RESUMEN
Obsessive-compulsive disorder is a neuropsychiatric condition with notable genetic involvement. Against this background, laboratory-housed deer mice of both sexes varyingly present with excessive and persistent large nesting behavior (LNB), which has been validated for its resemblance of clinical compulsivity. Although LNB differs from normal nesting behavior (NNB) on both a biological and cognitive level, it is unknown to what extent the expression of LNB and NNB is related to familial background. Here, we randomly selected 14 NNB- and 14 LNB-expressing mice (equally distributed between sexes) to constitute 7 breeding pairs of each phenotype. Pairs were allowed to breed two successive generations of offspring, which were raised until adulthood (12 weeks) and assessed for nesting expression. Remarkably, our findings show that offspring from LNB-expressing pairs build significantly larger nests compared to offspring from NNB-expressing pairs and the nesting expression of the offspring of each breeding pair, irrespective of parental phenotype or litter, is family specific. Collectively, the results of this investigation indicate that LNB can be explored for its potential to shed light on heritable neurocognitive mechanisms that may underlie the expression of specific persistent behavioral phenotypes.
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Comportamiento de Nidificación , Peromyscus , Animales , Comportamiento de Nidificación/fisiología , Masculino , Femenino , Peromyscus/fisiología , Ratones , Modelos Animales de Enfermedad , Trastorno Obsesivo Compulsivo/fisiopatología , Trastorno Obsesivo Compulsivo/genética , Conducta Compulsiva/fisiopatología , Fenotipo , Conducta Animal/fisiologíaRESUMEN
BACKGROUND: An increasing body of research implicates inflammatory processes, including alterations in the neutrophil-lymphocyte ratio (NLR), in the pathophysiology of psychiatric illness. The deer mouse (Peromyscus maniculatus bairdii) is commonly studied for its naturalistic expression of compulsive-like behaviour. Towards future efforts to gain an understanding of how innate and adaptive immune processes might be involved in this model, we aimed to study the effects of pegfilgrastim, a pegylated recombinant human granulocyte colony-stimulating factor (g-CSF) analogue, on the NLR of both male and female deer mice. METHODS: Briefly, 54 deer mice (equally distributed between sexes) were exposed to a single injection with either control or pegfilgrastim (0.1 or 1 mg/kg) (n = 18 per group). Six mice of each group (three per sex) were euthanized on days two, four and seven post-administration, their blood collected and the NLR calculated. Data were analysed by means of ordinary three-way ANOVA, followed by Bonferroni post-hoc testing. RESULTS: Irrespective of dose, pegfilgrastim resulted in higher NLR values in mice of both sexes at days four and seven of testing. However, female mice exposed to the higher dose, presented with significantly higher NLR values irrespective of time, compared to male mice exposed to the same. CONCLUSION: The data generated from this work highlight important dose- and sex-specific aspects of pegfilgrastim with female mice showing heighted elevation of the NLR in response to high-dose pegfilgrastim administration only. Since the innate immune components of male and female deer mice is differentially sensitive to g-CSF stimulation, our results provide a useful basis for further study of sex-specific immunological processes in deer mice.
