J Neural Transm. Spatio-temporal expression of tryptophan hydroxylase isoforms in murine and human brain: convergent data from Tph2 knockout mice. However, early studies reported that TPH expression, turnover, and distribution in DRN are complex, in line with the existence of different subpopulations of 5-HT neurons in this area. Variation of tryptophanhydroxylase concentration in the rat raphe dorsalis nucleus after p-chlorophenylalanine administration.
Anatomical distribution of the tryptophanhydroxylase protein and regional variation of its turnover rate. Estrogen selectively increases tryptophan hydroxylase-2 mRNA expression in distinct subregions of rat midbrain raphe nucleus: association between gene expression and anxiety behavior in the open field. Elevated expression of tryptophan hydroxylase-2 mRNA at the neuronal level in the dorsal and median raphe nuclei of depressed suicides. TPH2 variants have also been extensively reported to be associated with major depression.
SNP and haplotype analysis of a novel tryptophan hydroxylase isoform TPH2 gene provide evidence for association with major depression. Association of brain-specific tryptophan hydroxylase, TPH2, with unipolar and bipolar disorder in a Northern Swedish, isolated population.
Arch Gen Psychiatry. Genetic architecture of the human tryptophan hydroxylase 2 Gene: existence of neural isoforms and relevance for major depression. However, whether these changes might reflect alterations in possible modulatory effects of other neurotransmitter systems on 5-HT systems is still largely unknown. To address this question directly, TPH2 mRNA expression was measured in three different transgenic mouse models, all related to pathological states of depression and anxiety, but caused by mutations affecting different neurotransmitter systems.
Mol Pharmacol. Targeting the murine serotonin transporter: insights into human neurobiology. Nat Rev Neurosci. By mediating 5-HT reuptake in the nerve terminal and other parts of the 5-HT neuron , 5-HTT fine-tunes the magnitude and duration of serotoninergic signaling, 52 Lesch KP, Mossner R.
Inactivation of 5HT transport in mice: modeling altered 5HT homeostasis implicated in emotional dysfunction, affective disorders, and somatic syndromes.
Handb Exp Pharmacol. Canli T, Lesch KP. Long story short: the serotonin transporter in emotion regulation and social cognition. The serotonin transporter and depression. Depress Anxiety. These animals exhibit major adaptive changes in 5-HT neurotransmission when compared with their wild-type controls.
However, in terms of their target areas such as hippocampus and forebrain, increased or unaltered expression of these receptors has been reported. Functional consequences of 5-HT transporter gene disruption on 5-HT 1a receptor-mediated regulation of dorsal raphe and hippocampal cell activity.
J Neurosci. Adaptive changes of serotonin 5-HT2A receptors in mice lacking the serotonin transporter. Neurosci Lett.
Mice lacking the serotonin transporter exhibit 5-HT 1A receptor-mediated abnormalities in tests for anxiety-like behavior. Abnormal behavioral phenotypes of serotonin transporter knockout mice: parallels with human anxiety and depression. Int J Neuropsychopharmacol. An essential role for vesicular glutamate transporter 1 VGLUT1 in postnatal development and control of quantal size. Identification of a vesicular glutamate transporter that defines a glutamatergic phenotype in neurons.
VGLUT1 has been shown to have a high level of expression in glutamatergic neurons in the cerebral cortex. Hisano S. Vesicular glutamate transporters in the brain. Anat Sci Int. By concentrating glutamate in synaptic vesicles, VGLUT1 mediates glutamate release from synaptic terminals and facilitates efficient glutamatergic transmission. Vesicular glutamate transporters 1 and 2 target to functionally distinct synaptic release sites. Vesicular glutamate transporter VGLUT1 has a role in hippocampal long-term potentiation and spatial reversal learning.
Cereb Cortex. Enhanced anxiety, depressive-like behaviour and impaired recognition memory in mice with reduced expression of the vesicular glutamate transporter 1 VGLUT1. Aberrations in glutamate synthesis and its dysregulation also appear to play a relevant role in major depression. Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments.
In keeping with this, recent postmortem studies showing decreased cortical VGLUT1 in depressed subjects 70 Vesicular glutamate transporter mRNA expression in the medial temporal lobe in major depressive disorder, bipolar disorder, and schizophrenia. Bipolar Disord. Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression.
