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Background We recently showed that a neurosteroid analogue, (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH), induced hypnosis in rats. The aim of the present study was to evaluate the hypnotic and anaesthetic potential of 3β-OH further using electroencephalography. Methods We used behavioural assessment and cortical electroencephalogram (EEG) spectral power analysis to examine hypnotic and anaesthetic effects of 3β-OH (30 and 60 mg kg−1) administered intraperitoneally or intravenously to young adult male and female rats. Results We found dose-dependent sex differences in 3β-OH-induced hypnosis and EEG changes. Both male and female rats responded similarly to i.p. 3β-OH 30 mg kg−1. However, at the higher dose (60 mg kg−1, i.p.), female rats had two-fold longer duration of spontaneous immobility than male rats (203.4 [61.6] min vs 101.3 [32.1] min), and their EEG was suppressed in the low-frequency range (2–6 Hz), in contrast to male rats. Although a sex-dependent hypnotic effect was not confirmed after 30 mg kg−1 i.v., female rats appeared more sensitive to 3β-OH with relatively small changes within delta (1–4 Hz) and alpha (8–13 Hz) bands. Finally, 3β-OH had a rapid onset of action and potent hypnotic/anaesthetic effect after 60 mg kg−1 i.v. in rats of both sexes; however, all female rats and only half of the male rats reached burst suppression, an EEG pattern usually associated with profound inhibition of thalamocortical networks. Conclusions Based on its behavioural effects and EEG signature, 3β-OH is a potent hypnotic in rats, with female rats being more sensitive than male rats.

The genetic architecture of innate fear behavior in chickens is poorly understood. Here, we performed quantitative trait loci (QTL) analysis of innate responses to tonic immobility (TI) and open field (OF) fears in 242 newly hatched chicks of an F2 population between the native Japanese Nagoya breed and the White Leghorn breed using 881 single nucleotide polymorphism markers obtained by restriction site-associated DNA sequencing. At genome-wide 5% significance levels, four QTL for TI traits were revealed on chromosomes 1-3 and 24. Two of these loci had sex-specific effects on the traits. For OF traits, three QTL were revealed on chromosomes 2, 4 and 7. The TI and OF QTL identified showed no overlaps in genomic regions and different modes of inheritance. The three TI QTL and one OF QTL exerted antagonistic effects on the traits. The results demonstrated that context-dependent QTL underlie the variations in innate TI and OF behaviors.

β-hydroxybutyrate, a ketone body metabolite, has been shown to suppress depression-like behavior in rodents. In this study, we examined its antidepressive property in acute and chronic administration modes in mice by using forced swim test and tail suspension test. Results showed that the decrease effect of β-hydroxybutyrate (300 mg/kg) on immobility time in the tail suspension test and forced swim test in stress-naive mice began to be significant at day 11. In a dose-dependent experiment, β-hydroxybutyrate treatment (11 days) showed significant antidepressant activities at the dose of 200 and 300 mg/kg. Unlike fluoxetine, β-hydroxybutyrate treatment (300 mg/kg) showed no antidepressant activities in the acute (1 hour before the test) and three times administration mode within 24 hours (1, 5, and 24 hours before the test). But in a co-administration mode, β-hydroxybutyrate (100 mg/kg) -fluoxetine (2.5 mg/kg) co-administration exhibited an obvious antidepressant activity in the tail suspension test and forced swim test. Further analysis showed that the antidepressant effects of β-hydroxybutyrate and fluoxetine were not associated with the change in mouse locomotor activity. Furthermore, both chronic β-hydroxybutyrate treatment and β-hydroxybutyrate-fluoxetine co-treatment suppressed chronic unpredictable stress-induced increase in immobility time in the tail suspension test and forced swim test as well as chronic unpredictable stress-induced decrease in mouse body weight. Taken together, these results indicate that β-hydroxybutyrate (1) needs a relatively long time to show comparable behavioral activity to that of fluoxetine in assays that are sensitive to the behavioral effects of established antidepressant compounds and (2) can augment the antidepressant action of a sub-therapeutic dose of fluoxetine.

The dorsal immobility response (DIR) and the tonic immobility response (TIR) are cutaneo-motor reflexes typically triggered when a prey is seized. The neurochemical basis of the DIR appears to pass through the basal ganglia via dopaminergic fibers, while the neurochemical basis of the TIR appears to include a circuit comprising the amygdala, the periaqueductal gray (PAG), the dorsal raphe, and the nucleus magnus raphe (NMR) via glutamatergic, serotonergic, cholinergic, GABAergic, and opioid fibers. For the DIR, the basal ganglia also seem to be involved in regard to estradiol, while for the TIR, the HPA axis appears involved at the level of the amygdala and the oral pontine reticular nucleus.

Questions: Does advice from a physiotherapist about the importance of staying physically active during hospitalisation improve activity, mobility, strength, length of stay, and complications in older inpatients? What barriers to physical activity during hospitalisation do older inpatients perceive? Design: Randomised controlled trial with concealed allocation, intention-to-treat analysis, and blinded assessment. Participants: Sixty-eight people who were aged > 60 years and admitted to a university hospital ward. Intervention: In addition to usual hospital care, the experimental group received a booklet with content about the deleterious effects of hospitalisation and the importance of staying active during hospitalisation. The control group received usual hospital care only. Outcome measures: The amount of physical activity was measured via accelerometry during the hospital admission. Mobility was assessed using the de Morton Mobility Index (DEMMI), and muscle strength was assessed using a handgrip dynamometer. Length of stay and complications were extracted from hospital records. The barriers to staying active during hospitalisation were investigated via a questionnaire. Results: Accelerometry showed a mean between-group difference of 974 steps/day (95% CI 28 to 1919) in favour of the experimental group. The intervention also increased moderate-intensity physical activity and reduced sedentary time, although these effects might be trivially small. Experimental group participants were about one-fifth as likely to lose mobility during their hospital admission (two of 33) than control group participants (10 of 35), relative risk 0.21 (95% CI 0.05 to 0.90). Effects of the intervention were unclear regarding muscle strength, length of stay and incidence of complications between the groups. Patients reported that the main barriers to remaining active during hospitalisation were dyspnoea, lack of space, and fear of contracting infection. Conclusion: In older inpatients, the addition of advice from a physiotherapist about maintaining activity during hospitalisation increases the level of physical activity and prevents loss of mobility. Registration: ClinicalTrials.gov NCT03297567. Key words: Elderly, Hospitalisation, Immobility, Exercise, Accelerometry

Reduction of natural illumination in fall/winter months causes seasonal affective disorders (SAD) in vulnerable individuals. Neurotransmitter serotonin (5-HT) is involved in the mechanism of SAD. Tryptophan hydroxylase-2 (TPH2) is the key enzyme of 5-HT synthesis in the brain. C1473 G polymorphism in the Tph2 gene is a key factor defining the enzyme activity in the mouse brain. The main aims of the study were to investigate the effects of C1473 G polymorphism on behavior and brain 5-HT system responses to photoperiod alterations. The experiment was carried out on adult mouse males of B6-1473C and B6-1473 G congenic lines with normal and low TPH2 activities, respectively. B6-1473C and B6-1473 G mice were divided into four groups of 8 each and exposed for 28 days to standard-day (14 h light and 10 h darkness) or short-day (4 h light and 20 h darkness) conditions. No effect of photoperiod on locomotor, exploratory activities and anxiety in the open field test was observed. At the same time, photoperiod alterations affected depressive-like immobility in the forced swim test, the 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) levels, 5-HIAA/5-HT ratio and the Htr2a mRNA level in hippocampus and midbrain. The effect of the interaction between C1473 G polymorphism and photoperiod on 5-HT level and 5-HIAA/5-HT ratio in hippocampus was revealed. Short-day conditions reduced the level and increased 5-HIAA/5-HT ratio in this structure only in B6-1473 G mice. At the same time, C1473 G polymorphism does not alter effects of short-day conditions on immobility time in the forced swim test and the Htr2a mRNA level in the brain.

