Deneysel Modellerin Değerlendirilmesinde Kullanılan Davranış Testleri: Öğrenme, Hafıza, Anksiyete, Depresyon, Lokomotor Aktivite ve Ağrı Testleri
Özet
Deneysel hayvan davranış testleri, merkezi sinir sistemi işlevlerinin kontrollü ve tekrarlanabilir koşullar altında değerlendirilmesine olanak tanıyan, sinirbilim araştırmalarının temel bileşenlerinden biridir. Öğrenme, hafıza, anksiyete, stres, depresyon, lokomotor aktivite ve ağrı gibi karmaşık davranışsal ve bilişsel alanlar, yalnızca moleküler ya da hücresel düzeyde yapılan analizlerle yeterince değerlendirilememekte; bu nedenle bütüncül ve entegratif davranışsal paradigmalara ihtiyaç duyulmaktadır. Bu bölümde, deneysel sinirbilim ve preklinik araştırmalarda yaygın olarak kullanılan davranışsal testler kapsamlı bir yaklaşımla ele alınmış; bu testlerin metodolojik temelleri, ölçülen davranışsal parametreleri ve translasyonel önemleri tartışılmıştır. Öğrenme ve hafıza ile ilgili davranışların değerlendirilmesinde Morris su tankı, pasif sakınma, Y ve T-labirentleri, radyal kol labirenti ve yeni nesne tanıma testleri, anksiyete ve depresyon ile ilişkili davranışların değerlendirilmesinde yükseltilmiş artı labirent, açık alan ve zorunlu yüzme testleri, lokomotor aktivitenin değerlendirilmesinde rotarod testi, ağrı duyusunun değerlendirilmesinde ise Von Frey, tail flick, hot plate, formalin, writhing testleri gibi literatürde sıkça karşılaşılan ve kabul görmüş testler uygulamalarıyla birlikte sunulmuştur. Bu davranışsal testler, nörolojik ve psikiyatrik bozuklukların fonksiyonel sonuçlarının ortaya konulmasında ve farmakolojik ya da deneysel müdahalelerin etkilerinin değerlendirilmesinde kritik bilgiler sağlamaktadır. Bununla birlikte, tek bir davranışsal testin altta yatan nörobiyolojik süreçlerin tüm karmaşıklığını yansıtamayacağı göz önünde bulundurulmalıdır. Bu nedenle, tamamlayıcı davranış testlerinin moleküler, elektrofizyolojik ve yapısal analizlerle birlikte kullanılması, verilerin sağlam yorumlanması ve translasyonel geçerliliğin artırılması açısından büyük önem taşımaktadır. Bu bölüm, deneysel sinirbilim araştırmalarında standartlaştırılmış, etik açıdan duyarlı ve bütüncül davranışsal yaklaşımların önemini vurgulamaktadır.
Experimental animal behavior testing is a fundamental component of neuroscience research, providing an essential framework for the functional assessment of central nervous system processes under controlled and reproducible conditions. Many complex behavioral and cognitive processes, including learning, memory, anxiety, stress, depression, locomotor activity and pain, cannot be adequately evaluated through molecular or cellular approaches alone. Instead, these processes require integrative behavioral paradigms that capture the functional output of distributed neural networks. This chapter presents a comprehensive overview of the most widely used behavioral tests employed in experimental neuroscience and preclinical research, with an emphasis on their methodological principles, measured behavioral parameters, and translational relevance. The behavioral tests that are frequently encountered in the literature and well accepted are presented along with their applications. These include Morris water tank, passive avoidance test, Y and T-mazes, radial arm maze, and novel object recognition tests for evaluating learning and memory-related behaviors; the elevated plus maze, open field, and forced swim tests for evaluating behaviors related to anxiety and depression; the rotarod test for evaluating locomotor activity; and the Von Frey, tail flick, hot plate, formalin, and writhing tests for evaluating pain sensation. Collectively, these behavioral assays provide critical insights into the functional consequences of neurological and psychiatric disorders, as well as the effects of pharmacological and experimental interventions. However, no single behavioral test can fully capture the complexity of the underlying neurobiological processes. Therefore, the combined use of complementary behavioral tests together with molecular, electrophysiological, and structural analyses, is essential for robust data interpretation and enhanced translational validity. This chapter underscores the importance of standardized, ethically sound, and integrative behavioral approaches in advancing experimental neuroscience research.
Referanslar
Ericsson AC, Crim MJ, Franklin CL. A brief history of animal modeling. Mo Med. 2013;110(3):201–205.
Rabiei Z, Hojjati M, Rafieian-Kopaei M, Alibabaei Z. Effect of Cyperus rotundus tubers ethanolic extract on learning and memory in an animal model of Alzheimer’s disease. Biomed Aging Pathol. 2013;3(4):185–191.
