Recent studies indicated a connection between trace amine-associated receptor 5 (TAAR5) and emotional behaviors related to anxiety and depression; however, the neurobiological basis of this link is still unclear. Using mutant TAAR5 knockout (TAAR5-KO) mice, we explored the consequences of receptor deletion on dopamine (DA) dynamics in the ventral striatum and stress-related behaviors. Voltammetric measurements of DA in the nucleus accumbens (NAc) coupled with electrical stimulation of the ventral tegmental area (VTA) revealed that mice lacking TAAR5 display a greater DA release, while its reuptake is not affected. Behaviorally, mutants were significantly less anxious in the elevated plus maze (EPM) and consumed more sucrose in comparison with wild-type (WT) controls. The new object recognition test (NOR) did not uncover a difference between these genotypes. During predator (rat) stress exposure, mutant and WT mice showed quite distinct responses versus the behavior observed in stressless conditions. Control animals demonstrated a substantial increase in “freezing” (a sign of passive coping), while “running” and “exploring” patterns (signs of active coping) were significantly extended in mice lacking TAAR5. Short-term consequences of stress were explored 24 h following the predator exposure. The absence of TAAR5 did not prevent or reduce stress-induced anxiety in the EPM. In fact, the level of anxiety in mutants reached that observed in control mice. Furthermore, activity in NOR was significantly decreased in mice lacking TAAR5 but not in WT animals. On the other hand, predator exposure resulted in impaired NOR in the WT control, whereas mutants’ performance was not altered. These findings indicate that TAAR5 deletion leads to significant DA imbalance, which might at least partly explain the better stress-coping strategy and other stress-induced behavioral consequences observed in mutant animals.

Черепно-мозговая травма (ЧМТ) часто приводит к прогрессирующему хроническому состоянию, обусловленному вторичным нейровоспалением с чередующимися волнами обострения и разрешения. Молекулярные и клеточные механизмы, определяющие прогрессирование невропатологии при ЧМТ, остаются всё ещё недостаточно изученными, что приводит к отсутствию эффективных методов лечения долгосрочных последствий ЧМТ. Цель: определить особенности поведения животных, функциональное состояние лимфоцитов, экспрессию генов цитокинов и толл-подобного рецептора 4 (TLR4) в гипоталамусе травмированных крыс на 30-е сутки после черепно-мозговой травмы (ЧМТ) и изменение этих параметров после введения рекомбинантного рецепторного антагониста IL-1 (rIL-1RА). Материалы и методы. Работа выполнена на крысах линии Wistar. ЧМТ средней тяжести моделировали, используя модель «падающего груза». rIL-1RA вводили подкожно в дозе 50 мг/кг через 1 ч после ЧМТ, и далее ежедневно в течение двух суток. Поведенческие реакции изучали в тесте «Открытое поле». Определяли экспрессию генов IL-1β, IL-10, TNF-α, TLR4 в гипоталамусе, а также пролиферативную и цитотоксическую активность лимфоцитов селезенки. Результаты. На 30-е сутки после ЧМТ у животных наблюдали уменьшение дистанции и скорости движения, увеличение количества и длительности актов фризинга, уменьшение количества вертикальных стоек и обследованных отверстий. Активации или системного угнетения функции лимфоцитов не наблюдалось. В гипоталамусе экспрессия генов провоспалительных (IL-1β, TNF-α) и противовоспалительных (IL-10) цитокинов, а также TLR4 была существенно повышена. Лечение препаратом rIL-1RA не приводило к коррекции поведенческих нарушений и не влияло на функции лимфоцитов, однако приводило к ещё большему повышению степени экспрессии генов исследованных цитокинов и существенному снижению степени экспрессии гена TLR4. Заключение. Нейровоспаление после ЧМТ проявляется как поведенческими нарушениями, так и высокой экспрессией генов провоспалительных (IL-1β, TNF-α) и противовоспалительных (IL-10) цитокинов и TLR4 в гипоталамусе. Введение rIL-1RA в раннем посттравматическом периоде не предотвращает поведенческих нарушений на 30-е сутки после травмы, но в некоторой степени уменьшает гипоталамические нарушения. Traumatic brain injury (TBI) often leads to the development of a progressive chronic painful condition, caused by secondary neuroinflammation with alternating waves of inflammation and resolution. The molecular and cellular mechanisms that determine the progression of neuropathology during TBI are poorly understood, that leads to the lack of effective treatment for the long-term consequences of TBI. Aim: To determine the behavioral characteristics of animals, functional state of lymphocytes, cytokine and toll like receptor 4 (TLR4) gene expression in the hypothalamus of traumatized rats on the 30th day after traumatic brain injury and their changes after administration of recombinant receptor antagonist IL-1 (rIL-1RA). Materials and methods: The study was performed on Wistar rats. A “weight-drop” model was used to induce moderate TBI. rIL-1RA (50 mg/kg) was administered subcutaneously 1 hour after TBI and then every day for 2 days. Behavioral reactions were assessed in the open field test. Gene expression of IL-1β, IL-10, TNFα, TLR4 in the hypothalamus, as well as proliferative and cytotoxic activities of spleen lymphocytes were determined. Results. On the 30th day after TBI, untreated animals showed reduced distance and speed of movement, increased frequency and duration of freezing acts, decreased number of vertical rears and explored holes. In the hypothalamus, the gene expression of cytokines was significantly higher in untreated rats compared to control animals, as well as TLR4 gene expression. Treatment with rIL-1RA had no influence on anxious behavior and lymphocytes functions, and led to elevated gene expression of cytokines, but decreased expression of TLR4 gene. Conclusion: Persistent neuroinflammation on the 30th day after TBI is manifested by anxious behavior and high expression of cytokines and TLR4 genes in the hypothalamus. The administration of rIL-1RA in the early...

