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Advances In Modelling Depression And Anxiety In Mice Notes

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Advances in modeling depression and anxiety in mice GOOD FIRST QUOTE TO OPEN ESSAYS: Charles Darwin, The Descent of Man, 1871: "Nevertheless the difference in mind between man and the higher animals, great as it is, certainly is one of degree and not of kind. We have seen that the senses and intuitions, the various emotions and faculties, such as love, memory, attention, curiosity, imitation, reason, etc., of which man boasts, may be found in an incipient, or even sometimes in a well-developed condition, in the lower animals."

While Darwin emphasized in his thesis that "the difference between the mind of the lowest man and that of the highest animal is immense", his writings provided a foundation ideology for the development of the modern scientific fields of ethology and comparative psychology, in which behaviour in animals is studied to gain insight into the neural processes underlying behaviour in humans Psychiatry as a field has proven to be among the least penetrable clinical discipline for productively amalgamating knowledge of human pathology with animal behaviour to develop satisfactory in vivo animal models for evaluating novel treatment approaches Due to the growing costs of clinical trials, there is a growing emphasis on first obtaining proof that a new chemical entity designed to alter the function of a specific target will do so in a predictable and safe manner Of central importance to this approach is the availability of valid preclinical animal models for evaluating the potential efficacy of novel pharmacotherapeutics

Defining depression and anxiety

There are various diagnostic tools that are used to identify and evaluate depression These include the Diagnostic and Statistical Manual (DSM-IV) of the American Psychiatric Association and rating instruments such as the Hamilton Depression Scale The hallmark of anxiety disorders is a "marked, persistent, and excessive or unreasonable fear" that is experienced to a degree that significantly interferes with everyday life These criteria are important to bear in mind because, unlike a depressive episode, a transient anxiety response to real danger is an appropriate, adaptive response in patients and non-patients alike Another difference with depression is that DSM-IV classification of clinical anxiety distinguishes between numerous subdisordres of anxiety, the most common being generalized anxiety disorder, panic disorder, specific phobia, social phobia, OCD, PTSD These disorders are largely distinguished from one another by the nature of the stimulus provoking the anxiety

Moreover, although there is epidemiological comorbidity between anxiety disorders, they are, to some degree, differentially responsive to different classes of anxiolytic drug treatments, suggesting discrete neurobiological and genetic aetiologies Psychiatrists have several rating scales to quantify anxiety severity, primarily the Hamilton Rating Scale for Anxiety and the Clinical Global Impression Scale Historically, depression and anxiety disorders have been regarded as separate clinical entities, since different drug treatments have been used to treat the disorders, usually tricyclic antidepressants and benzodiazepines respectively However, clinically, there is considerable comorbidity between the 2 disorders The issue of comorbidity has important implications for the treatment of these conditions in that drugs that are effective in both anxiety and depression would be particularly beneficial and cost effective, and there has been more focus on the development of such drugs in recent years SSRIs can successfully treat both depression and certain anxiety disorders

Why the mouse?

Historically, research in non-humans, mostly rodents, has been central to efforts to understand the neural systems mediating emotion, how these systems dysfunction under pathological conditions and how they can be therapeutically modulated For decades the rat was the species of choice in preclinical research - rats perform well in many of the cognitive and operant tasks that are the pillars of modern behavioural pharmacology Size and robustness of the rat, compared with the smaller mouse, aids the application of invasive techniques such as catheterisation and cannula implantation HOWEVER, in the past decade, as in other biomedical disciplines, there has been an explosion in the use of mice in neuropsychiatric research The key driving force behind this has been the development and application of novel molecular technologies such as gene targeting, which enable researchers to engineer precise genetic alterations to study the neural basis of behaviour The mouse is uniquely amenable to these techniques Mice are also easy to breed and house in large numbers As a result, whereas mice were certainly commonly used in behavioural pharmacological research before the application of these techniques, the proliferation of KO, KI and transgenic mice has force researchers to quickly embrace the mouse in their research programmes

Manipulating mice

About 80 different mutant lines have been reported to have phenotypes interpreted as abnormal "depression-related" or "anxiety-related" behaviour In some cases these phenotypes were predictable from existing knowledge regarding the role of the gene/gene product in emotional behaviour and served

to reinforce and refine existing hypotheses regarding the importance of certain systems in mediating these behavioiurs For example, the antidepressant-related phenotype found in noradrenaline transporter (NET) KO mouse fits the profile of antidepressant efficacy of drugs that antagonize NET However, there are also numerous examples of phenotypic abnormalities in KO and transgenic mice that potentially reveal novel mechanisms that subserve emotion Such findings in mutant mice are particularly valuable when more traditional approaches (e.g. selective agonists, antagonists) to study the specific function of a gene product are impractical For example, the engineering of mice with various mutations in the GABA(A) receptor has driven development of novel anxiolytics that target specific subunits of the receptor with a better side-effect profile

Validity of mouse models

Jacqueline Crawley's admonition not to anthropomorphize (humanize) putative emotion-related behaviours in mice has been well taken We can never fully recapitulate human depression of anxiety in the mouse and, indeed, cannot truly know whether a mouse is depressed or feeling anxious Given the considerable differences in brain anatomy between humans and mice, particularly in the greatly elaborated human cerebral cortex and the resultant capacity for processing complex psychological concepts, certain aspects of disease symptomatology such as low self-esteem or suicidal ideation are impossible to model in mice Nonetheless, the cerebral cortex does not function in isolation - it is intimately interconnected with subcortical structures that are well conserved across mammalian species The brains of vertebrates have a common structural organization, consisting of the cerebral hemispheres, diencephalon, midbrain, cerebellum, pons and medulla Among mammals, and frequently across other vertebrate classes, the neural structures within these division and the circuits that interconnect them have marked similarities There are also many fundamental physiological and behavioural responses that have been evolutionarily conserved between species Therefore we can study these responses to elucidate behaviours and the neural circuits and genetic factors subserving them as a means to use lower species to understand human behaviour and disease Researchers have proposed specific criteria for evaluating whether an experimental procedure in an animal has validity as a model of a psychiatric disease McKinney and Bunney suggest that the minimum requirements for a valid animal model of depression are that it: o Is "reasonably analogous" to the human disorder in its manifestations or symptomatology o Causes a behavioural change that can be monitored objectively

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