Clark RE. The classical origins of Pavlov’s conditioning. Integr Physiol Behav Sci. 2004;39(4):279–294.
Cambiaghi M, Sacchetti B. Ivan Petrovich Pavlov (1849–1936). J Neurol. 2015;262(6):1599–1600.
Hånell A, Marklund N. Structured evaluation of rodent behavioral tests used in drug discovery research. Front Behav Neurosci. 2014;8:252.
Porsolt RD, Anton G, Blavet N, Jalfre M. Behavioural despair in rats: A new model sensitive to antidepressant treatments. Eur J Pharmacol. 1978;47(4):379–391.
Dunham NW, Miya TS. A note on a simple apparatus for detecting neurological deficit in rats and mice. J Am Pharm Assoc (Baltim). 1957;46(3):208–209.
Harrison FE, Hosseini AH, McDonald MP. Endogenous anxiety and stress responses in water maze and Barnes maze spatial memory tasks. Behav Brain Res. 2009;198(1):247–251.
Blizard DA, Weinheimer VK, Klein LC, Petrill SA, Cohen R, McClearn GE. “Return to home cage” as a reward for maze learning in young and old genetically heterogeneous mice. Comp Med. 2006;56(3):196–201.
Whishaw IQ, Coles BLK, Bellerive CHM. Food carrying: A new method for naturalistic studies of spontaneous and forced alternation. J Neurosci Methods. 1995;61(1–2):139–143.
Hall JE. Guyton and Hall Textbook of Medical Physiology. 13th ed. Philadelphia: Elsevier; 2016.
Pittenger C, Kandel ER. In search of general mechanisms for long-lasting plasticity: Aplysia and the hippocampus. Philos Trans R Soc Lond B Biol Sci. 2003;358(1432):757–763.
Gasparini L, Racchi M, Binetti G, Trabucchi M, Solerte SB, Alkon DL, et al. Peripheral markers in testing pathophysiological hypotheses and diagnosing Alzheimer’s disease. FASEB J. 1998;12(1):17–34.
Phelps EA, LeDoux JE. Contributions of the amygdala to emotion processing: From animal models to human behavior. Neuron. 2005;48(2):175–187.
Morgane PJ, Galler JR, Mokler DJ. A review of systems and networks of the limbic forebrain/limbic midbrain. Prog Neurobiol. 2005;75(2):143–160.
Waxman A, Chugani H, Seibyl J. Medical imaging in neurological disorders. J Am Pharm Assoc (Wash). 2002;42(5 Suppl 1):S20–S27.
Mineur YS, Obayemi A, Wigestrand MB, Fote GM, Calarco CA, Li AM, et al. Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety- and depression-like behavior. Proc Natl Acad Sci U S A. 2013;110(9):3573–3578.
Woolf CJ, Wiesenfeld-Hallin Z. Substance P and calcitonin gene-related peptide synergistically modulate the gain of the nociceptive flexor withdrawal reflex in the rat. Neurosci Lett. 1986;66(2):226–230.
Almeida TF, Roizenblatt S, Tufik S. Afferent pain pathways: A neuroanatomical review. Brain Res. 2004;1000(1–2):40–56.
Dickenson AH. Spinal cord pharmacology of pain. Br J Anaesth. 1995;75(2):193–200.
Todd AJ. Neuronal circuitry for pain processing in the dorsal horn. Nat Rev Neurosci. 2010;11(12):823–836.
Savage S, Ma D. Experimental behaviour testing: Pain. Br J Anaesth. 2015;114(5):721–724.
Deuis JR, Dvorakova LS, Vetter I. Methods used to evaluate pain behaviors in rodents. Front Mol Neurosci. 2017;10:284.
Ghafarimoghadam M, Mashayekh R, Gholami M, Fereydani P, Shelley-Tremblay J, Kandezi N, et al. A review of behavioral methods for the evaluation of cognitive performance in animal models: Current techniques and links to human cognition. Physiol Behav. 2022;244:113652.
Morris R. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods. 1984;11(1):47–60.
Shultz SR, McDonald SJ, Corrigan F, Semple BD, Salberg S, Zamani A, et al. Clinical relevance of behavior testing in animal models of traumatic brain injury. J Neurotrauma. 2020;37(22):2381–2400.
Quillfeldt JA. Behavioral methods to study learning and memory in rats. In: Rodent Models as Tools in Ethical Biomedical Research. Cham: Springer; 2015. p. 271–311.
Burešová O, Bureš J, Oitzl MS, Zahálka A. Radial maze in the water tank: An aversively motivated spatial working memory task. Physiol Behav. 1985;34(6):1003–1005.
Liu L, Ikonen S, Heikkinen T, Heikkilä M, Puoliväli J, van Groen T, et al. Effects of fimbria-fornix lesion and amyloid pathology on spatial learning and memory in transgenic APP/PS1 mice. Behav Brain Res. 2002;134(1–2):433–445.
