Environmental interventions reduced repetitive behavior in a mouse model.

Repetitive motor behaviors are associated with several neurodevelopmental disorders including autism spectrum disorder. Non-invasive environmental interventions that can ameliorate repetitive behavior and be introduced in early development could benefit many. In Experiment 1, we characterized the development of repetitive circling in mice reared in standard and enriched environments. Environmental enrichment was associated with reduced repetitive behavior. In Experiment 2, two weekly injections of an A2A adenosine receptor agonist reduced repetitive behavior in mice fed a ketogenic diet. Together, these two approaches modified the environment and reduced repetitive behavior with potential implications for increased functioning of the indirect basal ganglia pathway.

Toward better characterization of restricted and repetitive behaviors in individuals with germline heterozygous PTEN mutations.

This study aimed to further our understanding of restricted and repetitive behaviors (RRB) among individuals with germline pathogenic mutations in PTEN by providing multimethod characterization and comparison of key RRB subdomains across individuals with PTEN mutations with autism spectrum disorder (ASD) (PTEN-ASD), with PTEN mutations without ASD (PTEN-No ASD) and with ASD and macrocephaly but without PTEN mutations (Macro-ASD). Of 86 total research participants, 38 had PTEN-ASD (Mage  = 8.93 years, SDage  = 4.75), 25 Macro-ASD (Mage  = 11.99 years; SDage  = 5.15), and 23 PTEN-No ASD (Mage  = 8.94 years; SDage  = 4.85). The Repetitive Behavior Scale-Revised (RBS-R) and the Autism Diagnostic Interview-Revised (ADI-R) were used as measures of distinct RRB domains. There were significant group differences in the RBS-R repetitive motor behaviors (RMB; F = 4.52, p = 0.014, ω2  = 0.08), insistence on sameness (IS; F = 4.11, p = 0.02, ω2  = 0.05), and circumscribed interests (CI; F = 7.80, p = 0.001, ω2  = 0.14) scales. Post hoc comparisons showed that the PTEN-No ASD group had significantly lower RMB, IS, and CI scores compared to both PTEN-ASD and Macro-ASD groups. Importantly, PTEN-No ASD group still showed elevated RRB levels. Furthermore, there was a portion of individuals in PTEN-No ASD group whose Full-Scale Intelligence Quotient (FSIQ) was >70 that did not show floor level scores in the RMB domain. After adjusting for age and FSIQ scores, group differences were no longer statistically significant. RMB, IS, and CI domains showed distinct association patterns with sex, age, and FSIQ. This investigation provides the largest and most comprehensive characterization of distinct RRB domains in individuals with PTEN mutations to date. Despite the limitations, our findings have important assessment and treatment implications.

Stereotypy and spontaneous alternation in deer mice and its response to anti-adenosinergic intervention.

Repetitive behavioral phenotypes are a trait of several neuropsychiatric disorders, including obsessive-compulsive disorder (OCD). Such behaviors are typified by complex interactions between cognitive and neurobiological processes which most likely contribute to the suboptimal treatment responses often observed. To this end, exploration of the adenosinergic system may be useful, since adenosine-receptor modulation has previously shown promise to restore control over voluntary behavior and improve cognition in patients presenting with motor repetition. Here, we employed the deer mouse (Peromyscus maniculatus bairdii) model of compulsive-like behavioral persistence, seeking to investigate possible associations between stereotypic motor behavior and cognitive flexibility as measured in the T-maze continuous alternation task (T-CAT). The effect of istradefylline, a selective adenosine A2A receptor antagonist at two doses (10 and 20 mg kg-1  day-1 ) on the expression of stereotypy and T-CAT performance in high (H) and non-(N) stereotypical animals, was investigated in comparison to a control intervention (six groups; n = 8 or 9 per group). No correlation between H behavior and T-CAT performance was found. However, H but not N animals presented with istradefylline-sensitive spontaneous alternation and stereotypy, in that istradefylline at both doses significantly improved the spontaneous alternation scores and attenuated the stereotypical expression of H animals. Thus, evidence is presented that anti-adenosinergic drug action improves repetitive behavior and spontaneous alternation in stereotypical deer mice, putatively pointing to a shared psychobiological construct underlying naturalistic stereotypy and alterations in cognitive flexibility in deer mice.

