3.1.4 Animal models of psychiatric disease

Animal models of psychiatric disease

The subjective character of many crucial symptoms, the paucity of biomarkers and objective diagnostic tests, and the early state of relevant neurobiology and genetics make animal modelling of human psychiatric diseases extremely difficult (Nestler, 2010).

Animal models of schizophrenia:

Schizophrenia is a debilitating condition that typically manifests itself between the late teen years and the early thirties. Twin and adoption studies reveal that schizophrenia is strongly impacted by genetics, but genetics have proven to be astonishingly complicated, with risk emerging from the interaction of numerous genetic variations and environmental factors. In schizophrenia, three major symptom clusters have been identified: positive, negative, and cognitive symptoms, which presumably reflect various downstream effects of the beginning developmental problems.

Focus of schizophrenia model:	Summary:
22q11.2	Developing genetic animal models from highly penetrant human mutations may be an effective way to meet construct validity. In around 30% of instances, chromosome 22q11.2 microdeletions that cause velocardiofacial syndrome are associated with a schizophrenia-like condition. Mice with missing genes in homologous areas of the mouse genome have been created.
Disc1	Translocation that causes gene disruption ‘Disrupted in schizophrenia-1’ (Disc1), which was linked to schizophrenia in a Scottish family for the first time. Several laboratories have created mice with Disc1 mutations, and some of them exhibit behavioural problems resembling schizophrenia.

Animal models of depression:

No single anomaly has proven robust or persistent enough to be used to diagnose depression in humans or to validate an animal model. Depression is diagnosed following a highly variable cluster of symptoms.

The focus of depression model:	Summary:
Chronic unpredictable stress	Entails repeatedly subjecting normal rodents to physical stimuli (e.g., restraint, footshock, cold temperature) over a period of weeks or longer. Animals display indications of anhedonia (e.g., lower sucrose preference) at the conclusion of the stress, which can be restored by chronic antidepressant medications (Willner, 2005).
Chronic social defeat stress	Chronic social defeat stress is caused by repeatedly putting rodents through social subordination, after which the rodents exhibit a variety of depression-like symptoms, including anhedonia and social disengagement, which can be alleviated by chronic antidepressants (Krishnan, 2007).
Early life stress (maternal separation)	Maternal separation, induces lifelong behavioural and neuroendocrine abnormalities in the pups, some of which can be reversed by antidepressant medications (Meaney, 2001)
Social isolation	Adult rodents exposed to social isolation for extended periods of time (weeks to months) develop anhedonia, which can be treated with chronic antidepressants (Wallace, 2009)

Animal models of bipolar disorder:

Mania episodes, with or without depression, are used to diagnose bipolar disorder. While bipolar illness is strongly influenced by genetics, the discovery of genetic risk factors is still in its early stages. The field has struggled to develop rodents that exhibit mania-like symptoms and has been unable to develop rodent models exhibiting spontaneously alternating episodes of mania- and depression-like behaviours due to a lack of well-replicated, highly penetrant mutations or a deep understanding of pathophysiology.

The focus of bipolar model:	Summary:
Psychostimulants	Repeated use of psychostimulants on rodents causes sensitization of the locomotor-activating effects, these can subsequently be blunted by lithium or sodium valproate.
Amygdala kindling	Lack of construct and face validity.
Lithium-pilocarpine induced seizures	Lack of construct and face validity.
Glycogen synthase kinase-3β (GSK3β)	GSK3β induces hypophagia and hyperlocomotion, reduces immobility and reduced anxiety-like behaviour. Lithium inhibits GSK3β, however, lithium has numerous molecular actions.
Clock gene	When the clock gene is inhibited the mouse exhibits mania-like symptoms which can be reversed by chronic lithium administration.

(Nestler, 2010)

References:

(1) Krishnan V, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131:517–522. 

(2) Meaney MJ. Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annu Rev Neurosci. 2001;24:1161–1192.

(3) Nestler, E.J. and Hyman, S.E. (2010). Animal models of neuropsychiatric disorders. Nature Neuroscience, 13(10), pp.1161–1169. doi:10.1038/nn.2647.

(4) Wallace DL, et al. CREB regulation of nucleus accumbens excitability mediates social isolation-induced behavioral deficits. Nat Neurosci. 2009;12:200–209.

(5) Willner P. Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology. 2005;52:90–110.