Nunez J. Morris water maze experiment. J Vis Exp. 2008;(19):897.
Vorhees CV, Williams MT. Assessing spatial learning and memory in rodents. ILAR J. 2014;55(2):310–332.
Mifflin MA, Winslow W, Surendra L, Tallino S, Vural A, Velazquez R. Sex differences in the IntelliCage and the Morris water maze in the APP/PS1 mouse model of amyloidosis. Neurobiol Aging. 2021;101:130–140.
Tanila H. Testing cognitive functions in rodent disease models: Present pitfalls and future perspectives. Behav Brain Res. 2018;352:23–27.
Moser MB, Moser EI, Forrest E, Andersen P, Morris RGM. Spatial learning with a minislab in the dorsal hippocampus. Proc Natl Acad Sci U S A. 1995;92(21):9697–9701.
Wu C, Yang L, Li Y, Dong Y, Yang B, Tucker LD, et al. Effects of exercise training on anxious- and depressive-like behavior in an Alzheimer rat model. Med Sci Sports Exerc. 2020;52(7):1456–1469.
McGaugh JL. Time-dependent processes in memory storage. Science. 1966;153(3742):1351–1358.
Dalkıran B, Açikgöz B, Dayı A. Behavioral tests used in the evaluation of learning and memory in experimental animals. J Basic Clin Health Sci. 2022;6(3):938–945.
Branchi I, Ricceri L. Active and passive avoidance. In: Behavioral Genetics of the Mouse. 2013. p. 291–298.
Spear NE, Miller JS, Jagielo JA. Animal memory and learning. Annu Rev Psychol. 1990;41:169–211.
Stehouwer DJ, Campbell BA. Ontogeny of passive avoidance: Role of task demands and development of species-typical behaviors. Dev Psychobiol. 1980;13(4):385–398.
Ray D, Nagy ZM. Emerging cholinergic mechanisms and ontogeny of response inhibition in the mouse. J Comp Physiol Psychol. 1978;92(2):335–349.
Nagy ZM, Thaller K, Mazzaferri TA. Acquisition and retention of a passive-avoidance task as a function of age in mice. Dev Psychobiol. 1977;10(6):563–573.
Mysliveček J. Inhibitory learning and memory in newborn rats. Prog Neurobiol. 1997;53(4):399–430.
Spear LP. The use of psychopharmacological procedures to analyse the ontogeny of learning and retention: Issues and concerns. In: Ontogeny of Learning and Memory. London: Psychology Press; 2014. p. 135–156.
Bammer G. Pharmacological investigations of neurotransmitter involvement in passive avoidance responding: A review and some new results. Neurosci Biobehav Rev. 1982;6(3):247–296.
Bignami G, Michałek H. Cholinergic mechanisms and aversively motivated behaviors. In: Psychopharmacology of Aversively Motivated Behavior. New York: Springer; 1978. p. 173–255.
Myhrer T. Neurotransmitter systems involved in learning and memory in the rat: A meta-analysis based on studies of four behavioral tasks. Brain Res Rev. 2003;41(2–3):268–287.
Bignami G. Nonassociative explanations of behavioral changes induced by central cholinergic drugs. Acta Neurobiol Exp (Wars). 1976;36(1–2):5–90.
Adriani W, Felici A, Sargolini F, Roullet P, Usiello A, Oliverio A, et al. N-methyl-D-aspartate and dopamine receptor involvement in the modulation of locomotor activity and memory processes. Exp Brain Res. 1998;121(1):52–59.
Venable N, Kelly PH. Effects of NMDA receptor antagonists on passive avoidance learning and retrieval in rats and mice. Psychopharmacology (Berl). 1990;100(2):215–221.
Wilson WJ, Cook JA. Cholinergic manipulations and passive avoidance in the rat: Effects on acquisition and recall. Acta Neurobiol Exp (Wars). 1994;54(4):377–391.
Everitt BJ, Robbins TW. Central cholinergic systems and cognition. Annu Rev Psychol. 1997;48:649–684.
Leanza G, Nilsson OG, Wiley RG, Björklund A. Selective lesioning of the basal forebrain cholinergic system by intraventricular 192 IgG–saporin: Behavioural, biochemical and stereological studies in the rat. Eur J Neurosci. 1995;7(2):329–343.
Deacon RMJ, Bannerman DM, Kirby BP, Croucher A, Rawlins JNP. Effects of cytotoxic hippocampal lesions in mice on a cognitive test battery. Behav Brain Res. 2002;133(1):57–68.
Cordner ZA, Tamashiro KLK. Effects of high-fat diet exposure on learning and memory. Physiol Behav. 2015;152:363–371.
Zhang X, Yi H, Bai W, Tian X. Dynamic trajectory of multiple single-unit activity during a working memory task in rats. Front Comput Neurosci. 2015;9:118.
