Polyamines are ubiquitous organic cations implicated in many physiological processes. Because they are positively charged at physiological pH, carrier-mediated systems are necessary for effective membrane permeation, but the identity of specific polyamine transporter proteins in eukaryotic cells remains unclear. Polyspecific organic cation transporters (OCTs) interact with many natural and xenobiotic monovalent cations and have been reported to transport dicationic compounds, including the short polyamine putrescine. In this study, we used Xenopus oocytes expressing mammalian OCT1 (SLC22A1), OCT2 (SLC22A2) or OCT3 (SLC22A3) to assess binding and transport of longer-chain polyvalent polyamines. In OCT-expressing oocytes, [3H]MPP+ uptake rates were 15– to 35–fold higher than in non-injected oocytes, whereas those for [3H]spermidine increased more modestly above the background, up to 3–fold. This reflected up to 20–fold lower affinity for spermidine than for MPP +; thus, K0.5 for MPP+ was ~50 μM in OCT1, ~170 μM in OCT2, and ~60 μM in OCT3, whereas for spermidine, K0.5 was ~1 mM in OCT1, OCT2 and OCT3. Jmax values for MPP+ and spermidine were within the same range, suggesting that both compounds are transported at a similar turnover rate. To gain further insight into OCT substrate specificity, we screened a selection of structural polyamine analogs for effect on [3H]MPP+ uptake. In general, blocking potency increased with overall hydrophobic character, which indicates that, as for monovalent cations, hydrophobicity is a major requirement for recognition in polyvalent OCT substrates and inhibitors. Our results demonstrate that the natural polyamines are low affinity, but relatively high turnover, substrates for OCTs. The identification of OCTs as polyamine transport systems may contribute to further understanding of the mechanisms involved in polyamine homeostasis, and aid in the design of polyamine-like OCT-targeted drugs.
The social environment influences neurodevelopment. Investigations using rodents to study this phenomenon commonly isolate subjects, then assess neurobehavioral consequences while animals are still isolated. This approach precludes one from dissociating the effects of on-going versus prior isolation, hindering our complete understanding of the consequences of social experience during particular developmental periods. Here, we socially isolated adolescent mice from postnatal day (P)31 to P60, then re-housed them into social groups. We tested their ability to select actions based on expected outcomes using multiple reinforcer devaluation and instrumental contingency degradation techniques. Social isolation in adolescence (but not adulthood) weakened instrumental response updating, causing mice to defer to habit-like behaviors. Habit biases were associated with glucocorticoid insufficiency in adolescence, oligodendrocyte marker loss throughout cortico-striatal regions, and dendritic spine and synaptic marker excess in the adult orbitofrontal cortex (OFC). Artificial, chemogenetic stimulation of the ventrolateral OFC in typical, healthy mice recapitulated response biases following isolation, causing habit-like behaviors. Meanwhile, correcting dendritic architecture by inhibiting the cytoskeletal regulatory protein ROCK remedied instrumental response updating defects in socially isolated mice. Our findings suggest that adolescence is a critical period during which social experience optimizes one's ability to seek and attain goals later in life. Age-typical dendritic spine elimination appears to be an essential factor, and in its absence, organisms may defer to habit-based behaviors.Humans and rodents who experience early-life traumas or adversities appear to be prone to habit-based behaviors, often occurring at the expense of goal-oriented actions. Despite consistencies across species, how adversity, particularly during specific developmental periods, causes long-term behavioral biases remains unclear. Compounding this issue, many rodent investigations using social isolation to model adversity test mice or rats while they are isolated, making it difficult to dissociate the consequences of current versus developmental hardship. We reveal that mice with a history of social isolation during adolescence are biased toward habit-like behaviors, despite social reintegration in adulthood. Biases are linked with abnormalities in glucocorticoid tone and prefrontal cortical dendritic spine elimination during adolescence and were corrected by manipulating actin cytoskeletal regulatory factors.
Specific corticostriatal structures and circuits are important for flexibly shifting between goal-oriented versus habitual behaviors. For example, the orbitofrontal cortex and dorsomedial striatum are critical for goal-directed action, while the dorsolateral striatum supports habits. To determine the role of neurotrophin signaling, we overexpressed a truncated, inactive form of tropomyosin receptor kinase B [also called tyrosine receptor kinase B (TrkB)], the high-affinity receptor for Brain-derived Neurotrophic Factor, in the orbitofrontal cortex, dorsomedial striatum and dorsolateral striatum. Overexpression of truncated TrkB interfered with phosphorylation of full-length TrkB and ERK42/44, as expected. In the orbitofrontal cortex and dorsomedial striatum, truncated trkB overexpression also occluded the ability of mice to select actions based on the likelihood that they would be reinforced. Meanwhile, in the dorsolateral striatum, truncated trkB blocked the development of habits. Thus, corticostriatal TrkB-mediated plasticity appears necessary for balancing actions and habits.
We demonstrate that in over half of PFH patients, psychotropic medication usage was discontinued after ETS, which is consistent with our findings on postoperative improvements in Hyperhidrosis Impact Questionnaires, Leibowitz Social Anxiety Scales and Center for Epidemiological Studies Depression Scales scores. Furthermore, our findings suggest that a considerable proportion of PFH patients who experience psychopathology may be doing so secondary to excessive sweating. Thus, improved awareness or recognition of these associations in the diagnosis and management of PFH patients is warranted.
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