life

Review
Advancing Post-Stroke Depression Research: Insights from
Murine Models and Behavioral Analyses
Mădălina Iuliana Mus, at 1 , Bogdan Cătălin 1, * , Michael Hadjiargyrou 2, * , Aurel Popa-Wagner 1,3
and Andrei Gres, it, ă 1,4

1 Experimental Research Centre for Normal and Pathological Aging, University of Medicine and Pharmacy of
Craiova, 200349 Craiova, Romania; madalina.musat3@gmail.com (M.I.M.);
aurel.popa-wagner@geriatrics-healthyageing.com (A.P.-W.)
2 Department of Biological and Chemical Sciences, New York Institute of Technology,
Old Westbury, NY 11568, USA
3 Department of Neurology, Vascular Neurology and Dementia, University of Medicine Essen,
45122 Essen, Germany
4 Department of Biomedical Sciences, New York Institute of Technology, Old Westbury, NY 11568, USA
* Correspondence: bogdan.catalin@umfcv.ro (B.C.); mhadji@nyit.edu (M.H.)

Abstract: Post-stroke depression (PSD) represents a significant neuropsychiatric complication that

affects between 39% and 52% of stroke survivors, leading to impaired recovery, decreased quality
of life, and increased mortality. This comprehensive review synthesizes our current knowledge of
PSD, encompassing its epidemiology, risk factors, underlying neurochemical mechanisms, and the
existing tools for preclinical investigation, including animal models and behavioral analyses. Despite
the high prevalence and severe impact of PSD, challenges persist in accurately modeling its complex
symptomatology in preclinical settings, underscoring the need for robust and valid animal models to
better understand and treat PSD. This review also highlights the multidimensional nature of PSD,
where both biological and psychosocial factors interplay to influence its onset and course. Further,
we examine the efficacy and limitations of the current animal models in mimicking the human
PSD condition, along with behavioral tests used to evaluate depressive-like behaviors in rodents.
This review also sets a new precedent by integrating the latest findings across multidisciplinary
Citation: Mus, at, M.I.; Cătălin, B.;
studies, thereby offering a unique and comprehensive perspective of existing knowledge. Finally, the
Hadjiargyrou, M.; Popa-Wagner, A.;
development of more sophisticated models that closely replicate the clinical features of PSD is crucial
Gres, it, ă, A. Advancing Post-Stroke
in order to advance translational research and facilitate the discovery of future effective therapies.
Depression Research: Insights from
Murine Models and Behavioral
Analyses. Life 2024, 14, 1110. https://
Keywords: post-stroke depression; behavioral tests; cognition; social activity; motor function;
doi.org/10.3390/life14091110 antidepressants; murine models of depression

Academic Editors: Stefanos Roumeliotis

and Giuseppe Minervini

Received: 30 July 2024 1. Background

Revised: 31 August 2024 Studies estimate that annually, 15 million people are affected by a stroke worldwide.
Accepted: 2 September 2024 Roughly 5 million people die due to the ischemic event, while another 5 million survivors
Published: 3 September 2024 are permanently disabled [1,2]. Unfortunately, prevention cannot successfully reduce the
stroke occurrence rate due to the high number of risk factors and comorbidities linked to its
onset [3]. These include the most important factors, cardiovascular disease [4], high body
mass index [5], chronic stress [6], and more importantly, aging [7]. Current therapeutic
Copyright: © 2024 by the authors.
approaches are mostly focused on limiting the long-term multiple medical conditions of
Licensee MDPI, Basel, Switzerland.
This article is an open access article
stroke survivors as well as the overall burden on the healthcare system and society [8].
distributed under the terms and
Following stroke, motor complications, such as hemiparesis [9], hemiplegia, or postural
conditions of the Creative Commons
instability [10], significantly challenge patient rehabilitation efforts [11]. Additionally, patients
Attribution (CC BY) license (https:// are faced with urinary and bowel incontinence [12], cognitive impairment and dementia [13],
creativecommons.org/licenses/by/ depression [14], anxiety [15], fatigue [16], and sleep disorders [17,18], all of which pose a
4.0/). significant challenge for successful diagnosis and treatment. While significant motor [11]

Life 2024, 14, 1110. https://doi.org/10.3390/life14091110 https://www.mdpi.com/journal/life

Life 2024, 14, 1110 2 of 31

and cognitive [19] dysfunction represent long-term consequences of ischemic injury, PSD
represents the most frequent and challenging neuropsychiatric complication [20,21].
Estimating the exact prevalence of PSD is challenging, particularly due to methodolog-
ical complexities, such as variations in the timing of patient evaluations after stroke onset
and differences in instruments and criteria utilized in experimental settings [21]. However,
recent findings suggest that PSD occurs in approximately 18–33% of cases [22,23], with
the greatest number of occurrences observed within the first year following the ischemic
insult [24]. Also, ~53% of individuals who were depressed within 3 months after stroke
experienced persistent depression [21]. These results are concerning, especially because
the mortality rate is higher among patients who suffer from PSD [22]. The risk of suici-
dal death is ~2 times higher for stroke patients compared to the general population [25],
and in addition to suicidal ideation [26], cognitive deficits [27], long-term disability [28],
and a substantially lower quality of life [29] are additional symptoms in patients who
develop PSD.
Thus, it is of paramount importance to understand the underlying mechanisms of
this disease and to accurately identify efficient screening tools and therapeutic modalities.
However, studying the pathopsychological mechanisms underlying PSD, such as affected
cellular plasticity [30], neuroinflammation, and neurodegeneration [31], as well as intrinsic
recovery pathways (neurogenesis) [32], requires a highly accurate and performant experi-
mental approach. But, establishing preclinical models can also pose challenges, particularly
given the subjective nature of the psychological and physiological PSD symptoms [33].
Researchers have endeavored to create rodent models that capture key aspects of PSD,
allowing for the evaluation of behavioral manifestations and underlying neurobiolog-
ical changes [34–36]. One such approach involves inducing focal cerebral ischemia in
rodents [37] and simulating the conditions of stroke observed in humans. Following
a stroke, protocols for inducing depressive behavior [38] and behavioral tests tailored
to assess depressive-like symptoms are used [39] and encompass a wide range of as-
says designed to evaluate various aspects of depressive behavior, including despair-like
behavior [40], anhedonia [41], and alterations in locomotor activity and exploration [42,43].
Despite recent progress in PSD-related research, challenges persist in accurately re-
producing the multifaceted nature of this condition in in vivo animal models. To advance
translational research and the development of new therapeutic treatments for PSD, it is cru-
cial to develop valid animal models that accurately replicate the complex symptomatology
of the condition. According to the International Classification of Diseases, 11th Revision
(ICD 11) criteria [44], psychiatrists diagnosing depression in patients typically confirm
the presence of five or more symptoms from the depressive spectrum (i.e., depressed
mood, anhedonia, appetite or weight changes, sleep disturbances, psychomotor agitation
or retardation, fatigue, reduced concentration, feelings of worthlessness or excessive guilt,
and recurrent thoughts of suicide or death) [45]. Accurate replication of the human con-
dition in these models is crucial for understanding the pathology and to effectively test
various therapeutic interventions. Variability in individual responses [46], differences in
genetic backgrounds [47–51], and the subjective nature of depressive symptoms [52,53]
all present challenges in interpreting the data effectively. Moreover, the environmental
and social factors that can influence the onset and progression of PSD in humans [54,55]
are difficult to replicate in murine models, limiting the validity and effectiveness of these
studies. The complexity of stroke-induced brain injury, which involves not just the neural
circuits traditionally associated with mood regulation [56,57] but also the broader neurolog-
ical disruptions [58], complicates the accuracy of modeling PSD. Additionally, the lack of
biomarkers or a valid genetic model for depression further contributes to the difficult task of
studying neuropsychiatric disorders, including PSD, in a preclinical setting [59]. These chal-
lenges highlight the need for continued refinement of animal models and methodologies to
enhance the translational potential of PSD preclinical research.
The purpose of this review was to conduct a thorough investigation of the current
literature on murine models for PSD, highlighting both the strengths and weaknesses of these
 for depression further contributes to the difficult task of studying neuropsychiatric
disorders, including PSD, in a preclinical setting [59]. These challenges highlight the need
for continued refinement of animal models and methodologies to enhance the
translational potential of PSD preclinical research.
Life 2024, 14, 1110 The purpose of this review was to conduct a thorough investigation of the current
3 of 31
literature on murine models for PSD, highlighting both the strengths and weaknesses of
these models, as well as the behavioral assessments employed. Our goal is to identify
effective animal models and behavioral evaluations so that their inherent limitations can
models, as well as the behavioral assessments employed. Our goal is to identify effective
be overcome. Further, this review aims not only to underline the tools available for such
animal
studiesmodels
but alsoand behavioral
discuss evaluations
the challenges so that
faced their inherent
in translating theselimitations
preclinicalcan be overcome.
results into
Further, this
the clinic. review aims not only to underline the tools available for such studies but also
discuss the challenges faced in translating these preclinical results into the clinic.
2. Materials and Methods
2. Materials and Methods
We have used PubMed and ClinicalTrials.gov in order to identify a thorough range
We have
of relevant used PubMed
scientific manuscripts.and Importantly,
ClinicalTrials.gov in order
our search to identify
extended a thorough
to encompass animalrange
of relevant scientific manuscripts. Importantly, our search extended
models of PSD and various behavioral studies and provides a comprehensive overview to encompass animal
models of PSDused
of the methods and in
various
exploringbehavioral
PSD. Thestudies and provides
search terms employed a mostly
comprehensive overview
included “post-
of the methods used in exploring PSD. The search terms
stroke depression murine models” and “post-stroke depression murine behavioral employed mostly included
“post-stroke depression murine models” and “post-stroke depression
studies”. Also, to ensure thorough coverage, we used derived terms such as “vascular murine behavioral
studies”.
depression”, Also, to ensure tests’,
“behavioral thorough coverage,
“cognition in we used derived
rodents”, “social terms
activitysuch as “vascular
in rodents”,
depression”, “behavioral tests’, “cognition in rodents”, “social activity
“motor function in rodents”, “stroke in rodents”, “chronic mild stress”, “depressive-like in rodents”, “motor
function
behavior”, in and
rodents”,
“anxiety“stroke in rodents”,
and depression “chronic mild
assessments stress”,
in murine “depressive-like
models”. Additionally,behavior”,
we
and “anxiety
manually and depression
reviewed the referenceassessments
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models”. Additionally,
to uncover furtherwe manually
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that the initial databaselists of all
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specifically chose the relevance
articles and manageability
published within the
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past two decades,We specifically
spanning chose
from 2004 to articles
2024, thus published
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of up-to-date
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spanning from 2004 A tolanguage
2024, thuscriterion wasthe
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inclusiontoofonly considerresearch
up-to-date articles findings.
written A
in English. This review primarily adopts a narrative approach and
language criterion was established to only consider articles written in English. This does not adhere to the
review
Preferred Reporting Items for Systematic Reviews and Meta-Analysis
primarily adopts a narrative approach and does not adhere to the Preferred Reporting (PRISMA)
guidelines.
Items However, the
for Systematic article and
Reviews selection process was(PRISMA)
Meta-Analysis meticulously structured,However,
guidelines. ensuring the
that included articles were scrutinized by a panel of three independent
article selection process was meticulously structured, ensuring that included articles reviewers (Figurewere
1).
scrutinized by a panel of three independent reviewers (Figure 1).