Sohn E, Lim HS, Kim YJ, Kim BY, Jeong SJ. Annona atemoya leaf extract improves scopolamine-induced memory impairment by preventing hippocampal cholinergic dysfunction and neuronal cell death. Int J Mol Sci. 2019;20(14):3539.
Yerkes RM. The intelligence of earthworms. J Anim Behav. 1912;2(5):332–352.
Tolman EC. Purpose and cognition: The determiners of animal learning. Psychol Rev. 1925;32(4):285–297.
Dennis W, Sollenberger RT. Negative adaptation in the maze exploration of rats. J Comp Psychol. 1934;18(2):197–206.
Dennis W. A comparison of the rat’s first and second explorations of a maze unit. Am J Psychol. 1935;47(3):488–495.
Dennis W, Henneman RH. The non-random character of initial maze behavior. Pedagog Semin J Genet Psychol. 1932;40(2):396–405.
Dennis W. Spontaneous alternation in rats as an indicator of the persistence of stimulus effects. J Comp Psychol. 1939;28(2):305–312.
Deacon RMJ, Rawlins JNP. T-maze alternation in the rodent. Nat Protoc. 2006;1(1):7–12.
Dember WN, Fowler H. Spontaneous alternation behavior. Psychol Bull. 1958;55(6):412–428.
Montgomery KC. Exploratory behavior and its relation to spontaneous alternation in a series of maze exposures. J Comp Physiol Psychol. 1952;45(1):50–57.
Henderson ND. A genetic analysis of spontaneous alternation in mice. Behav Genet. 1970;1(2):125–132.
Kirkby RJ, Lackey GH. Spontaneous alternation in Mesocricetus auratus: Age differences. Psychon Sci. 1968;10(7):257–258.
Douglas RJ, Peterson JJ, Douglas DP. The ontogeny of a hippocampus-dependent response in two rodent species. Behav Biol. 1973;8(1):27–37.
d’Isa R, Comi G, Leocani L. Apparatus design and behavioural testing protocol for the evaluation of spatial working memory in mice through the spontaneous alternation T-maze. Sci Rep. 2021;11:21177.
Jaffard R, Dubois M, Galey D. Memory of a choice direction in a T-maze as measured by spontaneous alternation in mice: Effects of intertrial interval and reward. Behav Processes. 1981;6(1):11–21.
Clayton KN. T-maze acquisition and reversal as a function of intertrial interval. J Comp Physiol Psychol. 1966;62(3):409–414.
Reisel D, Bannerman DM, Schmitt WB, Deacon RMJ, Flint J, Borchardt T, et al. Spatial memory dissociations in mice lacking GluR1. Nat Neurosci. 2002;5(9):868–873.
Tolman EC, Ritchie BF, Kalish D. Studies in spatial learning. V. Response learning versus place learning by the non-correction method. J Exp Psychol. 1947;37(4):285–292.
Tolman EC, Ritchie BF, Kalish D. Studies in spatial learning. II. Place learning versus response learning. J Exp Psychol. 1946;36(3):221–229.
Packard MG. Glutamate infused post-training into the hippocampus or caudate-putamen differentially strengthens place and response learning. Proc Natl Acad Sci U S A. 1999;96(22):12881–12886.
Packard MG, McGaugh JL. Inactivation of hippocampus or caudate nucleus with lidocaine differentially affects expression of place and response learning. Neurobiol Learn Mem. 1996;65(1):65–72.
Goodman J. Place versus response learning: History, controversy, and neurobiology. Front Behav Neurosci. 2021;14:603570.
Olton DS, Samuelson RJ. Remembrance of places passed: Spatial memory in rats. J Exp Psychol Anim Behav Process. 1976;2(2):97–116.
Iwasaki K, Mishima K, Egashira N, Al-Khatib IH, Ishibashi D, Irie K, et al. Effect of nilvadipine on cerebral ischemia-induced impairment of spatial memory and hippocampal apoptosis in rats. J Pharmacol Sci. 2003;93(2):188–196.
Dost T, Firat Z, Tamer M, Ulugöl A, Karadağ CH. The role of the histaminergic system in learning and memory functions. Balkan Med J. 2002;19(1):11–18.
Setkowicz Z, Gaździńska A, Osoba JJ, Karwowska K, Majka P, Orzeł J, et al. Does long-term high-fat diet always lead to smaller hippocampal volumes, altered metabolite concentrations, and worse learning and memory? A magnetic resonance and behavioral study in Wistar rats. PLoS One. 2015;10(10):e0140418.
Sanz-Martos AB, Roca M, Ruiz-Gayo M, del Olmo N. Tributyrin reverses the deleterious effect of saturated fat on working memory and synaptic plasticity in juvenile mice: Differential effects in males and females. Eur J Pharmacol. 2024;977:176479.
