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Background: The Transient Receptor Potential Melastatin 8 (TRPM8) is a cold/pain-sensitive Ca2+ channel. Testosterone is a high-affinity agonist for TRPM8, and TRPM8 -/- male mice exhibit disrupted sexual behavior: indiscriminate approach, increased mounting, and delayed satiety, possibly due to decreased ventral tegmental area dopamine (DA) neuron activity. DA plays a critical role in motivated behaviors, including behavioral activation, detection of reward-relevant stimuli, and reinforcement learning. Hypothesis: It is hypothesized that TRPM8 KO mice will exhibit disruptions across a range of motivationally-relevant behaviors, including spontaneous locomotor activation, detection of novel stimuli, sucrose preference, and sensitivity to the psychomotor stimulant amphetamine. Methods: Adult mice (Jackson Laboratory) were individually housed and locomotor activity was assessed for 48 hours. To assess detection of novel stimuli, a novel object recognition task was performed. Mice were habituated to two identical objects for two hours. A novel object was introduced and interaction with the novel vs familiar object was recorded. Sucrose (0.1%) preference was assessed using a two-bottle choice procedure. Tests for amphetamine sensitization (1.0 mg/kg i.p.) are in progress. Results: Female mice were more active compared to male mice (F (1,26) = 7.14, p < 0.05). Time course analysis of the nocturnal activity of males revealed a statistically significant decrease (F (1,12) = 23.41, p < 0.001) in activity among TRPM8 -/- compared to wildtype mice. In contrast, the TRPM8 deletion had no effect on the activity of female mice (F (1,12) = 0.32, n.s.). Preliminary analysis of the novel object recognition task revealed a trend towards increased exploration of the novel object and decreased time with the familiar object among male TRPM8 -/- mice compared to wildtype (Cohen’s d > 0.58). Finally, male TRPM8 -/- mice exhibited a robust preference for sucrose compared to wildtype mice. Additional data collection is in progress. Conclusion: TRPM8-/- mice were less active during the active phase of the day/night cycle compared to wildtype mice. However, TRPM8-/- mice exhibited increased interest in a novel object and a robust preference for sucrose, indicating increased sensitivity to motivationally-relevant stimuli. These behavioral data suggest that TRPM8 -/- mice are likely to exhibit decreased basal DA levels in reward-relevant brain areas, but that motivationally relevant stimuli likely elicit robust increases in DA.
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This content will become publicly available on January 1, 2026
Transcriptomic Profile Analysis of Brain Tissue in the Absence of Functional TRPM8 Calcium Channel
Background/Objectives: Transient Receptor Potential Melastatin 8 (TRPM8) is a non-selective, Ca2+-permeable cation channel involved in thermoregulation and other physiological processes, such as basal tear secretion, cell differentiation, and insulin homeostasis. The activation and deactivation of TRPM8 occur through genetic modifications, channel interactions, and signaling cascades. Recent evidence suggests a significant role of TRPM8 in the hypothalamus and amygdala related to pain sensation and sexual behavior. Notably, TRPM8 has been implicated in neuropathic pain, migraines, and neurodegenerative diseases such as Parkinson’s disease. Our laboratory has identified testosterone as a high-affinity ligand of TRPM8. TRPM8 deficiency appears to influence behavioral traits in mice, like increased aggression and deficits in sexual satiety. Here, we aim to explore the pathways altered in brain tissues of TRPM8-deficient mice using the expression and methylation profiles of messenger RNA (mRNA) and long non-coding RNA (lncRNA). Specifically, we focused on brain regions integral to behavioral and hormonal control, including the olfactory bulb, hypothalamus, amygdala, and insula. Methods: RNA was isolated and purified for microarray analysis collected from male wild-type and TRPM8 knockout mice. Results: We identified various differentially expressed genes tied to multiple signaling pathways. Among them, the androgen–estrogen receptor (AR-ER) pathway, steroidogenesis pathway, sexual reward pathway, and cocaine reward pathway are particularly worth noting. Conclusions: These results should bridge the existing gaps in the knowledge regarding TRPM8 and inform potential targets for future studies to elucidate its role in the behavior changes and pathology of the diseases associated with TRPM8 activity.
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- Award ID(s):
- 1922428
- PAR ID:
- 10563712
- Publisher / Repository:
- MDPI
- Date Published:
- Journal Name:
- Biomedicines
- Volume:
- 13
- Issue:
- 1
- ISSN:
- 2227-9059
- Page Range / eLocation ID:
- 75
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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