Tonic immobility (TI) is a temporary state of profound motor inhibition associated with great danger as the attack of a predator. Previous studies carried out in our laboratory evidenced high Fos-IR in the posteroventral region of the medial nucleus of the amygdala (MEA) after induction of the TI response. Here, we investigated the effects of GABAA and GABAB of the MEA on TI duration. Intra-MEA injections of the GABAA agonist muscimol and GABAB agonist baclofen reduced TI response, while intra-MEA injections of the GABAA antagonist bicuculline and GABAB antagonist phaclofen increased the TI response. Moreover, the effects observed with muscimol and baclofen administrations into MEA were blocked by pretreatment with bicuculline and phaclofen (at ineffective doses per se). Finally, the activation of GABAA and GABAB receptors in the MEA did not alter the spontaneous motor activity in the open field test. These data support the role of the GABAergic system of the MEA in the modulation of innate fear.

ObjectivesNMDA antagonists and nitric oxide synthase (NOS) inhibitors induce antidepressant-like effects and may represent treatment options for depression. The behavioural effects of NMDA antagonists seem to depend on Tyrosine kinase B receptor (TrkB) activation by BDNF and on mechanistic target of rapamycin (mTOR), in the medial prefrontal cortex (mPFC). However, it is unknown whether similar mechanisms are involved in the behavioural effects of NOS inhibitors. Therefore, this work aimed at determining the role of TrkB and mTOR signalling in the prelimbic area of the ventral mPFC (vmPFC-PL) in the antidepressant-like effect of NOS inhibitors.MethodsPharmacological treatment with LY235959 or ketamine (NMDA antagonists), NPA or 7-NI (NOS inhibitors), BDNF, K252a (Trk antagonist) and rapamycin (mTOR inhibitor) injected systemically or into vmPFC-PL followed by behavioural assessment.ResultsWe found that bilateral injection of BDNF into the vmPFC-PL induced an antidepressant-like effect, which was blocked by pretreatment with K252a and rapamycin. Microinjection of LY 235959 into the vmPFC-PL induced antidepressant-like effect that was suppressed by local rapamycin but not by K252a pretreatment. Microinjection of NPA induced an antidepressant-like effect insensitive to both K252a and rapamycin. Similarly, the antidepressant-like effects of a systemic injection of ketamine or 7-NI were not affected by blockade of mTOR or Trk receptors in the vmPFC-PL.ConclusionOur data support the hypothesis that NMDA blockade induces an antidepressant-like effect that requires mTOR but not Trk signalling into the vmPFC-PL. The antidepressant-like effect induced by local NOS inhibition is independent on both Trk and mTOR signalling in the vmPFC-PL.

The objective of the present study is to investigate the role of α4, α5, α6 or β2 nAChR subunits in the antidepressant-like effect of bupropion. Adult male mice were treated with subcutaneous acute doses of bupropion (3 and 10 mg/kg) 30 min before the forced swim test (FST) in α4, α5, α6, or β2 nAChR subunit knockout (KO) and wild-type (WT) mice. In addition, the effects of β2* antagonist dihydro-β-erythroidine (DHβE, 3 mg/kg) on antidepressant-like effects of bupropion in C57BL/6 J mice were assessed. Our results showed that baseline immobility and climbing time did not differ between KO and corresponding WT mice except for β2 KO. Bupropion significantly decreased immobility time and increased climbing time in the α4, α6 and β2 nAChR KO mice in comparison to WT littermates, indicating that lack of these nAChR subunits enhanced antidepressant effects of bupropion. On the contrary, the α5 nAChR subunit deletion did not alter the FST behavior in the bupropion-treated mice. Not only in the transgenic mice, bupropion also showed antidepressant-like effects in the WT mice. In addition, DHβE pretreatment before bupropion administration resulted in decreased immobility time and increased climbing time. Taken together, the present study provides evidence on the involvement of α4*, α6*, and β2* (* indicates possible presence of other subunits) nAChRs in the antidepressant-like effects of bupropion in the FST.

Accumulating evidence indicates that the antidepressant effects of ketamine are, in part, mediated by an increase in the AMPA receptor-mediated neurotransmission in depression related areas, such as the prefrontal cortex (PFC). Therefore, activity in PFC-projecting areas related to major depression, such as the dorsal raphe nucleus (DR), may also be modulated by ketamine. We used whole-cell patch-clamp recordings and western blot experiments to determine whether ketamine promotes acute and maintained alterations in glutamatergic transmission and mTOR pathway in the DR. Bath perfusion of ketamine, but not the NMDA receptor antagonist D-AP5, increased the frequency of AMPA receptor-mediated spontaneous EPSCs (sEPSCs) in DR neurons. However, ketamine did not affect evoked EPSCs or spontaneous inhibitory currents (sIPSCs). Pre-incubation of DR slices with the mTOR inhibitor PP242 decreased the frequency of sEPSCs and prevented the effect of ketamine. The results also show that while no electrophysiological effects were detected 24 h after ketamine administration, phosphorylation levels of mTOR were significantly increased in the DR. Nevertheless, expression levels of synaptic proteins were unaffected at that time. Altogether, the present data demonstrate that ketamine transiently increases spontaneous AMPA receptor-mediated neurotransmission in the DR.

Childhood absence epilepsy (CAE) is the most common pediatric epilepsy syndrome and is characterized by typical absence seizures (AS). AS are non-convulsive epileptic seizures characterized by a sudden loss of awareness and bilaterally generalized synchronous 2.5–4 Hz spike and slow-wave discharges (SWD). Gamma butyrolactone (GBL) is an acute pharmacological model of AS and induces bilaterally synchronous SWDs and behavioral arrest. Despite the long use of this model, little is known about its strain and sex-dependent features. We compared the dose-response profile of GBL-evoked SWDs in three rat strains (Long Evans, Sprague-Dawley, and Wistar), and examined the modulatory effects of estrous cycle on SWDs in female Wistar rats. We evaluated the number of seizures, the cumulative time seizing, and the average seizure duration as a function of dose, strain, and sex/estrous phase. Long Evans rats displayed the greatest sensitivity to GBL, followed by Wistar rats, and then by Sprague-Dawley rats. GBL-evoked SWDs were modulated by estrous cycle in female rats, with the lowest sensitivity to GBL occurring during metestrus. Wistar rats showed the greatest variability as a function of dose, and the least variability within dose; these features make this strain desirable for interventional studies. Moreover, our finding that the SWD response to GBL differs as a function of estrous cycle underscores the importance of cycle monitoring in studies examining female animals using this model. Together, these strain and sex-dependent findings provide guidance for future studies.

BACKGROUND A group of diplegic cerebral palsied (CP) children presents six precise signs that can be easily observed during clinical examinations, physiotherapy sessions and everyday activities. These signs are: startle reaction, upper limbs in startle position, averted-eye gaze, grimaces, eye blinking and posture freezing. METHODS In a population of 32 diplegic CP children (aged 1-8 years) perceptual signs were retrospectively identified through videos to verify their stability in the same child over time. RESULTS Startle reaction, upper limb in startle position and posture freezing were the most frequently observed signs and the easiest to recognize with the highest agreement in both observations (P

The aim of this study was to investigate the differences in fearfulness between two Japanese native chicken breeds, Tosa-Kukin (TOK) and Yakido (YKD). In a tonic immobility test, TOK breed chicks showed longer duration and lower induction number compared with YKD. The number of peeps in YKD in an isolation test was lower than that in TOK, whereas there were more bouts of peeping in YKD than in TOK. In a manual restraint test, YKD showed more active responses and initiated peeps and struggling earlier than TOK. The three behavioral tests all indicated that YKD are less fearful than TOK chickens. A latent structures discriminant (OPLS-DA) analysis was used to identify behavioral parameters that contributed to the differences between the breeds. The major parameters were duration and number of inductions in the tonic immobility test and number of struggle in the manual restraint test. These results suggest that three behavioral tests can be used together to evaluate fearfulness of Japanese native breeds of chickens.