Nascimento C, Guerreiro-Pinto V, Pawlak S, Caulino-Rocha A, Amat-Garcia L, Cunha-Reis D. Impaired response to mismatch novelty in the Li⁺–pilocarpine rat model of temporal lobe epilepsy: Correlation with hippocampal monoaminergic inputs. Biomedicines. 2024;12(3):631.
Stolberg A. Ranking of memories and behavioral strategies in the radial maze. Acta Neurobiol Exp (Wars). 2005;65(1):39–49.
Jarrard LE. Selective hippocampal lesions and behavior. In: The Hippocampus. Boston: Springer; 1986. p. 93–126.
Stafstrom CE. Behavioral and cognitive testing procedures in animal models of epilepsy. In: Models of Seizures and Epilepsy. San Diego: Elsevier; 2006. p. 613–628.
Broadbent NJ, Gaskin S, Squire LR, Clark RE. Object recognition memory and the rodent hippocampus. Learn Mem. 2010;17(1):5–11.
Barker GRI, Bird F, Alexander V, Warburton EC. Recognition memory for objects, place, and temporal order: A disconnection analysis of the role of the medial prefrontal cortex and perirhinal cortex. J Neurosci. 2007;27(11):2948–2957.
Jessberger S, Clark RE, Broadbent NJ, Clemenson GD, Consiglio A, Lie DC, et al. Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats. Learn Mem. 2009;16(2):147–154.
Clark RE, Zola SM, Squire LR. Impaired recognition memory in rats after damage to the hippocampus. J Neurosci. 2000;20(23):8853–8860.
Bevins RA, Besheer J. Object recognition in rats and mice: A one-trial non-matching-to-sample learning task to study recognition memory. Nat Protoc. 2006;1(3):1306–1311.
Ennaceur A, Delacour J. A new one-trial test for neurobiological studies of memory in rats. I: Behavioral data. Behav Brain Res. 1988;31(1):47–59.
Prickaerts J, van Staveren WCG, Ik A, Markerink-van Ittersum M, Niewöhner U, van der Staay FJ, et al. Effects of two selective phosphodiesterase type 5 inhibitors, sildenafil and vardenafil, on object recognition memory and hippocampal cyclic GMP levels in the rat. Neuroscience. 2002;113(2):351–361.
Winters BD, Forwood SE, Cowell RA, Saksida LM, Bussey TJ. Double dissociation between the effects of perirhinal cortex and hippocampal lesions on tests of object recognition and spatial memory: Heterogeneity of function within the temporal lobe. J Neurosci. 2004;24(26):5901–5908.
Sutcliffe JS, Marshall KM, Neill JC. Influence of gender on working and spatial memory in the novel object recognition task in the rat. Behav Brain Res. 2007;177(1):117–125.
Matsumoto J, Uehara T, Urakawa S, Takamura Y, Sumiyoshi T, Suzuki M, et al. Three-dimensional video analysis of the novel object recognition test in rats. Behav Brain Res. 2014;272:16–24.
Antunes M, Biala G. The novel object recognition memory: Neurobiology, test procedure, and its modifications. Cogn Process. 2012;13(2):93–110.
Ramos A. Animal models of anxiety: Do I need multiple tests? Trends Pharmacol Sci. 2008;29(10):493–498.
Kraeuter AK, Guest PC, Sarnyai Z. The elevated plus maze test for measuring anxiety-like behavior in rodents. In: Methods in Molecular Biology. 2019. p. 69–74.
Hu C, Luo Y, Wang H, Kuang S, Liang G, Yang Y, et al. Re-evaluation of the interrelationships among behavioral tests in rats exposed to chronic unpredictable mild stress. PLoS One. 2017;12(9):e0185129.
Komada M, Takao K, Miyakawa T. Elevated plus maze for mice. J Vis Exp. 2008;(22):1088.
Sweis BM, Bachour SP, Brekke JA, Gewirtz JC, Sadeghi-Bazargani H, Hevesi M, et al. A modified beam-walking apparatus for assessment of anxiety in a rodent model of blast traumatic brain injury. Behav Brain Res. 2016;296:149–156.
Kraeuter AK, Guest PC, Sarnyai Z. The open field test for measuring locomotor activity and anxiety-like behavior. In: Methods in Molecular Biology. 2019. p. 99–103.
Sturman O, Germain PL, Bohacek J. Exploratory rearing: A context- and stress-sensitive behavior recorded in the open-field test. Stress. 2018;21(5):443–452.
Prut L, Belzung C. The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: A review. Eur J Pharmacol. 2003;463(1–3):3–33.
Gellért L, Varga D. Locomotion activity measurement in an open field for mice. Bio Protoc. 2016;6(13):e1857.
Lebedev IV, Pleskacheva MG, Anokhin KV. C57BL/6 mice open field behaviour qualitatively depends on arena size. Zh Vyssh Nerv Deiat Im I P Pavlova. 2012;62(4):485–496.