Figure 1. Flowchart of the literature search using PubMed.

3. Incidence and Prevalence of PSD

The incidence and prevalence of PSD exhibit considerable variability in the literature
due to differences in methodology, population demographics, and stroke characteristics
that underscore its recognition as a frequent consequence of cerebral ischemia [21]. Stud-
ies show that between 39% and 52% of stroke survivors experience symptoms of PSD
within the first five years after the ischemic event [60]. Studies have also shown that the
risk of developing depression is highest within the initial months following stroke [24],
with a gradual decline over time [61]. This acute onset suggests a complex interplay of
Life 2024, 14, 1110 4 of 31

biological, psychological, and social factors, which includes inflammatory mechanisms,

the hypothalamic–pituitary–adrenal (HPA) axis, limited capacity for independent living,
economic status, negative life events, family burden, and social family support. Collectively,
they all contribute to the development of PSD [51]. Additionally, the prevalence of PSD
tends to be higher in individuals with more severe strokes, those with a history of depres-
sion, and those experiencing greater functional impairment post-stroke [60]. While certain
studies suggest that the prevalence of depression after stroke does not significantly differ
between sexes, it appears to vary depending on the individual’s pre-stroke depression
status [62]. But, other reports state that elderly female stroke patients are 20% more likely
to develop PSD in comparison to males [63]. Collectively, all of the aforementioned point
to the need for new, effective, and preventive therapeutic approaches [64].

4. Risk Factors Involved in PSD

4.1. Stroke Characteristics and Lesion Localization
Increased lesion volumes, cerebral atrophy, silent infarcts, and white matter lesions are
factors that may correlate with an elevated risk of PSD [65] (Figure 2). Lesion location within
the brain is a critical determinant of PSD risk, as specific brain regions play distinct roles
in mood regulation and emotional processing. Previous studies have demonstrated that
the site of stroke lesions (i.e., prefrontal cortex, limbic area, and basal ganglia) significantly
influences the likelihood of developing PSD [56,66,67]. The neuroanatomical model proposed
by Soares in 1997 also links mood disorders, including PSD, to specific brain regions such as
the frontal lobe, basal ganglia, amygdala–hippocampus complex, and thalamus [68]. This
model emphasizes the importance of the basal ganglia for the transmission of 5-HT and
DA and how ischemic damage to brainstem monoaminergic nuclei or their projections can
decrease monoamine levels, affecting mood and cognition. Damage to the left frontal cortex
is also often linked to depressive symptoms; individuals with lesions in the left hemisphere
may be particularly susceptible to developing depression and anxiety following a stroke [69].
Although there are data suggesting a significant risk for depression following right hemisphere
strokes during the subacute phase [70], it appears that a higher risk is associated with left
Life 2024, 14, x FOR PEER REVIEW 5 of 33
hemisphere lesions [71]. Overall, while the link between the lesion site and PSD is generally
acknowledged, the exact relationship remains subject to ongoing research.

Figure2.2. Diagram
Figure Diagramshowing
showingriskrisk
factors associated
factors with PSD.
associated withSerotonin transporter
PSD. Serotonin (SERT), brain-
transporter (SERT),
derived neurotrophic factor (BNF), apolipoprotein E (ApoE), methylenetetrahydrofolate reductase
brain-derived neurotrophic factor (BNF), apolipoprotein E (ApoE), methylenetetrahydrofolate reduc-
(MTHFR), and Protein Kinase C Eta Gene (PRKCH).
tase (MTHFR), and Protein Kinase C Eta Gene (PRKCH).
4.2. Demographic Factors
Demographic factors play a significant role in influencing the risk and occurrence of
PSD. Gender disparities exist in the prevalence of PSD, with women generally exhibiting
higher rates of depression following a stroke compared to men [63,72,73]. Hormonal
fluctuations, psychosocial factors, and differences in coping mechanisms may contribute
to these gender differences observed [72]. Socioeconomic factors, including education
level, income, and access to healthcare resources, also play a crucial role in the
Life 2024, 14, 1110 5 of 31

4.2. Demographic Factors

Demographic factors play a significant role in influencing the risk and occurrence of
PSD. Gender disparities exist in the prevalence of PSD, with women generally exhibiting
higher rates of depression following a stroke compared to men [63,72,73]. Hormonal fluctua-
tions, psychosocial factors, and differences in coping mechanisms may contribute to these
gender differences observed [72]. Socioeconomic factors, including education level, income,
and access to healthcare resources, also play a crucial role in the development and course
of PSD [55]. Stroke survivors from lower socioeconomic backgrounds are more likely to
experience financial strain, social isolation, and limited access to mental health services,
exacerbating their risk of developing PSD [74]. Marital status is another factor associated
with PSD risk, with unmarried individuals, including those who are divorced, widowed, or
single, exhibiting higher rates of depression or suicidal ideations following a stroke [75].

4.3. Age
Studies have shown that the incidence and severity of PSD increase with advancing age,
highlighting the importance of age-related considerations in its management [76,77]. The inci-
dence of PSD is especially high in elderly stroke survivors [78], with 34% in stroke patients vs.
13% in the matched general population [79]. As most candidate therapies for PSD are being
developed and studied on young animal models [34], age, which is proven to be detrimental
to recovery, may aid in ushering a certain degree of accuracy to existing murine models, thus
reducing the translational gap between preclinical and clinical studies [80]. Although a vast array
of risk factors such as diabetes [81], hypertension [82], obesity, or dyslipidemia [83] are linked to
ischemic brain injury, age represents a non-modifiable risk factor that is not only linked to an
increased susceptibility to stroke but also to significantly decreased functional recovery [76,77,84].
It is, therefore, considered that age is a key modulatory factor for both stroke and PSD.

