Spontaneous Locomotor Activity Research Articles

Acute nicotine exposure attenuates neurological deficits, ischemic injury and brain inflammatory responses and restores hippocampal long-term potentiation in ischemic stroke followed by lipopolysaccharide-induced sepsis-like state

Ischemic stroke is followed by an increased susceptibility to bacterial infections, which exacerbate histological stroke outcome, neurological deficits and memory impairment due to increased neuroinflammation and neurotransmitter dysfunction. Pharmacological activation of nicotinic acetylcholine receptors was suggested to mitigate brain inflammatory responses in ischemic stroke. The functional responses associated with nicotinic acetylcholine receptor activation were unknown. In this study, male NMRI mice subjected to transient intraluminal middle cerebral artery occlusion (MCAO) were intraperitoneally exposed to vehicle treatment or Escherichia coli lipopolysaccharide (LPS; 4 mg/kg)-induced sepsis-like state 24 h post-MCAO, followed by intraperitoneal administration of vehicle or nicotine (0.5 mg/kg) 30 min later. Over 96 h, rectal temperature, neurological deficits, spontaneous locomotor activity, working memory, ischemic injury, synaptic plasticity, and brain inflammatory responses were evaluated by temperature measurement, behavioral analysis, infarct volumetry, electrophysiological recordings, and polymerase-chain reaction analysis. LPS-induced sepsis induced hypothermia, increased general and focal neurological deficits, reduced spontaneous exploration behavior, reduced working memory, and increased infarct volume post-MCAO. Additional treatment with nicotine attenuated LPS-induced hypothermia, reduced neurological deficits, restored exploration behavior, restored working memory, and reduced infarct volume. Local field potential recordings revealed that LPS-induced sepsis decreased long-term potentiation (LTP) in the dentate gyrus post-MCAO, whereas concomitant nicotine exposure restored LTP in the contralateral dentate gyrus. LPS-induced sepsis increased microglial/ macrophage Iba-1 mRNA and astrocytic GFAP mRNA levels post-MCAO, whereas add-on nicotine treatment reduced astrocytic GFAP mRNA. Taken together, these findings indicate that acute nicotine exposure enhances functional stroke recovery. Future studies will have to evaluate the effects of (1) chronic nicotine exposure, a clinically relevant vascular risk factor, and (2) the cessation of nicotine exposure, which is widely recommended post-stroke, but might have detrimental effects in the early stroke recovery phase.

Alpha-asarone alleviates cutaneous hyperalgesia by inhibiting hyperexcitability and neurogenic inflammation via TLR4/NF-κB/NLRP3 signaling pathway in a female chronic migraine rat model

Migraine is a highly prevalent neurological disorder. Alpha-asarone (ASA), a major active component found in Acorus tatarinowii, plays a crucial role in analgesia and anti-inflammation for neuropathic pain. This study aimed to assess the efficacy of ASA against migraine and elucidate its potential mechanisms using a well-established inflammatory soup (IS) migraine female rat model. Mechanical pain thresholds were assessed daily before IS infusion, followed by post-infusion administration of ASA. Subsequently, spontaneous locomotor activities, exploratory behavior, short-term spatial memory, and photophobia were blindly evaluated after the final drug administration. The rats were then sacrificed for investigation into the underlying mechanisms of action. Network pharmacology was also employed to predict potential targets and pathways of ASA against migraine. The anti-inflammatory activity of ASA and pathway-related proteins were examined in BV2 cells stimulated with lipopolysaccharides (LPS). The results demonstrated that ASA ameliorated cutaneous hyperalgesia and photophobia while improving spatial memory and increasing exploratory behavior in IS rats. ASA attenuated central sensitization-related indicators and excessive glutamate levels while enhancing GABA synthesis. ASA rescued neuronal loss in the cortex and hippocampus of IS rats. Notably, the ability of ASA to improve spatial memory performance in the Y maze test was not observed with sumatriptan, a first-line treatment drug, suggesting the potential involvement of the TLR4 pathway. Moreover, ASA suppressed microglial activation, reduced pro-inflammatory factors, and downregulated TLR4, MyD88, p–NF–κB/NF-κB, NLRP3, caspase-1, IL-1β, and IL-18. Overall, ASA demonstrated its potential to alleviate hyperalgesia and improve behavioral performance in migraine rats by inhibiting hyperexcitability and microglia-related inflammation.

