Anxiety Disorders: Kalueff AV

Kalueff AV, Murphy DL. · Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, MD 20892-1264, USA. · Neural Plast. · Pubmed #18288249 links to  free full text

Abstract: Cognitive dysfunctions are commonly seen in many stress-related disorders, including anxiety and depression-the world's most common neuropsychiatric illnesses. Various genetic, pharmacological, and behavioral animal models have long been used to establish animal anxiety-like and depression-like phenotypes, as well as to assess their memory, learning, and other cognitive functions. Mounting clinical and animal evidences strongly supports the notion that disturbed cognitions represent an important pathogenetic factor in anxiety and depression, and may also play a role in integrating the two disorders within a common stress-precipitated developmental pathway. This paper evaluates why and how the assessment of cognitive and emotional domains may improve our understanding of animal behaviors via different high-throughput tests and enable a better translation of animal phenotypes into human brain disorders.

Kalueff AV, Ishikawa K, Griffith AJ. · Laboratory of Clinical Science, Building 10, Room 3D41, National Institute of Mental Health, 10 Center Dr. MSC 1264, NIH, Bethesda, MD 20892-1264, USA. · Behav Brain Res. · Pubmed #17822783 No free full text.

Abstract: Human anxiety and vestibular disorders have long been known to co-occur. Paralleling human clinical and non-clinical data, mounting genetic, pharmacological and behavioral evidence confirms that animal anxiety interplays and co-exists with vestibular/balance deficits. However, relatively few animal models have addressed the nature of this relationship. This paper examines side-by-side human psychiatric and otovestibular phenotypes with animal experimentation data, and outlines future directions of translational research in this field. Discussed here are recently developed specific animal models targeting this interplay, other traditional animal tests sensitive to altered anxiety and vestibular domains, and the existing problems with translation of animal data into human phenotypes. The role of hearing deficits and their contribution to anxiety and vestibular phenotypes are also outlined. Overall, the overlap between anxiety and balance disorders emerges as an important phenomenon in both animal and clinical studies, and may contribute markedly to the complexity of behavioral and physiological phenotypes. Animal experimental models that focus on the interplay between anxiety and vestibular disorders are needed to improve our understanding of this important biomedical problem.

Kalueff AV, Wheaton M, Murphy DL. · Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, MD 20892-1264, USA. · Behav Brain Res. · Pubmed #17306892 No free full text.

Abstract: Stress plays a key role in pathogenesis of anxiety and depression. Animal models of these disorders are widely used in behavioral neuroscience to explore stress-evoked brain abnormalities, screen anxiolytic/antidepressant drugs and establish behavioral phenotypes of gene-targeted or transgenic animals. Here we discuss the current situation with these experimental models, and critically evaluate the state of the art in this field. Noting a deficit of fresh ideas and especially new paradigms for animal anxiety and depression models, we review existing challenges and outline important directions for further research in this field.

Kalueff AV, Nutt DJ. · Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland, USA. · Depress Anxiety. · Pubmed #17117412 No free full text.

Abstract: This review assesses the parallel data on the role of gamma-aminobutyric acid (GABA) in depression and anxiety. We review historical and new data from both animal and human experimentation which have helped define the key role for this transmitter in both these mental pathologies. By exploring the overlap in these conditions in terms of GABAergic neurochemistry, neurogenetics, brain circuitry, and pharmacology, we develop a theory that the two conditions are intrinsically interrelated. The role of GABAergic agents in demonstrating this interrelationship and in pointing the way to future research is discussed.

Kalueff AV, Keisala T, Minasyan A, Kumar SR, LaPorte JL, Murphy DL, Tuohimaa P. · Department of Anatomy, Medical School, University of Tampere, Tampere 33014, Finland. · Nat Protoc. · Pubmed #18193029 No free full text.

Abstract: Animal behavioral models are crucial for neurobiological research, allowing for the thorough investigation of brain pathogenesis to be performed. In both animals and humans, anxiety has long been linked to vestibular disorders. However, although there are many tests of anxiety and vestibular deficits, there are few protocols that address the interplay between these two domains. The Suok test and its light-dark modification presented here appear to be suitable for testing this pathogenetic link in laboratory rodents. This protocol adds a new dimension to previously used tests by assessing animal anxiety and balancing simultaneously, resulting in efficient, high-throughput screens for testing psychotropic drugs, phenotyping genetically modified animals, and modeling clusters of human disorders related to stress/anxiety and balancing.