4.4. Genetic Factors

Genetic factors can also contribute to the complex interplay of biological and environ-
mental determinants underlying PSD [85]. Polymorphisms within the serotonin transporter
gene (SERT) are associated with PSD in stroke survivors [86], and BDNF is a significant con-
tributor to the pathophysiological mechanisms underlying PSD [87]. Research also suggests
that both apolipoprotein E (ApoE) and methylenetetrahydrofolate reductase (MTHFR) may
contribute to an increased risk of major depressive disorder after a stroke. Interestingly, the
catechol-O-methyltransferase (COMT) gene, crucial for DA degradation in the brain, along
the 5-HT2A receptor gene that is crucial in serotonin signaling, were studied for their roles in
ADHD, schizophrenia, mood regulation, and aggressive behavior [88]. Given their implica-
tions in such diverse neurological and behavioral conditions, it is particularly compelling to
explore these genes within the context of PSD. The COMT and 5-HT2A genes, through their
respective pathways in DA and 5-HT metabolism and signaling, could provide insightful
connections to the neuropsychiatric and emotional challenges seen in PSD. While advance-
ments in this area have been limited, certain genes such as protein kinase Cη (PRKCH),
angiotensin-converting enzyme, and apolipoprotein may also play an important role in the
development of vascular-related depression [89,90]. Additional investigations are ongoing to
further delineate the precise genetic factors influencing genetic susceptibility to PSD [91].

4.5. Medical and Psychiatric History

The burden of comorbidities and the severity of pre-stroke functional impairment can
influence the development and severity of PSD [81–83]. Additionally, a history of psychiatric
disorders is a strong predictor of PSD [92]. It is concerning that one out of every six stroke
patients has experienced PSD [93]. Attention to lifestyle factors, stress management, and social
support networks can offer additional layers of prevention and therapeutic intervention, po-
tentially mitigating the impact of pre-existing conditions and enhancing the overall wellbeing
of stroke survivors. After-stroke rehabilitation programs, including progressive resistance
training [94], modified cardiac rehabilitation [95], vocational rehabilitation [96], family-based
Life 2024, 14, 1110 6 of 31

programs [97], aquatic [98], music [99], cognitive behavioral therapy [100], repetitive transcra-
nial magnetic stimulation [101], pet therapy [102], and robotic devices [103], can all significantly
improve the quality of life and prevent or reduce PSD symptoms.

5. Valid Animal Models for PSD

PSD poses significant challenges in behavioral assessment due to the subjective nature
of its psychological and physiological symptoms [33]. This subjectivity further complicates
the development of accurate and reliable experimental animal models capable of capturing
the full spectrum of human symptoms. Researchers seek to navigate this complexity by
creating models that not only mimic the neuroanatomical and biochemical alterations
following a stroke but also elicit behavioral changes consistent with depressive pheno-
types. This endeavor extends to identifying and validating behavioral assays that can
reliably quantify depressive-like behaviors in animals. However, the translation from
animal models to the human condition is fraught with challenges, including differences
in brain structure and function, the complexity of human emotions, and the influence of
environmental and social factors on mental health [104]. Moreover, the heterogeneity of
stroke in terms of location, severity [65], and individual patient factors, like pre-existing
mental health conditions [93], further complicates the accuracy of modeling PSD. As such,
ongoing research aims to refine these models, increase their translational value, and ulti-
Life 2024, 14, x FOR PEER REVIEW 7 of 33
mately, enhance our understanding of PSD pathophysiology. Below, we outline several
useful animal models that can contribute to PSD-related research (Figure 3).

Figure 3.3. Diagram

Figure Diagram showing
showing murine
murine models
models ofof PSD.
PSD.Bilateral
BilateralCommon
CommonCarotid
CarotidArtery
ArteryOcclusion
Occlusion
(BCCAO), chronic unpredictable mild stress (CUMS), Middle Cerebral Artery Occlusion
(BCCAO), chronic unpredictable mild stress (CUMS), Middle Cerebral Artery Occlusion (MCAO), (MCAO),
5-Hydroxytryptamine [5-HT, serotonin), and brain-derived neurotrophic factor (BDNF).
5-Hydroxytryptamine (5-HT, serotonin), and brain-derived neurotrophic factor (BDNF).

5.1. Middle Cerebral Artery Occlusion (MCAO) Model

The MCAO model is one of the most widely used protocols to mimic stroke in
rodents [105]. In this model, the middle cerebral artery is occluded either transiently or
permanently [106], resulting in focal cerebral ischemia and subsequent stroke-like
symptoms, including depressive-like behavior [107]. This model allows for precise
quantitation of neurological deficits, infarct sizes, and the impact of therapeutic
Life 2024, 14, 1110 7 of 31

5.1. Middle Cerebral Artery Occlusion (MCAO) Model

The MCAO model is one of the most widely used protocols to mimic stroke in
rodents [105]. In this model, the middle cerebral artery is occluded either transiently
or permanently [106], resulting in focal cerebral ischemia and subsequent stroke-like symp-
toms, including depressive-like behavior [107]. This model allows for precise quantitation
of neurological deficits, infarct sizes, and the impact of therapeutic interventions. However,
the MCAO model comes with its own set of challenges, one of them being the technical
complexity of the procedure, which demands high surgical expertise to ensure consistency
in ischemia severity and reduce variability among animals [108]. The procedure entails
slowly lifting the right MCAO using a tungsten hook connected to a micromanipulator
and then thermocoagulating it. Both common carotid arteries are subsequently ligated for
90 min. After this period, the common carotid arteries are reopened [109,110]. The muscle
and soft tissue are then repositioned, and the skin is sutured. Initially, the occlusion is con-
firmed visually, followed by measuring and comparing the blood flow to normal levels. An
80% reduction in blood flow is deemed successful [111]. Researchers use various durations
of MCAO to mimic different levels of stroke severity [112,113]. This approach allows them
to investigate the underlying mechanisms of brain injury and assess potential therapeutic
interventions. The occlusion periods can range from 20 [114], 30 [115], 45 [116], 50, 60,
70 [113], 90 [117], and 120 [118] minutes to permanent occlusion [119]. However, the success
rate of PSD modeling using the MCAO model alone is limited. While some mice/rats
with MCAO may exhibit depressive behaviors, these are often short lived and can include
anxiety-like behaviors. To achieve more consistent and prolonged depressive behaviors,
it is necessary to combine MCAO with other techniques, such as chronic unpredictable
mild stress (CUMS). This combined approach enhances the validity and reliability of PSD
models by more accurately replicating the complex pathophysiological and behavioral
aspects of PSD. Such methodologies help to create a more comprehensive model, allowing
for more in-depth studies and better understanding of PSD mechanisms [35].

5.2. MCAO Model Combined with CUMS

Animals undergoing MCAO followed by chronic mild stress exhibit a heightened
severity of depression-like behavior compared to those undergoing MCAO alone [35].
This model is advantageous as it mimics the chronic stress often experienced by stroke
survivors and allows for the study of PSD. This model was successfully demonstrated in
both rats [120,121] and mice [122,123]. Stressors may include mild physical stress (electric
shock, tail clamp, restraint stress, forced swim), social stress (isolation, overcrowding),
and environmental stress (altered light–dark cycle, food or water deprivation, cage tilt
or cage shaking, wet bedding). The stressors and duration for implementing CUMS can
vary significantly, between 21 [124], 28 [125–127], 35 [128–130], 42 [131,132], 49 [133], and
56 days [134,135], involving both group and individual housing (Table 1).
Life 2024, 14, 1110 8 of 31

Table 1. CUMS models of depression according to stressors and duration.

Days of
Stressors and Duration CUMS/Mice
Housing
Alterations of Food
Gaignier F., Illumination Soiled cage Paired 21 days
the Cage tilt deprivation Small cage
2018 at night overnight housing Individually
light-dark 1 h, 2 h, 15 h overnight 1 h, 2 h
[124] 15 h 15 h 2h housing
cycle 15 h
Food and Crowding:
Zhang M., Exposure to a Traffic noise Food Illumination Water 28 days
Cage tilt water ten mice per Level shaking
2023 stroboscope (70–90 dB) deprivation at night deprivation Individually
12 h deprivation cage 15 min
[125] 12 h 6h 12 h 12 h 12 h housing
24 h 12 h
Exposure to
Ice water Food Illumination Restraint Exposure to a Water 28 days
Yan W., 2021 Cage tilt an empty Soiled cage
swimming deprivation at night stress foreign object deprivation Group
[126] 5 min bottle 24 h
5 min 24 h 12 h 2h 24 h 24 h housing
1h
Ice water Foot electric Food Restraint Water 35 days
Wu J., 2021 Cage tilt Continuous illumination Wet bedding Tail-clamp Cage shaking
swimming shock deprivation stress deprivation Individually
[128] 24 h 24 h 24 h 90 s 15 min
5 min twice 24 h 2h 24 h housing
Wang Y.I., Ice water Food Restraint Water 35 days
Cage tilt Continuous illumination Wet bedding Cage shaking
2021 swimming deprivation stress deprivation Individually
24 h 24 h 24 h 30 min
[129] 5 min 24 h 6h 24 h housing
Plantar
Wang G., Ice water Food Water 35 days
Cage tilt electrical Continuous illumination White noise Soiled cage Tail nipping Exposure to a stroboscope
2019 swimming deprivation deprivation Group
12 h stimulation 36 h 12 h 24 h 2 min 2h
[130] 5 min 12 h 12 h housing
10 min
Exposure to a Food Restraint Water 42 days
Wen G., 2019 Cage tilt 120-dB noise Alterations of the light-dark Wet bedding
stroboscope deprivation stress deprivation Individually
[131] 4h overnight cycle 4h
overnight 24 h 4h 24 h housing
Alterations of Exposure to
Li M., Food White noise Exposure to a Water 42 days
the Cage tilt an empty Overnight Overhang Soiled cage Tail pinch Oscillation
2014 deprivation 1h foreign object deprivation Group
light-dark 12 h bottle illumination 10 min 24 h 1 min 5 min
[132] 24 h 12 h 24 h housing
cycle 10 min
Food Restraint Water 49 days
Xie M., 2022 No bedding Cage tilt Overnight illumination (twice Wet bedding Tail pinching Cage shaking
deprivation stress deprivation Individually
[133] 24 h 24 h per week) 24 h 5 min 15 min
24 h 6h 24 h housing
Switched
Wassouf Z., Food Illumination Restraint Rat Water 56 days
day/night- Cage tilt
2019 deprivation at night stress confrontation deprivation Individually
cycle 2h
[134] 16 h 12 h 1h 30 min 16 h housing
48 h
Wang Y., Food Restraint Damp Water 56 days
4 ◦ C exposure Cage tilt Cage shaking
2021 deprivation Day/night inversion stress bedding deprivation Group
1h 12 h 30 min
[135] 23 h 1h 24 h 23 h housing
Life 2024, 14, 1110 9 of 31

