Biology subjects

Kalliokoski, O.

Publications and source records attributed to Kalliokoski, O..

11 recordsLinked to original sources

bioRxiv2026

Vertical climbing in mice: a translationally relevant measure of pain-related impact on natural behaviour

Despite urgent need for better analgesics, drug development has been complicated by incomplete bench-to-bedside translation. A likely contributing factor is the poor connection between the experimenter-evoked pain-related measures often used in preclinical models, and the clinical symptoms, like broader functional impairment, reported by patients. Here, we asked whether vertical climbing, a species-specific elective behaviour in mice, could serve as a measure of pain-related impairment. We tested male and female mice in a wide range of pain-related models including models of post-operative pain, inflammatory injury, osteoarthritis, rheumatoid arthritis, cancer-induced bone pain, fibrous dysplasia, neuropathic pain, migraine-related pain and facial neuropathy. Vertical climbing was reduced in all models, across five different laboratories, demonstrating the robustness and consistency of this type of behaviour as a novel pain-related outcome measure. Reduced climbing correlated significantly with established pain-related measures, but its time course diverged from that of evoked mechanical allodynia, while aligned more closely with other non-evoked behaviours, like burrowing, home cage activity, wheel running or weight bearing. Pharmacological validation was bidirectional: gabapentin restored climbing in mice with neuropathic injury, and naltrexone reinstated the climbing deficit in mice that had recovered from intraplantar CFA, consistent with persistent pain held in remission by endogenous opioid signalling. Overall, our results indicate that voluntary vertical climbing is a stable, elective behaviour that provides a robust and translationally relevant measure of pain-related functional impairment in mice.

neuroscience↗

bioRxiv2026

Evaluating home-cage-activity metrics for detecting postprocedural pain in a plantar incision mouse model

Detection of postoperative pain in mice is challenging, and there is a need for unbiased, automated methods. Home-cage monitoring systems are promising, but their ability to detect mild pain remains unclear. We evaluated whether home-cage activity measures can be used to detect pain-related changes in a plantar incision model of postoperative pain. First, we confirmed the presence of local hypersensitivity using von Frey filaments on 48 C57BL/6JRj mice (24 males, 24 females). Subsequently, we pair-housed 64 mice (32 males, 32 females) and allocated them to receive either a 4 mm plantar incision on the hind paw under anaesthesia, or anaesthesia alone. Baseline locomotion and voluntary wheel-running activity were recorded over five days, followed by four days of postprocedural monitoring in the home cages. Both procedure groups (incision and anaesthesia-only) showed reduced locomotion and running wheel activity relative to baseline. However, activity measures did not differ between incised and anaesthesia-only mice, and we detected no sex-related effects. Under these conditions, home cage activity measures did not reliably discriminate pain-related behavioural changes in the model, despite the model showing local mechanical hypersensitivity in the von Frey test. Together, these findings indicate that, given the mild and localised nature of the plantar incision mouse model, commonly used home-cage metrics cannot yet reliably detect subtle pain-related behavioural changes.

animal behavior and cognition↗

bioRxiv2025

Structural enrichment for captive macaques - a systematic review and meta-analysis of behavioral outcomes

Macaques play an important role in biomedical research due to their genetic and physiological similarities to humans. However, their use raises significant ethical concerns regarding welfare, particularly in laboratory environments often lacking natural complexity. Environmental enrichment aims to promote welfare by encouraging natural behaviors and providing choice. This systematic review and meta-analysis synthesizes 61 years of research assessing the impact of structural modifications to the home cage (structural enrichment) on the behavior of captive macaques. We employed multilevel meta-analytical models to pool our data. Our findings demonstrate a net beneficial effect of structural enrichment on macaque behavior, notably in significantly reducing negative behaviors such as stereotypies, self-directed harm, and aggression. This positive effect was evident even when enrichment was added to already enriched conditions. We found that enrichment that incorporates varied physical and feeding strategies were most effective, underscoring that complex, varied environmental elements are crucial for welfare improvement. Simple increases in unfurnished space, by contrast, showed minimal benefit. The promotion of positive, species-typical behaviors was less consistent across studies, but nonetheless highlights structural enrichments potential to foster a broader natural behavioral repertoire. We also observed considerable variability in outcomes, suggesting that enrichment efficacy is influenced by multiple factors, and requires careful contextual assessment, as a one-size-fits-all approach is rarely optimal.