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Filgrastim , Factor Estimulante de Colonias de Granulocitos , Neutrófilos , Peromyscus , Polietilenglicoles , Proteínas Recombinantes , Animales , Femenino , Masculino , Polietilenglicoles/farmacología , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Peromyscus/inmunología , Filgrastim/farmacología , Recuento de Leucocitos , Proteínas Recombinantes/farmacologíaRESUMEN
Visual stimuli and limbic activation varyingly influence obsessive-compulsive symptom expression and so impact treatment outcomes. Some symptom phenotypes, for example, covert repugnant thoughts, are likely less sensitive to sensory stimuli compared to symptoms with an extrinsic focus, that is, symptoms related to contamination, safety, and "just-right-perceptions." Toward an improved understanding of the neurocognitive underpinnings of obsessive-compulsive psychobiology, work in naturalistic animal model systems is useful. Here, we explored the impact of visual feedback and limbic processes on 24 normal (NNB) and large (LNB) nesting deer mice, respectively (as far as possible, equally distributed between sexes). Briefly, after behavioral classification into either the NNB or LNB cohorts, mice of each cohort were separated into two groups each and assessed for nesting expression under either standard light conditions or conditions of complete visual deprivation (VD). Nesting outcomes were assessed in terms of size and neatness. After nesting assessment completion, mice were euthanized, and samples of frontal-cortical and hippocampal tissues were collected to determine serotonin and noradrenaline concentrations. Our results show that LNB, as opposed to NNB, represents an inflexible and excessive behavioral phenotype that is not dependent on visually guided action-outcome processing, and that it associates with increased frontal-cortical and hippocampal noradrenaline concentrations, irrespective of lighting condition. Collectively, the current results are informing of the neurocognitive underpinnings of nesting behavior. It also provides a valuable foundation for continued investigations into the noradrenergic mechanisms that may influence the development and promulgation of excessive, rigid, and inflexible behaviors.
Asunto(s)
Trastorno Obsesivo Compulsivo , Humanos , Animales , Trastorno Obsesivo Compulsivo/metabolismo , Peromyscus , Conducta Animal/fisiología , Modelos Animales de Enfermedad , NorepinefrinaRESUMEN
Nesting is a normal, evolutionary conserved rodent behavioural phenotype that is expressed for purposes of breeding, safety, and thermal regulation. Further, nesting is commonly assessed as marker of overall rodent health and wellbeing, with poorer nesting performance generally proposed to resemble a worse state of health. Deer mice can be bidirectionally separated with 30 % of mice presenting with excessively large nesting behaviour (LNB). All laboratory-housed deer mice are exposed to identical environmental conditions. Thus, the functional purpose of LNB remains unknown. Considering the evolutionary functions of nesting, we hypothesized that LNB will be related to an inflated drive to breed and nurse offspring. After breeding two generations of offspring from six 'normal' nesting (NNB) and seven LNB expressing pairs, our data showed that while as fertile as NNB expressing pairs, offspring survival of LNB mice were notably worse (67.9 % vs. 98.3 %). In conclusion, variance in nesting behaviour should be considered when animal health and wellbeing is considered, since it may point to underlying biobehavioural perturbations.
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Fertilidad , Peromyscus , Animales , Peromyscus/fisiologíaRESUMEN
Cognitive rigidity (CR) refers to inadequate executive adaptation in the face of changing circumstances. Increased CR is associated with a number of psychiatric disorders, for example, obsessive-compulsive disorder, and improving cognitive functioning by targeting CR in these conditions, may be fruitful. Levetiracetam (LEV), clinically used to treat epilepsy, may have pro-cognitive effects by restoring balance to neuronal signalling. To explore this possibility, we applied apomorphine (APO) exposure in an attempt to induce rigid cue-directed responses following a cue (visual pattern)-reward (social conspecifics) contingency learning phase and to assess the effects of LEV on such behaviours. Briefly, zebrafish were divided into four different 39-day-long exposure groups ( n â =â 9-10) as follows: control (CTRL), APO (100â µg/L), LEV (750â µg/L) and APO + LEV (100â µg/Lâ +â 750â µg/L). The main findings of this experiment were that 1) all four exposure groups performed similarly with respect to reward- and cue-directed learning over the first two study phases, 2) compared to the CTRL group, all drug interventions, but notably the APO + LEV combination, lowered the degree of reward-directed behaviour during a dissociated presentation of the cue and reward, and 3) temporal and spatial factors influenced the manner in which zebrafish responded to the presentation of the reward. Future studies are needed to explore the relevance of these findings for our understanding of the potential cognitive effects of LEV.
