Too Depressed to Swim or Too Afraid to Stop? A Reinterpretation of the Forced Swim Test as a Measure of Anxiety-Like Behavior

Anyan, Jeffrey; Amir, Shimon

doi:10.1038/npp.2017.260

Cited by 86 publications

(56 citation statements)

References 13 publications

(21 reference statements)

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“…center of the OF apparatus and the immobility time during the tail suspension test. As suggested by a recent commentary (49), and in validation of our correlational results, we believe that the reduced immobility in the FST and TST is a measure of anxiety behavior/hyperactivity rather than an antidepressant effect of tau deletion in mice. The mechanisms underlying the increase in anxiety-like behavior following tau ablation in mice are unknown and may involve several mechanisms.…”

Section: Discussionsupporting

confidence: 84%

“…In this context, increased immobility time indicates depressive-like behavior (36,39). However, studies have suggested the use of TST and FST for the detection of anxiety-related behavior arguing that reduced immobility time in these tests results from exacerbated escape-directed behavior caused by an anxiogenic phenotype (49). Here, we report reduced immobility time of 15-19 weeks old TauKO and hTau mice in the FST ( Figure 2F) and TST ( Figure 2G) when compared to WT animals.…”

Section: Patterns Of Anxiety-related Behaviors In Tauko and Htau Micementioning

confidence: 99%

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Behavioral Abnormalities in Knockout and Humanized Tau Mice

et al. 2020

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Microtubule-associated protein tau assists in stabilizing microtubules and has been particularly implicated in Alzheimer's disease (AD). Given the importance of tau to AD pathogenesis and therapies, it is important to understand non-classic physiological functions for this protein inside and outside the central nervous system (CNS). Our group has previously shown that tau ablation triggers glucose intolerance and pancreatic dysfunction in mice, suggesting that tau plays a role in peripheral metabolic regulation. Little is known about the role of tau in anxiety. Moreover, inconsistent results have been generated regarding the effects of tau deletion in memory. Here, we characterize systemic insulin resistance, anxiety-related behavior and memory in 15 to 20 weeks old Wild-Type (WT), Tau knockout (TauKO) and a distinct hTau mouse model consisting of tau knockout expressing the longest isoform (2N4R) of a non-mutant WT human Tau protein under the prion promoter (hTau). Our findings demonstrate that tau deletion leads to anxiety-related behavior, impaired contextual and cued fear memory. The presence of a human Tau transgene did not ameliorate the phenotypes observed in animals lacking the mouse tau protein and it elicited impairments in learning, memory, and peripheral insulin sensitivity. Our results suggest that tau protein plays a role in memory and anxiety-related behavior. Our findings also indicate that previously unrecognized functions for tau protein may be a complicating factor in using animal models on the TauKO background. Understanding the link between tau pathophysiology and cognitive and metabolic alterations is of great importance to establish the complete contribution of tau protein to AD pathogenesis.

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Section: Discussionsupporting

confidence: 84%

Section: Patterns Of Anxiety-related Behaviors In Tauko and Htau Micementioning

confidence: 99%

Behavioral Abnormalities in Knockout and Humanized Tau Mice

et al. 2020

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“…Therefore, both procedures are postulated to induce depression-like behaviours. However, maLPA 1 -null mice exhibited an excessive emotional response, showing anxiogenic-like reactions in both tests ( Anyan and Amir, 2018 ), as previously described ( Moreno-Fernández et al, 2017 ), reflecting a comorbid phenotype between depression and anxiety-like behaviours ( Anyan and Amir, 2018 ; Moreno-Fernández et al, 2017 ). Antagonist-treated animals only exhibited anxious behaviours in the TST.…”

Section: Discussionsupporting

confidence: 74%

Effects of genetic deletion versus pharmacological blockade of the LPA1 receptor on depression-like behaviour and related brain functional activity

