Habenula as a Possible Target for Treatment-Resistant Depression Phenotype in Wistar Kyoto Rats

Korlatowicz, Agata; Pabian, Paulina; Solich, Joanna; Kolasa, Magdalena; Latocha, Katarzyna; Dziedzicka-Wasylewska, Marta; Faron-Górecka, Agata

doi:10.1007/s12035-022-03103-y

Cited by 8 publications

(3 citation statements)

References 57 publications

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“…In addition, the WKY rats show hypoactivity in open field tests, high anxiety (Dugovic et al, 2000) and depressive behaviour (Pare, 1992(Pare, , 1994. Of particular relevance to the present study, there are significant differences in dopamine transporter expression in the nucleus accumbens and VTA of WKY rats compared to Wistar and SD strains (Jiao et al, 2003) and differences in dopamine receptor expression (Korlatowicz et al, 2023;Morganstern & Tejani-Butt, 2010;Yaroslavsky et al, 2006). These behavioural and neurochemical characteristics make WKY unsuitable as a reference strain in the current study.…”

Section: Sd Rats As the Comparison Strain For Shrsmentioning

confidence: 77%

Phasic dopamine signals are reduced in the spontaneously hypertensive rat and increased by methylphenidate

Li,

Huang,

Chen

et al. 2024

Eur J of Neuroscience

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The spontaneously hypertensive rat (SHR) is a selectively bred animal strain that is frequently used to model attention‐deficit hyperactivity disorder (ADHD) because of certain genetically determined behavioural characteristics. To test the hypothesis that the characteristically altered response to positive reinforcement in SHRs may be due to altered phasic dopamine response to reward, we measured phasic dopamine signals in the SHRs and Sprague Dawley (SD) rats using in vivo fast‐scan cyclic voltammetry. The effects of the dopamine reuptake inhibitor, methylphenidate, on these signals were also studied. Phasic dopamine signals during the pairing of a sensory cue with electrical stimulation of midbrain dopamine neurons were significantly smaller in the SHRs than in the SD rats. Over repeated pairings, the dopamine response to the sensory cue increased, whereas the response to the electrical stimulation of dopamine neurons decreased, similarly in both strains. However, the final amplitude of the response to the sensory cue after pairing was significantly smaller in SHRs than in the SD rats. Methylphenidate increased responses to sensory cues to a significantly greater extent in the SHRs than in the SD rats, due largely to differences in the low dose effect. At a higher dose, methylphenidate increased responses to sensory cues and electrical stimulation similarly in SHRs and SD rats. The smaller dopamine responses may explain the reduced salience of reward‐predicting cues previously reported in the SHR, whereas the action of methylphenidate on the cue response suggests a potential mechanism for the therapeutic effects of low‐dose methylphenidate in ADHD.

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Section: Sd Rats As the Comparison Strain For Shrsmentioning

confidence: 77%

Phasic dopamine signals are reduced in the spontaneously hypertensive rat and increased by methylphenidate

Li,

Huang,

Chen

et al. 2024

Eur J of Neuroscience

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“…In addition, downregulation of several serotonergic receptor genes was reported in stressed rats compared to non-stressed controls (73). Serotonergic dysfunction has also been reported in the Hb of the Wistar Kyoto rat, an endogenous model of treatment resistant depression (89), with downregulation of the serotonergic receptor genes Htr7 and Htr2a in both the MHb and LHb and increased expression of Htr4 in the LHb but not MHb (80). Similarly, a reduction in 5-HTR7 receptor expression was isolated to the LHb (80).…”

Section: Resultsmentioning

confidence: 99%

The disappointment centre of the brain gets exciting: A systematic review of habenula dysfunction in depression