Sodium phenylbutyrate reduces repetitive self-grooming behavior and rescues social and cognitive deficits in mouse models of autism.

Autism spectrum disorder (ASD) is a neurodevelopment disorder characterized by deficits in social interaction and restrictive, repetitive, and stereotypical patterns of behavior. However, there is no pharmacological drug that is currently used to target these core ASD symptoms. Sodium phenylbutyrate (NaPB) is a well-known long-term treatment of urea cycle disorders in children. In this study, we assessed the therapeutic effects of NaPB, which is a chemical chaperone as well as histone deacetylase inhibitor on a BTBR T + Itpr3tf/J (BTBR) mice model of ASD. We found that acute and chronic treatment of NaPB remarkably improved, not only core ASD symptoms, including repetitive behaviors and sociability deficit, but also cognitive impairment in the BTBR mice. NaPB substantially induced histone acetylation in the brain of the BTBR mice. Intriguingly, the therapeutic effects of NaPB on autistic-like behaviors, such as repetitive behaviors, impaired sociability, and cognitive deficit also showed in the valproic acid (VPA)-induced mouse model of autism. In addition, pentylenetetrazole (PTZ)-induced seizure was significantly attenuated by NaPB treatment in C57BL/6J and BTBR mice. These findings suggest that NaPB may provide a novel therapeutic approach for the treatment of patients with ASD.

Pharmacological targeting of striatal indirect pathway neurons improves subthalamic nucleus dysfunction and reduces repetitive behaviors in C58 mice.

Repetitive behaviors (e.g., stereotypic movements, compulsions, rituals) are common features of a number of neurodevelopmental disorders. Clinical and animal model studies point to the importance of cortical-basal ganglia circuitry in the mediation of repetitive behaviors. In the current study, we tested whether a drug cocktail (dopamine D2 receptor antagonist + adenosine A2A receptor agonist + glutamate mGlu5 positive allosteric modulator) designed to activate the indirect basal ganglia pathway would reduce repetitive behavior in C58 mice after both acute and sub-chronic administration. In addition, we hypothesized that sub-chronic administration (i.e. 7 days of twice-daily injections) would increase the functional activation of the subthalamic nucleus (STN), a key node of the indirect pathway. Functional activation of STN was indexed by dendritic spine density, analysis of GABA, glutamate, and synaptic plasticity genes, and cytochrome oxidase activity. The drug cocktail used significantly reduced repetitive motor behavior in C58 mice after one night as well as seven nights of twice-nightly injections. These effects did not reflect generalized motor behavior suppression as non-repetitive motor behaviors such as grooming, digging and eating were not reduced relative to vehicle. Sub-chronic drug treatment targeting striatopallidal neurons resulted in significant changes in the STN, including a four-fold increase in brain-derived neurotrophic factor (BDNF) mRNA expression as well as a significant increase in dendritic spine density. The present findings are consistent with, and extend, our prior work linking decreased functioning of the indirect basal ganglia pathway to expression of repetitive motor behavior in C58 mice and suggest novel therapeutic targets.

An Adenosine A2A Receptor Antagonist Improves Multiple Symptoms of Repeated Quinpirole-Induced Psychosis.

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder characterized by the repeated rise of concerns (obsessions) and repetitive unwanted behavior (compulsions). Although selective serotonin reuptake inhibitors (SSRIs) is the first-choice drug, response rates to SSRI treatment vary between symptom dimensions. In this study, to find a therapeutic target for SSRI-resilient OCD symptoms, we evaluated treatment responses of quinpirole (QNP) sensitization-induced OCD-related behaviors in mice. SSRI administration rescued the cognitive inflexibility, as well as hyperactivity in the lateral orbitofrontal cortex (lOFC), while no improvement was observed for the repetitive behavior. D2 receptor signaling in the central striatum (CS) was involved in SSRI-resistant repetitive behavior. An adenosine A2A antagonist, istradefylline, which rescued abnormal excitatory synaptic function in the CS indirect pathway medium spiny neurons (MSNs) of sensitized mice, alleviated both of the QNP-induced abnormal behaviors with only short-term administration. These results provide a new insight into therapeutic strategies for SSRI-resistant OCD symptoms and indicate the potential of A2A antagonists as a rapid-acting anti-OCD drug.