Eilam D. Open-field behavior withstands drastic changes in arena size. Behav Brain Res. 2003;142(1–2):53–62.
Hurst JL, West RS. Taming anxiety in laboratory mice. Nat Methods. 2010;7(10):825–826.
Varga D, Herédi J, Kánvási Z, Ruszka M, Kis Z, Ono E, et al. Systemic L-kynurenine sulfate administration disrupts object recognition memory, alters open-field behavior, and decreases c-Fos immunopositivity in C57BL/6 mice. Front Behav Neurosci. 2015;9:157.
Carola V, D’Olimpio F, Brunamonti E, Mangia F, Renzi P. Evaluation of the elevated plus-maze and open-field tests for the assessment of anxiety-related behaviour in inbred mice. Behav Brain Res. 2002;134(1–2):49–57.
Harro J. Animal models of depression: Pros and cons. Cell Tissue Res. 2019;377(1):5–20.
Yankelevitch-Yahav R, Franko M, Huly A, Doron R. The forced swim test as a model of depressive-like behavior. J Vis Exp. 2015;(97):52587.
Commons KG, Cholanians AB, Babb JA, Ehlinger DG. The rodent forced swim test measures stress-coping strategy, not depression-like behavior. ACS Chem Neurosci. 2017;8(5):955–960.
Sahin Z. Assessment of commonly used tests in experimental depression studies according to behavioral patterns of rodents. Med Rev. 2023;3(6):526–531.
Widjaja JH, Sloan DC, Hauger JA, Muntean BS. Customizable open-source rotating rod (rotarod) enables robust low-cost assessment of motor performance in mice. eNeuro. 2023;10(9):ENEURO.0123-23.2023.
Hickey MA, Chesselet MF. Behavioral assessment of genetic mouse models of Huntington’s disease. Neuromethods. 2011;62:3–19.
Magen I, Chesselet MF. Genetic mouse models of Parkinson’s disease: The state of the art. In: Prog Brain Res. 2010. p. 53–87.
Hickey MA, Gallant K, Gross GG, Levine MS, Chesselet MF. Early behavioral deficits in R6/2 mice suitable for use in preclinical drug testing. Neurobiol Dis. 2005;20(1):1–11.
· Chesselet M-F, Fleming SM, Hickey MA. Motor behaviors and neuroanatomical phenotypes in mouse models of Huntington’s and Parkinson’s diseases. Short Course I. 2007;1.
· Adwanikar H, Noble-Haeusslein L, Levin HS. Traumatic brain injury in animal models and humans. In: Neuromethods. Totowa (NJ): Humana Press; 2011. p. 237–265.
· Fujimoto ST, Longhi L, Saatman KE, McIntosh TK. Motor and cognitive function evaluation following experimental traumatic brain injury. Neurosci Biobehav Rev. 2004;28(4):365–378.
· Hamm RJ, Pike BR, O’Dell DM, Lyeth BG, Jenkins LW. The rotarod test: An evaluation of its effectiveness in assessing motor deficits following traumatic brain injury. J Neurotrauma. 1994;11(2):187–196.
· Schaar KL, Brenneman MM, Savitz SI. Functional assessments in the rodent stroke model. Exp Transl Stroke Med. 2010;2:13.
· Shan HM, Maurer MA, Schwab ME. Four-parameter analysis in a modified rotarod test for detecting minor motor deficits in mice. BMC Biol. 2023;21(1):177.
· Lubrich C, Giesler P, Kipp M. Motor behavioral deficits in the cuprizone model: Validity of the rotarod test paradigm. Int J Mol Sci. 2022;23(19):11547.
Mandillo S, Heise I, Garbugino L, Tocchini-Valentini GP, Giuliani A, Wells S, et al. Early motor deficits in mouse disease models are reliably uncovered using an automated home-cage wheel-running system: A cross-laboratory validation. Dis Model Mech. 2014;7(3):397–407.
Brooks SP, Dunnett SB. Tests to assess motor phenotype in mice: A user’s guide. Nat Rev Neurosci. 2009;10(7):519–529.
Mann A, Chesselet MF. Techniques for motor assessment in rodents. In: Movement Disorders: Genetics and Models. 2nd ed. Elsevier; 2015. p. 139–157.
Borse LB, Kottai Muthu A, Thangatripathi A, Borse SL. CNS activity of the methanol extracts of heartwood of Tecoma stans in experimental animal models. Pharmacologyonline. 2011;3:959–968.
Deacon RMJ. Measuring motor coordination in mice. J Vis Exp. 2013;(75):2609.
Keane SP, Chadman KK, Gomez AR, Hu W. Pros and cons of narrow- versus wide-compartment rotarod apparatus: An experimental study in mice. Behav Brain Res. 2024;463:114901.
