Explore the vast range of titles available.

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.

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.

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.

Treatment of pain with morphine leads to paradoxical hyperalgesia. The authors provide evidence that morphine-induced hyperalgesia is a result of downregulation of the chloride transporter KCC2 in spinal lamina I neurons. Microglial expression of P2X4 receptors and release of BDNF may underlie this change in neuronal chloride homeostasis and morphine-induced hyperalgesia. A major unresolved issue in treating pain is the paradoxical hyperalgesia produced by the gold-standard analgesic morphine and other opiates. We found that hyperalgesia-inducing treatment with morphine resulted in downregulation of the K + -Cl − co-transporter KCC2, impairing Cl − homeostasis in rat spinal lamina l neurons. Restoring the anion equilibrium potential reversed the morphine-induced hyperalgesia without affecting tolerance. The hyperalgesia was also reversed by ablating spinal microglia. Morphine hyperalgesia, but not tolerance, required μ opioid receptor–dependent expression of P2X4 receptors (P2X4Rs) in microglia and μ-independent gating of the release of brain-derived neurotrophic factor (BDNF) by P2X4Rs. Blocking BDNF-TrkB signaling preserved Cl − homeostasis and reversed the hyperalgesia. Gene-targeted mice in which Bdnf was deleted from microglia did not develop hyperalgesia to morphine. However, neither morphine antinociception nor tolerance was affected in these mice. Our findings dissociate morphine-induced hyperalgesia from tolerance and suggest the microglia-to-neuron P2X4-BDNF-KCC2 pathway as a therapeutic target for preventing hyperalgesia without affecting morphine analgesia.

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.

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.

Enhanced NMDA receptor function and social interaction deficits are observed in mice lacking the excitatory postsynaptic scaffolding protein IRSp53. Reducing NMDAR activity by pharmacological methods rescues the impaired social interaction observed in these mice. This suggests that enhanced NMDA receptor function may be associated with social deficits. Social deficits are observed in diverse psychiatric disorders, including autism spectrum disorders and schizophrenia. We found that mice lacking the excitatory synaptic signaling scaffold IRSp53 (also known as BAIAP2) showed impaired social interaction and communication. Treatment of IRSp53 −/− mice, which display enhanced NMDA receptor (NMDAR) function in the hippocampus, with memantine, an NMDAR antagonist, or MPEP, a metabotropic glutamate receptor 5 antagonist that indirectly inhibits NMDAR function, normalized social interaction. This social rescue was accompanied by normalization of NMDAR function and plasticity in the hippocampus and neuronal firing in the medial prefrontal cortex. These results, together with the reduced NMDAR function implicated in social impairments, suggest that deviation of NMDAR function in either direction leads to social deficits and that correcting the deviation has beneficial effects.

Rationale Opioid use during pregnancy can lead to negative infant health outcomes, including neonatal opioid withdrawal syndrome (NOWS). NOWS comprises gastrointestinal, autonomic nervous system, and neurological dysfunction that manifest during spontaneous withdrawal. Variability in NOWS severity necessitates a more individualized treatment approach. Ultrasonic vocalizations (USVs) in neonatal mice are emitted in isolation as a stress response and are increased during opioid withdrawal, thus modeling a negative affective state that can be utilized to test new treatments. Objectives We sought to identify the behavioral and USV profile, brainstem transcriptomic adaptations, and role of kappa opioid receptors in USVs during neonatal opioid withdrawal. Methods We employed a third trimester-approximate opioid exposure model, where neonatal inbred FVB/NJ pups were injected twice-daily with morphine (10mg/kg, s.c.) or saline (0.9%, 20 ul/g, s.c.) from postnatal day(P) 1 to P14. This protocol induces reduced weight gain, hypothermia, thermal hyperalgesia, and increased USVs during spontaneous morphine withdrawal. Results On P14, there were increased USV emissions and altered USV syllables during withdrawal, including an increase in Complex 3 syllables in FVB/NJ females (but not males). Brainstem bulk mRNA sequencing revealed an upregulation of the kappa opioid receptor ( Oprk1) , which contributes to withdrawal-induced dysphoria. The kappa opioid receptor (KOR) antagonist, nor-BNI (30 mg/kg, s.c.), significantly reduced USVs in FVB/NJ females, but not males during spontaneous morphine withdrawal. Furthermore, the KOR agonist, U50,488h (0.625 mg/kg, s.c.), was sufficient to increase USVs on P10 (both sexes) and P14 (females only) in FVB/NJ mice. Conclusions We identified an elevated USV syllable, Complex 3, and a female-specific recruitment of the dynorphin/KOR system in increased USVs associated with neonatal opioid withdrawal severity.

The Wistar-Kyoto rat strain (WKY) is a model for treatment-resistant depression, exhibiting behaviors indicative of anhedonia. Although anhedonia is measured using the sucrose preference test (SPT), 50-kHz ultrasonic vocalizations (USVs) hold promise as a complementary assessment tool. This study aimed to detect whether 50-kHz USVs differ in the WKY rats compared to control Wistar (W) rats. First, WKY and W rats were compared for their basal 50-kHz calls. Then, rats were repeatedly treated with four administrations of either amphetamine (AMPH) or morphine (MORPH), and 50-kHz calls were recorded. In addition, the drug-evoked locomotor activity, sucrose consumption in the SPT, and the time spent in the drug- vs. saline-paired compartment in the conditioned place preference (CPP) test were collected. WKY rats emitted fewer basal calls and fewer calls following the first and the fourth AMPH administration. Contrary to controls, AMPH did not affect the number of calls in WKY rats following the first administration. WKY also displayed reduced AMPH-induced locomotor activity and sucrose consumption in the SPT. MORPH did not affect USVs or locomotion in either strain. The results highlight the benefits of 50-kHz calls as a complementary behavioral marker for assessing anhedonia in preclinical models of depression.

Chronic pain affects a significant percentage of the United States population, and available pain medications like opioids have drawbacks that make long-term use untenable. Cannabinoids show promise in the management of pain, but long-term treatment of pain with cannabinoids has been challenging to implement in preclinical models. We developed a voluntary, gelatin oral self-administration paradigm that allowed male and female mice to consume ∆9-tetrahydrocannabinol, cannabidiol, or morphine ad libitum. Mice stably consumed these gelatins over 3 weeks, with detectable serum levels. Using a real-time gelatin measurement system, we observed that mice consumed gelatin throughout the light and dark cycles, with animals consuming less THC-gelatin than the other gelatin groups. Consumption of all three gelatins reduced measures of allodynia in a chronic, neuropathic sciatic nerve injury model, but tolerance to morphine developed after 1 week while THC or CBD reduced allodynia over three weeks. Hyperalgesia gradually developed after sciatic nerve injury, and by the last day of testing, THC significantly reduced hyperalgesia, with a trend effect of CBD, and no effect of morphine. Mouse vocalizations were recorded throughout the experiment, and mice showed a large increase in ultrasonic, broadband clicks after sciatic nerve injury, which was reversed by THC, CBD, and morphine. This study demonstrates that mice voluntarily consume both cannabinoids and opioids via gelatin, and that cannabinoids provide long-term relief of chronic pain states. In addition, ultrasonic clicks may objectively represent mouse pain status and could be integrated into future pain models.