The Locus Coeruleus (LC) is a critical area in the brain that plays an important role in several neural pathways associated with a range of physiological and behavioral processes. Its activity can modulate both norepinephrine (NE) and dopamine neurotransmission, particularly in the prefrontal cortex (PFC). In the present study, we show that a chemogenetically induced increase in norepinephrine release from the LC to the PFC reduced hyperactive behavioral patterns in rats lacking the dopamine transporter (DAT-KO rats) with spontaneously elevated dopamine transmission. These manipulations in hyperdopaminergic mutants also caused amelioration of cognitive abnormalities in spatial learning task as evidenced by decreases in perseverative activity and the number of visits to the error zone. Furthermore, chemogenetic activation of NE neurotransmission in these animals significantly improved their performance in in this maze test. Thus, the results obtained of this study highlight an important modulatory role of NE on hyperactivity and cognitive dysfunctions of hyperdopaminergic DAT-KO rats lacking the dopamine transporter.

BACKGROUND: A traumatic brain injury causes both primary brain damage and secondary inflammation. This inflammation can contribute to further neuronal damage and dysfunction. Microglial cells are key players in neuroinflammation, which can remain activated for a long time after a traumatic brain injury. Microglial cells are the main source of elevated interleukin-1β (IL-1β) levels in the brain after traumatic brain injury. Therefore, it is essential to investigate their status following the administration of a recombinant IL-1 receptor antagonist (rIL-1Ra), particularly in the long term. The study tested the hypothesis that administration of an IL-1 receptor antagonist during the early post-traumatic period would sufficiently reduce neuroinflammatory activity 30 days after traumatic brain injury. AIM: The study aimed to evaluate the effect of rIL-1Ra on morphological characteristics of microglia in brain areas susceptible to injury, as well as to assess gene expression of neurotrophic factors Bdnf, Ngf, and Vegf and the inflammatory marker S100a12 in the hypothalamus as a potential structure with secondary inflammation on day 30 after traumatic brain injury. METHODS: A drop-weight model was used to induce a diffuse brain injury, and rIL-1Ra was administered subcutaneously at 50 mg/kg one hour after traumatic brain injury, and then twice more over the next two days. Microglial cell activation was assessed using immunohistochemistry and morphometry. The expression of Bdnf, Ngf, Vegf, and S100a12 was determined using a real-time polymerase chain reaction. RESULTS: On day 30 after injury, there were no significant changes in hypothalamic gene expression of neurotrophic factors (Bdnf, Ngf) or S100a12. However, a significant increase in Vegf expression was observed in animals that received rIL-1Ra. Immunohistochemistry showed that activated microglial cells remained in some areas of the brain after treatment, but their numbers were substantially reduced compared to the untreated injured animals. CONCLUSION: rIL-1Ra influences the inflammatory response to traumatic brain injury by reducing microglial activity and enhancing neurotrophic processes. These findings suggest the potential of using rIL-1Ra to treat the sequelae of traumatic brain injury.