In the present study we have monitored dose dependent effects of midazolam; a benzodiazepine (CNS depressant). It is the primary drug of choice for procedural sedation, preoperative sedation, and in emergency departments. Repeated administration of this drug is reported to have abuse potential and may cause this by increasing dopaminergic neurotransmission. Since an important role of 5-hydroxy tryptamine (5-HT) is there in the pathophysiology of anxiety and addiction, administration of midazolam may involve altered 5-HT metabolism as well. Present study was designed to monitor dose-dependent effects of midazolam and select the optimum dose for further experiments. Effects of midazolam were monitored on food intake, growth rate, activities in familiar and novel environments, light dark box activity, hot plate test, forced swim test and levels of dopamine, 5-HT and their metabolites. Midazolam was administered orally (0mg/kg, 2.5mg/kg, 5.0mg/kg and 10mg/kg) and behaviors were monitored post single midazolam administrations. Rats were decapitated and whole brain samples were collected and stored at -70°C until neurochemical analysis by HPLC-EC. Findings from the present study could be implicated to increased therapeutic utility of midazolam and related benzodiazepines.

The lateral habenula (LHb) processes information about aversive experiences that contributes to the symptoms of stress disorders. Previously, we found that chemogenetic inhibition of rat LHb neurons reduced immobility in the forced swim test, but the downstream target of these neurons was not known. Using an intersectional viral vector strategy, we selectively transduced three different output pathways from the LHb by injecting AAV8-DIO-hM(4)Di into the LHb and CAV2-CRE (a retrograde viral vector) into one of the three target areas as follows: dorsal raphe nucleus (DRN), ventral tegmental area (VTA), or rostromedial tegmentum (RMTg). Using the forced swim test, we found that chemogenetic inhibition of DRN-projecting LHb neurons reduced passive coping (immobility), whereas inhibition of the other pathways did not. Chemogenetic activation of DRN-projecting neurons using hM3Dq in another cohort did not further exacerbate immobility. We next examined the impact of inhibiting DRN-projecting LHb neurons on reward sensitivity, perseverative behavior, and anxiety-like behavior using saccharin preference testing, reward-omission testing, and open-field testing, respectively. There was no effect of inhibiting any of these pathways on reward sensitivity, locomotion, or anxiety-like behavior, but inhibiting DRN-projecting LHb neurons reduced perseverative licking during reward-omission testing, whereas activating these neurons increased perseverative licking. These results support the idea that inhibiting LHb projections to the DRN provides animals with resilience during highly stressful or frustrating conditions but not under low-stress circumstances, and that inhibiting these neurons may promote persistence in active coping strategies.

Depression is the most common psychiatric disorder in diabetic patients, showing higher rates in women than in men. This comorbidity has been studied in rodents using the streptozotocin (STZ)-induced diabetes (DM) model, consistently reporting a depressive-like profile in males. Few articles have examined these disturbances in females (ovariectomized or combined with male rats) yielding controversial results. This work was aimed to study whether there are sex differences in the depressive-like profile of STZ-treated male and naturally cycling female Wistar rats. We also analyzed the possible influence of the estrous cycle in females. DM was induced by injecting STZ (50 mg/kg, i.p.) in 2 consecutive days. Ten days later, the depressive-like profile was assessed in the Forced-Swim Test (FST). Locomotion and motor coordination were also evaluated. Body weight and blood glucose levels were registered at the beginning and at the end of the experiment; the estrous cycle, food and water intake were daily monitored. All diabetic subjects showed increased blood glucose levels, polyphagia, polydipsia and decreased body weight as compared to controls, but males were more susceptible to STZ-treatment than females pooled in all phases of the estrous cycle. After treatment with STZ, males and females in proestrus/estrus (P/E) exhibited a depressive-like profile in the FST (increased immobility and reduced swimming); females in metestrus/diestrus were unaffected. The only sex difference observed was a more pronounced reduced swimming in STZ-treated P/E females compared with hyperglycemic males. No changes in locomotion or motor coordination were found. This work emphasizes estrous cycle differences in STZ-treated rats, and in the resultant depressive-like profile. It also supports clinical evidences made in women with DM and stresses the importance of studying STZ-treated naturally cycling females and their estrous cycle phases.

Scopolamine, a muscarinic cholinergic receptor antagonist, exerts fast and prolonged antidepressant effects in the clinic. In contrast, the current treatments for major depressive disorder (MDD) require long-term drug administration. On the other hand, the sole use of scopolamine might be related to the high risk of adverse effects. Therefore, it may be preferable to reduce its therapeutic dose. A new approach might include the co-administration of low-dose scopolamine with selected ligands of metabotropic glutamate (mGlu) receptors, which are known to possess antidepressant-like activity in several rodent tests and models of depression. The aim of the present study was to evaluate the potential antidepressant activity of low-dose scopolamine combined with an allosteric agonist of mGlu7 receptors, AMN082 in C57BL/6 mice. It was found that the combination of scopolamine (0.1 mg/kg) and AMN082 (1 mg/kg) exerted significant antidepressant-like effects in the tail suspension test (TST), but these effects were not observed in the mGlu7−/− mice. Furthermore, low-dose AMN082 co-administered with low-doses scopolamine (0.03 and 0.1 mg/kg) induced antidepressant-like activity in the forced swim test (FST) in mice. The tested compounds did not affect locomotor activity and did not impair spatial memory in the Morris water maze (MWM) test or motor coordination in the rotarod test. The results strongly indicated that there is an enhanced antidepressant-like action of scopolamine by AMN082. Co-administration of scopolamine with AMN082 might be a new strategy with better efficacy and a lower risk of adverse effects compared with the sole use of scopolamine or AMN082.

Tonic immobility (TI) is an innate defensive response exhibited by prey when physical contact with a predator is prolonged and inescapable. This defensive response is able to activate analgesia mechanisms; this activation has adaptive value because, during an attack by a predator, the manifestation of recuperative behaviors can affect the appropriate behavioral defense strategy. Some studies have suggested that similar structures of the central nervous system can regulate the response of both TI and nociception. Thus, this study evaluated the effect of chemical lesion through the administration of ibotenic acid in restricted brain areas of the periaqueductal gray matter (PAG) in guinea pig on the TI response and nociception evaluated in the hot plate test before and after emission of TI. The data showed that an irreversible chemical lesion in the ventrolateral PAG reduced of the TI response as well as defensive antinociception. However, a lesion in the dorsal PAG blocked the defensive antinociception induced by TI but did not alter TI duration. In summary, one could hypothesize that the neural substrates responsible for defensive behavior and antinociception represent similar systems that are distinct in modulation. Thus, the ventrolateral PAG has been associated with the modulation of TI and the defensive antinociception induced by TI. In contrast, the integrity of the dorsal PAG should be necessary for defensive antinociception to occur but not to elicit TI behavior in guinea pigs.

Considering the pivotal role of nitric oxide (NO) pathway in depressive disorders, the aim of the present study was to investigate the antidepressant-like effect of selegiline in mice forced swimming test (FST), and possible involvement of NO-cyclic guanosine monophosphate (cGMP) pathway in this action. After assessment of locomotor activity in open-field test, mice were forced to swim individually and the immobility time of the last 4 min was evaluated. All drugs were given intraperitoneally (ip). Selegiline (10 mg/kg) decreased the immobility time in the FST similar to fluoxetine (20 mg/kg). Pretreatment with l-arginine (NO precursor, 750 mg/kg) or sildenafil (a phosphodiesterase 5 inhibitor, 5 mg/kg) significantly reversed the selegiline anti-immobility effect. Sub-effective dose of selegiline (1 mg/kg) showed a synergistic antidepressant effect with NG-nitro-l-arginine methyl ester (L-NAME, inhibitor of NO synthase, 10 mg/kg) or 7-nitroindazole (specific neuronal NO synthase inhibitor, 30 mg/kg), but not with aminoguanidine (specific inducible NO synthase inhibitor, 50 mg/kg). Pretreatment of mice with methylene blue (an inhibitor of NO synthase and soluble guanylyl cyclase, 10 mg/kg) significantly produced a synergistic response with the sub-effective dose of selegiline. Neither of the drugs changed the locomotor activity. Also, hippocampal and prefrontal cortex (PFC) nitrite content was significantly lower in selegiline-injected mice compared to saline-administrated mice. Also, co-injection of 7-nitroindazole with selegiline produced a significant reduction in hippocampal or PFC nitrite contents. It is concluded that selegiline possesses antidepressant-like effect in mice FST through inhibition of l-arginine-NO-cyclic guanosine monophosphate pathway.