Behavioural changes in young ovariectomized mice via GPR30-dependent serotonergic nervous system.

Fluctuations in estradiol levels at each stage of life in women are considered one of the causes of mental diseases through their effects on the central nervous system. During menopause, a decrease in estradiol levels has been reported to affect the serotonin nervous system and induce depression-like and anxiety symptoms. However, the regulation of brain and behaviour during childhood and adolescence is poorly understood. Moreover, the role of oestrogen receptors α and β in the regulation of the serotonergic nervous system has been reported, but little is known about the involvement of G protein-coupled receptor 30. Therefore, in this study, we used an ovariectomized childhood mouse model to analyse behaviour and investigate the effects on the serotonin nervous system. We showed that ovariectomy surgery at 4 weeks of age, which is the weaning period, induced a decrease in spontaneous locomotor activity during the active period and a preference for novel mice over familiar mice in the three-chamber social test at 10weeks of age. In addition, the administration of G-1, a protein-coupled receptor 30 agonist, to ovariectomized mice suppressed spontaneous locomotor activity and the preference for novel mice. Furthermore, we demonstrated that childhood ovariectomy induces increased tryptophan hydroxylase gene expression in the raphe nucleus and increased serotonin release in the amygdaloid nucleus, and administration of G-1 ameliorated these effects. Our study suggests that G protein-coupled receptor 30-mediated regulation of serotonin synthesis is involved in changes in activity and social-cognitive behaviour due to decreased estradiol levels during childhood.

Transitional photoperiod induces a mania-like behavior in male mice.

This study aimed to investigate the behavioral responses and circadian rhythms of mice to both rapid and gradual increases in photoperiod, mimicking the transition from winter to summer, which is associated with a heightened prevalence of hospitalizations for mania and suicidal behavior. Behavioral tests were performed in C57BL/6 male mice exposed to a transitional photoperiod, from short to long durations. To determine if circadian rhythms are affected, we measured spontaneous locomotor activity and body temperature. Mice exhibited heightened exploratory and risk-taking behaviors compared with equatorial and static long (16:8 h of light-dark cycle for several days) groups. These behaviors were prevented by lithium. Spontaneous locomotor activity and body temperature rhythms persisted and were effectively synchronized; however, the relative amplitude of activity and interdaily stability were diminished. Additionally, the animals displayed increased activity during the light phase. Photoperiodic transition modulates behavior and circadian rhythms, mirroring certain features observed in bipolar disorder patients. This study introduces an animal model for investigating mania-like behavior induced by photoperiodic changes, offering potential insights for suicide prevention strategies and the management of mood disorders.

Antidepressant effects of selective adenosine receptor antagonists targeting the A1 and A2A receptors administered jointly with NMDA receptor ligands: behavioral, biochemical and molecular investigations in mice