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Epilepsia , Piracetam , Animales , Levetiracetam/farmacología , Levetiracetam/uso terapéutico , Pez Cebra , Anticonvulsivantes/uso terapéutico , Apomorfina/farmacología , Epilepsia/tratamiento farmacológicoRESUMEN
Trauma-related psychopathology transpires in some individuals after exposure to a life-threatening event. While aberrant adrenergic processes may contribute to this, a clear understanding of how said processes influence trauma-related conditions, remain inadequate. Here, we aimed to develop and describe a novel zebrafish (Danio rerio) model of life-threatening trauma-induced anxiety that may be representative of trauma related anxiety, and to evaluate the impact of stress-paired epinephrine (EPI) exposure in the model system. Four groups of zebrafish were each exposed to different and unique stress-related paradigms, i.e., i) a sham (trauma free), ii) high-intensity trauma (triple hit; THIT), iii) high-intensity trauma in the presence of EPI exposure (EHIT), and iv) EPI exposure on its own, all applied in the presence of a color context. Novel tank anxiety was subsequently assessed at 1, 4, 7 and 14 days after the traumatic event. The present results demonstrate that 1) through day 14, THIT or EPI exposure alone induced persistent anxiety-like behavior, 2) EHIT blunted the delayed anxiety-like sequalae associated with severe trauma, 3) exposure to a trauma-paired color context prior to anxiety testing bolstered the subsequent anxiety-like behavior of THIT, but not EHIT -exposed fish, and 4) despite this, THIT- and EPI-exposed fish showed a lesser degree of contextual avoidance behavior compared to sham- or EHIT-exposed fish. These results indicate that the stressors induced long-lasting anxiety-like behavior reminiscent of post trauma anxiety, while EPI displays complex interactions with the stressor, including a buffering effect to subsequent exposure of a trauma-paired cue.
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Ansiedad , Pez Cebra , Animales , Ansiedad/inducido químicamente , Trastornos de Ansiedad , Epinefrina/farmacología , Conducta AnimalRESUMEN
BACKGROUND: Some deer mice (Peromyscus maniculatus bairdii) exhibit various phenotypes of persistent behaviors. It remains unknown if and how said phenotypes associate with early-life and adult cognitive perturbations, and whether potentially cognitive enhancing drugs might modify such associations. Here, we explored the longitudinal relationship between early-life behavioral flexibility and the expression of persistent behavior in adulthood. We also investigated how said phenotypes might associate with working memory in adulthood, and how this association might respond to chronic exposure to the putative cognitive enhancer, levetiracetam (LEV). METHODS: 76 juvenile deer mice were assessed for habit-proneness in the Barnes maze (BM) and divided into two exposure groups (n = 37-39 per group), i.e., control and LEV (75 mg/kg/day). After 56 days of uninterrupted exposure, mice were screened for nesting and stereotypical behavior, and then assessed for working memory in the T-maze. RESULTS: Juvenile deer mice overwhelmingly utilize habit-like response strategies, regardless of LNB and HS behavior in adulthood. Further, LNB and HS are unrelated in terms of their expression, while LEV reduces the expression of LNB, but bolsters CR (but not VA). Last, an increased level of control over high stereotypical expression may facilitate improved working memory performance. CONCLUSION: LNB, VA and CR, are divergent in terms of their neurocognitive underpinnings. Chronic LEV administration throughout the entire rearing period may be of benefit to some phenotypes, e.g., LNB, but not others (CR). We also show that an increased level of control over the expression of stereotypy may facilitate improved working memory performance.