animal behavior and cognition↗

bioRxiv2025

Refining the adjuvant-induced rat model of monoarthritis by optimizing the induction volume and injection site

Arthritis is a highly prevalent and disabling condition characterized by pathological joint-damage, clinical symptoms of pain and loss of normal joint function. Monoarthritis can be modelled in rodents via intraarticular injection of complete Freund's Adjuvant (CFA), inducing both joint inflammation and pain-like behaviours. This study aimed to compare the outcome of different injection-volumes and joint-locations, to refine the model's use and to improve its validity. Male and female rats were injected with CFA into the ankle (10, 20 or 50 {micro}l) or knee (10, 50 or 100 {micro}l), and assessed on dynamic weight bearing, locomotor activity, depressive- and anxiety-like behaviours, histology, and a variety of welfare and model-specific parameters. Induction of monoarthritis resulted in relatively similar behavioural profiles regardless of the injected joint. The animals were highly affected in the acute phase, while less in the chronic phase. Greater volumes of CFA were associated with more profound behavioural changes and joint swelling. The largest volumes induced a pronounced local spread of inflammation to adjacent joints, which was reduced with intermediate volumes without attenuating the model validity. Reducing induction volumes to 20 and 50 {micro}l CFA for ankle and knee injections, respectively, appears to be valuable refinement of these models.

neuroscience↗

bioRxiv2024

Fraudulent studies are undermining the reliability of systematic reviews - a study of the prevalence of problematic images in preclinical studies of depression

Systematic reviews are considered by many to constitute the highest level of scientific evidence. A caveat is that the methods used in a systematic review - combining information from multiple studies - are predicated on all of the reports being truthful. Currently, we do not know how frequent fraudulent studies are in systematic reviews, or how they affect the resulting evidence base. For a systematic review of preclinical studies of depression, we found that potentially fraudulent studies were not only common but also that they biased the findings of the review. In a sample of 1,035 studies, we found that 19 % of peer-reviewed reports displayed data in the form of problematic images. In a majority of the cases, images had been altered or recycled in a way that makes us suspect foul play. Making things worse, these studies reported larger effect sizes, on average, than did studies where we did not identify problems. Counter to commonly held beliefs, reports with problematic images were not cited less or published in lower-impact journals, nor were their authors isolated to any specific geographic area. The sheer prevalence of problematic studies, and the fact that we could not find a simple pattern for identifying them, undermines the validity of systematic reviews within our research field. We suspect that this is symptomatic of a broader problem that needs immediate addressing.

neuroscience↗

bioRxiv2024

The threshold for intracranial self-stimulation does not increase in rats exposed to chronic unpredictable stress, a systematic review and meta-analysis

The chronic unpredictable stress model is a laboratory rodent model of stress-induced anhedonia. The sucrose preference test, often used to validate it, suffers from being unreliable. Intracranial self-stimulation offers an alternative and is often cited as supporting evidence of the validity of the model. Our aim was to assess whether an increased self-stimulation threshold is found after stress and if such a change correlates with decreases in sweet consumption. We searched PubMed, Embase, and Web of Science for studies in rats exposed to chronic unpredictable stress that employed intracranial self-stimulation. Thresholds, for stressed and control animals, in 23 experiments (11 studies) were pooled. Over 50% of the data was contributed by one research group, so a three-level meta-analytical random effects model was fit to account for methodological differences between different networks of researchers. After this adjustment, we did not find that the self-stimulation thresholds were increased in stressed rats. Pioneering experiments with positive results failed to be replicated by others, although no specific factor could be pointed to as a likely explanation. What is more, the available evidence suggests a lack of connection between sweet preference and self-stimulation, although this relationship has been seldom investigated. Methods known to mitigate biases were frequently absent, as was a transparent report of crucial study details. Our findings challenge the claim made in support of the validity of the model. Further efforts would be well-invested in assessing how reliably other tests of anhedonia have found the effects of the chronic unpredictable stress model.