5.3. MCAO Model Combined with Social Isolation

Rodents are highly social mammals, and single housing, mimicking social isola-
tion, can lead to various behavioral and physiological changes, including depressive-like
behaviors [136]. Mice that underwent individual housing for 14 days following a stroke
exhibited exacerbated depressive-like behavior compared to pair-housed mice [137].

5.4. MCAO + Social Isolation + CUMS Model

The MCAO + social isolation + CUMS protocol stands out as the most extensively uti-
lized approach for modeling PSD in preclinical studies [38]. Following surgery, the ani-
mal is individually housed to facilitate postoperative recovery and, subsequently, it under-
goes exposure to various stressors throughout the course of the CUMS procedure [138–141].
Previously, it was shown that even without a stroke procedure, social isolation is
considered the most fitting housing condition during the CUMS regimen for studying
depression [127,142]. This integrative model effectively mimics the human experience of
PSD, incorporating both the physical impact of a vascular event and the psychological stress
from environmental changes, thereby providing a comprehensive framework for exploring
the complex interplay between physical and mental health and environmental factors in
post-stroke outcomes.

5.5. MCAO Model Combined with Spatial Restraint Stress

Restraint stress has been demonstrated to impair sociability in rodents [143] and
has also been successfully used as a stressor during the CUMS procedure for 2 h [126],
4 h [131], or 6 h [129]. Following MCAO, restraint stress-induced depressive-like behavior,
as assessed through behavioral tests, was applied, which resulted in dull hair color and a
poor general state [144].

5.6. Bilateral Common Carotid Artery Occlusion (BCCAO) Model

The BCCAO model, introduced as a stroke model, entails ischemic white matter
and eye injury and is simpler to establish compared to MCAO [145]. Following BCCAO
induction, depressive-like behavior was observed in 5-week-old Balb/c mice [146–148],
albino mice [149], and Wistar rats [150] without the need for an additional method to
induce PSD.

5.7. BCCAO Model Combined with CUMS

Recent research efforts have employed the BCCAO model, alongside a two-week
CUMS protocol, in order to develop a murine (C57B16J) model of PSD [151]. While this
model represents a significant advancement in replicating the complexities of PSD, it is
important to acknowledge the inherent variability in response among different rodent
strains and species.

5.8. Intracerebral Injection of Endothelin-1 (ET-1)

ET-1, a powerful vasoconstrictor produced internally during ischemic stroke, plays
a crucial role in neuronal damage and subsequent disability [152]. The administration
of ET-1 into the left medial prefrontal cortex (mPFC) of mice has been shown to cause a
pronounced and lasting anxiety and depressive phenotype, establishing its potential as a
murine model for PSD [153]. In contrast, experiments conducted in rats have demonstrated
that ET-1 leads to anxiety-like behaviors but not depressive-like behaviors. This disparity
suggests that additional damage to a secondary brain area might be necessary to elicit
a depression phenotype in rats, highlighting the complications of modeling PSD across
different rodent species [154].

5.9. Photothrombotic Model

Photothrombosis involves the induction of focal cerebral ischemia by illuminating a
photosensitive dye in the presence of a light source, leading to thrombus formation and
Life 2024, 14, 1110 10 of 31

vascular occlusion [155]. One commonly used dye is Rose Bengal, which, when activated
by green light (560 nm) [156], generates reactive oxygen species, leading to clot formation
and vascular occlusion [157]. Another example is Erythrosin B, which operates in a similar
manner but is activated by a different wavelength (near 660 nm) [158] and offers flexibility
in experimental setups. These dyes are selected for their high quantum yield of singlet
oxygen production, a key factor in inducing rapid and targeted vascular occlusion [159].
The photothrombosis model provides exceptional precision in dictating both the location
and extent of ischemic lesions, a feature that has been instrumental in linking specific
brain areas to behavioral outcomes. This level of control has facilitated research demon-
strating that rodents subjected to ischemic lesions exhibit behavioral changes reminiscent
of depression [38].

5.10. Genetic Models of PSD

Genetically modified animals with alterations in specific genes implicated in de-
pression or stroke pathophysiology can also be valuable for studying PSD. For example,
knockout mice lacking BDNF [160] and the 5-HT transporter [161] exhibit depressive-like
behaviors and impaired neurogenesis. However, future research should aim to elucidate
the complex interactions between genetic factors, environmental stressors, and stroke-
induced neurobiological changes to enhance the understanding of PSD in these knockout
murine models.

6. Assessing Symptoms and Behaviors: Key Tests for Studying PSD

This section outlines a range of behavioral tests crucial for investigating the patho-
physiological impacts of stroke and for evaluating the accuracy of animal models and the
efficacy of therapeutic interventions (Figure 4). These tests encompass motor function eval-
uations, assessing coordination and muscle strength, as well as cognition, which measures
Life 2024, 14, x FOR PEER REVIEW 11 of 33
memory and learning capabilities. Additionally, social behavior tests are discussed, which
are used to examine interaction patterns and anxiety levels among animals.

Figure 4.
Figure 4. Behavioral
Behavioral assessment
assessment methods
methods for
for post-stroke
post-stroke depression
depression in
in rodent
rodent models.
models.

6.1. Anhedonia Test: Sucrose Preference Test

Test (SPT)
(SPT)
Anhedonia, defined as a diminished capacity to experience pleasure or interest in
previously
previouslyrewarding
rewardingactivities,
activities,is is
a hallmark symptom
a hallmark symptomof depression that can
of depression thatsignificantly
can signifi-
impact prognosis
cantly impact and complicate
prognosis patient recovery
and complicate [162]. In[162].
patient recovery rodentInmodels, the assessment
rodent models, the as-
sessment of anhedonia primarily relies on measuring the preference for sucrose, a simple
yet effective indicator of pleasure-seeking behavior. SPT involves providing each mouse
with two identical bottles: one containing a sucrose solution and the other water. The an-
imals are then allowed to choose freely between them [163]. A marked decrease in sucrose
consumption is interpreted as an expression of anhedonia [164,165]. The test procedure
Life 2024, 14, 1110 11 of 31

of anhedonia primarily relies on measuring the preference for sucrose, a simple yet ef-
fective indicator of pleasure-seeking behavior. SPT involves providing each mouse with
two identical bottles: one containing a sucrose solution and the other water. The animals
are then allowed to choose freely between them [163]. A marked decrease in sucrose
consumption is interpreted as an expression of anhedonia [164,165]. The test procedure
encompasses several variables, including housing during the habituation, concentration
of sucrose solution, period at which the experiments are performed (light/dark), type of
habituation to the SPT procedure, type of food/water deprivation during the test, and test
duration [166]. SPT has proven to have satisfactory results in various studies on differ-
ent animal models of PSD. For example, it revealed severe anhedonia after MCAO and
18 consecutive days of CUMS [123]. Also, MCAO and spatial restraint stress led to a de-
creased percentage of sucrose consumption compared to stroke alone [113]. Lastly, MCAO
followed by social isolation showed a significant increase in sucrose consumption for
post-stroke pair-housed mice compared to those that were socially isolated [137].