Cameron,

Weston-Green,

Newell

2024

Preprint

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Background: The habenula is an epithalamic brain structure that acts as a neuroanatomical hub connecting the limbic forebrain to the major monoamine centres. Abnormal habenula activity is increasingly implicated in depression, with a surge in publications on this topic in the last 5 years. Direct stimulation of the habenula is sufficient to induce a depressive phenotype in rodents, suggesting a causative role in depression. However, the molecular basis of habenula dysfunction in depression remains elusive and it is unclear how the preclinical advancements translate to the clinical field. Methods: A systematic literature search was conducted following the PRISMA guidelines. The two search terms depress* and habenula* were applied across the databases Scopus, Web of Science and PubMed. Studies eligible for inclusion must have examined changes in the habenula in clinical cases of depression or preclinical models of depression. Results: Preclinical studies (n=57) measured markers of habenula activity (n=16) and neuronal firing (n=21), largely implicating habenula hyperactivity in depression. Neurotransmission was briefly explored (n=13), suggesting imbalances within excitatory and inhibitory habenula signalling. Additional preclinical studies reported neuroconnectivity (n=1), inflammatory (n=2), genomic (n=2) and circadian rhythm (n=2) abnormalities. Seven preclinical studies (12.2%) included both males and females. From these, 5 studies (71%) reported a significant difference between the sexes in at least one habenula measure taken. Clinical studies (n=18) reported abnormalities in habenula connectivity (n=11), volume (n=5) and molecular markers (n=2). Clinical studies generally included male and female subjects (n=15), however, few of these studies examined sex as a biological variable (n=5) Conclusions: Both preclinical and clinical evidence suggest the habenula is disrupted in depression. However, there are opportunities for sex-specific analyses across both areas. Preclinical evidence consistently suggests habenula hyperactivity as a primary driver for the development of depressive symptoms. Clinical studies support gross habenula abnormalities such as altered activation, connectivity, and volume, with emerging evidence of blood brain barrier dysfunction, however, progress is limited by a lack of detailed molecular analyses.

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“…Previous studies comparing the two strains of animals have shown that they differ significantly in terms of biochemistry [ 9 ]. Recently, we have demonstrated that several important miRNAs are expressed in the habenula, which differentiated WKY rats from WIS rats and were correlated with changes in the expression of target transcripts [ 41 ]. However, it turns out that the WKY strain is more complicated.…”

Section: Discussionmentioning

confidence: 99%

Altered Intracellular Signaling Associated with Dopamine D2 Receptor in the Prefrontal Cortex in Wistar Kyoto Rats

Korlatowicz

Kolasa

Pabian

et al. 2023

IJMS

Self Cite

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Wistar-Kyoto rats (WKY), compared to Wistar rats, are a well-validated animal model for drug-resistant depression. Thanks to this, they can provide information on the potential mechanisms of treatment-resistant depression. Since deep brain stimulation in the prefrontal cortex has been shown to produce rapid antidepressant effects in WKY rats, we focused our study on the prefrontal cortex. Using quantitative autoradiography, we observed a decrease in the binding of [3H] methylspiperone to the dopamine D2 receptor, specifically in that brain region—but not in the striatum, nor the nucleus accumbens—in WKY rats. Further, we focused our studies on the expression level of several components associated with canonical (G proteins), as well as non-canonical, D2-receptor-associated intracellular pathways (e.g., βarrestin2, glycogen synthase kinase 3 beta—Gsk-3β, and β-catenin). As a result, we observed an increase in the expression of mRNA encoding the regulator of G protein signaling 2-RGS2 protein, which is responsible, among other things, for internalizing the D2 dopamine receptor. The increase in RGS2 expression may therefore account for the decreased binding of the radioligand to the D2 receptor. In addition, WKY rats are characterized by the altered signaling of genes associated with the dopamine D2 receptor and the βarrestin2/AKT/Gsk-3β/β-catenin pathway, which may account for certain behavioral traits of this strain and for the treatment-resistant phenotype.

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Habenula as a Possible Target for Treatment-Resistant Depression Phenotype in Wistar Kyoto Rats

Cited by 8 publications

References 57 publications

Phasic dopamine signals are reduced in the spontaneously hypertensive rat and increased by methylphenidate

Phasic dopamine signals are reduced in the spontaneously hypertensive rat and increased by methylphenidate

The disappointment centre of the brain gets exciting: A systematic review of habenula dysfunction in depression

Altered Intracellular Signaling Associated with Dopamine D2 Receptor in the Prefrontal Cortex in Wistar Kyoto Rats

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