Increased oxidative stress in the cerebellum and peripheral immune cells leads to exaggerated autism-like repetitive behavior due to deficiency of antioxidant response in BTBR T + tf/J mice.

Autism is a neurodevelopmental disorder that affects social cognitive abilities resulting in communication or sensory deficits, and stereotyped behaviors in millions of people worldwide. Oxidant-antioxidant imbalance contributes significantly to the neurobehavioral dysregulations and severity of symptoms in patients with autism, however it has not been explored earlier whether it affects autism-like behavior directly. Therefore, we investigated oxidant-antioxidant balance in peripheral immune cells (neutrophils and CD3+ T cells) and cerebellum of BTBR T + tf/J (BTBR) mice which show autism-like behavior and the social C57BL/6 J (C57) mice. Further, we utilized buthionine sulfoximine (BSO), a glutathione depleting agent to assess the impact of oxidant-antioxidant dysregulation on autism-like behavior. Our study shows that BTBR mice have increased lipid/protein oxidation products in cerebellum and neutrophils/CD3+ T cells along with increased NADPH oxidase (NOX2) and inducible nitric oxide synthase (iNOS) expression. This was concurrent with lower levels of glutathione and enzymatic antioxidants such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the cerebellum and peripheral immune cells. BSO administration led to further lowering of glutathione with a concurrent upregulation of iNOS, and NOX2 in cerebellum and peripheral immune cells. However, there was deficiency of an adaptive antioxidant response which was associated with exaggerated repetitive behaviors in BTBR mice. On the other hand, C57 mice also had increased oxidative stress after BSO treatment, however there was an enzymatic antioxidant response both in cerebellum and periphery. Overall, this study suggests that BTBR mice have increased oxidative stress with a deficient enzymatic antioxidant response that is associated with autism-like repetitive behaviors.

Alcohol aggravates ketamine-induced behavioral, morphological and neurochemical alterations in adolescent rats: The involvement of CREB-related pathways.

Currently, an increasing proportion of adolescent ketamine users simultaneously consume alcohol. However, the potential behavioural and neurological alterations induced by such a drug combination and the underlying mechanisms have not been systematically examined. Therefore, in the present study, the behavioural and morphological changes and the underlying mechanisms were studied in adolescent rats after repeated alcohol and/or ketamine treatment. This study provided the first evidence that co-administration of alcohol (2 and 4 g/kg, i.g.) in adolescent rats significantly potentiated the neurotoxic properties of repeated ketamine (30 mg/kg, i.p.) treatments over 14 days, manifesting as increased locomotor activity, stereotypic behaviour, ataxia and morphological changes. This potentiation was associated with the enhancement by alcohol of ketamine-induced glutamate (Glu) and dopamine (DA) release in the cortex and hippocampus. Further mechanistic study demonstrated that alcohol potentiated ketamine-induced neurotoxicity through down-regulation of Akt (a serine/threonine kinase or protein kinase, PKB), protein kinase A (PKA), calmodulin-dependent kinase IV (CaMK-IV)-mediated cyclic AMP-responsive element binding protein (CREB) pathways and induction of neuronal apoptosis in the cortex and hippocampus of the adolescent rats. As this study provides strong evidence that repeated alcohol and ketamine co-exposure may cause serious neurotoxicity, attention needs to be drawn to the potential risk of this consumption behaviour, especially for adolescents.

The adenosine A2A receptor agonist, CGS 21680, attenuates a probabilistic reversal learning deficit and elevated grooming behavior in BTBR mice.