Kalueff AV, Jensen CL, Murphy DL. · Laboratory of Clinical Science, Building 10, Room 3D41, National Institute of Mental Health, 10 Center Dr. MSC 1264, Bethesda, MD 20892-1264, USA. · Brain Res. · Pubmed #17692295 No free full text.

Abstract: Serotonin transporter knockout (SERT-/-) mice are extensively used as a genetic model of several neuropsychiatric disorders, and consistently display anxiety-like behaviors and inactivity in different tests. To better understand how these mice organize their behavior, we assessed the open field and elevated plus maze spatiotemporal patterning of activity in adult male SERT wild type (+/+), heterozygous (+/-) and -/- mice on C57BL/6J genetic background using new videotracking and analytic procedures. In addition, we analyzed their spatial memory, assessing within- and between-trial habituation, and examined specific motor characteristics of their movement in these two tests. In the open field test, SERT-/- mice showed reduced vertical exploration throughout the arena, reduced central (but not peripheral) horizontal exploration, unaltered within-trial habituation, and slightly poorer between-trial habituation for horizontal activity. In the elevated plus maze, SERT-/- mice demonstrated anxiety-like avoidance of open arms, hypoactivity, as well as unaltered within-trial and between-trial habituation (except for poorer between-trial habituation of total horizontal activity). In both tests, SERT-/- mice showed greater prevalence of horizontal over vertical dimension of their exploration in the areas protected by the walls (open field periphery, plus maze closed arms), but not in open aversive areas, such as the center of the open field or center or open arms of the maze. In both arenas, SERT-/- mice consistently displayed increased turning behavior, potentially representing a perseverance-like phenotype or aberrant spatial strategies in novel environments. Overall, using a fine-graded behavioral analysis in two different novelty tests, this study revealed alterations in motor and spatiotemporal patterning of activity in SERT-/- mice. Given the relevance of exploratory strategies to human personality traits and brain disorders, our data may be useful for developing further neurobehavioral models using these mice.

Minasyan A, Keisala T, Lou YR, Kalueff AV, Tuohimaa P. · Department of Anatomy, Medical School, University of Tampere, Tampere 33014, Finland. · J Steroid Biochem Mol Biol. · Pubmed #17482806 No free full text.

Abstract: Vitamin D is a seco-steroid hormone with multiple actions in the brain, mediated through the nuclear vitamin D receptor (VDR). We have recently shown that mutant mice lacking functional VDR demonstrate altered emotional behavior and specific motor deficits. Here we further examine phenotype of these mice, testing their novelty responses, as well as cognitive and sensory (olfactory and gustatory) functions in the novel food, two-trial Y-maze and tastant consumption tests. In addition, we study depression-like behavior in these mice, using anhedonia-based sucrose preference test. Overall, VDR mutant mice showed neophobic response in several different tests, but displayed unimpaired olfactory and gustatory functions, spatial memory and baseline hedonic responses. Collectively, these data confirm that mutation of VDR in mice leads to altering emotional/anxiety states, but does not play a major role in depression, as well as in the regulation of some sensory and cognitive processes. These results support the role of the vitamin D/VDR neuroendocrine system in the regulation of behavior, and may have clinical relevance, enabling a better focus on psychiatric and behavioral disorders associated with dysfunctions in this neuroendocrine system.

Kalueff AV, Keisala T, Minasyan A, Kuuslahti M, Miettinen S, Tuohimaa P. · Medical School, University of Tampere, Finland. · Neurosci Res. · Pubmed #16427152 No free full text.

Abstract: Vitamin D is a steroid hormone with many important functions in the brain, mediated through the nuclear Vitamin D receptor (VDR). Mounting clinical data link VDR mutations to various psychiatric phenotypes. We have reported previously that mutant mice lacking functional VDR ("Tokyo" VDR mutant mice) display several behavioural anomalies, including high anxiety and aberrant grooming. Given the important role of Vitamin D and VDR in brain development and functioning, we hypothesized that several other important behavioural domains may be affected by disruption of the VDR gene in mice. Here we report that VDR mutants display unaffected depressive-like behaviour, but show abnormal social behaviours, reduced social barbering and aggressiveness, impaired nest building and aberrant maternal (pup neglect, cannibalism) behaviours. Taken together, these findings confirm the important role postulated for the VDR in the regulation of behaviour, and suggest the mice lacking functional VDR may be a useful tool to model different brain disorders.

Kalueff AV, Tuohimaa P. · Department of Anatomy, Medical School, University of Tampere, Tampere, 33014 Finland. · Brain Res Brain Res Protoc. · Pubmed #15721814 No free full text.

