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The localization of substance P in brain regions that coordinate stress responses and receive convergent monoaminergic innervation suggested that substance P antagonists might have psychotherapeutic properties. Like clinically used antidepressant and anxiolytic drugs, substance P antagonists suppressed isolation-induced vocalizations in guinea pigs. In a placebo-controlled trial in patients with moderate to severe major depression, robust antidepressant effects of the substance P antagonist MK-869 were consistently observed. In preclinical studies, substance P antagonists did not interact with monoamine systems in the manner seen with established antidepressant drugs. These findings suggest that substance P may play an important role in psychiatric disorders.

ObjectiveAn interesting and so far unexplained feature of chronic pain in autoimmune disease is the frequent disconnect between pain and inflammation. This is illustrated well in rheumatoid arthritis (RA) where pain in joints (arthralgia) may precede joint inflammation and persist even after successful anti-inflammatory treatment. In the present study, we have addressed the possibility that autoantibodies against citrullinated proteins (ACPA), present in RA, may be directly responsible for the induction of pain, independent of inflammation.MethodsAntibodies purified from human patients with RA, healthy donors and murinised monoclonal ACPA were injected into mice. Pain-like behaviour was monitored for up to 28 days, and tissues were analysed for signs of pathology. Mouse osteoclasts were cultured and stimulated with antibodies, and supernatants analysed for release of factors. Mice were treated with CXCR1/2 (interleukin (IL) 8 receptor) antagonist reparixin.ResultsMice injected with either human or murinised ACPA developed long-lasting pronounced pain-like behaviour in the absence of inflammation, while non-ACPA IgG from patients with RA or control monoclonal IgG were without pronociceptive effect. This effect was coupled to ACPA-mediated activation of osteoclasts and release of the nociceptive chemokine CXCL1 (analogue to human IL-8). ACPA-induced pain-like behaviour was reversed with reparixin.ConclusionsThe data suggest that CXCL1/IL-8, released from osteoclasts in an autoantibody-dependent manner, produces pain by activating sensory neurons. The identification of this new pain pathway may open new avenues for pain treatment in RA and also in other painful diseases associated with autoantibody production and/or osteoclast activation.

Both heterozygous loss and homozygous loss of Tsc1 in mouse cerebellar Purkinje cells (PCs) result in autistic-like behaviours, which can be prevented by treatment with the mTOR inhibitor, rapamycin; these findings demonstrate critical roles for PCs in autistic-like behaviours in mice. A novel mouse autism model Tuberous sclerosis is a rare tumour-causing genetic disorder that results from mutation of the genes TSC1 or TSC2 . Affected individuals often also have autism spectrum disorder associated with cerebellar pathology. Because clinical studies have implicated cerebellar dysfunction in the pathogenesis of autism, Mustafa Sahin and colleagues studied the functional consequences of disrupting the cerebellar Tsc1 gene in mice. The mutant mice exhibit pathological features common in patients with autism —reduced Purkinje cell numbers and increased markers of neuronal stress — and mice lacking Tsc1 in cerebellar Purkinje cells display autism-related behaviours. Both the cerebellar pathology and behavioural features are ameliorated by treating the mice with the mTOR inhibitor rapamycin. Autism spectrum disorders (ASDs) are highly prevalent neurodevelopmental disorders 1 , but the underlying pathogenesis remains poorly understood. Recent studies have implicated the cerebellum in these disorders, with post-mortem studies in ASD patients showing cerebellar Purkinje cell (PC) loss 2 , 3 , and isolated cerebellar injury has been associated with a higher incidence of ASDs 4 . However, the extent of cerebellar contribution to the pathogenesis of ASDs remains unclear. Tuberous sclerosis complex (TSC) is a genetic disorder with high rates of comorbid ASDs 5 that result from mutation of either TSC1 or TSC2, whose protein products dimerize and negatively regulate mammalian target of rapamycin (mTOR) signalling. TSC is an intriguing model to investigate the cerebellar contribution to the underlying pathogenesis of ASDs, as recent studies in TSC patients demonstrate cerebellar pathology 6 and correlate cerebellar pathology with increased ASD symptomatology 7 , 8 . Functional imaging also shows that TSC patients with ASDs display hypermetabolism in deep cerebellar structures, compared to TSC patients without ASDs 9 . However, the roles of Tsc1 and the sequelae of Tsc1 dysfunction in the cerebellum have not been investigated so far. Here we show that both heterozygous and homozygous loss of Tsc1 in mouse cerebellar PCs results in autistic-like behaviours, including abnormal social interaction, repetitive behaviour and vocalizations, in addition to decreased PC excitability. Treatment of mutant mice with the mTOR inhibitor, rapamycin, prevented the pathological and behavioural deficits. These findings demonstrate new roles for Tsc1 in PC function and define a molecular basis for a cerebellar contribution to cognitive disorders such as autism.