Numerous studies have attributed the psychopathology of anxiety and stress disorders to maladaptive behavioral responses such as an inability to extinguish fear. Therefore, understanding neural substrates of fear extinction is imperative for developing more effective therapies for anxiety and stress disorders. Although several studies indicated a role for cholinergic transmission and nicotinic acetylcholine receptors (nAChRs) in anxiety and stress disorder symptomatology, very little is known about the specific contribution of nAChRs in the fear extinction process. In the present study, we first examined the involvement of several brain regions essential for fear extinction (i.e., dorsal and ventral hippocampus, dHPC and vHPC; infralimbic, IL, and prelimbic, PL of the medial prefrontal cortex, mPFC; basolateral nucleus of the amygdala, BLA) in the impairing effects of a nAChR agonist, nicotine, on contextual fear extinction in mice. Our results showed that systemic administration of nicotine during contextual fear extinction increased c-fos expression in the vHPC and BLA while not affecting dHPC, IL or PL. In line with these results, local nicotine infusions into the vHPC, but not dHPC, resulted in impaired contextual fear extinction. Interestingly, we found that local nicotine infusions into the PL also resulted in impairment of contextual fear extinction. Second, we measured the protein levels of the GABA synthesizing enzymes GAD65 and GAD67 in the dHPC and vHPC during contextual fear extinction. Our results showed that in the group that received acute nicotine, both GAD65 and GAD67 protein levels were downregulated in the vHPC, but not in dHPC. This effect was negatively correlated with the level of freezing response during fear extinction suggesting that the downregulated GAD65/67 levels were associated with disrupted fear extinction. Finally, using c-fos/GAD65/67 double immunofluorescence, we showed that nicotine mainly increased c-fos expression in non-GABAergic ventral hippocampal cells, indicating that acute nicotine increases vHPC excitability. Overall, our results suggest that acute nicotine's impairing effects on fear extinction are associated with ventral hippocampal disinhibition. Therefore, these results further our understanding of the interaction between nicotine addiction and anxiety and stress disorders by describing novel neural mechanisms mediating fear extinction.

A single base mutation in the Gα(i2) protein (G184S) renders this Gα subunit insensitive to the negative modulatory effects of Regulator of G-protein Signaling (RGS) proteins. Mice expressing this RGS insensitive (RGSi) variant of Gα(i2) (RGSi Gα(i2)) display a spontaneous antidepressant-like phenotype that is reversible by treatment with the 5-HT1A receptor (5-HT1AR) antagonist WAY100635. Here we test the hypothesis that increased activity of 5-HT1ARs in the hippocampus of RGSi Gα(i2) knock-in mice is responsible for the expression of the observed antidepressant-like behavior. We administered the 5-HT1AR antagonist WAY100635 or the agonist 8-OH-DPAT via bilateral intra-hippocampal infusion cannulae and evaluated antidepressant-like behavior using the tail suspension test (TST). WAY100635 reversed the antidepressant-like phenotype of the RGSi Gα(i2) knock-in mice and 8-OH-DPAT produced an antidepressant-like response in wild type mice that was blocked by systemic WAY100635. Furthermore, intra-hippocampal infusion of the RGS4/19 inhibitor CCG-203769 produced an antidepressant-like effect in female mice. Ex-vivo slice recording confirmed the 5-HT1AR-mediated decrease in hippocampal CA1 pyramidal neuron excitability was enhanced in the RGSi Gα(i2) knock-in mice. There was no change in hippocampal 5-HT1AR expression as measured by ligand binding or in the ability of 8-OH-DPAT to activate G-protein as measured in the [(35)S]GTPγS binding assay. The findings demonstrate that RGS protein control of hippocampal 5-HT1AR signaling is necessary and sufficient to account for the antidepressant-like phenotype in the RGSi Gα(i2) knock-in mice and that RGS proteins highly expressed in the hippocampus should be investigated as targets for novel antidepressant therapies.

Rats emit 22 kHz ultrasonic vocalizations (USVs) in association with pain, fear, or distress. Whereas the capacity to produce USVs is innate, reactivity to them appears to require experience. Specifically, 22 kHz USVs fail to elicit freezing behavior in naive laboratory rats. However, these “alarm calls” do elicit freezing in rats that previously experienced foot shocks. These findings led to the hypothesis that acquired reactivity is based on “autoconditioning”—learning in which self-generated 22 kHz USVs serve as Pavlovian cues that become associated with foot shocks. The current study tested the autoconditioning hypothesis by devocalizing rats through a unilateral transection of the recurrent laryngeal nerve (Experimental group). Subsequently, animals in both the Experimental and sham-operated Control groups received five unsignaled foot shocks. One or two days later, both groups were tested for USV-elicited freezing in a novel context. Recurrent laryngeal nerve transection failed to prevent or even diminish USV-elicited freezing. In fact, both groups showed large and comparable increases in freezing to USV presentations. A subset of Control animals failed to vocalize during conditioning, while some Experimental animals did vocalize during conditioning. Animals were therefore re-grouped and reanalyzed based on whether they vocalized during conditioning. Again, both groups showed large and comparable increases in USV-elicited freezing. These results disconfirm the essential tenet or prediction of the autoconditioning hypothesis. Alternative mechanisms for acquired reactivity to 22 kHz USVs are therefore considered.

Stress exposure has been implicated in the development of mood disorders, although little is known about the lasting effects of repeated stress during the adolescent period on sex-specific differences in endocrine and plasticity-signaling responses in adulthood. Using a 10-day combinatory stress paradigm (postnatal day (PND) 26 to 35), we examined sex-specific impact of adolescent stress and inhibition of tyrosine-related kinase B (TrkB) receptor (ANA-12; 0.5 mg/kg, i.p.) on 1) adolescent blood corticosterone levels, 2) adult locomotion and anxiety-like behavior, and 3) region-specific differences in endogenous TrkB full-length (TrkB.FL) and truncated (TrkB.T1) receptor isoforms. Blood collected on days 1, 5 and 10 revealed elevated basal and stress-induced CORT secretion in females compared to males, while ANA-12 attenuated CORT elevations post stress in both sexes. As adults, all females exhibited higher locomotor and exploratory activity than males in the open field test and elevated plus maze, and differences were comparable in the forced swim within stress-naive and stress groups. Biochemically, vehicle-treated males showed elevated TrkB.T1 and TrkB.FL compared to vehicle-treated females in the PFC, hippocampus and NAc, and levels were consistently attenuated by ANA-12 treatment in non-stress males. With regards to stress exposure, expression of both isoforms was strongly down-regulated in the NAc of males only and was associated with increased TrkB.T1 in the PFC. ANA-12 enhanced expression in females, independent of stress exposure, compared to vehicle-treated counterparts, expression being increased for TrkB.T1 versus TrkB.FL and magnitude of the changes being region-specific. In contrast, ANA-12 effects in stressed males were restricted to inhibition of both isoforms in the hippocampus. Together, our findings support that TrkB activation, contingent on stress exposure, differentially affects TrkB isoform regulation during adulthood. Sex-specific biochemical responses at delayed intervals following adolescent stress exposure further support the need to include the sex variable in animal models.

Children with an extremely inhibited, anxious temperament (AT) are at increased risk for anxiety disorders and depression. Using a rhesus monkey model of early-life AT, we previously demonstrated that metabolism in the central extended amygdala (EAc), including the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST), is associated with trait-like variation in AT. Here, we use fMRI to examine relationships between Ce–BST functional connectivity and AT in a large multigenerational family pedigree of rhesus monkeys (n = 170 females and 208 males). Results demonstrate that Ce–BST functional connectivity is heritable, accounts for a significant but modest portion of the variance in AT, and is coheritable with AT. Interestingly, Ce–BST functional connectivity and AT-related BST metabolism were not correlated and accounted for non-overlapping variance in AT. Exploratory analyses suggest that Ce–BST functional connectivity is associated with metabolism in the hypothalamus and periaqueductal gray. Together, these results suggest the importance of coordinated function within the EAc for determining individual differences in AT and metabolism in brain regions associated with its behavioral and neuroendocrine components. SIGNIFICANCE STATEMENT Anxiety disorders directly impact the lives of nearly one in five people, accounting for substantial worldwide suffering and disability. Here, we use a nonhuman primate model of anxious temperament (AT) to understand the neurobiology underlying the early-life risk to develop anxiety disorders. Leveraging the same kinds of neuroimaging measures routinely used in human studies, we demonstrate that coordinated activation between the central nucleus of the amygdala and the bed nucleus of the stria terminalis is correlated with, and coinherited with, early-life AT. Understanding how these central extended amygdala regions work together to produce extreme anxiety provides a neural target for early-life interventions with the promise of preventing lifelong disability in at-risk children.