BackgroundThe objective of the study was to ascertain the antidepressant potential of the co-administration of NMDA receptor ligands and selective adenosine A1 and A2A receptor antagonists.MethodsThe forced swim test (FST) and spontaneous locomotor activity test were carried out in adult male naïve mice. Before the behavioral testing, animals received DPCPX (a selective adenosine A1 receptor antagonist, 1 mg/kg) or istradefylline (a selective adenosine A2A receptor antagonist, 0.5 mg/kg) in combination with L–701,324 (a potent NMDA receptor antagonist, 1 mg/kg), D–cycloserine (a partial agonist at the glycine recognition site of NMDA receptor, 2.5 mg/kg), CGP 37849 (a competitive NMDA receptor antagonist, 0.3 mg/kg) or MK–801 (a non-competitive NMDA receptor antagonist, 0.05 mg/kg). Additionally, serum BDNF level and the mRNA level of the Adora1, Comt, and Slc6a15 genes in the murine prefrontal cortex were determined.ResultsThe obtained results showed that DPCPX and istradefylline administered jointly with NMDA receptor ligands (except for DPCPX + D–cycloserine combination) produced an antidepressant effect in the FST in mice without enhancement in spontaneous motility of animals. An elevation in BDNF concentration was noted in the D–cycloserine-treated group. Adora1 expression increased with L–701,324, DPCPX + D–cycloserine, and DPCPX + CGP 37849, while D–cycloserine, CGP 37849, and MK–801 led to a decrease. Comt mRNA levels dropped with DPCPX + L–701,324, istradefylline + L–701,324/CGP 37849 but increased with D–cycloserine, MK–801, CGP 37849 and DPCPX + MK–801/ CGP 37849. Slc6a15 levels were reduced by D–cycloserine, DPCPX + L–701,324 but rose with DPCPX + CGP 37849/MK–801 and istradefylline + D–cycloserine/MK–801/CGP 37849.ConclusionOur study suggests that selective antagonists of adenosine receptors may enhance the antidepressant efficacy of NMDA receptor ligands highlighting a potential synergistic interaction between the adenosinergic and glutamatergic systems. Wherein, A2A receptor antagonists are seen as more promising candidates in this context. Given the intricate nature of changes in BDNF levels and the expression of Adora1, Comt, and Slc6a15 seen after drug combinations exerting antidepressant properties, further research and integrative approaches are crucial understand better the mechanisms underlying their antidepressant action.

A novel methodology utilizing microchip implants to monitor individual activity and body temperature for assessing knee pain in group-housed rats

The pain assessment in animals is challenging as they cannot verbally express the site and severity of pain. In this study, we tried a small implantable actimeter, “Nanotag”, to monitor spontaneous locomotor activity and body temperature in animals suffering from a chemical-induced rat knee arthritis as compared to naïve and steroid-treated rats. Nanotag could detect the decrease in locomotor activity quickly after the arthritis induction and anti-inflammation analgesic treatment by intra-articular injection of steroid significantly improved locomotor activity. These changes were in the same line with those of a conventional knee pain evaluation method (incapacitance test). Nanotag can be utilized as the non-interventional, continuous, and completely objective monitoring the amount of pain in rat knee arthritis model. This traditional yet innovative method may be universally applicable to various pain models and species, making it a worthwhile device for research across diverse fields.

Exploring the safety of lycorine in the central nervous system and its impact on pain-like behaviors in mice

Alkaloid analgesics have been associated with adverse effects on the central nervous system (CNS). Therefore, it is crucial to characterize the effects of alkaloid analgesics. Plants rich in lycorine, an alkaloid, have shown promise as analgesics. However, the exploration of their CNS side effects, and analgesic effectiveness remains incomplete. The aim of the present study was to investigate the CNS safety profiles of lycorine and its potential analgesic efficacy. Lycorine (3, 10, and 30 mg/kg, intraperitoneal) did not affect motor coordination, and doses of 3 and 10 mg/kg of lycorine did not lead to any impairment in spontaneous locomotor activity. However, the highest dose (30 mg/kg) demonstrated a significant impairment in rearing behavior and an increase in immobility. The safety doses were subsequently used to assess the analgesic efficacy of lycorine in a mouse model of inflammatory pain. Lycorine (1, 3, and 10 mg/kg, intraperitoneal) demonstrated a dose-dependent reduction in pain-like behaviors in formalin-induced mice. In the in vitro study, lycorine regulated immune cells, suggesting its involvement as a cellular mechanism underlying the suppression of pain-like behaviors observed in the formalin model. Overall, our findings delineate the CNS safety range of lycorine in mice and suggest its potential use as an analgesic.

Antinociceptive and anti-inflammatory activities of Ayapana triplinervis essential oil rich in thymohydroquinone dimethyl ether from Brazil.