6.2. Depression-like Behavior Tests: Forced Swim Test and Tail Suspension Test
Depression encompasses a complex array of symptoms, including profound feelings
of hopelessness, persistent sadness, and thoughts of death or suicide [167]. The forced swim
and tail suspension tests have been employed as a means to gauge aspects of despair and
motivational withdrawal in rodents, which are considered analogs to the human experience
of hopelessness and passive resignation.
The Forced Swim Test (FST) is widely utilized for evaluating despair-like behavior in
animal models, quantifying the duration of immobility, except for the minimal movements
necessary to maintain the animal’s head above water. This behavior is interpreted as a sign
of behavioral despair, mirroring aspects of depression [168]. Studies have shown that both
MCAO and chronic mild stress can induce despair-like behavior in C57BL/6 mice [35], as
well as in albino mice subjected to BCCAO [149].
The Tail Suspension Test (TST) is also used, but only in mouse models. In this test,
animals are suspended by their tails, and the duration of immobility is recorded [169], with
longer immobility times indicating a higher level of despair. The TST has demonstrated
a significant increase in immobility time in C57BL/6 mice five days post-BCCAO [170],
NMRI mice 72 h after permanent double ligation of the right common carotid artery [171],
and ICR mice following MCAO and spatial restraint stress [172].

6.3. Anxiety Tests: Open Field/Elevated Zero Maze/Novelty Suppressed Feeding/The

Light/Dark/Marble Burying
Before conclusively identifying PSD in animal models, it is critical to evaluate the
presence of anxiety, as it often coexists with depression and can influence the overall
behavior and response of the animal. Anxiety assessment in rodents can be integrated
with social interaction tests or conducted through specific behavioral assays designed to
measure anxiety levels, such as the ones outlined below.
The Elevated Zero Maze (EZM) [173,174] and Elevated Plus Maze (EPM) Tests [175]
use an elevated apparatus designed to invoke anxiety-related behaviors by exploiting the
rodent’s aversion to open and elevated spaces. The EZM, a circular platform divided
into open and closed sections, allows for the assessment of anxiety based on the animal’s
preference for the safer, enclosed areas over the exposed ones [173,174]. The EPM similarly
measures anxiety by recording the time spent in the open arms of a plus-shaped apparatus,
with decreased time indicating higher anxiety levels [175]. In experiments involving
C57BL/6 mice, the administration of ET-1, a procedure used to mimic stroke conditions,
was followed by an assessment using the EPM and indicated that post-ET-1 injection, mice
exhibited a marked reduction in the time spent in the open arms of the EPM, suggesting
heightened anxiety levels [153].
The Open Field Test (OFT) serves as a critical tool for assessing anxiety-like behavior
in rodents by tracking the amount of time they spend in the center of an open arena [176].
Life 2024, 14, 1110 12 of 31

Anxiety levels in this context are analyzed from the animal’s exploration patterns, with a
preference for the periphery over the center indicating higher anxiety [176]. Experiments
using C57Bl/6 mice subjected to MCAO and 17 days of chronic mild stress revealed
significant anxiety with OFT, as demonstrated by reduced central area exploration [35].
Similarly, MCAO followed by periods of social isolation also led to a noticeable decrease in
the time these mice spent in the center [137].
The Novelty Suppressed Feeding Test (NSFT) is a behavioral assay designed to evalu-
ate anxiety and depression-related behaviors by measuring both the amount of food intake
and the delay before the animal engages with a new, highly palatable food item [177].
This test is predicated on the natural conflict between the fear of a novel environment
and the motivation to eat, with increased latency and reduced food consumption indi-
cating heightened anxiety or depressive states [177]. Studies involving C57BL/6 mice
demonstrated that after microinjection of ET-1, mice exhibited a decreased interest in food
and a significant delay before beginning to eat the novel food, suggesting an increase
in anxiety or depressive-like behavior [153]. Similarly, following an MCAO procedure,
mice showed increased latency to approaching and consuming the food pellet three weeks
post-ischemia [178].
The Light/Dark Test (L/D Test) measures an animal’s willingness to explore or avoid
new environments [179,180]. This test utilizes a chamber divided into illuminated and dark
sections and allows measurement of the time taken to enter the light compartment and the
number of transitions between compartments, reflecting the animal’s exploratory behavior
and its aversion to brightly lit areas, respectively [179]. A preference for spending more
time in the dark compartment is interpreted as an indication of anxiety. The L/D Test has
been effectively employed in studying PSD in murine models [153].
In the Marble Burying Test, animals are placed into a cage layered with bedding, in
which marbles or similar small objects are evenly distributed. Researchers then measure the
number of marbles the rodent buries within a specified period. A tendency to bury more
marbles is interpreted as an indication of heightened anxiety or compulsive tendencies,
providing a straightforward method for assessing these behaviors [181,182].
Nestlet Shredding and Nest Building Tests also serve as valuable tools for determining
stress levels in rodents [183]. These tests examine the natural nesting behavior, where
rodents are provided with materials, like cotton nestlets, to build nests. The extent and
quality of the nest constructed, along with the degree of shredding of the provided materials,
are indicative of the animal’s well-being, with poor nesting behavior suggesting elevated
stress or discomfort [183].

6.4. Social Withdrawal Tests: Crawley’s Sociability/Social Preference-Avoidance/Tree

Chamber/Olfactory Habituation-Dishabituation/Resident-Intruder/Tube Dominance
Social withdrawal is a critical symptom observed in numerous psychiatric disorders,
notably depression [184]. The array of behavioral tests deployed to study this condition
in rodents not only sheds light on the underlying mechanisms but also holds significant
value in assessing social withdrawal symptoms associated with PSD [185–187]. These
tests, designed to evaluate interactions among rodents or their response to social stimuli,
provide insight into changes in social behavior potentially indicative of PSD and are briefly
described below.
Crawley’s Sociability Test is a key method for evaluating social behavior and novelty
preference in rodents [188]. This procedure involves an initial interaction phase where
the test animal is given the opportunity to interact with a “stranger” mouse that it has
not previously encountered. After a 10 min interaction period, a second, novel “stranger”
mouse is introduced into the apparatus. The subject mouse is then observed to see whether
it shows a preference for the already-investigated unfamiliar mouse or the new, novel
unfamiliar mouse. This test provides valuable insights into the nuances of rodent social
behavior, particularly after experiencing a stroke.
Life 2024, 14, 1110 13 of 31

The Social Preference–Avoidance Test is used for both mice and rats and is designed to
measure the dynamics of social interaction, specifically the speed of approach or avoidance
displayed by the animal during the test [189,190]. This test provides insight into the social
tendencies of rodents, offering a nuanced view of how they navigate social spaces and
whether they show a propensity towards engaging with or avoiding other animals.
The Three Chamber Test is employed to assess sociability and social memory by eval-
uating a rodent’s preference for an unfamiliar conspecific or an inanimate object and its
preference for a new or a familiar conspecific [191]. This test effectively distinguishes be-
tween the animal’s interest in social interactions and its ability to recognize and differentiate
between familiar and unfamiliar individuals.
The Olfactory Habituation–Dishabituation Test, while initially utilized in evaluating
autistic behaviors in mice, serves a broader purpose in assessing the olfactory system,
which is vital for studying sensory processing in the brain [192]. Mice naturally exhibit a
preference for novel scents over familiar ones [193]. Assessment of the olfactory system
has proven useful for studying sensory processing in the brain [194] but also serves as
a valuable tool for assessing social interaction, memory, and anxiety [195]. Social inter-
action is conditioned by the level of anxiety, while anxious behavior is often associated
with depression [196].
The Resident–Intruder Test is another significant behavioral assay where a resident
rodent is confronted with an unfamiliar “intruder” in its environment. The resultant
behaviors, ranging from aggressive to affiliative, are observed and scored. This test is
instrumental in evaluating behaviors such as territorial aggression, social dominance, and
social recognition memory [197].
The Tube Dominance Test is primarily employed to measure social hierarchy and
dominance in mice [198]. After a day of habituation and training, two mice enter a narrow
tube from opposite sides and meet in the middle. The mouse that persuades the other to
retreat is deemed the winner, respectively dominant. The test was successfully used in a
mouse model of depression involving CUMS [199] and could provide additional insights
regarding PSD.

