Search Results (9)

Among female rats, some individuals show estrus cycle-dependent irritability/aggressive behaviors, and these individual rats may be used as a model for premenstrual dysphoric disorder (PMDD). We wanted to investigate if these behaviors are related to the estrus cycle phase containing moderately increased levels of positive GABA-A receptor-modulating steroids (steroid-PAM), especially allopregnanolone (ALLO), and if the adverse behavior can be antagonized. The electrophysiology studies in this paper show that isoallopregnanolone (ISO) is a GABA-A-modulating steroid antagonist (GAMSA), meaning that ISO can antagonize the agonistic effects of positive GABA-A receptor-modulating steroids in both α1β2γ2L and α4β3δ GABA-A receptor subtypes. In this study, we also investigated whether ISO could antagonize the estrus cycle-dependent aggressive behaviors in female Wistar rats using a resident–intruder test. Our results confirmed previous reports of estrus cycle-dependent behaviors in that 42% of the tested rats showed higher levels of irritability/aggression at diestrus compared to those at estrus. Furthermore, we found that, during the treatment with ISO, the aggressive behavior at diestrus was alleviated to a level comparable to that of estrus. We noticed an 89% reduction in the increase in aggressive behavior at diestrus compared to that at estrus. Vehicle treatment in the same animals showed a minimal effect on the diestrus-related aggressive behavior. In conclusion, we showed that ISO can antagonize Steroid-PAM both in α1β2γ2L and α4β3δ GABA-A receptor subtypes and inhibit estrus cycle-dependent aggressive behavior. Full article

Depression is a neuropsychiatric disorder characterized by altered emotion and cognition. Alpha lipoic acid (ALA) is a potent natural antioxidant and exhibits neuroprotective effects. However, its antidepressant activity and its mechanism of action in rats exposed to chronic unpredictable mild stress (CUMS) need to be evaluated. The rats were divided into six groups. Group, I vehicle control (without stress), II- CUMS, III- fluoxetine (FLX) (50 mg/kg p.o.), IV, V, and VI were treated with ALA (50, 100, 200 mg/kg, p.o.), respectively. All the groups, except I, were subjected to CUMS + treatments from day 1 to day 42. Body weight and behavioral parameters like sucrose preference test (SPT), Morris water maze (MWM), resident intruder test (RIT), and marble-burying test (MBT) were performed on day 0, day 21, and day 42, and forced swim test (FST) on last day 42 and 43 only. The rats were further sacrificed for biochemical and histopathological evaluation. ALA significantly improved behavioral function, increased antioxidant strength, reduced lipid peroxidation, restored monoamines, and protected CA3 neurons. Further, docking studies revealed strong binding of ALA on the 5HT₃ receptor. The study demonstrates that ALA might be exhibiting antidepressant effects in part by restoring monoamines and modulating the 5HT₃ receptor. Full article

Preclinical studies on rodents should follow the 3R principle minimising the suffering of the animals. To do so, some researchers use inhalation anaesthetic induction even before intraperitoneal injection. However, several studies suggested that both interventions might influence the behaviour of the animals. We aimed to test whether intraperitoneal injection alone or in combination with isoflurane anaesthesia is a preferable treatment method 30 min before a social test. Male C57BL/6 mice were studied using a behavioural test battery comparing three groups (one control group and intraperitoneal saline-treated groups with or without short isoflurane inhalation). Our results confirmed that both interventions had no profound influence on the conventionally measured parameters of social tests (interest in sociability, social discrimination memory, social interaction as well as resident–intruder test) and were not acutely stressful (measured by similar ACTH levels between the groups) not even after repeated administration (similar body weight gain during the one-week observation period). Taking into consideration the possible long-term harmful effect of isoflurane inhalation, we recommend using intraperitoneal injection without it as saline injection did not violate the 3R principle inducing only mild stress. Full article