Monville C, Torres EM, Dunnett SB. Comparison of incremental and accelerating protocols of the rotarod test for the assessment of motor deficits in the 6-OHDA model. J Neurosci Methods. 2006;158(2):219–223.
Brolese G, Lunardi P, Lopes F, Gonçalves CA. Prenatal alcohol exposure and neuroglial changes in neurochemistry and behavior in animal models. In: Addictive Substances and Neurological Disease. Elsevier; 2017. p. 11–22.
Kokras N, Antoniou K, Mikail HG, Kafetzopoulos V, Papadopoulou-Daifoti Z, Dalla C. Forced swim test: What about females? Neuropharmacology. 2015;99:408–421.
Lambert GA, Mallos G, Zagami AS. Von Frey’s hairs: A review of their technology and use; a novel automated von Frey device for improved testing for hyperalgesia. J Neurosci Methods. 2009;177(2):420–426.
Keizer D, van Wijhe M, Post WJ, Uges DRA, Wierda JMKH. Assessment of the clinical relevance of quantitative sensory testing with von Frey monofilaments in patients with allodynia and neuropathic pain: A pilot study. Eur J Anaesthesiol. 2007;24(8):658–663.
Minett MS, Quick K, Wood JN. Behavioral measures of pain thresholds. Curr Protoc Mouse Biol. 2011;1(3):383–412.
Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994;53(1):55–63.
Woolfe G, Macdonald AD. The evaluation of the analgesic action of pethidine hydrochloride (Demerol). J Pharmacol Exp Ther. 1944;80(3):300–307.
Ankier SI. New hot plate tests to quantify antinociceptive and narcotic antagonist activities. Eur J Pharmacol. 1974;27(1):1–4.
Decosterd I, Woolf CJ. Spared nerve injury: An animal model of persistent peripheral neuropathic pain. Pain. 2000;87(2):149–158.
Deuis JR, Lim YL, De Sousa SR, Lewis RJ, Alewood PF, Cabot PJ, et al. Analgesic effects of clinically used compounds in novel mouse models of oxaliplatin- and cisplatin-induced polyneuropathy. Neuro Oncol. 2014;16(10):1324–1332.
Lu R, Schmidtko A. Direct intrathecal drug delivery in mice for detecting in vivo effects of cGMP on pain processing. Methods Mol Biol. 2013;1020:215–221.
Deuis JR, Vetter I. The thermal probe test: A novel behavioral assay to quantify thermal paw withdrawal thresholds in mice. Temperature. 2016;3(2):199–207.
Pitcher GM, Ritchie J, Henry JL. Paw withdrawal threshold in the von Frey hair test is influenced by the surface on which the rat stands. J Neurosci Methods. 1999;87(2):185–193.
D’Amour FE, Smith DL. A method for determining loss of pain sensation. J Pharmacol Exp Ther. 1941;72(1):74–79.
Irwin S, Houde RW, Bennett DR, Hendershot LC, Seevers MH. The effects of morphine, methadone, and meperidine on some reflex responses. J Pharmacol Exp Ther. 1951;101(2):132–143.
Chapman CR, Casey KL, Dubner R, Foley KM, Gracely RH, Reading AE. Pain measurement: An overview. Pain. 1985;22(1):1–31.
Jensen TS, Yaksh TL. Comparison of the antinociceptive action of μ- and δ-opioid receptor ligands in the periaqueductal gray matter and ventral medulla of the rat. Brain Res. 1986;372(2):301–312.
Yoburn BC, Morales R, Kelly DD, Inturrisi CE. Constraints on the tail-flick assay: Morphine analgesia and tolerance depend on locus of tail stimulation. Life Sci. 1984;34(18):1755–1762.
Berge OG, Garcia-Cabrera I, Hole K. Response latencies in the tail-flick test depend on tail skin temperature. Neurosci Lett. 1988;86(3):284–288.
Menéndez L, Lastra A, Hidalgo A, Baamonde A. Unilateral hot plate test: A simple and sensitive method for detecting central and peripheral hyperalgesia in mice. J Neurosci Methods. 2002;113(1):91–97.
Hargreaves K, Dubner R, Brown F, Flores C, Joris J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain. 1988;32(1):77–88.
Espejo EF, Mir D. Structure of the rat’s behaviour in the hot plate test. Behav Brain Res. 1993;56(2):171–176.
Ögren SO, Berge OG. Test-dependent variations in the antinociceptive effect of p-chloroamphetamine-induced release of serotonin. Neuropharmacology. 1984;23(8):915–924.
Zimmermann K, Deuis JR, Inserra MC, Collins LS, Namer B, Cabot PJ, et al. Analgesic treatment of ciguatoxin-induced cold allodynia. Pain. 2013;154(10):1999–2006.
Yalcin I, Charlet A, Freund-Mercier MJ, Barrot M, Poisbeau P. Differentiating thermal allodynia and hyperalgesia using dynamic hot and cold plate tests in rodents. J Pain. 2009;10(7):767–773.