6.5. Cognitive Impairments Tests: Morris Water Maze/Barnes Maze/Y-Maze/Novel Object

Recognition/Radial Arm Maze/Passive Avoidance
When dealing with depression, individuals often experience cognitive impairments,
including difficulties with memory and attention, loss of concentration, and problems with
learning processes [200]. These cognitive symptoms are critical components of the overall
clinical representation and can significantly affect the quality of life and daily functioning.
Recognizing the importance of these symptoms, cognitive assessment in PSD has also been
approached through various behavioral tests in research settings that are described below.
The Morris Water Maze Test is a widely recognized method for evaluating spatial
learning and memory in rodents. Animals are placed in a sizable water pool with a platform
submerged beneath the surface. Rodents must navigate using spatial cues in order to find
the platform. Through repeated trials, they gradually learn and remember the platform’s
location, demonstrating spatial memory retention [201]. Pre-experimental learning trials
are often conducted to familiarize rodents with the task [202,203]. Studies have shown
an increased latency to find the platform in MCAO mice in the 3rd [178] and 6th week
after stroke [35].
The Barnes Maze Test offers an alternative to the Morris Water Maze, utilizing a
dry, less stressful environment for the rodent. This test involves a circular platform with
multiple holes around its edge, one of which leads to an escape box. Rodents are required
to navigate using spatial cues to find this escape route, providing insights into their spatial
learning and memory capabilities [204].
The Y-Maze Test is another critical tool that measures the willingness of rodents to
explore a new environment by recording the number of arm entries and the sequence of
these entries to assess spontaneous alternation behavior [205]. This test is particularly useful
Life 2024, 14, 1110 14 of 31

for observing short-term memory by analyzing the percentage of correct alternations made
by the rodent, reflecting its ability to remember previously visited arms [205]. Research
involving C57BL/6 mice post-MCAO surgery and subsequent individual housing revealed
a decrease in the percentage of correct alternations in the Y-maze, suggesting impairments
in spatial working memory as compared to pair-housed mice [137].
The Novel Object Recognition Test (NORT) serves as a behavioral assay for evaluating
memory capability, particularly recognition memory [206]. Initially, animals are allowed to
familiarize themselves with an arena containing two identical objects [207]. Subsequently,
one of the original objects is replaced with a novel object, and the animal’s interaction
with both objects is observed [208]. A preference for exploring the novel object over the
familiar one is typically indicative of healthy recognition memory, as it suggests the animal
remembers the original object and finds the new one more interesting [207,208]. Studies
employing NORT have demonstrated its utility in detecting memory impairment. For
example, socially isolated mice subjected to MCAO showed impairment in recognition
memory, as evidenced by their equal interest in exploring both novel and familiar objects.
This lack of preference for the novel object indicates a difficulty in recognizing or remem-
bering the previously encountered object, underscoring the impact of social isolation and
stroke on cognitive functions [137].
The Radial Arm Maze Test typically consists of a central platform with multiple arms
extending outward, resembling the spokes of a wheel [209]. At the end of each arm,
food rewards or other incentives are placed to motivate the rodent. The animal is placed
in the central area and must efficiently navigate through the maze to collect the rewards.
Successful navigation involves remembering which arms have already been visited to avoid
unnecessary revisits, thereby demonstrating the animal’s ability to learn and remember
spatial information [210].
The Passive Avoidance Test is a specific behavioral assay used to assess learning
and memory after stroke [211]. Rodents are typically placed into a two-compartment
apparatus, one illuminated and one darkened. Initially, the animal is allowed to explore
both compartments freely. After a predetermined period of time, usually during the
training phase, the animal receives a mild aversive stimulus (i.e., foot shock) upon entering
one of the compartments, typically the darkened compartment. This creates an association
between the aversive stimulus and the compartment. During the testing phase, the animal
is again placed in the apparatus and allowed to freely explore both compartments. The
latency to enter the aversive compartment is recorded. Animals with intact memory will
exhibit a longer latency to enter the aversive compartment due to their association with
the stimulus [212].

6.6. Motor Function Tests: Rotarod/Cylinder/Grid-Walking/Beam-Walking/Pole/Wire

Hanging/Horizontal Ladder/Adhesive Removal/Forelimb Grip/Staircase/Corner/Pasta
Assessing motor function in murine models of PSD is essential for comprehending
the effects of stroke. Accordingly, a range of tests has been introduced to measure various
aspects of motor skills, including coordination, balance, skilled locomotion, muscle strength,
and forelimb functionality, and these are described below and shown in Figure 4.
The Rotarod Test stands as the benchmark for evaluating motor function, particularly
coordination and balance in mice [43,213]. In this test, mice are placed on a rod that rotates
at a controlled speed. The duration for which each mouse remains on the rod before
falling is recorded, serving as a measure of its motor coordination and balance [214]. Addi-
tionally, a variation of the Rotarod, the RotaWheel, has emerged as a novel experimental
tool for assessing locomotion in mice [215,216]. This apparatus offers a new dimension
to the evaluation of motor skills, providing insights into locomotion abilities as well
as endurance [215,216].
The Cylinder Test is a crucial assessment for evaluating forelimb asymmetry, particu-
larly in the context of sensorimotor function following stroke [217]. In this test, mice are
placed inside a transparent cylinder, and the use of their forelimbs during vertical explo-
Life 2024, 14, 1110 15 of 31

ration or rearing movements is carefully observed and recorded. Stroke-induced deficits

can lead to a noticeable asymmetry in forelimb use, where the animal might predominantly
use one limb over the other, reflecting the impairment of sensorimotor function to one side
of the body. This test has frequently been adopted to assess motor function recovery or de-
cline after stroke, providing valuable insights into the extent of motor rehabilitation or the
effectiveness of therapeutic interventions aimed at mitigating motor function deficits [153].
The ability of this test to detect subtle changes in limb usage offers a sensitive measure of
motor skills and recovery.
The Grid-Walking Test is specifically designed to evaluate skilled locomotion and
motor coordination [217]. Mice are placed on a grid that features widely spaced holes.
As the animals navigate across the grid, the incidence of foot slips through the holes is
recorded [218]. This approach allows for precise quantification of motor deficits, par-
ticularly those affecting coordination and the ability to perform complex movements.
Stroke-induced impairments are often manifested as an increase in the number of foot slips,
indicating a loss of motor control or diminished spatial awareness [217,219].
The Beam-Walking Test assesses balance, coordination, and skilled locomotion [220],
and it requires a raised-beam apparatus and training sessions for the subjects [221]. Ani-
mals have to traverse a narrow beam to reach a secure platform, with their performance
providing insight into their motor capabilities. Both the time taken to cross the beam and
the incidence of foot slips during the attempt are key metrics for assessing the presence
and extent of motor deficits, particularly those resulting from stroke-induced damage.
When the Beam-Walking Test was been applied to Sprague Dawley rats following MCAO,
significant functional impairments were documented [222,223].
The Pole Test involves placing animals at the top of a vertical pole, where they are
trained to perform a turnaround maneuver before descending the pole headfirst. Evaluation
focuses on the time it takes for the animal to initiate and complete the turnaround maneuver,
as well as the descent [43]. This approach allows researchers to assess motor coordination,
agility, and the animal’s overall ability to control and execute complex motor tasks. The
test proved useful in the evaluation of mice after MCAO [224].
The Wire Hanging Test examines the forelimb motor strength of mice after stroke [224].
The mice undergo training to hang their bodies from a steel wire, which measures 2 mm in
diameter, solely using their forelimbs. This training spans two days, including three trials
per day. The average holding time across the three trials is calculated and analyzed [225].
A lower holding time is indicative of a decrease in motor strength.
The Horizontal Ladder Test is used to evaluate walking ability [226]. The animals are
trained to cross the ladder from a neutral cage to reach their home cage [227]. During the test,
the number of successful steps, slips, or missed steps is measured [228]. These assessments
provide valuable insights into the animals’ motor skills and coordination abilities.
The Adhesive Removal Test is another method for evaluating sensorimotor deficits
and somatosensory function in rodent models after stroke [229,230]. Small adhesive stimuli,
such as sticky tape or adhesive-backed dots, are placed on the forepaws of the animal, and
their ability to detect, remove, and discriminate between the stimuli is assessed [231].
The Forelimb Grip Force Test is used to measure muscle strength, providing a quan-
titative assessment [223]. Studies have reported a decrease in grip force for both the
right and left hind paws in C57BL mice 7 days following Distal Middle Cerebral Artery
(DMCA) occlusion. Interestingly, this reduction in grip strength was not observed 28 days
post-stroke, indicating some degree of recovery over time [232]. Additionally, rats subjected
to MCAO combined with CUMS exhibited a significant decrease in grip force 22 days after
the injury [223].
The Staircase Test is commonly used with rodents to assess skilled reaching and
grasping abilities, particularly in the context of examining motor function and recovery
after stroke. In this test, rodents are typically placed in a cage equipped with a staircase
apparatus consisting of a series of steps with food rewards placed on each step. The animals’
Life 2024, 14, 1110 16 of 31

ability to navigate the staircase and retrieve the food rewards offers insight into their skilled
reaching and grasping capabilities and overall motor recovery [233].
The Corner Test also provides valuable insights into motor asymmetry and sensori-
motor function [43]. Following a stroke, the rodent is placed near a corner of a testing
apparatus, typically a rectangular or triangular enclosure with two converging walls form-
ing the corner. As the rodent approaches the corner, it tends to turn in the direction of its
more impaired side, leading to a higher frequency of turns toward the affected side com-
pared to the unaffected one. Researchers observe and record the direction of the turns as
well as any asymmetry in movement patterns [234]. This method allows for the assessment
of both the preference in turning direction and any motor deficits that might influence this
preference, offering a direct indication of unilateral sensorimotor impairment.
The Pasta Test provides valuable insights into the motor abilities and functional
recovery of rodents following neurological insults [235]. Animals are typically given a
piece of pasta to manipulate and eat. The researchers then observe and analyze the rodent’s
behavior, focusing on the symmetry and effectiveness of its forepaw movements during
the manipulation and consumption of the pasta. Impairments in fine motor skills or
asymmetrical use of the forepaws can indicate deficits in manual dexterity, indicative of
neurological damage or dysfunction [236].
Motor dysfunction and depressive symptoms frequently coexist in patients following
a stroke, and there is evidence to suggest that these motor deficits can influence the onset
and severity of depressive symptoms [237]. The DigiGait system provides detailed and
quantitative assessments of gait and offers a unique opportunity to study these motor
abnormalities in stroke models [43]. Although DigiGait has not been extensively used
specifically for PSD research, its ability to precisely measure changes in gait and coordi-
nation could be invaluable in understanding the relationship between motor deficits and
depressive behaviors post-stroke [238]. Incorporating DigiGait assessments in PSD studies
could enhance our understanding of how motor impairments contribute to or exacerbate
depressive symptoms. Future research may explore this intersection, potentially leading to
more comprehensive therapeutic strategies that address both the motor and psychological
aspects of post-stroke recovery.