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Memoria a Corto Plazo , Peromyscus , Animales , Levetiracetam/farmacología , Conducta Estereotipada , CogniciónRESUMEN
OBJECTIVES: The aim of this study was to repurpose a drug for the treatment of bipolar depression. METHODS: A gene expression signature representing the overall transcriptomic effects of a cocktail of drugs widely prescribed to treat bipolar disorder was generated using human neuronal-like (NT2-N) cells. A compound library of 960 approved, off-patent drugs were then screened to identify those drugs that affect transcription most similar to the effects of the bipolar depression drug cocktail. For mechanistic studies, peripheral blood mononuclear cells were obtained from a healthy subject and reprogrammed into induced pluripotent stem cells, which were then differentiated into co-cultured neurons and astrocytes. Efficacy studies were conducted in two animal models of depressive-like behaviours (Flinders Sensitive Line rats and social isolation with chronic restraint stress rats). RESULTS: The screen identified trimetazidine as a potential drug for repurposing. Trimetazidine alters metabolic processes to increase ATP production, which is thought to be deficient in bipolar depression. We showed that trimetazidine increased mitochondrial respiration in cultured human neuronal-like cells. Transcriptomic analysis in induced pluripotent stem cell-derived neuron/astrocyte co-cultures suggested additional mechanisms of action via the focal adhesion and MAPK signalling pathways. In two different rodent models of depressive-like behaviours, trimetazidine exhibited antidepressant-like activity with reduced anhedonia and reduced immobility in the forced swim test. CONCLUSION: Collectively our data support the repurposing of trimetazidine for the treatment of bipolar depression.
Asunto(s)
Trastorno Bipolar , Trimetazidina , Ratas , Humanos , Animales , Trimetazidina/farmacología , Trimetazidina/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/genética , Transcriptoma , Reposicionamiento de Medicamentos , Leucocitos Mononucleares , Modelos Animales de EnfermedadRESUMEN
Capture myopathy (CM), which is associated with the capture and translocation of wildlife, is a life-threatening condition that causes noteworthy morbidity and mortality in captured animals. Such wildlife deaths have a significant impact on nature conservation efforts and the socio-economic wellbeing of communities reliant on ecotourism. Several strategies are used to minimise the adverse consequences associated with wildlife capture, especially in ungulates, but no successful preventative or curative measures have yet been developed. The primary cause of death in wild animals diagnosed with CM stems from kidney or multiple organ failure as secondary complications to capture-induced rhabdomyolysis. Ergo, the development of accurate and robust model frameworks is vital to improve our understanding of CM. Still, since CM-related complications are borne from biological and behavioural factors that may be unique to wildlife, e.g. skeletal muscle architecture or flighty nature, certain differences between the physiology and stress responses of wildlife and rodents need consideration in such endeavours. Therefore, the purpose of this review is to summarise some of the major etiological and pathological mechanisms of the condition as it is observed in wildlife and what is currently known of CM-like syndromes, i.e. rhabdomyolysis, in laboratory rats. Additionally, we will highlight some key aspects for consideration in the development and application of potential future rodent models.
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Rabdomiólisis , Animales , Ratas , Roedores , Rabdomiólisis/complicaciones , Rabdomiólisis/veterinaria , Animales Salvajes , Mamíferos , RiñónRESUMEN
Obsessive-compulsive disorder is varyingly associated with cognitive impairment, that is, deficits in spatial working memory, although it seems unlikely that this is generalised across all domains of functioning. Further, it is unclear whether symptoms will respond to potentially novel, non-serotonergic drugs that have shown promise as so-called cognitive enhancers. Here, we studied low (Norm-N; n = 31) and compulsive-like high (Comp-H; n = 34) stereotypical deer mice (Peromyscus maniculatus bairdii) to establish (1) whether there is a relationship between stereotypical intensity and working memory ability as measured by spontaneous T-maze arm alternation and (2) if and how stereotypy and its association with changes in working memory, would respond to the known anti-compulsive agent, escitalopram, and the proposed cognitive enhancer, levetiracetam. After assessing the stereotypical and alternation behaviour of all animals at baseline, they were divided into three socially housed drug exposure groups, that is, water control (n = 11 per phenotype), escitalopram 50 mg/kg/d (n = 11 per phenotype) and levetiracetam 75 mg/kg/d (Norm-N: n = 9; Comp-H: n = 12). Drugs were administered for 28 days before stereotypy and alternation assessment were repeated. The present data indicate a weak negative relationship between stereotypical intensity and spontaneous alternation. While levetiracetam increased the time spent engaging in normal rodent activity by Comp-H, but not Norm-N animals, neither of the interventions affected the expression of Comp-H behaviour or the alternation behaviour of deer mice. In conclusion, this work points to some degree of cognitive involvement in Comp-H expression, which should be explored to further our understanding of compulsive-like stereotypy.