animal behavior and cognition↗

bioRxiv2023

Rethinking data treatment:The sucrose preference threshold for anhedonia in stress-induced rat models of depression

Exposing rats to repeated unpredictable stressors is a popular method for modelling depression. The sucrose preference test is used to assess the validity of this method, as it measures a rats preference for a sweet solution as an indicator of its ability to experience pleasure. Typically, if stressed rats show a lower preference compared to unstressed rats, it is concluded they are experiencing stress-induced anhedonia. While conducting a systematic review, we identified 18 studies that used thresholds to define anhedonia and to distinguish "susceptible" from "resilient" individuals. Based on their definitions, researchers either excluded "resilient" animals from further analyses or treated them as a separate cohort. We performed a descriptive analysis to understand the rationale behind these criteria, and found that the methods used for characterizing the stressed rats were largely unsupported. Many authors failed to justify their choices or relied exclusively on referencing previous studies. When tracing back the method to its origins, we converged on a pioneering article that, although employed as a universal evidence-based justification, cannot be regarded as such. What is more, through a simulation study, we provided evidence that removing or splitting data, based on an arbitrary threshold, introduces statistical bias by overestimating the effect of stress. Caution must be exercised when implementing a predefined cut-off for anhedonia. Researchers should be aware of potential biases introduced by their data treatment strategies and strive for transparent reporting of methodological decisions.

animal behavior and cognition↗

bioRxiv2023

Development and Application of Home Cage Monitoring in Laboratory Mice and Rats: a Systematic Review

Traditionally, in biomedical animal research, laboratory rodents are individually examined in test apparatuses outside their home cages at selected time points. However, the outcome of such tests can be influenced by the novel environment, the time of day, separation from the social group, or the presence of an experimenter. Moreover, valuable information may be missed when the animals are only monitored in short periods. These issues can be overcome by longitudinal monitoring mice and rats in their home cages. To shed light on the development of home cage monitoring (HCM) and the current state of the art, a systematic review was carried out on 521 publications retrieved through PubMed and Web of Science. Both the absolute ([~] x26) and relative ([~] x7) number of HCM-related publications increased from 1974 to 2020. In both mice and rats, there was a clear bias towards males and individually housed animals, but during the past decade (2011-2020), an increasing number of studies used both sexes and group housing. More than 70 % of the studies did not involve a disease model, but the percentage of studies using disease models increased since the 2000s. In most studies, animals were kept for short (up to 4 weeks) length periods in the HCM systems; intermediate length periods (4-12 weeks) increased in frequency in the years between 2011 and 2020. Before the 2000s, HCM techniques were predominantly applied for less than 12 hours, while 24-hour measurements have been more frequently since the 2000s. The systematic review demonstrated that manual monitoring is decreasing but still relevant. Until (and including) the 1990s, most techniques were applied manually but have been progressively replaced by automation since the 2000s. Independent of the publication year, the main behavioral parameters measured were locomotor activity, feeding, and social behaviors; the main physiological parameters were heart rate and electrocardiography. External appearance-related parameters were rarely examined in the home cages. Due to technological progress and application of artificial intelligence, more refined and detailed behavioral parameters could be investigated in the home cage in recent times. Over the period covered in this study, techniques for HCM of mice and rats has improved considerably. This development is ongoing and further progress and validation of HCM systems will extend the applications to allow for continuous, longitudinal, non-invasive monitoring of an increasing range of parameters in group-housed small rodents in their home cages.

animal behavior and cognition↗

bioRxiv2023

Reliability of sucrose preference testing following short or no food and water deprivation. A Systematic Review and Meta-analysis of rat models of chronic unpredictable stress