7. Pathophysiological Mechanisms Involved in PSD

The pathophysiological mechanisms underlying PSD are multifactorial, involving
biological, neurochemical, and psychosocial factors that interplay to reveal depressive
symptoms following a cerebrovascular event. Stroke lesions in critical brain areas, notably
the prefrontal cortex, limbic system, and basal ganglia, play a pivotal role in disrupting
neurotransmission pathways essential for mood regulation, thus contributing to the on-
set of PSD [56]. Specifically, lesions in the left hemisphere (left frontal cortex and basal
ganglia) are correlated with a higher incidence of depression, which is attributed to di-
minished levels of 5-HT and norepinephrine (NE) [56]. In contrast, another study also
points to the right hemisphere’s involvement in PSD, particularly during the subacute
phase (1–6 months) [70]. This neurotransmitter hypothesis further underscores the role of
monoamines (NE, 5-HT, DA) in mood regulation, as ischemic injury notably decreases their
production and availability. Ischemic lesions can disrupt the axons containing biogenic
amines that ascend from the brainstem to the cerebral cortex, resulting in reduced levels of
monoamines in limbic structures found in the frontal and temporal lobes, as well as the basal
ganglia. In turn, this influences motivation-related behaviors such as salience detection,
reward and punishment learning, processing incentives, decision making, goal-directed
actions, and regulation of anxiety levels [239]. Additionally, genetic predispositions, such
as the 5-HTTLPR genotype, also modulate susceptibility to PSD [240–242].
Inflammatory cytokines also play significant roles in the pathophysiology of both
stroke and depression. Specifically, the IL-10 -1082A/A genotype has been linked to PSD in
general, while the IL-4 + 33C/C genotype has shown an association with major PSD [243].
These genetic variants highlight the interplay between immune response and psychiatric
Life 2024, 14, 1110 17 of 31

outcomes following stroke, suggesting potential genetic markers for susceptibility to PSD
subtypes. Inflammation is a critical contributor, with elevated levels of pro-inflammatory
cytokines (IL-1β, IL-4, IL-8, TNF-α) [244,245] and the activation of pathways, such as
NLRP3, signifying an influence on PSD pathophysiology [246]. Neuroendocrine dysregu-
lation, especially concerning the HPA axis and resultant elevated cortisol levels, also con-
tributes significantly to PSD, highlighting the neuroendocrine system’s critical role in mood
regulation [247,248]. Poor post-stroke prognosis is linked to alterations in the HPA axis,
elevated levels of catecholamines and natriuretic peptides, and reduced levels of melatonin
and IGF-1 [249]. Moreover, neurotrophic factors, like brain-derived neurotrophic factor
(BDNF) and glial cell line-derived neurotrophic factor (GDNF), essential for neuronal
health and regeneration post-injury, are also linked to PSD development, with varia-
tions in their levels and methylation status closely associated with depressive outcomes
post-stroke [250,251]. Together, these mechanisms offer a comprehensive insight into the
intricate number of factors contributing to PSD [56].

8. Strain Differences in Rodents

Strain differences in rodents can significantly influence the manifestation and under-
standing of PSD [252]. The injection of ET-1 produced a pronounced and persistent anxiety
and depression phenotype in C57/BL6 mice [153]. However, in Sprague Dawley rats, it
resulted in anxiety-like behavior while it failed to induce depressive-like responses [154].
Even in various rat strains, distinct behavior patterns emerge following stroke. Lewis rats
exhibited behavior indicative of depression but not fatigue, whereas Wistar and Sprague
Dawley rats displayed behavior indicative of fatigue but not depression [252]. A future
and comprehensive analysis of rodent strain-related differences should provide insight into
symptom pathophysiology as well as guide researchers in choosing the appropriate mouse
or rat strain. Additionally, the development of transgenic animals may also play a critical
role in enhancing the translatability of preclinical tests for PSD. Introducing specific genetic
modifications will enable researchers to generate animal models that more closely mimic
the genetic and molecular aspects of human PSD.

9. Translatability of PSD Research

Examining clinical trial registries is essential in order to gain a broad understanding
of the progress made in ongoing PSD research. An analysis of PSD research indicates a
significant disparity between the abundance of preclinical studies and the relatively limited
number of clinical trials. A PubMed search with the keyword “post stroke depression” over
the past twenty years produces a total of 3273 entries. This includes 127 meta-analyses, 463
reviews, 180 systematic reviews, and 331 manuscripts related to clinical trials specifically
focusing on PSD.
Further examination of the National Institutes of Health’s (NIH) ClinicalTrials.gov
registry (accessed up to and including 20 April 2024] revealed 68 clinical studies at various
stages. This search encompassed studies marked both as completed and actively enrolling.
Of these, only thirteen are actively recruiting patients, an additional three are not yet
enrolling, and one is active but not recruiting. These trials, which primarily involve adult
participants of both sexes, range from early Phase 1 to Phase 4, with 43 categorized as
“Not applicable” regarding their phase. Fifty-three of these trials are interventional, with a
focus on directly modifying participant treatment or behavior to assess efficacy and safety
outcomes. There are also 15 observational studies, which typically gather data on PSD
without altering the treatment regimen. Additionally, there are four patient registries that
systematically collect information about patients with PSD to facilitate future research.
None of the studies are classified under expanded access, intermediate-size populations, or
treatment IND/Protocol categories, indicating a focus on controlled research settings rather
than broad or emergency-use interventions. Remarkably, only four of these studies have
reported results on ClinicalTrials.gov. This stark contrast to the abundance of preclinical
studies highlights a significant translational gap. As such, there is a pressing need for
Life 2024, 14, 1110 18 of 31

innovative methodologies and testing that can bridge this divide, which are essential in
accelerating the development of effective clinical PSD treatments.

10. Future Directions

PSD represents a prevalent and severe human neuropsychiatric complication that
impacts a significant number of stroke survivors, presenting challenges not only for the
patients but also for the healthcare system and support networks [60]. In this comprehen-
sive review, we compiled and analyzed the current scientific literature on PSD, covering
its epidemiological landscape, identifiable risk factors, and the biological and neurolog-
ical underpinnings. We also explored the tools available for studying PSD in preclinical
settings, including various animal (rodent) models and behavioral analyses. Our findings
highlighted the complex nature of PSD and underscored the challenges associated with
accurately modeling and evaluating its manifestations in preclinical settings. Recent stud-
ies have highlighted several pharmacological treatments for PSD. For example, selective
serotonin reuptake inhibitors (SSRIs) are commonly prescribed and have demonstrated
efficacy in alleviating depressive symptoms in stroke patients. Other antidepressants, such
as trazodone and tricyclic antidepressants, like nortriptyline, have also been used with
varying degrees of success [253,254]. These treatments work by modulating neurotrans-
mitter levels, thereby reducing depressive symptoms and enhancing the overall quality of
life. However, the selection of medication must be carefully considered due to the potential
side effects and interactions with other drugs frequently prescribed to stroke patients.
Neuromodulation techniques, such as repetitive transcranial magnetic stimulation and
transcranial direct current stimulation, along with innovative psychosocial interventions,
hold promise as effective treatments and warrant further investigations [254]. Furthermore,
effective management of PSD necessitates a multidisciplinary approach that integrates
pharmacological treatments with psychological, rehabilitative, and social interventions.
This strategy ensures that all aspects of the patient’s condition are addressed, promot-
ing better overall outcomes. Concurrently, ongoing research is focused on developing
novel therapeutic strategies, aiming to enhance the efficacy of treatments and minimize
side effects [255].
The combination of MCAO with social isolation and CUMS has emerged as a prevalent
murine model for studying PSD [38]. The duration of the CUMS procedure can vary for 3,
4, or 6 weeks, reflecting the different intensities and duration of stress exposure in studies
that induce depressive-like behaviors [138–140,256,257]. Numerous studies utilizing the
MCAO+CUMS model explored different aspects of PSD [120–123], indicating that social
isolation on its own can significantly contribute to the induction of rodent depressive-like
behavior [136]. This underscores the importance of social factors in the development of
depressive symptoms post-stroke, suggesting that the most effective animal models of
PSD must incorporate a multifaceted approach, mirroring the complex interplay of human
symptoms. Animal models of PSD exhibit distinct pathophysiological changes, which are
important for understanding the mechanisms underlying this condition. The MCAO model
shows microglial activation [258,259] and elevated levels of pro-inflammatory cytokines
in the brain [260,261] that are also involved in the neurodegenerative process [262]. The
additional chronic restraint stress and foot shock stress have been observed to decrease
BDNF levels [263]. The CUMS model induces the activation of the HPA axis [264], leading
to elevated cortisol levels [134]. Finally, the combined models of PSD provide insights into
the interaction between ischemia-induced brain damage and stress-induced neuroinflam-
mation, offering a more complex understanding of PSD pathophysiology. By integrating
findings from different models, researchers can better elucidate the complex biological
processes contributing to PSD and develop more effective therapeutic strategies.
In order to develop a comprehensive animal model of PSD, it is imperative to
thoroughly assess all depression-related aspects, such as the association between left
hemisphere stroke lesions and the manifestation of depressive symptoms [56,265]. Ap-
proximately 40% of individuals who experience left hemispheric infarctions develop de-
Life 2024, 14, 1110 19 of 31