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Trastorno Obsesivo Compulsivo , Peromyscus , Animales , Escitalopram , Levetiracetam/farmacología , Trastorno Obsesivo Compulsivo/tratamiento farmacológico , Trastorno Obsesivo Compulsivo/metabolismo , Conducta EstereotipadaRESUMEN
The capacity to be self-aware is regarded as a fundamental difference between humans and other species. However, growing evidence challenges this notion, indicating that many animals show complex signs and behaviors that are consonant with self-awareness. In this review, we suggest that many animals are indeed self-aware, but that the complexity of this process differs among species. We discuss this topic by addressing several different questions regarding self-awareness: what is self-awareness, how has self-awareness been studied experimentally, which species may be self-aware, what are its potential adaptive advantages. We conclude by proposing alternative models for the emergence of self-awareness in relation to species evolutionary paths, indicating future research questions to advance this field further.
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Concienciación , Percepción , Animales , Evolución Biológica , HumanosRESUMEN
Introduction: Stereotypical expression in laboratory-housed rodents can be explained by different motivational, coping, and motor dysfunction theories. Here, we aimed to explore the neurocognitive underpinnings of high stereotypical (HS) expression in deer mice (Peromyscus maniculatus bairdii), previously proposed as a model system of compulsive-like behavioral persistence. Specifically, we aimed to establish whether HS behavior is related to an underlying escape-related trigger. Methods: One-hundred and sixteen deer mice were classified as either non-stereotypical (NS) or HS. Mice of each cohort were further subdivided and exposed to either sub-acute (3-day) or chronic (25-day) behavioral restriction (R), and high-dose escitalopram (ESC), lorazepam (LOR), alone and in combination with R (ESC+R and LOR+R, respectively). Mice were reassessed for stereotypical behavior at both time points. Results: Our results indicate that HS behavior is likely not temporally and functionally related to an anxiogenic trigger, i.e., R, but rather that HS is associated with parallel changes in anxiogenic feedback processing. We also show that chronic R alone significantly decreased the time spent in expressing HS behavior in animals of the HS, but not NS phenotype. Discussion: This points to the possibility that HS-expressing mice represent a subgroup of P. maniculatus bairdii in which unique interactions between neurobiology and processes of gradual behavioral organization, may contribute to the expression of the typical behaviors observed in this cohort. Collectively, our findings highlight the value of the deer mouse model system to investigate the potential neurocognitive mechanisms that may underlie the development of persistent phenotypes that can likely not be explained entirely by current theories.
RESUMEN
Large nest building behaviour (LNB), as expressed by a subpopulation of laboratory housed deer mice (Peromyscus maniculatus bairdii), is persistent and repetitive. However, the response of LNB to an anxiogenic environment has not yet been investigated. Here, we employed LNB and normal nesting (NNB) expressing mice, subdivided into three drug-exposed groups per cohort, i.e. water (28 days), escitalopram (50 mg/kg/day, 28 days) and lorazepam (2 mg/kg/day; 4 days) to investigate this theme. During the last 4 days of drug exposure, mice were placed inside anxiogenic open field arenas which contained a separate enclosed and dark area for 4 consecutive nights during which open field and/or nest building assessments were performed. We show that LNB behaviour in deer mice is stable, irrespective of the anxiety-related context in which it is assessed, and that LNB mice find an open field arena to be less aversive compared to NNB mice. Escitalopram and lorazepam differentially affected the nesting and open field behaviour of LNB expressing mice, confirming deer mouse LNB as a repetitive behavioural phenotype that is related to a compulsive-like process which is regulated by the serotonergic system.