ObjectiveThe aims of this study were to replicate previously published experiments and to modify the protocol to detect the effects of chronic antidepressant treatment in mice.MethodsMale Swiss mice (n=6–8/group) housed in reversed light/dark cycle were randomly assigned into receive vehicle (10% sucrose), sub-effective doses (1 and 3 mg/kg) or effective doses (10 and 30 mg/kg) of bupropion, desipramine, and fluoxetine and a candidate antidepressant, sodium butyrate (1–30 mg/kg) per gavage (p.o.) 1 h before the forced swim test (FST). Treatments continued daily for 7 and 14 days during retests 1 and 2, respectively. In an additional experiment, mice received fluoxetine (20 mg/kg) or vehicle (10% sucrose or 0.9% saline) p.o. or i.p. before the FST. Mice housed in reversed or standard light/dark cycles received fluoxetine (20 mg/kg) prior FST. Video recordings of behavioural testing were used for blind assessment of the outcomes.ResultsAccording to the expected, doses of antidepressants considered sub-effective failed to affect the immobility time of mice in the FST. Surprisingly, acute and chronic treatment with the high doses of bupropion, desipramine, and fluoxetine or sodium butyrate also failed to reduce the immobility time of mice in the FST. Fluoxetine 20 mg/kg was also ineffective in the FST when injected i.p. or in mice housed in normal light/dark cycle.ConclusionData suggest the lack of efficacy of orally administered bupropion, desipramine, fluoxetine in the FST in Swiss mice. High variability, due to high and low immobility mice, may explain the limited effects of the treatments.

Deep brain stimulation (DBS) is being investigated for a number of psychiatric indications, including posttraumatic stress disorder (PTSD). Preclinical studies continue to be a cornerstone for the development of new DBS applications. We investigate whether DBS delivered to the infralimbic cortex (IL), a region involved in mechanisms of stress resiliency, may counter behavioral abnormalities in rats that present persistent extinction deficits and long-term anxiety after exposure to fear conditioning. Rats undergoing fear conditioning/extinction were segregated into weak and strong extinction groups (WE >70% or SE

Some individuals recover quickly from stressful events, while others do not; this suggests that there are individual differences in stress resilience. Previous studies in rats have shown that an animal’s ability to extinguish conditioned fear can predict their stress resilience. In the present study, we investigated whether rats who are resilient or vulnerable to fear conditioning would consistently show resilient or vulnerable behaviors in other behavioral tests. Male Wistar-Imamichi rats were subjected to a series of behavioral tests, including open field, conditioned place-preference (CPP), forced swim and auditory fear conditioning. The subjects were assigned to one of two different groups: resilient or vulnerable, based on their level of freezing during fear extinction, and their other behavioral phenotypes were then compared. Rats in the resilient group showed faster extinction in the methamphetamine-induced CPP test than rats in the vulnerable group. The results suggest that resilience to stressful events is associated with drug-dependence and that individuals’ abilities to recover from stressful situations and drug-dependence may share a common mechanism.

Background: Resolvin D1 and D2 are bioactive lipid mediators that are generated from docosahexaenoic acid. Although recent preclinical studies suggest that these compounds have antidepressant effects, their mechanisms of action remain unclear. Methods: We investigated mechanisms underlying the antidepressant effects of resolvin D1 and resolvin D2 in lipopolysaccharide (0.8 mg/kg, i.p.)-induced depression model mice using a tail suspension test. Results: I.c.v. infusion of resolvin D1 (10 ng) and resolvin D2 (10 ng) produced antidepressant effects; these effects were significantly blocked by a resolvin D1 receptor antagonist WRW4 (10 µg, i.c.v.) and a resolvin D2 receptor antagonist O-1918 (10 µg, i.c.v.), respectively. The mammalian target of rapamycin complex 1 inhibitor rapamycin (10 mg/kg, i.p.) and a mitogen-activated protein kinase kinase inhibitor U0126 (5 µg, i.c.v.) significantly blocked the antidepressant effects of resolvin D1 and resolvin D2. An AMPA receptor antagonist NBQX (10 mg/kg, i.p.) and a phosphoinositide 3-kinase inhibitor LY294002 (3 µg, i.c.v.) blocked the antidepressant effects of resolvin D1 significantly, but not of resolvin D2. Bilateral infusions of resolvin D1 (0.3 ng/side) or resolvin D2 (0.3 ng/side) into the medial prefrontal cortex or dentate gyrus of the hippocampus produced antidepressant effects. Conclusions: These findings demonstrate that resolvin D1 and resolvin D2 produce antidepressant effects via the mammalian target of rapamycin complex 1 signaling pathway, and that the medial prefrontal cortex and dentate gyrus are important brain regions for these antidepressant effects. These compounds and their receptors may be promising targets for the development of novel rapid-acting antidepressants, like ketamine and scopolamine.

Orchestrating appropriate behavioral responses in the face of competing signals that predict either rewards or threats in the environment is crucial for survival. The basolateral amygdala (BLA) and prelimbic (PL) medial prefrontal cortex (mPFC) have been implicated in reward-seeking and fear-related responses, but how information flows between these reciprocally-connected structures to coordinate behavior is unknown. We recorded neuronal activity from the BLA and PL while rats performed a task where in shock- and sucrose-predictive cues were simultaneously presented to induce competition. The correlated firing primarily displayed a BLA→PL directionality during the shock-associated cue. Furthermore, the majority of optogenetically-identified PL-projecting BLA neurons recorded encoded the shock-associated cue, and more accurately predicted behavioral responses during competition than unidentified BLA neurons. Finally, BLA→PL photostimulation increased freezing, whereas both chemogenetic and optogenetic inhibition reduced freezing. The BLA→PL circuit plays a critical role in governing the selection of behavioral responses in the face of competing signals.

Perreyia flavipes Konow, 1899 (Pergidae: Perreyinae) is a sawfly species with gregarious larvae commonly found in open areas in southern Brazil through Uruguay and northern Argentina. The combination of highly gregarious larvae with the production of a variety of toxins in P. flavipes has led to severe cases of intoxication in a variety of livestock species. Over the years, considerable information was discovered on the larval natural history of P. flavipes; however, virtually nothing is known about the adult behavior, particularly because of its short life-span. In this study, we report on the first extensive study on the adult behavior of P. flavipes, including movement, mating (with oviposition and maternal care), and thanatosis. Our results show some unusual behavioral adaptations presented by P. flavipes, such as irregular activity behavior (i.e., deficient gait pattern), thanatosis behavior-like display, and primitive maternal care. Individual behavioral acts are described and compared among sexes, and their potential functions are discussed.

Major depressive disorder is the most severe and debilitating disease among psychiatric illnesses. The abrupt interruption of antidepressant treatment may lead to a complex physiological and neuropsychiatric syndrome. The organoselenium compound (MeOPhSe)2 has been reported to have neuroprotective properties in animal models. The study aimed to investigate the effects of single or repeated administration of (MeOPhSe)2 on depressive-like behavior and if the compound administration, and its discontinuation, may affect the anxiolytic-like phenotype in Swiss mice. The results showed that repeated intragastric administration of (MeOPhSe)2 (dose range: 0.1-5mg/kg), different from a single administration, reduced the immobility time in the mouse tail suspension test. A single administration of (MeOPhSe)2 at a dose of 5mg/kg decreased the immobility time, increased the swimming time and did not alter the climbing behavior in the modified forced swimming test (mFST). Repeated administration of (MeOPhSe)2 decreased the immobility time, did not alter the swimming time and increased the climbing behavior in the mouse mFST. Repeated administration of (MeOPhSe)2 at a dose of 5mg/kg elicited a mouse anxiolytic-like phenotype in the elevated plus maze and light-dark tests. Markers of hepatic and renal function tests were not altered by repeated administration of (MeOPhSe)2 to mice. The findings indicate that a single or repeated administration of (MeOPhSe)2 elicited an antidepressant-like action in mice. Moreover, repeated treatment with (MeOPhSe)2 produced an anxiolytic-like action in mice and its profile remained stable after discontinuation.