The sucrose preference test is a popular test for anhedonia in the chronic unpredictable stress model of depression. Yet, the test does not always produce consistent results. Long food and water deprivation before the test, while often implemented, confounds the results by introducing unwanted drives in the form of hunger and thirst. We assessed the reliability of the test when only short or no fasting was used. We searched PubMed, Embase, and Web of Science for studies in rats exposed to chronic unpredictable stress that used no more than six hours of food and/or water deprivation before the test. Sweet consumptions, for stressed and control/antidepressant-treated animals, in 132 studies were pooled using random effects models. We found a decrease in sweet consumption in stressed rats, compared to controls, that was halved when a non-caloric sweetener was used and significantly reduced when sucrose consumption was corrected for body weight. What is more, the length of food and water deprivation was found to confound the effect. The effect was reversed when the stressed rats were treated with antidepressants. Methodological strategies meant to control for recognized sources of bias when conducting the test were often missing, and so was a clear and complete report of essential study information. Our results indicate that not only is food and water deprivation before the test unnecessary, but not recommended. Even in absence of long fasting, we found evidence of an additional effect on sweet consumption that is unrelated to anhedonia. Without properly controlling for non-hedonic drivers of consumption, the test is unreliable as a proxy measure of anhedonia. Strengthening the methodological rigor and addressing the confounding effect of metabolic factors in the sucrose preference test prevents misleading conclusions that harm the translatability of the associated research and perpetuates the use of animals for little gain.

animal behavior and cognition↗

bioRxiv2020

Hair glucocorticoids are not a historical marker of stress - exploring the time-scale of corticosterone incorporation into hairs in a rat model

Hair glucocorticoids are increasingly popular biomarkers, used across numerous research fields as a measure of stress. Although they are suggested to be a proxy of the average HPA axis activity spanning a period of weeks or months into the past, this theory has never been tested. In the present study, adrenalectomized rats with no endogenous (adrenal) glucocorticoid production were used to study how circulating glucocorticoid levels would be reflected in the glucocorticoid levels found in hair samples. By dosing the animals daily with high levels of corticosterone for seven days, while sampling hairs before, during, and after treatments, a timeline for glucocorticoid uptake into hairs was constructed. This kinetic profile was compared to two hypothetical models, and the theory that hair glucocorticoids are a record of historical stress had to be rejected. Corticosterone concentrations in hairs were found to increase within three hours of the first injection, the highest concentrations were found on the seventh day of treatments, and the decrease in concentrations post-treatment suggests rapid elimination. We speculate that hair glucocorticoid levels can only be used to characterize a stress-response for a few days following a postulated stressor. An updated model, where glucocorticoids diffuse into, along, and out of hairs needs to be adopted to reconcile the experimentally obtained data. The inescapable consequence of this updated model is that hair glucocorticoids become a marker of - and can only be used to study - recent, or ongoing, stress, as opposed to historical events, weeks or months in the past.

physiology↗

bioRxiv2018

Are we overestimating the utility of hair glucocorticoids? A systematic review exploring the empirical evidence supporting hair glucocorticoids as a measure of stress

Quantitating glucocorticoids (GCs) in hairs is a popular method for assessing chronic stress in studies of humans and animals alike. The cause-and-effect relationship between stress and elevated GC levels in hairs, sampled weeks later, is however hard to prove. This systematic review evaluated the evidence supporting hair glucocorticoids (hGCs) as a biomarker of stress.\n\nOnly a relatively small number of controlled studies employing hGC analyses have been published, and the quality of the evidence is compromised by unchecked sources of bias. Subjects exposed to stress mostly demonstrate elevated levels of hGCs, and these concentrations correlate significantly with GC concentrations in serum, saliva and feces. This supports hGCs as a biomarker of stress, but the dataset provided no evidence that hGCs are a marker of historical stress. Only in cases where the stressor persisted at the time of hair sampling could a clear link between stress and hGCs be established.

physiology↗