Moreno‐Fernández

Nieto-Quero

Gómez-Salas

et al. 2018

Disease Models &Amp; Mechanisms

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Animal models of psychopathology are particularly useful for studying the neurobiology of depression and characterising the subtypes. Recently, our group was the first to identify a possible relationship between the LPA1 receptor and a mixed anxiety-depression phenotype. Specifically, maLPA1-null mice exhibited a phenotype characterised by depressive and anxious features. However, the constitutive lack of the gene encoding the LPA1 receptor (Lpar1) can induce compensatory mechanisms that might have resulted in the observed deficits. Therefore, in the present study, we have compared the impact of permanent loss and acute pharmacological inhibition of the LPA1 receptor on despair-like behaviours and on the functional brain map associated with these behaviours, as well as on the degree of functional connectivity among structures. Although the antagonist (intracerebroventricularly administered Ki16425) mimicked some, but not all, effects of genetic deletion of the LPA1 receptor on the results of behavioural tests and engaged different brain circuits, both treatments induced depression-like behaviours with an agitation component that was linked to functional changes in key brain regions involved in the stress response and emotional regulation. In addition, both Ki16425 treatment and LPA1 receptor deletion modified the functional brain maps in a way similar to the changes observed in depressed patients. In summary, the pharmacological and genetic approaches could ultimately assist in dissecting the function of the LPA1 receptor in emotional regulation and brain responses, and a combination of those approaches might provide researchers with an opportunity to develop useful drugs that target the LPA1 receptor as treatments for depression, mainly the anxious subtype.

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“…However, under the same experimental conditions, SERT -/rats submitted to stereotaxic surgery targeting GFP virus infusion in the PrL also did not present increased immobility behavior in the forced swim test (Diniz et al unpublished observations). Interestingly, BDNF upregulation in the vHIP decreased immobility time in SERT -/rats in comparison to GFP-treated SERT -/animals, suggesting that BDNF overexpression contributed to an adaptive learned response (Anyan and Amir, 2018). In line with this finding, Karpova et al (2009) demonstrated that an increase in hippocampal BDNF IV caused by postnatal SSRI exposure was associated with decreased immobility in the forced swim test.…”

Section: Discussionmentioning

confidence: 65%

BDNF overexpression in the ventral hippocampus promotes antidepressant- and anxiolytic-like activity in serotonin transporter knockout rats

Diniz¹,

Calabrese

Brivio

et al. 2020

Preprint

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AbstractBrain-derived neurotrophic factor is one of the most studied proteins playing a pivotal role in neuroplasticity events and vulnerability and resilience to stress-related disorders. Most importantly, BDNF is decreased in depressive patients, and increased after antidepressant treatment. Additionally, BDNF was found to be reduced in a genetic subset of depression susceptible patients carrying the human polymorphism in the serotonin transporter promoter region (5-HTTLPR). The serotonin knockout rat (SERT-/-) is one of the animal models used to investigate the underlying molecular mechanisms behind the genetic susceptibility to depression in humans. SERT-/- rats present decreased BDNF levels, especially BDNF exon IV, in the prefrontal cortex (PFC) and ventral hippocampus (vHIP), and display anxiety- and depression-like behavior. To investigate whether upregulating BDNF in the vHIP would meliorate the phenotype of SERT-/- rats, we overexpressed BDNF locally into the rat brain by means of stereotaxic surgery and submitted the animals to behavioral challenges, including the sucrose consumption, the open field, and forced swim tests. Additionally, we measured hypothalamus-pituitary-adrenal (HPA)-axis reactivity. The results showed that lentivirus-induced BDNF IV overexpression in the vHIP of SERT-/- rats promoted higher sucrose preference and sucrose intake, on the first day of the sucrose consumption test, indicative for decreased anhedonia-like behavior. Moreover, it decreased immobility time in the forced swim test, suggesting adaptive passive coping. Additionally, BDNF upregulation increased the time spent in the center of a novel environment, implying decreased novel-induced anxiety-like behavior. Finally, it promoted a stronger decrease in plasma corticosterone levels 60 minutes after restraint stress. In conclusion, modulation of BDNF IV levels in the vHIP of SERT-/- rats led to a positive behavioral outcome placing BDNF upregulation in the vHIP as a potential candidate for the development new therapeutic approaches targeting the improvement of depressive symptoms.

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Too Depressed to Swim or Too Afraid to Stop? A Reinterpretation of the Forced Swim Test as a Measure of Anxiety-Like Behavior

Cited by 86 publications

References 13 publications

Behavioral Abnormalities in Knockout and Humanized Tau Mice

Behavioral Abnormalities in Knockout and Humanized Tau Mice

Effects of genetic deletion versus pharmacological blockade of the LPA1 receptor on depression-like behaviour and related brain functional activity

BDNF overexpression in the ventral hippocampus promotes antidepressant- and anxiolytic-like activity in serotonin transporter knockout rats

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