Ayapana triplinervis (M.Vahl) R.M.King & H.Rob. (Asteraceae), popularly known as japana, is a tropical, aromatic subshrub widely used as tea to combat some diseases. The essential oil was obtained from the leaves by hydrodistillation (3h), and the chemical composition was analyzed by gas chromatography coupled to mass spectrometry. For in vivo assays, Mus musculus/Swiss mice were used to evaluate oral acute toxicological (at dose of 2000mg/kg); peripheral and central analgesic for abdominal contortion (doses of 6.25, 12.5, 25, 50 and 100mg/kg), hot plate test (12.5, 25, 50, and 100mg/kg) and formalin (25, 50 and 100mg/kg); open field test (100mg/kg); and anti-inflammatory by ear swelling induced by xylene (6.25,12.5, 25, 50, and 100mg/kg). The yield of A. triplinervis essential oil (AtEO) was 4.6%, and the oxygenated monoterpene 2,5-dimethoxy-p-cymene was the major compound in this study (63.6%). AtEO at a dose of 2,000mg/kg orally did not change the behavior patterns or mortality of the animals; liver and kidney biochemical levels were similar to the control group, indicating no liver and kidney toxicity. Moreover, AtEO, at doses of 6.25, 12.5, 25, 50, and 100mg/kg, reduced abdominal contortions by 21%, 54%, 91%, 58%, and 55%, respectively. In the hot plate test, AtEO showed a significant increase in latency time in the 60-min interval at doses of 25mg/kg (11.3 ± 3.3s) and 100mg/kg (11.9 ± 0.9s). In the first phase of the formalin test, AtEO decreased paw licking time at doses of 25, 50, and 100mg/kg, with inhibition of 22%, 38%, and 83%; in the second phase, the same doses, decreased licking time with inhibition of 24%, 34%, and 76%. AtEO did not present a significant change in the spontaneous locomotor activity of the animals. Doses of 6.25, 12.5, 25, 50, and 100mg/kg significantly reduced ear edema induced by topical application of xylene with percentages of 40%, 39%, 54%, 45%, and 45%, respectively. So, AtEO demonstrated low acute oral toxicity and exhibited significant antinociceptive and anti-inflammatory actions, consistent with the use of A. triplinervis in traditional medicine.

Locomotion changes in methamphetamine and amphetamine withdrawal: a systematic review.

Despite extensive preclinical research over the years, a significant gap remains in our understanding of the specific effects of methamphetamine (METH) and amphetamine (AMPH) withdrawal. Understanding these differences could be pivotal to unveiling the unique pathophysiology underlying each stimulant. This may facilitate the development of targeted and effective treatment strategies tailored to the specific characteristics of each substance. Following PRISMA guidelines, this systematic review was conducted to examine alterations in spontaneous locomotor activity, specifically horizontal activity, in animals experiencing withdrawal from extended and repeated administration of AMPH or METH. Original articles were retrieved from four electronic databases, supplemented by a review of the references cited in the published papers. A total of thirty-one full-length articles (n = 31) were incorporated in the analysis. The results indicated that six studies documented a significant increase in horizontal activity among animals, seven studies reported decreased locomotion, and eighteen studies (8 AMPH; 10 METH) reported no significant alterations in the animals' locomotor activity. Studies reporting heightened locomotion mainly employed mice undergoing withdrawal from METH, studies reporting diminished locomotion predominantly involved rats undergoing withdrawal from AMPH, and studies reporting no significant changes in horizontal activity employed both rats and mice (12 rats; 6 mice). Drug characteristics, routes of administration, animal models, dosage regimens, duration, and assessment timing seem to influence the observed outcomes. Despite more than 50% of papers enlisted in this review indicate no significant changes in the locomotion during the stimulant withdrawal, the unique reactions of animals to withdrawal from METH and AMPH reported by some underscore the need for a more nuanced understanding of stimulant withdrawal.