A high proportion of young methamphetamine (MA) users simultaneously consume alcohol. However, the potential neurological and behavioural alterations induced by such a drug combination have not been systematically examined. We studied in adolescent rats the long-term effects of alcohol, MA, and alcohol and MA combined on anxiety-like behaviour, memory, and neurogenesis in the adult hippocampus. Rats received saline, ethanol (ETOH, 1.5g/kg), MA (MA, 2mg/kg), or ethanol and MA combined (ETHOH-MA, 1.5g/kg ethanol plus 2mg/kg MA) via oral gavage, once daily for 5 consecutive days. Open field (OF), elevated plus maze (EPM) and radial arm maze (RAM) tests were conducted following a 15-day withdrawal period. The results showed alterations in exploratory behaviour in the OF in the MA and ETOH-MA groups, and anxiety-like effects in the EPM in all three drug treatment groups. All three drug groups exhibited reference memory deficits in the RAM, but only the combination treatment group displayed alterations in working memory. Both MA and ETOH-MA treatments increased the length of doublecortin (DCX)-void gaps in the dentate gyrus but only ETOH-MA treatment increased the number of such gaps. An increased number and length of DCX-void gaps correlated with decreased exploratory activity in the OF, and impaired working memory in the RAM was associated with an augmented number of gaps. These findings suggest that alterations in adult hippocampal neurogenesis are linked to the persistent cognitive and behavioural deficits produced by alcohol and MA exposure.

There is a lack of information about the molecular events underlying the depressive-like effect of an intracerebroventricular injection of streptozotocin (ICV-STZ) in mice. Elevated activity of the tryptophan-degrading enzyme indoleamine-2,3-dioxygenase (IDO) has been proposed to mediate depression in inflammatory disorders. In this study, we report that ICV-STZ activates IDO in the hippocampus of mice and culminates in depressive-like behaviors, measured by an increased duration in immobility time in the forced swimming test and decreased total time of grooming in the splash test. Indirect blockade of IDO activation with the cytokine inhibitor minocycline prevents the development of depressive-like behaviors and attenuates STZ-induced upregulation of proinflammatory cytokines in the hippocampus. Minocycline abrogates the increase in tryptophan and kynurenine levels as well as prevents serotonin dysfunction in the hippocampus of STZ-injected mice. These results suggest that hippocampal IDO activation in STZ-associated depressive-like behavior is mediated by proinflammatory cytokine-dependent mechanisms. Our study not only extends the evidence that IDO has a critical role in mediating inflammation-induced depression but also supports the notion that neuroinflammation and the kynurenine pathway are important targets of novel therapeutic drugs for depression. In addition, our study provides new insights into the neurobiological mechanisms underlying ICV-STZ and indicates that this model could be employed in the preclinical research of depression.

Early-life stress is a potent risk factor for development of psychiatric conditions such as depression. The underlying mechanisms remain poorly understood. Here, we used the early-life social isolation (ESI) model of early-life stress in rats to characterize development of depressive-like behavior, the role of microglia, levels of histone methylation, as well as expression of glutamate receptor subunits in the hippocampus. We found that depressive-like behavior was induced after ESI as determined by sucrose preference and forced swimming tests. Increased expression of microglial activation marker, Iba1, was observed in the hippocampus of the ESI group, while expression of the microglial CD200 receptor, which promotes microglial quiescence, significantly decreased. In addition, increased levels of proinflammatory cytokines, interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-α) were observed in the hippocampus of the ESI group. Moreover, ESI increased levels of neuronal H3K9me2 (a repressive marker of transcription) and its associated "writer" enzymes, G9a and G9a-like protein, in the hippocampus. ESI also decreased expression of hippocampal NMDA receptor subunits, NR1, and AMPA receptor subunits, GluR1 and GluR2, which are involved in synaptic plasticity, but it did not affect expression of PSD95 and NR2B. Interestingly, treatment with minocycline to block microglial activation induced by ESI inhibited increases in hippocampal microglia and prevented ESI-induced depressive-like behavior as well as increases in IL-1β, IL-6, and TNF-α. Notably, minocycline also triggered downregulation of H3K9me2 expression and restored expression of NR1, GluR1, and GluR2. These results suggest that ESI induces depressive-like behavior, which may be mediated by microglial signaling.

Alcohol use disorder and depression are highly comorbid, and both conditions exhibit important sexual dimorphisms. Here, we aimed to investigate voluntary alcohol consumption after 6 weeks of chronic mild stress (CMS) in Wistar rats – employed as an animal model of depression. Male and female rats were investigated, and changes in several molecular markers were analysed in frontal cortex (FCx) and hippocampal formation (HF). CMS induced depressive-like responses in the forced swimming test - increased immobility time - in male and female animals, without affecting anhedonia (sucrose preference test) nor motor activity (holeboard); body weight gain and food intake were diminished only among CMS males. Voluntary alcohol consumption was evaluated in a two-bottle choice paradigm (ethanol 20% versus tap water) for 4 consecutive days; females exhibited a higher preference for alcohol compared to male animals. In particular, alcohol consumption was significantly higher among CMS females compared to CMS male animals. Remarkably, similar changes in both male and female animals exposed to CMS were observed regarding the expression levels of NCAM-140 KDa (decrease), GFAP and CB1R expression (increase) within the FCx as well as for HF PSD-95 levels (increase). However, contrasting effects in males and females were reported in relation to synaptophysin (SYN) protein levels within the FCx, HF CB1R expression (a decrease among male animals but an increase in females); while the opposite pattern was observed for NCAM-140 KDa protein levels in the HF. A decrease in CB2R expression was only observed in the HF of CMS-females. The present study suggests that male and female animals might be differentially affected by CMS regarding later voluntary alcohol consumption. In this initial approach, cortical SYN, and NCAM-140 KDa, CB1R and CB2R expression within the HF have arisen as potential candidates to explain such sex differences in behaviour. However, the depression-alcoholism relationship still deserves further investigation.

Depression is a major public health concern with symptoms that are often poorly controlled by treatment with common antidepressants. This problem is compounded in juveniles and adolescents, because therapeutic options are limited to selective serotonin reuptake inhibitors (SSRIs). Moreover, therapeutic benefits of SSRIs are often especially limited in certain subpopulations of depressed patients, including children and carriers of low-expressing serotonin transporter (SERT) gene variants. Tricyclic antidepressants (TCAs) offer an alternative to SSRIs; however, how age and SERT expression influence antidepressant response to TCAs is not understood. We investigated the relation between antidepressant-like response to the TCA desipramine using the tail suspension test and saturation binding of [3H]nisoxetine to the norepinephrine transporter (NET), the primary target of desipramine, in juvenile (21 days postnatal [P21]), adolescent (P28), and adult (P90) wild-type (SERT+/+) mice. To model carriers of low-expressing SERT gene variants, we used mice with reduced SERT expression (SERT+/−) or lacking SERT (SERT−/−). The potency and maximal antidepressant-like effect of desipramine was greater in P21 mice than in P90 mice and was SERT genotype independent. NET expression decreased with age in the locus coeruleus and increased with age in several terminal regions (e.g., the cornu ammonis CA1 and CA3 regions of the hippocampus). Binding affinity of [3H]nisoxetine did not vary as a function of age or SERT genotype. These data show age-dependent shifts for desipramine to produce antidepressant-like effects that correlate with NET expression in the locus coeruleus and suggest that drugs with NET-blocking activity may be an effective alternative to SSRIs in juveniles.