Mate recognition systems evolve rapidly to reinforce the reproductive boundaries between species, but the underlying neural mechanisms remain enigmatic. Here we leveraged the rapid coevolution of female pheromone production and male pheromone perception in Drosophila 1 , 2 to gain insight into how the architecture of mate recognition circuits facilitates their diversification. While in some Drosophila species females produce unique pheromones that act to arouse their conspecific males, the pheromones of most species are sexually monomorphic such that females possess no distinguishing chemosensory signatures that males can use for mate recognition 3 . We show that Drosophila yakuba males evolved the ability to use a sexually monomorphic pheromone, 7-tricosene, as an excitatory cue to promote courtship. By comparing key nodes in the pheromone circuits across multiple Drosophila species, we reveal that this sensory innovation arises from coordinated peripheral and central circuit adaptations: a distinct subpopulation of sensory neurons has acquired sensitivity to 7-tricosene and, in turn, selectively signals to a distinct subset of P1 neurons in the central brain to trigger courtship. Such a modular circuit organization, in which different sensory inputs can independently couple to parallel courtship control nodes, may facilitate the evolution of mate recognition systems by allowing novel sensory modalities to become linked to male arousal. Together, our findings suggest how peripheral and central circuit adaptations can be flexibly coordinated to underlie the rapid evolution of mate recognition strategies across species. Peripheral and central circuit adaptations can be flexibly coordinated in Drosophila , and such a modular circuit organization may facilitate the evolution of mate recognition systems by allowing novel sensory modalities to become linked to male arousal.

Altered sensitivity to environmental stimuli is a core feature of autism spectrum disorder (ASD) that may drive vulnerability to stress-related and anxiety disorders. To investigate this relationship, we evaluated autonomic and behavioral responses to tactile, nociceptive, and social stressors in juvenile Wistar rats prenatally exposed to valproic acid (VPA), a well-established model of ASD. VPA-exposed and saline-treated control (CTL) rats were subjected to a behavioral paradigm measuring defecation, freezing, and ultrasonic vocalizations (USVs) in response to handling, electro-tactile stimulation, classical fear conditioning, and an emotional contagion task. Compared to CTLs, VPA rats exhibited sustained hyperdefecation during handling and a higher prevalence of defecation during electro-tactile stimulation, independent of freezing changes. During fear conditioning, VPA rats demonstrated a delayed onset but subsequent enhancement of freezing responses, alongside disrupted temporal coordination between freezing and defecation behaviors. 22-kHz USVs positively correlated with freezing across both groups. In the emotional contagion task, observing a distressed conspecific increased freezing prevalence and suppressed vocalization rates in both cohorts; however, these effects were prolonged in VPA rats, which showed persistent freezing and an earlier reduction in vocalization rate. These findings indicate that VPA-treated rats display heightened stress reactivity, habituation deficit and suggest disrupted coordination of fear responses, supporting the VPA model as a relevant tool for investigating the neurobiological basis of stress vulnerability and social dysfunction in ASD.

Ultrasonic vocalizations (USVs) are a useful tool for evaluating emotion and motivation in rodents. Rhythmic stroking in rats induces positive affective 50-kHz USVs and reward-seeking behavior. This response involves the dorsal column tract as the ascending pathway; however, supraspinal mechanisms remain unknown. We hypothesized that the ventral posterolateral nucleus of the thalamus (VPL), which receives somatosensory inputs from the spinal cord via the dorsal column-medial lemniscus pathway, might be involved in positive 50-kHz USV production and motivated tactile reward-induced behavior. To test the hypothesis, we used young adult male rats before and after inactivation of the VPL with bilateral infusion of muscimol, a potent γ-aminobutyric acid (GABA)-A type receptor agonist. We measured 50-kHz USVs, approach latency, and spontaneous behaviors pre- and post-muscimol injection, focusing on two emotional (during rhythmic stroking and receiving reward) and motivational (after rhythmic stroking and reward-seeking) conditions. Increased GABAergic inhibition in the VPL completely impaired approach behavior without causing obvious sensory and motor dysfunctions, but only slightly affected 50-kHz USVs. The present data indicate that the GABAergic system in the VPL is substantially involved in execution of reward-seeking behavior but not in the 50-kHz USVs induced by tactile rewards.