Histidine-containing dipeptide deficiency links to hyperactivity and depression-like behaviors in old female mice

Carnosine, anserine, and homocarnosine are histidine-containing dipeptides (HCDs) abundant in the skeletal muscle and nervous system in mammals. To date, studies have extensively demonstrated effects of carnosine and anserine, the predominant muscular HCDs, on muscular functions and exercise performance. However, homocarnosine, the predominant brain HCD, is underexplored. Moreover, roles of homocarnosine and its related HCDs in the brain and behaviors remain poorly understood. Here, we investigated potential roles of endogenous brain homocarnosine and its related HCDs in behaviors by using carnosine synthase-1-deficient (Carns1−/−) mice. We found that old Carns1−/− mice (female 12 months old) exhibited hyperactivity- and depression-like behaviors with higher plasma corticosterone levels on light-dark transition and forced swimming tests, but had no defects in spontaneous locomotor activity, repetitive behavior, olfactory functions, and learning and memory abilities, as compared with their age-matched wild-type (WT) mice. We confirmed that homocarnosine and its related HCDs were deficient across brain areas of Carns1−/− mice. Homocarnosine deficiency exhibited small effects on its constituent γ-aminobutyric acid (GABA) in the brain, in which GABA levels in hypothalamus and olfactory bulb were higher in Carns1−/− mice than in WT mice. In WT mice, homocarnosine and GABA were highly present in hypothalamus, thalamus, and olfactory bulb, and their brain levels did not decrease in old mice when compared with younger mice (3 months old). Our present findings provide new insights into roles of homocarnosine and its related HCDs in behaviors and neurological disorders.

Phenytoin causes behavioral abnormalities and suppresses kisspeptin expression, reducing reproductive performance in Japanese medaka

Phenytoin, an antiepileptic drug, induces neurotoxicity and abnormal embryonic development and reduces spontaneous locomotor activity in fish. However, its effects on other endpoints remain unclear. Therefore, we investigated the effects of phenytoin on the swimming behavior and reproductive ability of Japanese medaka. Abnormalities in swimming behavior, such as imbalance, rotation, rollover, and vertical swimming, were observed. However, when phenytoin exposure was discontinued, the behavioral abnormality rates decreased. Phenytoin exposure also significantly reduced reproductive ability. By investigating reproduction-related gene expression of gnrh1, gnrh2, fshb, and lhb remained unchanged in males and females. In contrast, kiss1 expression was significantly suppressed due to phenytoin exposure in males and females. kiss2 expression was also significantly suppressed in females but not in males. We filmed videos to examine phenytoin exposure effects on sexual behavior. Females showed no interest in the male's courtship. As the kisspeptin 1 system controls sexual behavior in Japanese medaka, phenytoin exposure may have decreased kiss1 expression, which decreased female reproductive motivation; hence, they did not spawn eggs. This is the first study to show that phenytoin exposure induces behavioral abnormalities, and suppresses kiss1 expression and reproductive performance in Japanese medaka.

Repeated Sulforaphane Treatment Reverses Depressive-like Behavior and Exerts Antioxidant Effects in the Olfactory Bulbectomy Model in Mice.

Growing evidence suggests that activators of nuclear factor erythroid-derived 2-like 2 (Nrf2), such as sulforaphane, may represent promising novel pharmacological targets for conditions related to oxidative stress, including depressive disorder. Therefore, we conducted a study to explore the behavioral and biochemical effects of repeated (14 days) sulforaphane (SFN) treatment in the olfactory bulbectomy (OB) animal model of depression. An open field test (OFT), splash test (ST), and spontaneous locomotor activity test (LA) were used to assess changes in depressive-like behavior and the potential antidepressant-like activity of SFN. The OB model induced hyperactivity in mice during the OFT and LA as well as a temporary loss of self-care and motivation in the ST. The repeated administration of SFN (10 mg/kg) effectively reversed these behavioral changes in OB mice across all tests. Additionally, a biochemical analysis revealed that SFN (10 mg/kg) increased the total antioxidant capacity in the frontal cortex and serum of the OB model. Furthermore, SFN (10 mg/kg) significantly enhanced superoxide dismutase activity in the serum of OB mice. Overall, the present study is the first to demonstrate the antidepressant-like effects of repeated SFN (10 mg/kg) treatment in the OB model and indicates that these benefits may be linked to improved oxidative status.