Restricted interests and repetitive behaviors (RRBs) are a defining feature of autism spectrum disorder (ASD). To date there are limited options for treating this core symptomology. Treatments that stimulate adenosine A2A receptors may represent a promising approach for reducing RRBs in ASD. This is because A2A receptors are expressed on striatal neurons of the basal ganglia indirect pathway. Under activation of this pathway has been associated with RRBs while activation of A2A receptors leads to increased activity of the indirect basal ganglia pathway. The present studies investigated whether acute, systemic treatment with CGS21680, an A2A receptor agonist attenuates elevated self-grooming and a probabilistic reversal learning deficit in the BTBR T+ Itpr3tf /J (BTBR) mouse model of idiopathic autism. The effects of this treatment were also investigated in C57BL/6J (B6) mice as a comparison strain. Using a spatial reversal learning test with 80/20 probabilistic feedback, comparable to one in which ASD individuals exhibit deficits, CGS 21680 (0.005 and 0.01mg/kg) attenuated a reversal learning deficit in BTBR mice. Enhancement in probabilistic reversal learning performance resulted from CGS 21680 improving the consistent maintenance of new adaptive behavioral choice patterns after reversal. CGS 21680 at 0.01 mg, but not 0.005 mg, also reduced self-grooming behavior in BTBR mice. CGS 21680 did not affect self-grooming or reversal learning in B6 mice. These findings demonstrate that A2A receptor agonists may be a promising receptor target in the treatment of RRBs in ASD. Autism Res 2018, 11: 223-233. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The present experiments determined whether the drug, CGS 21680, that facilitates activation of adenosine A2A receptors in the brain, would reduce repetitive and inflexible behaviors in the BTBR mouse model of idiopathic autism. CGS 21680 treatment in BTBR mice reduced repetitive and inflexible behaviors. In the control C57BL/6J (B6) mouse strain, CGS 21680 did not affect performance. These findings suggest that stimulation of brain adenosine A2A receptors may be a promising therapeutic strategy in ASD.

Survey of cat owners on features of, and preventative measures for, feline scratching of inappropriate objects: a pilot study.

Objectives The objective of this study was to collect preliminary data on relevant features and preventative measures of feline inappropriate scratching. Preliminary data could then be used to inform future randomized controlled studies. Methods A paper questionnaire was distributed to 140 cat-owning clients of a small animal practice. The response rate was 82.9%. Questions related to features of inappropriate and designated items scratched, frequency of the behavior and how owners attempted to modify the behavior. The frequency of scratching was ranked and analyzed with repeated-measures models for differences between features of items. The effectiveness of techniques to modify scratching was analyzed with Student's t-tests comparing frequencies of scratching between cats of survey participants who did and did not use specific techniques. Results Scratching of inappropriate items was reported for 83.9% of cats. Most cats (81.5%) scratched chairs or other furniture and 64.1% scratched carpet. The frequency of scratching inappropriate items was significantly influenced by type and material of the items scratched, with furniture and carpet, and fabric and carpet, respectively, being scratched most often. Most cats (76.1%) had a designated scratching item. The frequency of scratching designated items was significantly influenced by type, with cats using scratching posts and other items more often than scratch pads. Owners used a variety of punishment- and reward-based techniques to stop inappropriate scratching and encourage scratching of designated items; only one technique was found to have a significant effect, with the frequency of scratching designated items being significantly lower in cats that were placed near the item. Conclusions and relevance Furniture covered with fabric was an object frequently scratched. Fabric should be further investigated as a potential material to encourage desired scratching behavior. Scratch pads appeared less desired than scratching posts. Punishment was a common strategy to deter scratching but did not appear to influence the frequency of scratching.

Effects of confinement duration and parity on stereotypic behavioral and physiological responses of pregnant sows.

The aim of this study was to evaluate the effects of space restriction stress on the stereotypic behavioral and physiological responses of different parity sows, and it is necessary to understand such effects due to space restriction to improve the welfare of the sows in confined conditions. We selected fifty pregnant sows (Large White) at primiparity and first to fifth parity in a confined farm with the same body condition and due date (3±1.5days). Behavioral observations and physiological analysis were carried out during spatial confinement throughout pregnancy. The results showed that there were no significant changes in vacuum-chewing, bar-biting, trough-biting and the concentrations of serum IL-6 in primiparous sows during the initial confinement (0-8days). With the increase of the confinement duration, the serum cortisol, IgA, IL-6 concentrations and the vacuum-chewing frequency of sows in all groups increased significantly, and the serum concentrations of C-reactive protein and Pig-MAP increased significantly except for the sows in the first and second parity groups. The serum cortisol, IgA, IL-6 concentrations and the vacuum-chewing frequency of older sows were significantly higher than those of the young sows throughout the entire restricted feeding period, but the serum C-reactive protein concentrations of primiparous gilts was significantly higher than those of the other groups. The serum cortisol, IgA, IL-6 concentrations and bar-biting and trough-biting frequencies of all parity sows decreased significantly after entering the delivery bed. In conclusion, long-lasting and recurrent environmental constraints can significantly increase the frequency of stereotypical behavior and serious psychological and physical stress, seriously damaging sow welfare.

