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Neuronal connectivity is essential for adaptive brain responses and can be modulated by dendritic spine plasticity and the intrinsic excitability of individual neurons. Dysregulation of these processes can lead to aberrant neuronal activity, which has been associated with numerous neurological disorders including autism, epilepsy, and Alzheimer's disease. Nonetheless, the molecular mechanisms underlying abnormal neuronal connectivity remain unclear. We previously found that the serine/threonine kinase Microtubule Affinity Regulating Kinase 2 (MARK2), also known as Partitioning Defective 1b (Par1b), is important for the formation of dendritic spines in vitro. However, despite its genetic association with several neurological disorders, the in vivo impact of MARK2 on neuronal connectivity and cognitive functions remains unclear. Here, we demonstrate that the loss of MARK2 in vivo results in changes to dendritic spine morphology, which in turn leads to a decrease in excitatory synaptic transmission. Additionally, the loss of MARK2 produces substantial impairments in learning and memory, reduced anxiety, and defective social behavior. Notably, MARK2 deficiency results in heightened seizure susceptibility. Consistent with this observation, electrophysiological analysis of hippocampal slices indicates underlying neuronal hyperexcitability in MARK2-deficient neurons. Finally, RNAseq analysis reveals transcriptional changes in genes regulating synaptic transmission and ion homeostasis. These results underscore the in vivo role of MARK2 in governing synaptic connectivity, neuronal excitability, and cognitive functions., (© 2024 Federation of American Societies for Experimental Biology.)

Timing and quantity of sleep depend on a circadian (∼24-h) rhythm and a specific sleep requirement. 1 Sleep curtailment results in a homeostatic rebound of more and deeper sleep, the latter reflected in increased electroencephalographic (EEG) slow-wave activity (SWA) during non-rapid eye movement (NREM) sleep. 2 Circadian rhythms are synchronized by the light-dark cycle but persist under constant conditions. 3 , 4 , 5 Strikingly, arctic reindeer behavior is arrhythmic during the solstices. 6 Moreover, the Arctic's extreme seasonal environmental changes cause large variations in overall activity and food intake. 7 We hypothesized that the maintenance of optimal functioning under these extremely fluctuating conditions would require adaptations not only in daily activity patterns but also in the homeostatic regulation of sleep. We studied sleep using non-invasive EEG in four Eurasian tundra reindeer (Rangifer tarandus tarandus) in Tromsø, Norway (69°N) during the fall equinox and both solstices. As expected, sleep-wake rhythms paralleled daily activity distribution, and sleep deprivation resulted in a homeostatic rebound in all seasons. Yet, these sleep rebounds were smaller in summer and fall than in winter. Surprisingly, SWA decreased not only during NREM sleep but also during rumination. Quantitative modeling revealed that sleep pressure decayed at similar rates during the two behavioral states. Finally, reindeer spent less time in NREM sleep the more they ruminated. These results suggest that they can sleep during rumination. The ability to reduce sleep need during rumination-undisturbed phases for both sleep recovery and digestion-might allow for near-constant feeding in the arctic summer., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Neuronal connectivity is essential for adaptive brain responses and can be modulated by dendritic spine plasticity and the intrinsic excitability of individual neurons. Dysregulation of these processes can lead to aberrant neuronal activity, which has been associated with numerous neurological disorders including autism, epilepsy, and Alzheimer's disease. Nonetheless, the molecular mechanisms underlying aberrant neuronal connectivity remains unclear. We previously found that the serine/threonine kinase Microtubule Affinity Regulating Kinase 2 (MARK2), also known as Partitioning Defective 1b (Par1b), is important for the formation of dendritic spines in vitro. However, despite its genetic association with several neurological disorders, the in vivo impact of MARK2 on neuronal connectivity and cognitive functions remains unclear. Here, we demonstrate that loss of MARK2 in vivo results in changes to dendritic spine morphology, which in turn leads to a decrease in excitatory synaptic transmission. Additionally, loss of MARK2 produces substantial impairments in learning and memory, anxiety, and social behavior. Notably, MARK2 deficiency results in heightened seizure susceptibility. Consistent with this observation, RNAseq analysis reveals transcriptional changes in genes regulating synaptic transmission and ion homeostasis. These findings underscore the in vivo role of MARK2 in governing synaptic connectivity, cognitive functions, and seizure susceptibility.

Microglia serve as resident immune cells in the brain, responding to insults and pathological developments. They have also been implicated in shaping synaptic development and regulation. The present study examined microglial cell density in a number of brain regions across select postnatal (P) ages along with the effects of valproic acid (VPA) on microglia density. Specifically, C57BL/6JCx 3 CR1 +/GFP mice were examined for microglial cell number changes on P7, P14, P30, and P60 under baseline conditions and following 400 mg/kg VPA or saline. The prefrontal cortex (PFC), hippocampus and cerebellum were observed. Under control conditions, the results showed a shift in the number of microglia in these brain areas throughout development with a peak density in the hippocampus at P14 and an increase in PFC microglial numbers from P15 to P30. Interestingly, VPA treatment enhanced microglial numbers in a region-specific manner. VPA at P7 increased microglial cell number in the hippocampus and cerebellum whereas P14 VPA treatment altered microglial density in the cerebellum only. Cerebellar increases also occurred after VPA at P30, and were attended by an effect of increased numbers in the PFC. Finally, animals treated with VPA at P60 exhibited decreased microglia density in the hippocampus only. These results suggest rapid VPA-induced increases in microglial cell density in a developmentally-regulated fashion which differs across distinct brain areas. Furthermore, in the context of prior reports that early VPA causes excitotoxic damage, the present findings suggest early VPA exposure may provide a model for studying altered microglial responses to early toxicant challenge., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.)

