala were included in the analysis. Based on the
criteria, one of 28 rats was excluded.
Next day, Test 2 (T2) was performed. Rats were returned to the
testing context and after 2 min baseline period a single CS (2 min) was
presented. Two hours after T2, locomotor activity was assessed in the
M.P. Rysakova et al.
OF.
Twenty-four hours after T2, extinction training started. Two
extinction sessions (1–2 days inter-session interval) were performed.
Each extinction session consisted of ten 30 s CS presentations (80 dB,
2000 Hz) with a 20 s ITI after the 2 min context exposure (Fig. 1). No
foot-shock was delivered. One-two days after the second extinction
session, fear extinction recall was tested (Test 3, T3).
2.6. Histology
After the end of the behavioral experiments, animals were overdosed
with chloral hydrate (1000 mg/kg) and perfused intracardially with 0.9
% saline. The brains were removed, stored in 10 % formalin for 48 h,
sectioned in coronal 50-μm slices and stained with 0.1 % сresyl violet.
The slices were used to verify cannula and recording electrode positions
and to evaluate the volume of tissue damage produced by the needle
insertion. Localization and volume of the damage were reconstructed on
stereotaxic atlas templates from Paxinos and Watson [7] using a light
Fig. 2. Localization of micro-injury sites in the amygdala and photomicrographs of the typical amygdala lesion. Scale bar is 1 mm.
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Behavioural Brain Research 416 (2022) 113559
microscope.
2.7. Statistical analysis
Statistical analyses were performed using Statistica software 8.0
(StatSoft). All datasets were tested for a normal distribution using the
Shapiro-Wilk’s W test, and for sphericity using Mauchley Sphericity
Test. Two-way Repeated Measures ANOVA with Group as a between-
subjects factor and Session (T0, T1, T2 and T3) as a within-subject fac­
tor was used. For within-subject analysis all measures were compared to
T1. Freezing time to tone during extinction sessions and behavior in OF
were compared between groups via nonparametric Kruskal-Wallis
ANOVA with multiple comparisons. The differences in volumes of the
amygdala damage between different groups were estimated using
Mann–Whitney test. The significance was set at p < 0.05. Data were
shown as mean ± SEM.
M.P. Rysakova et al. Behavioural Brain Research 416 (2022) 113559

3. Results expression, irrespective of triggering SD.

One hour after memory reactivation in T1 (during reconsolidation
window), implanted rats were subjected to bilateral amygdala micro-
injury with simultaneous recording of cortical activity (0− 30 Hz). To
produce amygdala micro-injury, a 30-gauge needle was inserted
through a guide cannula so that it protruded 1 mm below the tip of the
cannula. The injury localization and typical lesion produced by the
procedure are shown in Fig. 2. The mean volume of the amygdala
damage was 0.29 ± 0.026 mm3 (penetration depth of 1.07 ± 0.03 mm
and injury width of 0.5 ± 0.02 mm). As reported previously, such me­
chanical amygdala micro-injury produces a single wave of SD propa­
gating to the ipsilateral cortex [6]. Out of 17 implanted rats, the bilateral
amygdala micro-injury induced bilateral SD in six rats (Am injury/bi SD
group), unilateral SD in six rats (Am injury/uni SD group) and no SD in
five rats (Am injury/no SD group). Typical DC- and AC-recordings of
cortical activity in the groups are shown in Fig. 3, A-C. The lesion size
was 0.34 ± 0.04 mm3 in animals with bilateral SD, 0.22 ± 0.039 mm3 in
rats with unilateral SD and 0.32 ± 0.048 mm3 in injured rats without SD.
There was no difference in the lesion size between groups without SD
and with bilateral SD (p = 0.73, Mann-Whitney U test), although ani­
mals with unilateral SD had a smaller lesion size compared to rats
without SD (p = 0.016, Mann-Whitney U test). In general, mean lesion
sizes for injuries that induced SD (0.28 ± 0.035 mm3, n = 17) and did
not induce SD (0.29 ± 0.039 mm3, n = 14) did not differ significantly (p
= 0.57, Mann-Whitney U test).
Rats of all groups showed a significant increase in freezing time to
tone in T1 compared to T0 (F1,23 = 256.59, p < 0.001), thus demon­
strating successful learning of fear memory. There was no between-
group difference in cued freezing in T1 (F3,23 = 0.44, p = 0.72, Fig. 3, D).