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Escitalopram , Peromyscus , Animales , Ansiedad/inducido químicamente , Humanos , Lorazepam , RatonesRESUMEN
Capture myopathy (CM) is a metabolic disease associated with mortality in mass boma captured (MBC) wildlife. The condition is induced by the forced pursuit, capturing, and restraint of wild animals, although its causal biology remains to be confirmed. A core feature of MBC-CM is rhabdomyolysis, which is associated with myoglobinuria and hyperthermia. Towards developing a translational model of CM-associated rhabdomyolysis, we investigated forced treadmill running to induce physical exhaustion and trigger rhabdomyolysis in Sprague Dawley (SD) rats. Twenty-four (24) SD rats (12 per sex) were subjected to treadmill habituation in a speed-tiered approach. Forty-eight hours after the last habituation session, one strenuous exercise (SE) session was performed at 75% of the theoretical VO2MAX (30 m/min) until animals reached physical exhaustion. Core and skin surface temperatures were measured before the SE session and after rats reached exhaustion, after which a 1-h-cumulative urine sample was collected, and the myoglobin content assayed. We show that most SE, but not control-exposed (non-exercise) rats presented with myoglobinuria, while core and surface body temperatures in both male and female rats were significantly higher post-exercise. This pre-clinical model framework shows potential for investigating the pathophysiology of MBC-CM.
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Prueba de Esfuerzo , Enfermedades Musculares/etiología , Carrera , Animales , Modelos Animales de Enfermedad , Femenino , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Repetitive behavioral phenotypes are a trait of several neuropsychiatric disorders, including obsessive-compulsive disorder (OCD). Such behaviors are typified by complex interactions between cognitive and neurobiological processes which most likely contribute to the suboptimal treatment responses often observed. To this end, exploration of the adenosinergic system may be useful, since adenosine-receptor modulation has previously shown promise to restore control over voluntary behavior and improve cognition in patients presenting with motor repetition. Here, we employed the deer mouse (Peromyscus maniculatus bairdii) model of compulsive-like behavioral persistence, seeking to investigate possible associations between stereotypic motor behavior and cognitive flexibility as measured in the T-maze continuous alternation task (T-CAT). The effect of istradefylline, a selective adenosine A2A receptor antagonist at two doses (10 and 20 mg kg-1 day-1 ) on the expression of stereotypy and T-CAT performance in high (H) and non-(N) stereotypical animals, was investigated in comparison to a control intervention (six groups; n = 8 or 9 per group). No correlation between H behavior and T-CAT performance was found. However, H but not N animals presented with istradefylline-sensitive spontaneous alternation and stereotypy, in that istradefylline at both doses significantly improved the spontaneous alternation scores and attenuated the stereotypical expression of H animals. Thus, evidence is presented that anti-adenosinergic drug action improves repetitive behavior and spontaneous alternation in stereotypical deer mice, putatively pointing to a shared psychobiological construct underlying naturalistic stereotypy and alterations in cognitive flexibility in deer mice.