Aggressive behavior is one of congenital social behaviors in many species, which could be promoted by social neglect or isolation in the early stages of life. Many brain regions including the medial prefrontal cortex (mPFC), medial amygdala (MeA) and ventromedial hypothalamus (VMH) are demonstrated to relate to aggressive behavior; however, the dynamic patterns of neural activities during the occurrence of this behavior remain unclear. In this study, 21-day-old male CD-1 mice were reared in social isolation conditions and cohousing conditions for two weeks. Aggressive behaviors of each subject were estimated by the resident–intruder test. Simultaneously, the local field potentials of mPFC, MeA and VMH were recorded for exploring differences in the relative power spectra of different oscillations when aggressive behaviors occurred. The results showed that the following: (1) Compared with the cohousing mice, the socially isolated mice exhibited more aggression. (2) Regardless of “time condition” (pre-, during- and post- attack), the relative power spectra of beta band in the cohousing mice were significantly greater than those in the socially isolated mice, and inversely, the relative power spectra of gamma band in the cohousing mice were significantly smaller than those in the socially isolated mice. (3) The bilateral mPFC exhibited significantly smaller beta power spectra but greater gamma power spectra compared with other brain areas regardless of rearing patterns. (4) For the right VMH of the socially isolated mice, the relative power spectra of the gamma band during attacks were significantly greater than those before attack. These results suggest that aggressive behaviors in mice could be shaped by rearing patterns and that high-frequency oscillations (beta and gamma bands) may engage in mediating aggressive behaviors in mice. Full article

The Trace Amine-Associated Receptor 1 (TAAR1) is one of the six functional receptors belonging to the family of monoamine-related G protein-coupled receptors (TAAR1-TAAR9) found in humans. However, the exact biological mechanisms of TAAR1 central and peripheral action remain to be fully understood. TAAR1 is widely expressed in the prefrontal cortex and several limbic regions, interplaying with the dopamine system to modulate the reward circuitry. Recent clinical trials suggest the efficacy of TAAR1 agonists as potential novel antipsychotic agents. Here, we characterize behavioral and neurochemical phenotypes of TAAR1 knockout mice, focusing on aggression and self-grooming behavior that both strongly depend on the monoaminergic signaling and cortico-striatal and cortico-limbic circuits. Overall, we report increased aggression in these knockout mice in the resident-intruder test, accompanied by reduced self-grooming behavior in the novelty-induced grooming test, and by higher cortical serotonin (5-HT) tissue levels. Further studies are necessary to explore whether TAAR1-based therapies can become potential novel treatments for a wide range of neuropsychiatric disorders associated with aggression. Full article

Behavioural and psychological symptoms of dementia (BPSD) are presented in 95% of Alzheimer’s Disease (AD) patients and are also associated with neurotrophin deficits. The molecular mechanisms leading to age-related diseases are still unclear; however, emerging evidence has suggested that epigenetic modulation is a key pathophysiological basis of ageing and neurodegeneration. In particular, it has been suggested that G9a methyltransferase and its repressive histone mark (H3K9me2) are important in shaping learning and memory by modulating autophagic activity and synaptic plasticity. This work deepens our understanding of the epigenetic mechanisms underlying the loss of cognitive function and BPSD in AD. For this purpose, several tasks were performed to evaluate the parameters of sociability (three-chamber test), aggressiveness (resident intruder), anxiety (elevated plus maze and open field) and memory (novel object recognition test) in mice, followed by the evaluation of epigenetic, autophagy and synaptic plasticity markers at the molecular level. The behavioural alterations presented by senescence-accelerated mice prone 8 (SAMP8) of 12 months of age compared with their senescence-accelerated mouse resistant mice (SAMR1), the healthy control strain was accompanied by age-related cognitive deficits and alterations in epigenetic markers. Increased levels of G9a are concomitant to the dysregulation of the JNK pathway in aged SAMP8, driving a failure in autophagosome formation. Furthermore, lower expression of the genes involved in the memory-consolidation process modulated by ERK was observed in the aged male SAMP8 model, suggesting the implication of G9a. In any case, two of the most important neurotrophins, namely brain-derived neurotrophic factor (Bdnf) and neurotrophin-3 (NT3), were found to be reduced, along with a decrease in the levels of dendritic branching and spine density presented by SAMP8 mice. Thus, the present study characterizes and provides information regarding the non-cognitive and cognitive states, as well as molecular alterations, in aged SAMP8, demonstrating the AD-like symptoms presented by this model. In any case, our results indicate that higher levels of G9a are associated with autophagic deficits and alterations in synaptic plasticity, which could further explain the BPSD and cognitive decline exhibited by the model. Full article