The following day, rats were tested for cued memory (a post-
reactivation long-term memory, T2). Neither group showed changes in
the cue response in T2 relative to T1 and no group differences were
found in T2 (Group effect: F3,23 = 1.007, p = 0.41; Session effect: F1,23 =
0.83, p = 0.37) (Fig. 3, D). Thus, being induced shortly after memory
reactivation, the amygdala micro-injury had no effect on fear
One-two days after T2, rats were subjected to two-day extinction
training. As shown in Fig. 3, E-F, injured rats without SD exhibited
higher cued freezing compared to injured rats with bilateral SD (p <
0.05) and naïve animals (p < 0.05) in both extinction sessions. Freezing
response in injured rats with unilateral SD showed intermediate dy­
namics of extinction. At the start of the sessions these rats exhibited high
freezing as injured rats without SD but by the end of each session
reduced freezing score to that observed in naïve rats and rats with
bilateral SD. In the second extinction session, animals with unilateral SD
showed spontaneous recovery of extinguished fear: the freezing time in
the group (trials 1–2) was higher compared to naïve animals (p =
0.0002) and rats with bilateral SD (p = 0.007) but then decreased
abruptly (Fig. 3, F). The freezing scores of rats with injured amygdala
and bilateral SD did not differ from those of naïve rats (p > 0.05).
The day after completion of the extinction training, the retention test
(T3) showed successful extinction of cue memory in all rats except those
with injured Am and no SD (Fig. 3, D). The repeated measures ANOVA
showed a decrease in freezing response at T3 compared to T1 (Session
effect: F1, 23 = 46.57, p < 0.001; Group effect: F3,23 = 2.41, p = 0.09).
Within-subject post-hoc comparison revealed that the freezing per­
centage significantly decreased in naïve (p = 0.001), Am injury with
unilateral SD (p = 0.006) and Am injury with bilateral SD (p = 0.001)
groups but remained unchanged in the group with injured Am and no SD
(p = 0.46). Between-subject post-hoc comparison showed that the
freezing time in T3 was significantly higher in injured rats without SD
compared to animals with bilateral SD (p = 0.007) and naïve rats (p =
0.041) (Fig. 3, D). Thus, fear extinction was impaired in rats with
bilaterally injured amygdala without SD while animals with the same
amygdala injury triggering SD were successfully extinguished similarly
to naïve rats.
Similar changes were found for context freezing response (including
only data on the pre-CS baseline period) (Fig. 4, A). All the animals
exhibited a significant increment of the freezing time in T1 compared to
T0 (F1,23 = 172.32, p = 0.0001) without group differences in T1 (F3,23 =
1.82, p = 0.17) and T2 (F3,23 = 2.62, p = 0.075). The ANOVA showed

Fig. 3. Effects of intra-amygdala micro-injury on cued fear extinction. (A-C) Representative DC- and AC-recordings of electrical activity of the frontal cortex in the
right (R) and left (L) hemispheres after an amygdala injury (dashed line) triggering bilateral SD (A), unilateral SD (B) and no SD (C). Scale bars – 2 mV (DC), 0.2 mV
(AC) and 50 s. (D) Freezing time to tone in T0 – T3 tests in naïve (n = 10), Am injury/no SD (n = 5), Am injury/uni SD (n = 6) and Am injury/bi SD (n = 6) rats. (E, F)
Freezing to tone during first (E) and second (F) extinction sessions. Freezing during extinction sessions was binned into 2 CS trial blocks. Data are presented as means
± SEM. # p < 0.01 relative to Test 1; * p < 0.05, ** p < 0.01, *** p < 0.001 relative to naïve rats; o p < 0.05, oo p < 0.01 relative to Am injury/bi SD group.

4
M.P. Rysakova et al.
Fig. 4. Effects of intra-amygdala micro-injury on context fear extinction and behavioral activity. (A) Freezing time to context in T0 – T3 tests in naïve (n = 10), Am
injury/no SD (n = 5), Am injury/uni SD (n = 6) and Am injury/bi SD (n = 6) rats. (B-D) Comparison of distance moved (B), velocity (C) and time along walls (D) in
the open field test. For more details see the legend of Fig. 3.
that freezing to context significantly decreased in T3 relative to T1
(Group effect: F3,23 = 4.66, p = 0.01; Session effect: F 1,23 = 55.32, p <
0.001). Within-subject post-hoc comparison revealed that the freezing
percentage significantly decreased in injured rats with unilateral SD (p =
0.0004), bilateral SD (p = 0.007) and naïve rats (p = 0.018) but no
change was found in injured animals without SD (p = 0.11). Between-
subject post-hoc comparison showed that the injured group without
SD exhibited significantly higher freezing time relative to the injured
rats with unilateral (p = 0.04) and bilateral (p = 0.03) SD (Fig. 4, A).
To assess an influence of the amygdala injury and SD on general
behavioral activity, open field test was performed two hours after T2.
The test showed no group effects on the distance moved (H(3, 27) =
0.78, p = 0.85), velocity (H(3, 27) = 0.66, p = 0.88) and border time (H
(3, 27) = 5.85, p = 0.12) (Fig. 4, B-D).
4. Discussion
The present study shows that amygdala micro-injury performed
shortly after memory reactivation and associated SD have no impact on
conditioned fear expression 24 h later but profoundly affect fear mem­
ory in the extinction phase.
Memory retrieval triggers a number of processes that either reinforce
or alter stored information. The considerable evidence now indicates
that consolidated memories, when reactivated through retrieval,
become labile and again sensitive to protein synthesis inhibition [9,10].