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Antagonistas del Receptor de Adenosina A2/uso terapéutico , Trastorno Obsesivo Compulsivo/metabolismo , Purinas/farmacología , Receptor de Adenosina A2A/metabolismo , Conducta Estereotipada/fisiología , Antagonistas del Receptor de Adenosina A2/farmacología , Animales , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Trastorno Obsesivo Compulsivo/tratamiento farmacológico , Trastorno Obsesivo Compulsivo/genética , Peromyscus , Purinas/uso terapéutico , Receptor de Adenosina A2A/genética , Conducta Estereotipada/efectos de los fármacosRESUMEN
This study aimed to further dissect the deer mouse (Peromyscus maniculatus bairdii) model of compulsive-like behavior with respect to two persistent-like behavioral phenotypes viz. large nest building (LNB) and high marble-burying (HMB), which may be relevant to understanding the neurobiology of different symptom dimensions in obsessive-compulsive and related disorders. Since LNB is sensitive to chronic, high dose escitalopram intervention but HMB is not, we assessed whether the two behaviors could be further distinguished based on their response to 4 weeks of uninterrupted serotoninergic intervention (i.e. escitalopram; ESC; 50â¯mg/kg/day), dopaminergic antagonism, i.e. flupentixol; FLU; 0.9â¯mg/kg/day), dopaminergic potentiation (i.e. rasagiline; RAS; 5â¯mg/kg/day), and their respective combinations with escitalopram (ESC/FLU and ESC/RAS). Here we show LNB to be equally responsive to chronic ESC and ESC/FLU. HMB was insensitive to either of these interventions but was responsive to ESC/RAS. Additionally, we report that scoring preoccupied interaction with marbles over several trials is an appropriate measure of compulsive-like behavioral persistence in addition to the standard marble burying test. Taken together, these data provide further evidence that LNB and HMB in deer mice have distinctive neurobiological underpinnings. Thus, the naturally occurring compulsive-like behaviors expressed by deer mice may be useful in providing a platform to test unique treatment targets for different symptom dimensions of OCD and related disorders.
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Conducta Compulsiva/fisiopatología , Dopamina/fisiología , Comportamiento de Nidificación/fisiología , Serotonina/fisiología , Animales , Citalopram/administración & dosificación , Antagonistas de Dopamina/administración & dosificación , Femenino , Flupentixol/administración & dosificación , Indanos/administración & dosificación , Masculino , Inhibidores de la Monoaminooxidasa/administración & dosificación , Comportamiento de Nidificación/efectos de los fármacos , Peromyscus , Fenotipo , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificaciónRESUMEN
Investigating the motivational triggers underlying naturalistic compulsive-like behavior is generally regarded as challenging. To this extent, the current study aimed to establish a proof-of-concept for future investigation by probing unconditioned and naturalistic operant responses aimed at obtaining nesting material by normal (NNB) and large (LNB) nest building deer mice (Peromyscus maniculatus bairdii). LNB mice and NNB controls were individually placed in cages equipped with a lever-operated nesting material (cotton rope) dispenser and allowed to become accustomed to the response (lever press)-outcome (obtaining cotton rope) contingency over seven nights. Subsequently, the contingency was manipulated by withdrawing the nesting material (experiment 1) or punishing the lever-press response with a mild electrical foot shock (experiment 2). Mice were then treated for 28 days with escitalopram (50 mg/kg/d) and retested. Our results indicate that (1) LNB mice generally made more operant responses compared to NNB controls, (2) withdrawal of nesting material and institution of punishment bolstered responding in LNB but not NNB mice and (3) escitalopram treatment tended to reduce increased responding in LNB mice following experimental manipulation, while normalizing the total number of lever-press counts in the LNB cohort. Therefore, LNB seems to diverge from NNB, not only as a spontaneous phenotype, but also in terms of the motivation to obtain nesting material, despite demotivating feedback. That such differences were abrogated by chronic escitalopram intervention, indicates that the uniquely motivated operant interactions displayed by LNB mice, may be founded upon serotonergic mechanisms, a finding in line with the neurobiological theory of obsessive-compulsive disorder.