Mice with deficiency in Pcdh15, a gene associated with bipolar disorders, exhibit significantly elevated diurnal amplitudes of locomotion and body temperature

Genetic factors significantly affect the pathogenesis of psychiatric disorders. However, the specific pathogenic mechanisms underlying these effects are not fully understood. Recent extensive genomic studies have implicated the protocadherin-related 15 (PCDH15) gene in the onset of psychiatric disorders, such as bipolar disorder (BD). To further investigate the pathogenesis of these psychiatric disorders, we developed a mouse model lacking Pcdh15. Notably, although PCDH15 is primarily identified as the causative gene of Usher syndrome, which presents with visual and auditory impairments, our mice with Pcdh15 homozygous deletion (Pcdh15-null) did not exhibit observable structural abnormalities in either the retina or the inner ear. The Pcdh15-null mice showed very high levels of spontaneous motor activity which was too disturbed to perform standard behavioral testing. However, the Pcdh15 heterozygous deletion mice (Pcdh15-het) exhibited enhanced spontaneous locomotor activity, reduced prepulse inhibition, and diminished cliff avoidance behavior. These observations agreed with the symptoms observed in patients with various psychiatric disorders and several mouse models of psychiatric diseases. Specifically, the hyperactivity may mirror the manic episodes in BD. To obtain a more physiological, long-term quantification of the hyperactive phenotype, we implanted nano tag® sensor chips in the animals, to enable the continuous monitoring of both activity and body temperature. During the light-off period, Pcdh15-null exhibited elevated activity and body temperature compared with wild-type (WT) mice. However, we observed a decreased body temperature during the light-on period. Comprehensive brain activity was visualized using c-Fos mapping, which was assessed during the activity and temperature peak and trough. There was a stark contrast between the distribution of c-Fos expression in Pcdh15-null and WT brains during both the light-on and light-off periods. These results provide valuable insights into the neural basis of the behavioral and thermal characteristics of Pcdh15-deletion mice. Therefore, Pcdh15-deletion mice can be a novel model for BD with mania and other psychiatric disorders, with a strong genetic component that satisfies both construct and surface validity.

Ninjin'yoeito reduces fatigue-like conditions by alleviating inflammation of the brain and skeletal muscles in aging mice.

Fatigue can lead to several health issues and is particularly prevalent among elderly individuals with chronic inflammatory conditions. Ninjin'yoeito, a traditional Japanese herbal medicine, is used to address fatigue and malaise, anorexia, and anemia. This study aimed to examine whether relieving inflammation in the brain and skeletal muscle of senescence-accelerated mice prone 8 (SAMP8) could reduce fatigue-like conditions associated with aging. First, SAMP8 mice were divided into two groups, with and without ninjin'yoeito treatment. The ninjin'yoeito-treated group received a diet containing 3% ninjin'yoeito for a period of 4 months starting at 3 months of age. At 7 months of age, all mice underwent motor function, treadmill fatigue, and behavioral tests. They were then euthanized and the skeletal muscle weight, muscle cross-sectional area, and concentration of interleukin (IL)-1β and IL-1 receptor antagonist (IL-1RA) in both the brain and skeletal muscle were measured. The results showed that the ninjin'yoeito-treated group had higher motor function and spontaneous locomotor activity than the untreated group did and ran for significantly longer in the treadmill fatigue test. Moreover, larger muscle cross-sectional area, lower IL-1β concentrations, and higher IL-1RA concentrations were observed in both the brain and skeletal muscle tissues of the ninjin'yoeito-treated group than in the untreated group. The results suggest that ninjin'yoeito improves age-related inflammatory conditions in both the central and peripheral tissues and reduces fatigue.

Effect of dosage duration on oropharyngeal and locomotor in a toxicological rat model of Parkinson’s disease