α2* Nicotinic acetylcholine receptors influence hippocampus-dependent learning and memory in adolescent mice.

The absence of α2* nicotinic acetylcholine receptors (nAChRs) in oriens lacunosum moleculare (OLM) GABAergic interneurons ablate the facilitation of nicotine-induced hippocampal CA1 long-term potentiation and impair memory. The current study delineated whether genetic mutations of α2* nAChRs (Chrna2L9'S/L9'S and Chrna2KO) influence hippocampus-dependent learning and memory and CA1 synaptic plasticity. We substituted a serine for a leucine (L9'S) in the α2 subunit (encoded by the Chrna2 gene) to make a hypersensitive nAChR. Using a dorsal hippocampus-dependent task of preexposure-dependent contextual fear conditioning, adolescent hypersensitive Chrna2L9'S/L9'S male mice exhibited impaired learning and memory. The deficit was rescued by low-dose nicotine exposure. Electrophysiological studies demonstrated that hypersensitive α2 nAChRs potentiate acetylcholine-induced ion channel flux in oocytes and acute nicotine-induced facilitation of dorsal/intermediate CA1 hippocampal long-term potentiation in Chrna2L9'S/L9'S mice. Adolescent male mice null for the α2 nAChR subunit exhibited a baseline deficit in learning that was not reversed by an acute dose of nicotine. These effects were not influenced by locomotor, sensory or anxiety-related measures. Our results demonstrated that α2* nAChRs influenced hippocampus-dependent learning and memory, as well as nicotine-facilitated CA1 hippocampal synaptic plasticity.

Long term beneficial effect of neurotrophic factors-secreting mesenchymal stem cells transplantation in the BTBR mouse model of autism.

Autism spectrum disorders (ASD) are neurodevelopmental disabilities characterized by severe impairment in social communication skills and restricted, repetitive behaviors. We have previously shown that a single transplantation of mesenchymal stem cells (MSC) into the cerebral lateral ventricles of BTBR autistic-like mice resulted in an improvement across all diagnostic criteria of ASD. We suggested that brain-derived neurotrophic factor (BDNF), a protein which supports the survival and regeneration of neurons secreted by MSC, largely contributed to the beneficial behavioral effect. In this study, we investigated the behavioral effects of transplanted MSC induced to secrete higher amounts of neurotrophic factors (NurOwn®), on various ASD-related behavioral domains using the BTBR mouse model of ASD. We demonstrate that NurOwn® transplantation had significant advantages over MSC transplantation in terms of improving communication skills, one and six months following treatment, as compared to sham-treated BTBR mice. Furthermore, NurOwn® transplantation resulted in reduced stereotypic behavior for as long as six months post treatment, compared to the one month improvement observed in the MSC treated mice. Notably, NurOwn® treatment resulted in improved cognitive flexibility, an improvement that was not observed by MSC treatment. Both MSC and NurOwn® transplantation induced an improvement in social behavior that lasted for six months. In conclusion, the present study demonstrates that a single transplantation of MSC or NurOwn® have long-lasting benefits, while NurOwn® may be superior to MSC treatment.

Targeted Interneuron Depletion in the Dorsal Striatum Produces Autism-like Behavioral Abnormalities in Male but Not Female Mice.

BACKGROUND: Interneuronal pathology is implicated in many neuropsychiatric disorders, including autism spectrum disorder (ASD) and Tourette syndrome (TS). Interneurons of the striatum, including the parvalbumin-expressing fast-spiking interneurons (FSIs) and the large cholinergic interneurons (CINs), are affected in patients with TS and in preclinical models of both ASD and TS. METHODS: To test the causal importance of these neuronal abnormalities, we recapitulated them in vivo in developmentally normal mice using a combination transgenic-viral strategy for targeted toxin-mediated ablation. RESULTS: We found that conjoint ~50% depletion of FSIs and CINs in the dorsal striatum of male mice produces spontaneous stereotypy and marked deficits in social interaction. Strikingly, these behavioral effects are not seen in female mice; because ASD and TS have a marked male predominance, this observation reinforces the potential relevance of the finding to human disease. Neither of these effects is seen when only one or the other interneuronal population is depleted; ablation of both is required. Depletion of FSIs, but not of CINs, also produces anxiety-like behavior, as has been described previously. Behavioral pathology in male mice after conjoint FSI and CIN depletion is accompanied by increases in activity-dependent signaling in the dorsal striatum; these alterations were not observed after disruption of only one interneuron type or in doubly depleted female mice. CONCLUSIONS: These data indicate that disruption of CIN and FSI interneurons in the dorsal striatum is sufficient to produce network and behavioral changes of potential relevance to ASD, in a sexually dimorphic manner.