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J Neurochem. Moreover, the chronic absence of CB1R activity induces alterations in 5-HT-dependent negative feedback. In particular, enhanced extracellular 5-HT levels in the prefrontal cortex decreased 5-HTT binding site density and caused functional desensitization of the 5-HT1A autoreceptors.
Reduced 5-HT2C receptor expression in different brain regions has also been described in these mutants. Lack of CB1 receptor activity impairs serotonergic negative feedback. In addition, according to Mato et al. Although genetically modified animals can provide good models of human diseases, mood disorders such as depression are more difficult to represent, as these disorders are associated with changes in several genes, which are specific for each patient.
One of the tests most commonly used by researchers to investigate new antidepressant drugs is the FST, first described by Porsolt et al. Depression: a new animal model sensitive to antidepressant treatments. This test was developed as an animal model of depression that aimed to measure the effects of antidepressant compounds in mice. In this test, the animal is placed in a water-filled cylinder which it is unable to exit. Initially, the animal will try to escape, but eventually it adopts a posture of immobility, a passive behavior characterized by the absence of movements except for those necessary for the animal's snout to remain above the water level Figure 1A.
The test for rats consists of two swimming exposures. The first exposure is for 15 minutes and the second is performed 24 hours after the first, with an exposure period of 5 minutes.
The test for mice consists of a single 6-minute exposure, with the first 2 minutes serving as a habituation period and the last 4 minutes consisting of the test itself, which yields the duration of immobility. FST is easy to use, has very good reproducibility and is used for the selection of new antidepressant drugs. With respect to anti-immobility, it is known that drugs affecting noradrenergic neurotransmission e. Arch Gen Psychiatry ; 59 : — Exposure to chronic mild stress alters thresholds for lateral hypothalamic stimulation reward, subsequent responsiveness to amphetamine.
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These dimensions may be related to the functioning of specific neurobiological systems. Thus, rather than trying to recreate or mimic the entire spectrum of symptoms comprising the syndrome of depression, it may be more informative to develop animal models for these behavioral dimensions. Such models may then provide access not only to the neural regulatory mechanisms underlying effective antidepressant treatment, but may also provide clues to the processes underlying the development and manifestation of depression.
Depress Anxiety 28 : — Child Dev 71 : — Mol Psychiatry 8 : — Willner P Reliability of the chronic mild stress model of depression: a user survey. Neurobiol Stress 6 : 68 — Willner P , Towell A , Sampson D , Sophokleous S , Muscat R Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology Berl 93 : — Biol Psychiatry 80 : — Yirmiya R Endotoxin produces a depressive-like episode in rats.
Brain Res : — Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. What do we talk about when we talk about depression in rodents?
Stress-Induced Models of Depression. Neurobiological Models of Depression. Statement of Interest. Oxford Academic. Maria Lindskog. Revision received:. Select Format Select format. Permissions Icon Permissions. Abstract The diagnosis of a mental disorder generally depends on clinical observations and phenomenological symptoms reported by the patient. RDoC , stress , resilience , vulnerability. Table 1. Animal Model.
Possible Disease Relevance. Stress-Induced Chronic mild stress Katz, ; Willner et al. Open in new tab. Open in new tab Download slide. Table 2. Clinical Manifestations. Experimental Animal Tests. Negative valence Acute threat Powerlessness Lack of social interaction Porsolt swim test Sustained threat Exhaustion, powerlessness Porsolt swim test Lack of social interaction Frustrative non-reward Exhaustion Lack social interaction Responses to potential harm Anxiety Elevated plus maze, Open field, Novelty suppressed feeding Positive valence Reward valuation Anhedonia Sucrose preference, self stimulation Arousal Arousal, interaction with valence Appetite, sleep, sex, locomotors activity Sleep-pattern, social interaction, modified serial-5 choice Social processes Disrupted attachment Disorganized attachment Aggressive behavior Disrupted affiliation Victimization Subordination, Social withdrawal Social withdrawal.
Gene expression patterns in the hippocampus and amygdala of endogenous depression and chronic stress models.
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