Parkinson’s Disease (PD) is a prevalent and devastating neurodegenerative disorder that causes progressively worsening motor symptoms affecting locomotor and oropharyngeal function. There is limited research in animal models on swallowing dysfunction in PD. To examine how neurodegeneration in PD produces progressive impairment in the oropharyngeal and locomotor processes, rotenone, a type II mitochondrial inhibitor, was injected into Lewis rat models to reproduce a parkinsonian phenotype. We hypothesized that the animal models injected with the rotenone will exhibit both oropharyngeal dysfunction and locomotor deficiency with an increased deficit that correlates with prolonged treatment. We utilized 18 rats receiving either 2.75 mg/kg of rotenone or vehicle intraperitoneal injections. Animals received daily injections for 17 or 8 days. At the end of the injections in each group brains were perfused and immunostained for striatal tyrosine hydroxylase (TH). High speed (200 fps) videofluoroscopic recording was taken of these rats and average chew cycle length, chewing rate, and total chewing time data were collected from days 0, 1, 4, 7 and 16 of those recordings. The number of rears by a rat in a glass cylinder over 4 minutes was counted on the same days to assess locomotor behavior. We used mixed model ANOVA, controlling for the effect of individual variation, to test the impact of rotenone treatment on feeding and locomotor variables. We used a Kruskall-Wallis non parametric test to test the effect of rotenone treatment on striatal TH levels. Total chewing time, and average chew cycle duration increased in rotenone treated rats from day 0 to day 4, but the difference disappeared from day 7 onwards. However, rearing behavior was consistently reduced in rotenone treated rats for all 16 days. TH staining intensity in the striatum decreased consistently over the course of the injections. These results suggest that rotenone treated rats have temporary/short term deficiency in chewing function, despite sustained reduction in spontaneous locomotor activity. The restoration of function after day 4 may indicate a learned behavior to compensate for this dysfunction in chewing, or point to a different neurological impairment than that seen in locomotor behavior. Further research needs to be undertaken to understand this phenomenon. Internal Rowan funding to F. Gould supported this work. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Heukharang (Lactuca sativa L.) extracts enhanced the sleep behavior of mice: potential involvement of adenosine A1 and A2A receptors.

A significant proportion of the world's population suffers from insomnia, a disorder characterized by complications in initiating and maintaining sleep. Many medications used to treat insomnia target the γ-aminobutyric acid (GABA) neurotransmitter system. However, these substances, such as benzodiazepines, induce significant adverse consequences, including dependence and memory impairment, after prolonged use. Thus, current studies are aimed at developing therapeutic hypnotics derived from natural sources that may cause less severe side effects. Heukharang is a variety of lettuce from Korea that was discovered to contain sleep-promoting compounds. Therefore, we investigated the potential effects of sub-chronic administration of Heukharang extract (FSD-LS) on sleep behavior (pentobarbital-induced sleeping test), brain wave activity and sleep architecture (electroencephalography), and physiological behavior (open-field test and rota-rod) in mice, along with radioligand binding assays (GABAA, adenosine A1 and A2A receptors). We found that FSD-LS prolonged the total sleep duration and reduced the onset time of sleep, and enhanced delta wave power and non-rapid eye movement (NREM) sleep duration, all indicating persistent sleep-enhancing effects. FSD-LS lacked adverse effects on the spontaneous locomotor activity and motor coordination of mice, unlike diazepam. Pharmacological blocking using caffeine and bicuculline supported the possible involvement of adenosine receptors in the sleep-promoting effects of FSD-LS, with partial contribution from GABA receptor activity. Overall, our study recommends FSD-LS as a potential source for the development of sleep-aiding therapeutics.

Distinct lateral hypothalamic CaMKIIα neuronal populations regulate wakefulness and locomotor activity

For nearly a century, evidence has accumulated indicating that the lateral hypothalamus (LH) contains neurons essential to sustain wakefulness. While lesion or inactivation of LH neurons produces a profound increase in sleep, stimulation of inhibitory LH neurons promotes wakefulness. To date, the primary wake-promoting cells that have been identified in the LH are the hypocretin/orexin (Hcrt) neurons, yet these neurons have little impact on total sleep or wake duration across the 24-h period. Recently, we and others have identified other LH populations that increase wakefulness. In the present study, we conducted microendoscopic calcium imaging in the LH concomitant with EEG and locomotor activity (LMA) recordings and found that a subset of LH neurons that express Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) are preferentially active during wakefulness. Chemogenetic activation of these neurons induced sustained wakefulness and greatly increased LMA even in the absence of Hcrt signaling. Few LH CaMKIIα-expressing neurons are hypocretinergic or histaminergic while a small but significant proportion are GABAergic. Ablation of LH inhibitory neurons followed by activation of the remaining LH CaMKIIα neurons induced similar levels of wakefulness but blunted the LMA increase. Ablated animals showed no significant changes in sleep architecture but both spontaneous LMA and high theta (8 to 10 Hz) power during wakefulness were reduced. Together, these findings indicate the existence of two subpopulations of LH CaMKIIα neurons: an inhibitory population that promotes locomotion without affecting sleep architecture and an excitatory population that promotes prolonged wakefulness even in the absence of Hcrt signaling.