Efficacy of mGlu2 -positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures.

OBJECTIVE: The metabotropic glutamate receptor subtype 2 (mGlu2 ) possesses both orthosteric and allosteric modulatory sites, are expressed in the frontal cortex and limbic structures, and can affect excitatory synaptic transmission. Therefore, mGlu2 is a potential therapeutic target in the treatment of epilepsy. The present study seeks to evaluate the anticonvulsant potential of mGlu2 -acting compounds. METHODS: The anticonvulsant efficacy of two selective mGlu2 -positive allosteric modulators (PAMs) (JNJ-42153605 and JNJ-40411813/ADX71149) and one mGlu2/3 receptor agonist (LY404039) were evaluated alone and in combination with the antiseizure drug levetiracetam (LEV) in the mouse 6 Hz model. RESULTS: In the 6 Hz (32 mA stimulus intensity) model, median effective dose (ED50 ) values were determined for JNJ-42153605 (3.8 mg/kg), JNJ-40411813 (12.2 mg/kg), and LY404039 (10.9 mg/kg). At the 44 mA stimulus intensity, ED50 values were determined for JNJ-42153605 (5.9 mg/kg), JNJ-40411813 (21.0 mg/kg), LY404039 (14.1 mg/kg), and LEV (345 mg/kg). In addition, subprotective doses of each mGlu2 -acting compound, administered in combination with various doses of LEV, were able to shift the 6 Hz 44 mA ED50 for LEV by >25-fold. When JNJ-42153605 was administered at varying doses in combination with a single dose of LEV (10 mg/kg), the potency of JNJ-42153605 was increased 3.7-fold. Similarly, when a moderately effective dose of LEV (350 mg/kg) was administered in combination with varying doses of JNJ-40411813, the potency of JNJ-40411813 was increased approximately 14-fold. Plasma levels of JNJ-40411813 and LEV were not different when administered alone or in combination, suggesting that increases in potency are not due to pharmacokinetic effects. SIGNIFICANCE: These studies suggest a potential positive pharmacodynamic effect of mGlu2 -acting compounds in combination with LEV. If this effect is translated in a clinical setting, it can support a rational polypharmacy concept in treatment of epilepsy patients.

Long-term protective effects of AAV9-mesencephalic astrocyte-derived neurotrophic factor gene transfer in parkinsonian rats.

Intrastriatal injection of mesencephalic astrocyte-derived neurotrophic factor (MANF) protein has been shown to provide neuroprotective and neurorestorative effects in a 6-hydroxydopamine (6-OHDA) - lesioned rat model of Parkinson's disease. Here, we used an adeno-associated virus serotype 9 (AAV9) vector to deliver the human MANF (hMANF) gene into the rat striatum 10days after a 6-OHDA lesion to examine long-term effects of hMANF on nigral dopaminergic neurons and mechanisms underlying MANF neuroprotection. Intrastriatal injection of AAV9-hMANF vectors led to a robust and widespread expression of the hMANF gene in the injected striatum up to 24weeks. Increased levels of hMANF protein were also detected in the ipsilateral substantia nigra. The hMANF gene transfer promoted the survival of nigral dopaminergic neurons, regeneration of striatal dopaminergic fibers and an upregulation of striatal dopamine levels, resulting in a long-term improvement of rotational behavior up to 16weeks after viral injections. By using SH-SY5Y cells, we found that intra- and extracellular application of MANF protected cells against 6-OHDA-induced toxicity via inhibiting the endoplasmic reticulum stress and activating the PI3K/Akt/mTOR pathway. Our results suggest that AAV9-mediated hMANF gene delivery into the striatum exerts long-term neuroprotective and neuroregenerative effects on the nigrostriatal dopaminergic system in parkinsonian rats, and provide insights into mechanisms responsible for MANF neuroprotection.