RationaleSelective serotonin reuptake inhibitors (SSRIs) are the first choice of treatment for anxiety-like disorders. However, which aspects of anxiety are affected by SSRIs is not yet fully understood.ObjectiveWe aimed to systematically review the effect of six clinically effective SSRIs on four aspects of unconditioned anxiety: approach-avoidance behaviour (elevated plus maze), repetitive behaviour (marble burying), distress behaviour (ultrasonic vocalization), and activation of the autonomous nervous system (stress-induced hyperthermia).MethodsWe identified publications by searching Medline and Embase databases and assessed the risk of bias. A random effects meta-analysis was performed and moderator effects were analysed with Bayesian penalized meta-regression.ResultsOur search yielded 105 elevated plus maze, 63 marble burying, 11 ultrasonic vocalization, and 7 stress-induced hyperthermia articles. Meta-analysis suggested that SSRIs reduce anxiety-like behaviour in the elevated plus maze, marble burying and ultrasonic vocalization test and that effects are moderated by pre-existing stress conditions (elevated plus maze) and dose dependency (marble burying) but not by duration of treatment or type of SSRI. The reporting quality was low, publication bias was likely, and heterogeneity was high.ConclusionSSRIs seem to reduce a broad range of unconditioned anxiety-associated behaviours. These results should be interpreted with caution due to a high risk of bias, likely occurrence of publication bias, substantial heterogeneity and limited moderator data availability. Our review demonstrates the importance of including bias assessments when interpreting meta-analysis results. We further recommend improving the reporting quality, the conduct of animal research, and the publication of all results regardless of significance.

Abstract (E)-β-farnesene (EβF), a sesquiterpene widely recognized for its role in aphid alarm signaling, triggers escape behaviors and influences aphid population dynamics. Despite its potential as a biological control agent, the effects of EβF on the English grain aphid Sitobion avenae (Fabricius) (Hemiptera: Aphididae), a major wheat pest, remain insufficiently explored. In this study, we topically applied EβF at a concentration gradient (10 to 1,000 ng/μl) to various developmental stages of S. avenae and assessed their behavioral responses, development, reproduction, and winged offspring ratio under different population densities. Our results revealed that EβF at 10 ng/μl induced significant behavioral changes, including leg shaking, fast walking, and falling from host plants, across all developmental stages. Exposure to 200 ng/μl EβF significantly reduced fecundity by 19.6% and shortened lifespan by 17.8%, while increasing the proportion of winged offspring by 19.8%, particularly under low parental density combined with high offspring density. Field trials further revealed that a higher concentration of EβF (1,000 ng/μl) led to a 25% increase in the proportion of winged offspring compared to controls, with environmental factors such as population density influencing the response. These findings confirm the insecticidal and density-dependent effects of EβF on S. avenae, with transgenerational impacts on wing dimorphism, highlighting its potential for the sustainable aphid control in wheat ecosystems.

Steroid hormones regulate multiple but distinct aspects of social behaviors. Testosterone (T) has multiple effects on learned courtship song in that it regulates both the motivation to sing in a particular social context as well as the quality of song produced. The neural substrate(s) where T acts to regulate the motivation to sing as opposed to other aspects of song has not been definitively characterized. We show here that T implants in the medial preoptic nucleus (POM) of castrated male canaries (Serinus canaria) increase song rate but do not enhance acoustic features such as song stereotypy compared with birds receiving peripheral T that can act globally throughout the brain. Strikingly, T action in the POM increased song control nuclei volume, consistent with the hypothesis that singing activity induces neuroplasticity in the song control system independent of T acting in these nuclei. When presented with a female canary, POM-T birds copulated at a rate comparable to birds receiving systemic T but produced fewer calls and songs in her presence. Thus, POM is a key site where T acts to activate copulation and increase song rate, an appetitive sexual behavior in songbirds, but T action in other areas of the brain or periphery (e.g., HVC, dopaminergic cell groups, or the syrinx) is required to enhance the quality of song (i.e., stereotypy) as well as regulate context-specific vocalizations. These results have broad implications for research concerning how steroids act at multiple brain loci to regulate distinct sociosexual behaviors and the associated neuroplasticity.

Exposure to endocrine disrupting compounds (EDCs), such as bisphenol A (BPA), may cause adverse health effects in wildlife and humans, but controversy remains as to what traits are most sensitive to EDCs and might serve as barometers of exposure. Expression of sexually selected traits that have evolved through intrasexual competition for mates and intersexual choice of mating partner are more dependent on developmental and physical condition of an animal than naturally selected traits and thus might be particularly vulnerable to disruption by developmental exposure to EDCs. We have used the deer mouse (Peromyscus maniculatus) as a model to test this hypothesis. Adult male-male competition for mates in this species is supported by enhanced spatial navigational and exploratory abilities, which enable males to search for prospective, widely dispersed females. Male deer mice exposed to BPA or ethinyl estradiol (EE) through maternal diet showed no changes in external phenotype, sensory development, or adult circulating concentrations of testosterone and corticosterone, but spatial learning abilities and exploratory behaviors were severely compromised compared with control males. Because these traits are not sexually selected in females, BPA exposure predictably had no effect, although EE-exposed females demonstrated enhanced spatial navigational abilities. Both BPA-exposed and control females preferred control males to BPA-exposed males. Our demonstration that developmental exposure to BPA compromises cognitive abilities and behaviors essential for males to reproduce successfully has broad implications for other species, including our own. Thus, sexually selected traits might provide useful biomarkers to assess risk of environmental contamination in animal and human populations.