Abstract: In the present study, we suggest that long elevated horizontal rod (Suok test, ST) and its light-dark modification (LDST) may be used for behavioral characterization in mice, including simultaneous assessment of their anxiety, activity, and neurological phenotypes. To establish the ST and the LDST as murine models of anxiety, we used several different mouse strains which differ markedly in their anxiety and activity (C57BL/6, 129S1/SvImJ, NMRI, and BALB/c). Here we show that our tests are able to ethologically discriminate between high and low anxiety mouse strains, as assessed by horizontal and directed exploration, stops, and defecation boli. The spatial distribution of the LDST behaviors is also sensitive to these strain-specific anxiety phenotypes, showing clear avoidance of the brightly lit part of the test in stressed (rat exposed) vs. control NMRI mice. In addition, we validated the ST in 129S1/SvImJ and BALB/c mice by assessing the behavioral consequences of acute stress such as rat exposure. Finally, we showed that our test is able to detect high anxiety and poorer motor coordination in 129S1/SvImJ (vs. C57BL/6) mice. The results of our study show that the ST emerges as an experimental tool to analyze anxiety, motor-vestibular anomalies, as well as anxiety-induced motor impairments in mice. Overall, we suggest that the ST can be a useful protocol in neurobehavioral stress research including modeling stress-evoked states, pharmacological screening of potential anti-stress drugs, or behavioral phenotyping of genetically modified animals.

Kalueff AV, Lou YR, Laaksi I, Tuohimaa P. · Department of Anatomy, Medical School, Tampere University, 33014, Finland. · Physiol Behav. · Pubmed #15276805 No free full text.

Abstract: Vitamin D is a neuroactive secosteroid with several important functions in the nervous system. Many human and animal findings link alterations in the vitamin D system to various neurological and behavioral disorders. Since grooming is an important element of animal behavior, here we studied whether genetic ablation of vitamin D receptors (VDR) in mice may be associated with altered grooming behaviors. Overall, VDR knockout (VDRko) mice presented longer duration and higher frequency of grooming when tested in the actimeter, open field, elevated plus maze, and horizontal rod tests. Increased grooming did not, however, correlate with unaltered general activity level (actimeter test), anxiety-like behaviors (hole board and elevated plus maze tests), and emotional reactivity index (defecation boli). In general, our results confirm the role of vitamin D and VDR in the regulation of behavior, including grooming, and suggest that increased grooming behavioral phenotype may be associated with genetic ablation of VDR in mutant mice.

Kalueff AV, Lou YR, Laaksi I, Tuohimaa P. · Department of Anatomy, Medical School, University of Tampere, FIN-33014 Tampere, Finland. · Neuroreport. · Pubmed #15167547 No free full text.

Abstract: Vitamin D is a steroid hormone with many important functions in the brain, mediated through the vitamin D nuclear receptor. Numerous human and animal data link vitamin D dysfunctions to various behavioural disorders. To examine this problem, we studied whether genetic ablation of vitamin D receptors in mice may be associated with altered emotional behaviours. Here we show that the receptor-deficient mice demonstrate increased anxiety-like behaviours when subjected to a battery of behavioural tests. These studies suggest that vitamin D and its receptors are an important factor in the brain, whose imbalance may significantly affect emotional behaviour.

Kalueff AV, Maisky VA, Pilyavskii AI, Makarchuk NE. · Centre for Physiology and Biochemical Research, Cheshskaya Street 6-5, 01042, Kiev, Ukraine. · Neurosci Lett. · Pubmed #11248440 No free full text.

Abstract: Here we examine hypothesis that short-term peripheral ZnSO(4)-induced anosmia can produce effects on c-fos expression within spinal cord and caudal medulla in male Wistar rats (n=4). Fos-like-immunoreactive cells revealed by avidin-biotin-peroxidase method show a significant bilateral increase in the nucleus proprius (layers 3 and 4) and medial part of layers 5 and 6. In substantia gelatinosa (layer 2(i)) and area 10 Fos-positive neurons were intermixed together with nicotin-amide adenine dineucleotide phosphate-diaphorase (NADPH-d)-reactive cells. Short-term anosmia enhanced c-fos expression in ventral horn (layers 7 and 8), ventrolateral segment and dorsal part of the spinal trigeminal nuclei. In anosmic rats varicose fibres and numerous NADPH-d-stained neurons were present in the gelatinous layer of the spinal trigeminal nucleus caudalis, and a separate population of Fos-positive cells was detected within this layer. Nucleus tractus solitaris also contained a few NADPH-d-reactive, medium sized neurons intermixed with Fos-immunoreactive cells.