A neural pathway for social modulation of spontaneous locomotor activity (SoMo-SLA) in Drosophila

Social enrichment or social isolation affects a range of innate behaviors, such as sex, aggression, and sleep, but whether there is a shared mechanism is not clear. Here, we report a neural mechanism underlying social modulation of spontaneous locomotor activity (SoMo-SLA), an internal-driven behavior indicative of internal states. We find that social enrichment specifically reduces spontaneous locomotor activity in male flies. We identify neuropeptides Diuretic hormone 44 (DH44) and Tachykinin (TK) to be up- and down-regulated by social enrichment and necessary for SoMo-SLA. We further demonstrate a sexually dimorphic neural circuit, in which the male-specific P1 neurons encoding internal states form positive feedback with interneurons coexpressing doublesex (dsx) and Tk to promote locomotion, while P1 neurons also form negative feedback with interneurons coexpressing dsx and DH44 to inhibit locomotion. These two opposing neuromodulatory recurrent circuits represent a potentially common mechanism that underlies the social regulation of multiple innate behaviors.

A high salt intake in early life affects stress-coping response in males but not in female rats

Eating diets high in salt has been associated with alterations in the immune system and the potential development of neuropsychiatric disorders. This area of research shows promise, but there is currently a limited amount of research on this topic. The present study investigated whether a high salt diet (HSD) affects anhedonia and stress-coping response behaviors in young male and female Wistar rats. In this study, male and female Wistar rats were fed an HSD (8 % NaCl w/w) from weaning to post-natal day (PND) 64. From PND 60 to 64, the rats underwent a spontaneous locomotor activity test (SLA), sucrose splash test (SST), sucrose preference test (SPT), and forced swim test (FST), followed by euthanasia at PND 65. Male and female rats consuming the HSD exhibited an increase in water intake compared to the corresponding control diet (CD) groups. Male rats had lower body weight despite having similar food intakes compared to the CD group. Male rats displayed an active stress-coping behavior in the FST, characterized by increased mobility. Additionally, HSD-fed males exhibited a greater preference for sucrose solution in the SPT. However, no effect of diet and sex were detected in the SST and the SLA, and hypothalamic levels of leptin and ghrelin receptors. On the other hand, female rats were less susceptible to the experimental conditions applied in this protocol than males.

The novel peptide LCGM-10 attenuates metabotropic glutamate receptor 5 activity and demonstrates behavioral effects in animal models.

We employed a structural bioinformatics approach to develop novel peptides with predicted affinity to the binding site for negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGluR5). Primary screening in zebrafish (Danio rerio) revealed a stimulatory effect of two peptides, LCGM-10 and LCGM-15. Target validation studies using calcium ion flux imaging and a luciferase reporter assay confirmed mGluR5 as the target. LCGM-10 showed greater potency than LCGM-15; it was comparable to that of the mGluR5 NAM 2-methyl-6-(phenylethynyl) pyridine (MPEP). Rodent behavioral screening in the open field and elevated plus maze revealed increased locomotor activity in both tests after acute LCGM-10 treatment, supported by further analysis of home cage spontaneous locomotor activity (SLA). The stimulating effect of a single LCGM-10 administration on SLA was evident up to 60 min after administration and was not accompanied by hypokinetic rebound observed for caffeine. According to our results, LCGM-10 has therapeutic potential to treat hypo- and dyskinesias of various etiologies. Further investigation of LCGM-10 effects in the delay discounting model of impulsive choice in rats revealed reduced trait impulsivity after single and chronic administrations, suggesting potential implication for attention deficit hyperactivity disorder, obsessive compulsive disorder, and addictions.