[CYTOKINES SECRETION BY SPLENOCY-TES IN RESPONSE TO MICE F1 (C57BL/6XDBA/2) BEHAVIOR IN ENVIRONMENTS OF VARYING COMPLEXITY].

We study the dependence of the mitogen-induced cytokine secretion by splenocytes from the character of the behavior of F1 (C57BL/6XDBA/2) mice in environments with different degrees of spatial complexity: simple in the form of home box, enriched box and maze. Suppression of in-terleukins IL-2, IL-4, IL-6 and IL-10 expression, regardless of their structural and functional properties, was observed only in an enriched environment when aggressive and neurotic manifestations were increased. The opposite effect in the form of significant increase of the productions in all studied cytokines was observed in the case of the stereotypical goal-directed behavior in a maze. It was supposed that cytokines of the splenocytes are involved in the realization of highly 307 differentiated adaptive response of the organism due to the influence of social and cognitive factors, the expression of which depends on the specific physiological and biochemical systems.

Differential behavioral and molecular alterations upon protracted abstinence from cocaine versus morphine, nicotine, THC and alcohol.

Unified theories of addiction are challenged by differing drug-seeking behaviors and neurobiological adaptations across drug classes, particularly for narcotics and psychostimulants. We previously showed that protracted abstinence to opiates leads to despair behavior and social withdrawal in mice, and we identified a transcriptional signature in the extended amygdala that was also present in animals abstinent from nicotine, Δ9-tetrahydrocannabinol (THC) and alcohol. Here we examined whether protracted abstinence to these four drugs would also share common behavioral features, and eventually differ from abstinence to the prototypic psychostimulant cocaine. We found similar reduced social recognition, increased motor stereotypies and increased anxiety with relevant c-fos response alterations in morphine, nicotine, THC and alcohol abstinent mice. Protracted abstinence to cocaine, however, led to strikingly distinct, mostly opposing adaptations at all levels, including behavioral responses, neuronal activation and gene expression. Together, these data further document the existence of common hallmarks for protracted abstinence to opiates, nicotine, THC and alcohol that develop within motivation/emotion brain circuits. In our model, however, these do not apply to cocaine, supporting the notion of unique mechanisms in psychostimulant abuse.

The effect of visitor number and spice provisioning in pacing expression by jaguars evaluated through a case study / O efeito do número de visitantes e do provisionamento de especiaria na expressão do pacing por onças-pintadas avaliado por estudo de caso

Abstract Captive animals exhibit stereotypic pacing in response to multiple causes, including the inability to escape from human contact. Environmental enrichment techniques can minimize pacing expression. By using an individual-based approach, we addressed whether the amount of time two males and a female jaguar (Panthera onca) devote to pacing varied with the number of visitors and tested the effectiveness of cinnamon and black pepper in reducing pacing. The amount of time that all jaguars engaged in pacing increased significantly with the number of visitors. Despite the difference between the males regarding age and housing conditions, both devoted significantly less time to pacing following the addition of both spices, which indicates their suitability as enrichment techniques. Mean time devoted to pacing among the treatments did not differ for the female. Our findings pointed out to the validity of individual-based approaches, as they can reveal how suitable olfactory stimuli are to minimizing stereotypies irrespective of particular traits.

Resumo Animais cativos exibem a estereotipia pacing em resposta a múltiplos fatores, os quais incluem a incapacidade de escapar da exposição ao público. As técnicas de enriquecimento ambiental podem minimizar a expressão do pacing. Usando uma abordagem individual, nós investigamos se a extensão de tempo que dois machos e uma fêmea de onça-pintada (Panthera onca) dispendem com pacing variou em função do número de visitantes e testamos a eficácia da canela e da pimenta-do-reino na redução do pacing. A extensão de tempo em pacing aumentou significativamente com o número de visitantes para todos os indivíduos. Apesar da diferença entre os machos com relação à idade e às condições no cativeiro, ambos devotaram ao pacing menos tempo após a administração das duas especiarias, o que indica a adequabilidade dessas como técnicas de enriquecimento. Para a fêmea, o tempo médio dispendido com pacing não variou entre os tratamentos. Nossos resultados respaldam a validade da realização de abordagens individuais, uma vez que essas podem revelar o grau de eficácia dos estímulos olfativos na minimização de estereotipias independentemente de características particulares.