Transient receptor potential ankyrin 1 (TRPA1), a nonselective cation channel, contributes to several (patho)physiological processes. Smell loss is an early sign in several neurodegenerative disorders, such as multiple sclerosis, Parkinson’s and Alzheimer’s diseases; therefore, we focused on its role in olfaction and social behaviour with the aim to reveal its potential therapeutic use. The presence of Trpa1 mRNA was studied along the olfactory tract of mice by combined RNAscope in situ hybridisation and immunohistochemistry. The aversive effects of fox and cat odour were examined in parallel with stress hormone levels. In vitro calcium imaging was applied to test if these substances can directly activate TRPA1 receptors. The role of TRPA1 in social behaviour was investigated by comparing Trpa1 wild-type and knockout mice (KO). Trpa1 mRNA was detected in the olfactory bulb and piriform cortex, while its expression was weak in the olfactory epithelium. Fox, but not cat odour directly activated TRPA1 channels in TRPA1-overexpressing Chinese Hamster Ovary cell lines. Accordingly, KO animals showed less aversion against fox, but not cat odour. The social interest of KO mice was reduced during social habituation–dishabituation and social interaction, but not during resident–intruder tests. TRPA1 may contribute to odour processing at several points of the olfactory tract and may play an important role in shaping the social behaviour of mice. Thus, TRPA1 may influence the development of certain social disorders, serving as a potential drug target in the future. Full article

Pathological aggression is a debilitating feature of many neuropsychiatric disorders, and cingulate cortex is one of the brain areas centrally implicated in its control. Here we explore the specific role of midcingulate cortex (MCC) in the development of pathological aggression. To this end, we investigated the structural and functional degeneration of MCC in the BALB/cJ strain, a mouse model for pathological aggression. Compared to control animals from the BALB/cByJ strain, BALB/cJ mice expressed consistently heightened levels of aggression, as assessed by the resident-intruder test. At the same time, immunohistochemistry demonstrated stark structural degradation in the MCC of aggressive BALB/cJ mice: Decreased neuron density and widespread neuron death were accompanied by increased microglia and astroglia concentrations and reactive astrogliosis. cFos staining indicated that this degradation had functional consequences: MCC activity did not differ between BALB/cJ and BALB/cByJ mice at baseline, but unlike BALB/cByJ mice, BALB/cJ mice failed to activate MCC during resident-intruder encounters. This suggests that structural and functional impairments of MCC, triggered by neuronal degeneration, may be one of the drivers of pathological aggression in mice, highlighting MCC as a potential key area for pathologies of aggression in humans. Full article

Early life socialization of piglets has been shown to reduce piglet aggression at weaning, but information on sow health and long-term benefits is lacking. We aimed to assess how socialization impacts sow udder quality and long-term pig behaviour and growth. At two weeks of age, 65 litters either experienced socialization with one other litter (SOC) or did not (control; CON). Sows (housed in farrowing crates) were scored for teat damage and piglets were observed for aggressive behaviour (resident-intruder test) and growth and skin lesions up to 11 weeks under conventional farm conditions (including weaning and regrouping). At weaning, SOC sows had more teat damage than CON sows (p = 0.04). SOC piglets had double the number of lesions 24 h post-socialization compared to the control (19 versus 8; p < 0.001). In the resident-intruder test, more SOC pigs attacked the intruder (SOC 78%; CON 66%; p < 0.01), and attacked more quickly (p = 0.01). During regrouping (week 8), SOC pigs had 19% fewer lesions (SOC 68; CON 84; p < 0.05), but three weeks later, groups did not differ. Growth was unaffected by treatment. Overall, socialized piglets seem to be equipped with greater confidence or agonistic skills, leading to fewer injuries from fighting up to at least six weeks after socialization. Full article