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Citalopram/farmacología , Condicionamiento Operante/efectos de los fármacos , Extinción Psicológica/efectos de los fármacos , Castigo , Animales , Estimulación Eléctrica , Comportamiento de Nidificación , Peromyscus , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
Obsessive-compulsive disorder (OCD) is a psychiatric illness that significantly impacts affected patients and available treatments yield suboptimal therapeutic response. Recently, the role of the gut-brain axis (GBA) in psychiatric illness has emerged as a potential target for therapeutic exploration. However, studies concerning the role of the GBA in OCD are limited. To investigate whether a naturally occurring obsessive-compulsive-like phenotype in a rodent model, that is large nest building in deer mice, is associated with perturbations in the gut microbiome, we investigated and characterised the gut microbiota in specific-pathogen-free bred and housed large (LNB) and normal (NNB) nest-building deer mice of both sexes (n = 11 per group, including three males and eight females). Following baseline characterisation of nest-building behaviour, a single faecal sample was collected from each animal and the gut microbiota analysed. Our results reveal the overall microbial composition of LNB animals to be distinctly different compared to controls (PERMANOVA p < .05). While no genera were found to be significantly differentially abundant after correcting for multiple comparisons, the normal phenotype showed a higher loading of Prevotella and Anaeroplasma, while the OC phenotype demonstrated a higher loading of Desulfovermiculus, Aestuariispira, Peptococcus and Holdemanella (cut-off threshold for loading at 0.2 in either the first or second component of the PCA). These findings not only provide proof-of-concept for continued investigation of the GBA in OCD, but also highlight a potential underlying aetiological association between alterations in the gut microbiota and the natural development of obsessive-compulsive-like behaviours.
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Microbioma Gastrointestinal , Trastorno Obsesivo Compulsivo , Animales , Encéfalo , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , PeromyscusRESUMEN
Rodent marble-burying behavior in the marble-burying test (MBT) is employed as a model or measure to study anxiety- and compulsive-like behaviors or anxiolytic and anticompulsive drug action. However, the test responds variably to a range of pharmacological interventions, and little consensus exists regarding specific methodologies for its execution. Regardless, the test is widely applied to investigate the effects of pharmacological, genetic, and behavioral manipulations on purported behaviors related to the said neuropsychiatric constructs. Therefore, in the present review we attempt to expound the collective translational significance of the MBT. We do this by (1) reviewing burying behavior as a natural behavioral phenotype, (2) highlighting key aspects of anxiety and obsessive-compulsive disorder from a translational perspective, (3) reviewing the history and proof of concept of the MBT, (4) critically appraising potential methodological confounds in execution of the MBT, and (5) dissecting responses of the MBT to various pharmacological interventions. We conclude by underlining that the collective translational value of the MBT will be strengthened by contextually valid experimental designs and objective reporting of data.
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Ansiolíticos/farmacología , Trastornos de Ansiedad/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Carbonato de Calcio/farmacología , Trastorno Obsesivo Compulsivo/tratamiento farmacológico , Animales , Modelos Animales de EnfermedadRESUMEN
Animal models of human psychiatric illness are valuable frameworks to investigate the etiology and neurobiology underlying the human conditions. Accurate behavioral measures that can be used to characterize animal behavior, thereby contributing to a model's validity, are crucial. One such measure, i.e. the rodent marble-burying test (MBT), is often applied as a measure of anxiety- and compulsive-like behaviors. However, the test is characterized by noteworthy between-laboratory methodological differences and demonstrates positive treatment responses to an array of pharmacotherapies that are often of little translational value. Therefore, using a naturalistic animal model of obsessive-compulsive disorder, i.e. the deer mouse (Peromyscus maniculatus bairdii), the current investigation attempted to illuminate the discrepancies reported in literature by means of a methodological approach to the MBT. Five key aspects of the test that vary between laboratories, viz. observer/scoring, burying substrate, optional avoidance, the use of repeated testing, and determinations of locomotor activity, have been investigated. Following repeated MB tests in four different burying substrates and in two zone configurations, we have demonstrated that 1) observer bias may contribute to the significant differences in findings reported, 2) MB seems to be a natural exploratory response to a novel environment, rather than being triggered by aberrant cognition, 3) burying substrates with a small particle size and higher density deliver the most accurate results with respect to the burying phenotype, and 4) to exclude the influence of normal exploratory behavior on the number of marbles being covered, assessments of marble-burying should be based on pre-occupation with the objects itself.