Deuis JR, Zimmermann K, Romanovsky AA, Possani LD, Cabot PJ, Lewis RJ, et al. An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Nav1.6 in peripheral pain pathways. Pain. 2013;154(9):1749–1757.
Tjølsen A, Rosland JH, Berge OG, Hole K. The increasing-temperature hot-plate test: An improved test of nociception in mice and rats. J Pharmacol Methods. 1991;25(3):241–250.
Hunskaar S, Fasmer OB, Hole K. Acetylsalicylic acid, paracetamol, and morphine inhibit behavioral responses to intrathecally administered substance P or capsaicin. Life Sci. 1985;37(19):1835–1841.
Carter RB. Differentiating analgesic and non-analgesic drug activities on the rat hot plate: Effect of behavioral endpoint. Pain. 1991;47(2):211–220.
Plone MA, Emerich DF, Lindner MD. Individual differences in the hot plate test and effects of habituation on sensitivity to morphine. Pain. 1996;66(2–3):265–270.
Yeomans DC, Pirec V, Proudfit HK. Nociceptive responses to high and low rates of noxious cutaneous heating are mediated by different nociceptors in the rat: Behavioral evidence. Pain. 1996;68(1):133–140.
Yeomans DC, Proudfit HK. Nociceptive responses to high and low rates of noxious cutaneous heating are mediated by different nociceptors in the rat: Electrophysiological evidence. Pain. 1996;68(1):141–150.
Yeomans DC, Proudfit HK. Characterization of the foot withdrawal response to noxious radiant heat in the rat. Pain. 1994;59(1):85–94.
Gamble GD, Milne RJ. Repeated exposure to sham testing procedures reduces reflex withdrawal and hot-plate latencies. Neurosci Lett. 1989;96(3):312–317.
Abbott FV, Franklin KBJ, Westbrook RF. The formalin test: Scoring properties of the first and second phases of the pain response in rats. Pain. 1995;60(1):91–102.
Dubuisson D, Dennis SG. The formalin test: A quantitative study of the analgesic effects of morphine, meperidine, and brainstem stimulation in rats and cats. Pain. 1977;4:161–174.
López-Cano M, Fernández-Dueñas V, Llebaria A, Ciruela F. Formalin murine model of pain. Bio Protoc. 2017;7(23):e2628.
Hunskaar S, Hole K. The formalin test in mice: Dissociation between inflammatory and non-inflammatory pain. Pain. 1987;30(1):103–114.
Rosland JH, Tjølsen A, Mæhle B, Hole K. The formalin test in mice: Effect of formalin concentration. Pain. 1990;42(2):235–242.
Kohn DF, Wixson SK, White WJ, Benson GJ. Anesthesia and Analgesia in Laboratory Animals. San Diego: Elsevier; 1997.
Paul S, Saha D. Analgesic activity of methanol extract of Plumbago indica by acetic acid-induced writhing method. Int J Pharm Sci Res. 2012;2(2):74–76.
Hosen SMZ, Das R, Rahim ZB, Chowdhury N, Paul L, Saha D. Analgesic activity of methanolic extracts of Acorus calamus and Oroxylum indicum using acetic acid-induced writhing method. Bull Pharm Res. 2011;1(3):63-67.
Hannan A, Karan S, Chatterjee TK. Anti-inflammatory and analgesic activity of methanolic extract of Areca catechu seed. Int J Pharm Chem Sci. 2012;1(2):690–698.
Ezeja,M. I. and Ezeigbo,I. I. and Madubuike,K. G., 20113043741, English, Journal article, India, 0975-8585, 2, (1), Research Journal of Pharmaceutical, Biological and Chemical Sciences. 2011:187–193
Gawade SP. Acetic acid-induced painful endogenous infliction in writhing test on mice. J Pharmacol Pharmacother. 2012;3(4):348–350.
Hossain F, Saha S, Islam MM, Nasrin S, Suraj A. Analgesic and anti-inflammatory activity of Commelina benghalensis Linn. Turk J Pharm Sci. 2014;11(1):25–32.
Vaidya Kesha S, Modi Nilay B, Shah Rima B, Date Sanjay K. Evaluation of analgesic activity of herbal formulation Triphala and comparison with that of paracetamol in mice. Research & reviews. J Pharmacol Toxicol Studies. 2014;2(1):15-20.
Wardakhan WW, Abdel-Salam OME, Elmegeed GA. Screening for antidepressant, sedative, and analgesic activities of novel fused thiophene derivatives. Acta Pharm. 2008;58(1):1–14.
Patel PK, Sahu J, Chandel SS. A detailed review on nociceptive models for the screening of analgesic activity in experimental animals. Int J Neurol Phys Ther. 2016;2(6):44–50.