It was shown that the basolateral amygdala (BLA) is involved in the
reconsolidation of fear memory [9,11]. A number of BLA neurons are
activated by the retrieval of step-through passive avoidance [12]. The
pharmacological impairment of memory reconsolidation is a possible
new strategy for reducing PTSD symptoms [13].
Neurotoxic lesion and pharmacological inactivation of the amygdala
after fear reactivation/acquisition have been shown to disrupt fear
expression [12,14–16]. In our study, circumscribed mechanical injury of
the amygdala during post-retrieval restabilization period did not impair
fear expression 24 h later (T2) but profoundly affects fear extinction
during a few subsequent days and the effect critically depends on
whether the injury triggers SD. If no SD occurred, fear extinction was
disrupted and rats exhibited high freezing during two-day extinction
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Behavioural Brain Research 416 (2022) 113559
training procedure and in extinction recall test (T3). But if bilateral SD
was triggered by the amygdala damage, fear memory was successfully
and rapidly extinguished similarly to naïve rats. Rats in which bilateral
damage of the amygdala triggered unilateral SD showed intermediate
dynamics of extinction with spontaneous recovery at the onset of the
second extinction session and rapid decline by its end.
It has been reported that a nonreinforced retrieval may preferentially
drive the memory toward reconsolidation or extinction in agreement
with the hypothesis of trace dominance [17]. In our study prolonged
re-exposures to the CS (120 s) in Test 1 in the absence of the US most
likely trigger the formation of a new “extinction” trace rather than
reconsolidation. Spontaneous recovery of fear response that we
observed at the onset of the second extinction session in the injured rats
with unilateral SD is considered as a typical behavioral attribute of
extinction [18]. Moreover, freezing time in naïve rats (without amyg­
dala injury) had downward trend as early as Test 2. Thus, to clarify
whether injury-induced SD or amygdala damage alone affect the
memory reconsolidation additional experiments with shorter CS
re-exposure during the memory reactivation are required.
Impairment of fear extinction is suggested to be a major patho­
physiological mechanism of PTSD and facilitating extinction of trau­
matic memory is the main therapeutic strategy in treatment of the
disorder. The amygdala is known to play the critical role in fear
extinction [18,19]. Our study provides first experimental evidence that
SD triggered by the amygdala micro-damage and spreading to the
neocortex exerts pro-extinction effect while identical damaging without
SD impairs fear extinction. SD is known to produce both deleterious and
beneficial effects on neuronal function. Cortical SD facilitates cellular
death in areas with disturbed metabolism [1] but enhances local cere­
bral blood flow and upregulates stress response proteins, growth factors
and receptor subunits in healthy cortical tissue [20,21]. Since both the
neocortex and amygdala are involved in neural mechanisms of fear
extinction, SD induced in the injured amygdala and reliably propagating
to the intact cortex may exert complex impact on fear memory. By
triggering long-term plastic changes in healthy cortical tissue [20],
injury-induced SD could promote adaptive pro-extinction changes in
fear memory.
Information about SD effects on memory is very limited and
M.P. Rysakova et al.
controversial. Cortical SD acutely (10− 20 min) disrupts expression
conditioned responses [22] and memory consolidation of passive
avoidance reactions [3] but mild brain trauma triggering cortical SD
does not affect fear memory 24 h later [5]. On the other hand, cortical
SD does not modify spatial memory acutely [23] but disrupts it several
weeks later [24].
The present study does not provide any details about mechanisms
underlying the prolonged effects of amygdala injury-induced SD on fear
memory. However, based on previous studies it may be assumed that SD
induced by amygdala damage could lead to changes in protein synthesis
and gene expression. Extinction is a form of inhibitory learning
requiring protein synthesis. Repeated cortical SDs are known to produce
early decrease [25] and late (24 h) increase in protein synthesis in the
cortex and hippocampus [26]. Cortical SD is followed by long-term in­
crease in BDNF levels [27], playing an important role in fear extinction
memory [28].
Although the effect of amygdala injury-induced SD on fear memory is
quite clear, separate experiment with amygdala damage induced
immediately before extinction training could provide more details about
effects of injury-induced SD or amygdala damage alone on the fear
extinction.
In conclusion, the results of the present study suggest strong
involvement of SD induced by amygdala micro-injury in extinction of
fear memory. These data may be useful for design and interpretation of
experiments using local intracerebral microinjection and for under­
standing basic mechanisms of post-traumatic stress disorder.
Funding source
This work was supported by Russian Foundation for Basic Research
[RFBR 18-015-00418].
Author contributions
MR: Methodology, Formal analysis, Investigation, Writing the
manuscript, Visualization, IP: Methodology, Investigation, Reviewing;
LV: Conceptualization, Methodology, Validation, Investigation,
Writing/Editing the manuscript, Supervision, Funding acquisition.
All authors have read and approved the manuscript.
Declaration of Competing Interest
The authors declare that they have no conflicts of interest.
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