pression, typically exhibiting mild to moderate symptoms shortly after the stroke or
after several months [266]. However, the hypothesis that the location of the brain le-
sion influences the risk of PSD is contested, with several studies challenging the notion
that depression is more commonly associated with left-hemisphere strokes than with
right-hemisphere strokes [70,267,268].
Age and gender also represent crucial factors that significantly impact the study of
neurodegenerative diseases, including PSD. Research predominantly utilizes young an-
imal models, which may not accurately reproduce the age-related complexities of PSD
in humans [34,146–148]. Including older animals in these studies will enhance model
validity, improve our understanding of age as a critical factor in disease progression and
recovery [80], and hopefully reduce the translational gap in clinical applications. Moreover,
the prevalence of studies focusing on male rodents [35,113,123,137] may overlook key
sex-based dimorphic differences that could influence both the presentation and progression
of PSD. Males and females may respond differently to stroke, with potential variations
in motor function, mood, cognitive abilities, and memory tasks [269]. Notably, female
rodents are more prone to weight loss during chronic social stress and may exhibit height-
ened anxious behaviors [270]. These differences are modulated by sex hormones, like
estrogen and testosterone, which are also known to affect stroke responses and depres-
sive behaviors [271]. For example, estrogen was shown to alleviate depressive symptoms
post-stroke [272]; however, recent findings suggest that the estrous cycle in females does not
significantly impact behavior or neurogenesis under basal conditions [273,274], indicating
that sex differences might not drastically alter outcomes in commonly used behavioral
tests. However, the inflammatory response to stroke, which is integral to PSD pathology,
appears to vary between sexes, with females often showing a stronger anti-inflammatory
response [275]. Future research should continue to address these variables, providing
a deeper understanding of how age and sex influence the development, treatment, and
ultimately, recovery from PSD. Such insights are vital for designing tailored neuro- or
psychotherapeutic clinical approaches.
Behavioral tests play a crucial role in assessing depressive-like behaviors in animal
models that aid our understanding of the multifaceted nature of PSD. These tests evaluate
a range of symptoms, from mood disturbances and cognitive deficits to motor dysfunctions
and social behavior changes. Commonly employed tests include the sucrose preference test
for anhedonia, the forced swim and tail suspension tests for despair-like behavior, or social
interaction tests for assessing social withdrawal. Additionally, motor function tests also
help to gauge the physical aspects of depression, which are often impacted in post-stroke
conditions [39]. Each test is designed to measure specific symptoms associated with PSD,
providing a comprehensive view of the animal’s emotional and cognitive state post-stroke.
However, interpreting the results of these behavioral tests requires careful consideration
and interpretation. The inherent variability in rodent behavior, the subjective nature of
depressive symptoms, and the potential for human error in collecting data during the
experiment or subsequent analyses necessitate a cautious approach [33,252]. Variations in
test conditions, handling, and even the environment can influence the outcomes, potentially
affecting the accuracy of the data [166]. Given these challenges, there is a pressing need
for future research to focus on refining existing behavioral tests and also develop more
sophisticated and direct methods for assessing PSD. This involves enhancing the objec-
tivity, sensitivity, and specificity of behavioral assays to accurately capture the nuanced
manifestations of PSD in animal models. Improvements in test design, execution, and data
analysis can lead to more reliable and valid measurements of depressive-like behaviors,
facilitating the identification of effective treatments and interventions for PSD.
In conclusion, this review summarized the complex and multifaceted nature of PSD,
emphasizing the significant challenges involved in modeling and evaluating this condi-
tion in preclinical trials. Our exploration into the epidemiology, risk factors, underlying
mechanisms, and the development of animal models for PSD has underscored the crucial
need for advanced, nuanced approaches in preclinical research. Indeed, bridging the gap
Life 2024, 14, 1110 20 of 31

between animal studies and clinical applications requires focused efforts to refine and
develop animal models and sophisticated behavioral assessments that more accurately
mirror the human condition and behavior. Enhancing these models and assessments is
essential for improving the translation of research findings into the clinic, resulting in more
effective diagnostic tools and treatments for PSD. This includes addressing the variability
in rodent responses, the challenge of extending the results to human pathology, and the
integration of diverse biological, psychological, and social determinants of PSD. Addi-
tionally, considerations of age, gender differences, and strain variability among rodents
highlight the importance of a custom-tailored approach in understanding and treating PSD.
This approach will help ensure that the insights gained in the laboratory can be effectively
applied in the clinic, ultimately improving patient outcomes and accelerating recovery.
While most previous studies address these aspects individually, our aim was to integrate
all recent developments in PSD pathology within both clinical and experimental contexts
in order to provide a complete perspective, highlighting the gap between human clinical
data and preclinical research.

11. Summary
PSD stands as a significant barrier to recovery from stroke and is defined by its com-
plexity stemming from an interplay of physiological, psychological, and social factors.
PSD research has expanded our understanding, revealing that risk factors such as age,
gender, pre-stroke psychiatric history, and the physical location of the stroke significantly
influence the likelihood and severity of PSD. Animal models, particularly those involv-
ing rodents, are pivotal for understanding the pathophysiological underpinnings of PSD.
Models such as MCAO, BCAO, and various genetic models are utilized to mimic stroke
in rodents, enabling the study of depressive-like behaviors subsequent to cerebrovascular
insults. Techniques combining MCAO with CUMS or social isolation post-stroke have been
particularly insightful and highlight the role of PSD environmental and social stressors.
Further, behavioral assessments are crucial in measuring symptoms, like anhedonia, de-
spair, hopelessness, and motor dysfunctions, which help evaluate the efficacy of potential
treatments and the validity of the models themselves. Despite these advances, translating
findings from animal models to human patients remains challenging. Variability in rodent
responses, differences in stroke etiology, and the subjective nature of depressive symptoms
complicate the direct application of preclinical results to the clinic. Moreover, the outcomes
of these studies underline the need for a personalized approach to treatment, considering
individual risk factors such as age, sex, comorbidities, social network, etc. While animal
models and behavioral studies have greatly contributed to our understanding of PSD,
the relatively limited number of clinical studies compared to the many preclinical studies
underscores the complexity of this condition and the existing translational gap. Advance-
ments in these areas are vital for developing targeted psychiatric, neuro-, or psychological
interventions, ultimately improving the quality of life and recovery outcomes for stroke
survivors worldwide.

Author Contributions: M.I.M., A.G., B.C., M.H. and A.P.-W.: methodology. B.C., M.H., A.G. and
A.P.-W.: validation. M.I.M. and A.G.: formal analysis. M.I.M. and A.G.: investigation. A.G. and
M.I.M.: resources. M.I.M. and A.G.: data curation. M.I.M. and A.G.: original draft. B.C., M.H.
and A.P.-W.: final manuscript. B.C., M.H. and A.P.-W.: supervision. All authors contributed to
editorial changes in the manuscript. All authors have read and agreed to the published version of
the manuscript.
Funding: The Article Processing Charges were funded by the University of Medicine and Pharmacy
of Craiova, Romania.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Life 2024, 14, 1110 21 of 31

Data Availability Statement: No new data were created or analyzed in this study. Data sharing is
not applicable to this article.
Conflicts of Interest: The authors declare no conflicts of interest. The funders had no role in the design
of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or
in the decision to publish the results.

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