Neoechinulin A is an isoprenyl indole alkaloid that exhibits scavenging, neurotrophic factor-like, and anti-apoptotic activities. However, the effectiveness of neoechinulin A in animal models of disease has not yet been explored. In the present study, we investigated the effects of neoechinulin A on memory impairment in lipopolysaccharide (LPS)-treated mice and its antidepressant-like effects in mice. In the Y-maze test, the intracerebroventicular (i.c.v.) administration of LPS (10 μg/mouse) significantly decreased spontaneous alternation behavior, which was prevented by the prior administration of neoechinulin A (300 ng/mouse, i.c.v.). None of the treatments altered the locomotor activity of mice. Moreover, the administration of neoechinulin A decreased the immobility time in the forced-swim test or tail suspension test, which was prevented by the prior administration of WAY100635 (an antagonist of 5-HT1A receptors) and parachlorophenylalanine (an inhibitor of tryptophan hydroxylase). These results suggest that neoechinulin A improves memory functions in LPS-treated mice, and also exerts antidepressant-like effects through changes in the 5-HT system.

Current pharmacological treatments for Parkinson's disease (PD) are focused on symptomatic relief, but not on disease modification, based on the strong belief that PD is caused by irreversible dopaminergic neuronal death. Thus, the concept of the presence of dormant dopaminergic neurons and its possibility as the disease-modifying therapeutic target against PD have not been explored. Here we show that optogenetic activation of substantia nigra pars compacta (SNpc) neurons alleviates parkinsonism in acute PD animal models by recovering tyrosine hydroxylase (TH) from the TH-negative dormant dopaminergic neurons, some of which still express DOPA decarboxylase (DDC). The TH loss depends on reduced dopaminergic neuronal firing under aberrant tonic inhibition, which is attributed to excessive astrocytic GABA. Blocking the astrocytic GABA synthesis recapitulates the therapeutic effect of optogenetic activation. Consistently, SNpc of postmortem PD patients shows a significant population of TH-negative/DDC-positive dormant neurons surrounded by numerous GABA-positive astrocytes. We propose that disinhibiting dormant dopaminergic neurons by blocking excessive astrocytic GABA could be an effective therapeutic strategy against PD.

Background Oxidative stress plays a pivotal role in the pathophysiology and pathogenesis of mental diseases, such as depression or anxiety. Psychological stress induced by predatory stimulus is one of the models that explain how induced affective behavior is manifested as a depression-like state. Quercetin is a flavonoid that exhibits potential pharmacological activity on mental diseases. Thus, the present study was designed to investigate the effect of quercetin on innate fear and affective behavior induced by repeated predator stress exposure on mice. Materials and methods ICR mice were exposed to predatory stress for 3 days. Quercetin at a dose of 50 mg/kg was given intraperitoneally along with stress induction. The freezing behavior during the stress induction was analyzed. The anxiety-like and depressive-like behaviors and cognitive and motor functions were examined on the last day of induction. Results Predatory stress increased the affective behaviors (anxiety-like and depressive-like behaviors) and produced freezing behavior without alterations in the cognitive function and exploratory behavior. Treatment with quercetin 50 mg/kg attenuated the freezing, anxiety-like and depressive-like behaviors. Conclusions Repeated predator stress exposure causes both innate fear and depression-like state for the prey animals. Quercetin may have a protective effect against depression and alleviates the fear of traumatic events.

Sleep is crucial to improve athlete performance and their circadian rhythm, but sleep patterns may be disturbed because athletes participate in several competitions. In addition, intensive training programs can cause muscle pain and psychological stress in athletes, resulting in a lack of sleep. Sleep also plays a critical role in the recovery of muscle injury induced by exercise. The current study evaluated the effect of sleep deprivation on the recovery of muscle injury induced by high-intensity exercise in a mouse model. In this study, 28 mice were randomly assigned to four groups (N = 7): control (Control), exercise (EX), sleep deprivation (SD), and sleep deprivation with exercise (EX+SD). The mice from the EX and EX+SD groups were subjected to high-intensity swimming. The results showed that 72-h sleep deprivation increased food intake and reduced body weight. However, the manipulation of 8-week exercise and/or 72-h sleep deprivation did not have any effect in the elevated plus maze task and tail suspension test. Interestingly, the EX+SD group exhibited improved memory performance in the Morris water maze and impaired motor activity in the open field test. According to the TNF-α level and aspartate aminotransferase (AST), and creatine phosphokinase (CK) activities, only the EX+SD group exhibited muscle impairment. Overall, high-intensity exercise may cause muscle injury, and adequate sleep can recover muscle damage. However, sleep deprivation reduces protein synthesis, which decreases the ability to restore muscle damage and aggravates the harmful effect of high-intensity exercise.

Tonic immobility (TI; state of motor inhibition during threat) has been implicated in the onset of intrusive trauma memories, while controllability was associated with reduced anxiety. The present study investigated the interaction between TI and control in the development of intrusive memories of an analogue trauma. Sixty-four participants watched negative pictures while being allowed to close their eyes (InControl) or not (NoControl). They completed measures for spontaneous TI afterwards and recorded intrusive memories of the pictures in a diary in the subsequent week. Bayesian analyses were used to test informative hypotheses. Spontaneous TI during picture viewing was positively associated with increased intrusion frequency. Intrusion frequency did not differ for InControl versus NoControl. Moderation (control x TI) and non-moderation (main effect of TI only) were both adequate models, with no preference. Our results confirm the importance of TI in PTSD development. Implications of the findings regarding control merit more research.

Depression is a highly prevalent social disease. Despite significant medical progress, therapeutic solutions for optimising treatment of this disease are still being sought. The aim of this study was to assess, using the forced swimming test, locomotor activity test and two compartment exploratory test, for a reduction in immobility time (a measure of anti-depressant efficacy), locomotor activity and anxiolytic effectiveness after single, repeated, and combined administration of vortioxetine (2.5 mg/kg - a multimodal SMS), dapoxetine (3.0 mg/kg - an SSRI used in premature ejaculation disorders) and fluoxetine (5.0 mg/kg - an SSRI) in non-stressed and prenatally stressed rats. It was found that vortioxetine, fluoxetine and dapoxetine reduced immobility time and rat locomotor activity which suggests anti-depressant efficacy of these drugs both in monotherapy and in combined administration. The results also confirmed an anxiolytic effect of the study drugs in mono and combined therapy. Analysis of the pathomechanism of depression and the mechanisms of action of the individual drugs tested resulted in a prediction that combined administration of these drugs may be effective in the treatment of depressive disorders, although possible interactions between the drugs used must be assessed for. Considering the fact that dapoxetine is not currently used in depression treatment and vortioxetine is a relatively new drug, further research in this direction is vital, including within animal models.

This study examined low-frequency ultrasonic vocalizations (lUSVs) in rats during two types of sexual interactions; postejaculatory interval (PEI) and barrier - noncontact (NC) test. We report distinct classes of lUSVs that can be assigned to different emotional states; relaxation vs. frustration. Totally flat, 22-kHz calls (Class A), were observed during the relaxation state following ejaculation; characterized by immobilization or grooming during the PEI. On the other hand, two-three component lUSVs (Class B) that start at a higher frequency (45-kHz: flat, upward or short signal) and then shift to 35-23-kHz (mostly to 28-23-kHz), correspond as we assume, to arousal and frustration - active states associated with sniffing a hole or exploration during the NC test. We suggest that momentary, abrupt decreases of arousal during the frustration state correspond to Class B lUSVs. The detailed spectral analysis of the high-frequency component of two-component lUSVs is crucial for establishing the relationship between such lUSVs and the corresponding behavior and emotional states. Our studies indicate that while the two-component Class B 22-kHz lUSVs may relate to the frustration state, a single component, flat, Class A lUSV relates to the relaxation state. The results of these studies support a notion that rats emit distinct vocalization patterns, reflecting their emotional states.

The study was performed on a contagious behavior model based on drinking, behavior in rats. In the presence of familiar drink-motivated conspecific showing drinking behavior (rat-demonstrator), drink-unmotivated rat-viewer begins to demonstrate behavioral signs ofdrinking motivation that is the signs of behavioral contagion. In this paper; the changes in the ethogram of rats-viewers with behavioral contagion were studied by analyzing atransition probabilities matrix. Those animals showed a decrease in the frequency of aggression and defensive behavior patterns simultaneously with an increase in the frequency of exploratory activity, drinking and exploratory approaches to bottles as compared with the ethogram of rats-viewers with no signs of behavioral contagion when tested in the presence of familiar drink-unmotivated con specific-demonstrator.

Alzheimer's disease (AD) is characterized by progressive cognitive impairments as well as non-cognitive symptoms such as depressed mood. Physical exercise has been proposed as a preventive strategy against AD and depression, an effect that may be related, at least partially, to its ability to prevent impairments on cell proliferation and neuronal survival in the hippocampus, a structure implicated in both cognition and affective behavior. Here, we investigated the ability of treadmill exercise (4 weeks) to counteract amyloid β

Significant alterations in glutamatergic neurotransmission have been reported in major depressive disorder (MDD) that could underlie psychiatric traits. Studies were mainly interested in synaptic dysfunction in the prefrontal cortex, a key structure involved in depressive-like behavior, however hippocampus has been shown to be important in MDD. As cognitive deficits such as hippocampus-memory process were observed in MDD, we investigated in a mild hypoglutamatergic model behaviors related to depression and memory, synaptic transmission parameters and glutamatergic state specifically in the hippocampus. We thus characterized these phenotypes in adult male mice partially depleted in glutaminase type 1 or GLS1 (GLS1 HET), the enzyme responsible for glutamate synthesis in neurons, that we previously characterized as displaying moderate lower levels of glutamate in brain. We showed that GLS1 mutant mice display AMPA-R-mediated response deficits after prolonged repetitive stimulation with electrophysiological recording and inability to sustain glutamate release by microdialysis experiments with no consequences on behavioral spatial learning performances. However, their ability to escape from unpleasant but repeated escapable condition was attenuated whereas they were more immobile in the unescapable situation in the FST during re-test. These results show that GLS1 mutant mice display moderate impairments of hippocampal glutamatergic neurotransmission and moderate changes in adaptive behaviors that have been shown to participate to the development of depressive-like state.

Tonic immobility (TI) is an effective anti-predator strategy. However, long immobility status on the ground increases the risk of being eaten by predators, and thus insects must rouse themselves when appropriate stimulation is provided. Here, the strength of vibration causing arousal from the state of TI was examined in strains artificially selected for longer duration of TI (L-strains: long sleeper) in a beetle. We provided different strengths of vibration stimuli to the long sleepers in Tribolium castaneum. Although immobilized beetles were never awakened by the stimuli from 0.01 to 0.12 mm in amplitude, almost of the beetles were aroused from immobilized status by the stimulus at 0.21 mm. There was a difference in sensitivity of individuals when the stimuli of 0.14 mm and 0.18 mm were provided. F2 individuals were also bred by crossing experiments of the strains selected for shorter and longer duration of TI. The arousal sensitivity to vibration was well separated in the F2 individuals. A positive relationship was observed between the duration of TI and the vibration amplitude, suggesting that immobilized beetles are difficult to arouse from a deep sleep, while light sleepers are easily aroused by even small vibrations. The results indicate a genetic basis for sensitivity to arousal from TI.

Objective: Oxidative stress and alternation of renin-angiotensin system has been implicated in the pathophysiology of various cardio vascular, endocrine including mood and anxiety disorders. The present study evaluated the role of irbesartan in stress induced different models of depression. Materials and method: Mice were treated with irbesartan (40 mg/kg), fluoxetine (25 mg/kg) alone in combination orally. Drugs treatment started after 2 weeks from the beginning of the unpredictable mild stress (UCMS) protocol. Behavioural tests were performed on week 6, at least 24 h after the last treatment. Modified forced swim test (MFST), tail suspension test (TST) and open field test (OFT) were used followed by antioxidant markers and 5-HT levels determination. Result: Irbesartan increased swimming, climbing and decreased immobility times in MFST, decrease immobility time in TST. Irbesartan also increased no. of field crossings; rearings and also increased time spent in the centre of OFT. Thus, antidepressant like activity in UCMS mice was observed. Combination of irbesartan with fluoxetine showed potentiating effect of behavioural parameters in all animal models. Combination groups also showed antioxidant effects and elevated the 5-HT levels in UCMS mice. Conclusion: Chronic administration of Irbesartan exerted antidepressant like effect, reduced oxidative stress and elevated brain 5-HT levels.

Background: Similar to the N-methyl-D-aspartate receptor antagonist ketamine, the metabotropic glutamate 2/3 receptor antagonist, MGS0039, shows antidepressant effects. However, there are no reports comparing these 2 compounds in the social defeat stress model of depression. Methods: We examined the effects of MGS0039 (1 mg/kg) and ketamine (10 mg/kg) on depression-like behavior in susceptible mice after repeated social defeat stress. Protein levels of brain-derived neurotrophic factor, TrkB, phospho-TrkB, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (GluA1), postsynaptic density protein 95, and dendritic spine density in selected brain regions were measured. Results: In the tail suspension and forced swimming tests, both MGS0039 and ketamine significantly attenuated the increased immobility time observed in susceptible mice, compared with vehicle-treated animals, 1 or 2 days after a single dose of drug. In the sucrose preference test, both compounds significantly improved the reduced preference typically seen in susceptible mice at 3 to 7 days after a single dose of drug. Western-blot analyses showed that similar to ketamine, MGS0039 significantly attenuated the reduced brain-derived neurotrophic factor, phospho-TrkB/TrkB ratio, GluA1 and postsynaptic density protein 95 seen in the prefrontal cortex, dentate gyrus, and CA3 of the hippocampus from susceptible mice, 8 days after a single dose. Again, in a similar manner to ketamine, MGS0039 significantly attenuated the reduction of spine density in the prelimbic regions of the medial prefrontal cortex, dentate gyrus, and CA3 of the hippocampus, but not infralimbic regions of the medial prefrontal cortex and CA1, in susceptible mice 8 days after a single dose. In contrast, neither drug elicited an effect on altered brain-derived neurotrophic factor-TrkB signaling, GluA1, and postsynaptic density protein 95 levels and did not increase spine density observed in the nucleus accumbens of susceptible mice. Conclusions: Similar to ketamine, MGS0039 shows rapid and sustained antidepressant effects in the social defeat stress model. Long-lasting synaptogenesis in the prelimbic regions of medial prefrontal cortex, dentate gyrus, and CA3 might be implicated in this sustained antidepressant effect.

Tonic immobility (TI) is a response to a predator attack, or other inescapable danger, characterized by immobility, analgesia and unresponsiveness to external stimuli. In mammals, the periaqueductal gray (PAG) and deep tectal regions control the expression of TI as well as other defensive behaviors. In birds, little is known about the mesencephalic circuitry involved in the control of TI. Here, adult pigeons (both sex, n = 4/group), randomly assigned to non-handled, handled or TI groups, were killed 90 min after manipulations and the brains processed for detection of c-Fos immunoreactive cells (c-Fos-ir, marker for neural activity) in the mesencephalic central gray (GCt) and the adjacent nucleus intercollicularis (ICo). The NADPH-diaphorase staining delineated the boundaries of the sub nuclei in the ICo-GCt complex. Compared to non-handled, TI (but not handling) induced c-Fos-ir in NADPH-diaphorase-rich and -poor regions. After TI, the number of c-Fos-ir increased in the caudal and intermediate areas of the ICo (but not in the GCt), throughout the rostrocaudal axis of the dorsal stratum griseum periventriculare (SGPd) of the optic tectum and in the n. mesencephalicus lateralis pars dorsalis (MLd), which is part of the ascending auditory pathway. These data suggest that inescapable threatening stimuli such as TI may recruit neurons in discrete areas of ICo-GCt complex, deep tectal layer and in ascending auditory circuits that may control the expression of defensive behaviors in pigeons. Additionally, data indicate that the contiguous deep tectal SCPd (but not GCt) in birds may be functionally comparable to the mammalian dorsal PAG.