The high Arctic archipelago of Svalbard (74°-81° north) experiences extended periods of uninterrupted daylight in summer and uninterrupted night in winter, apparently relaxing the major driver for the evolution of circadian rhythmicity. Svalbard ptarmigan (Lagopus muta hyperborea) is the only year-round resident terrestrial bird species endemic to the high Arctic and is remarkably adapted to the extreme annual variation in environmental conditions. 1 Here, we demonstrate that, although circadian control of behavior disappears rapidly upon transfer to constant light conditions, consistent with the loss of daily activity patterns observed during the polar summer and polar night, Svalbard ptarmigans nonetheless employ a circadian-based mechanism for photoperiodic timekeeping. First, we show the persistence of rhythmic clock gene expression under constant light within the mediobasal hypothalamus and pars tuberalis, the key tissues in the seasonal neuroendocrine cascade. We then employ a "sliding skeleton photoperiod" protocol, revealing that the driving force behind seasonal biology of the Svalbard ptarmigan is rhythmic sensitivity to light, a feature that depends on a functioning circadian rhythm. Hence, the unusual selective pressures of life in the high Arctic have favored decoupling of the circadian clock from organization of daily activity patterns, while preserving its importance for seasonal synchronization., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Organisms use circadian rhythms to anticipate and exploit daily environmental oscillations. While circadian rhythms are of clear importance for inhabitants of tropic and temperate latitudes, its role for permanent residents of the polar regions is less well understood. The high Arctic Svalbard ptarmigan shows behavioral rhythmicity in presence of light-dark cycles but is arrhythmic during the polar day and polar night. This has been suggested to be an adaptation to the unique light environment of the Arctic. In this study, we examined regulatory aspects of the circadian control system in the Svalbard ptarmigan by recording core body temperature ( T b ) alongside locomotor activity in captive birds under different photoperiods. We show that T b and activity are rhythmic with a 24-h period under short (SP; L:D 6:18) and long photoperiod (LP; L:D 16:8). Under constant light and constant darkness, rhythmicity in T b attenuates and activity shows signs of ultradian rhythmicity. Birds under SP also showed a rise in T b preceding the light-on signal and any rise in activity, which proves that the light-on signal can be anticipated, most likely by a circadian system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Appenroth, Nord, Hazlerigg and Wagner.)

Organisms use changes in photoperiod to anticipate and exploit favourable conditions in a seasonal environment. While species living at temperate latitudes receive day length information as a year-round input, species living in the Arctic may spend as much as two-thirds of the year without experiencing dawn or dusk. This suggests that specialised mechanisms may be required to maintain seasonal synchrony in polar regions. Svalbard ptarmigan ( Lagopus muta hyperborea ) are resident at 74-81°N latitude. They spend winter in constant darkness (DD) and summer in constant light (LL); extreme photoperiodic conditions under which they do not display overt circadian rhythms. Here, we explored how Arctic adaptation in circadian biology affects photoperiodic time measurement in captive Svalbard ptarmigan. For this purpose, DD-adapted birds, showing no circadian behaviour, either remained in prolonged DD, were transferred into a simulated natural photoperiod (SNP) or were transferred directly into LL. Birds transferred from DD to LL exhibited a strong photoperiodic response in terms of activation of the hypothalamic thyrotropin-mediated photoperiodic response pathway. This was assayed through expression of the Eya3 , Tshβ and deiodinase genes, as well as gonadal development. While transfer to SNP established synchronous diurnal activity patterns, activity in birds transferred from DD to LL showed no evidence of circadian rhythmicity. These data show that the Svalbard ptarmigan does not require circadian entrainment to develop a photoperiodic response involving conserved molecular elements found in temperate species. Further studies are required to define how exactly Arctic adaptation modifies seasonal timer mechanisms., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

The repeated administration of high doses of amphetamine has been shown to cause long-lasting depletions of striatal dopamine which, when substantial enough, have been shown to result in cognitive and motor impairment. These amphetamine-induced lesions are slightly larger in males than that in females and can be partially ameliorated by pretreatment with antioxidants. The objective of the present study was to replicate these two latter observations using an amphetamine dosing regimen that yields only minor depletions of dopamine. It was found that a low-dose treatment of amphetamine using only two subcutaneous injections caused a 57% depletion of striatal dopamine with males slightly more affected than females. Furthermore, pretreatment with ascorbic acid reduced the magnitude of this dopamine depletion with males exhibiting a slightly enhanced protection as compared to females. Compared to the traditionally used high-dose regimens, these effects were mild but in the same direction. The advantage of this regimen is that it better reflects amphetamine-induced depletions of dopamine in humans.

Valproic acid (VPA) administered to mice during the early postnatal period causes social, cognitive, and motor deficits similar to those observed in humans with autism spectrum disorder (ASD). However, previous studies on the effects of early exposure to VPA have largely focused on behavioral deficits occurring before or during the juvenile period of life. Given that ASD is a life-long condition, the present study ought to extend our understanding of the behavioral profile following early postnatal VPA into adulthood. Male mice treated with VPA on postnatal day 14 (P14) displayed increased aggression, decreased avoidance of the open arms in the elevated plus maze, and impaired reversal learning in the Y maze. This may indicate a disinhibited or impulsive phenotype in male, but not female, mice treated with VPA during the second week of postnatal life. Decreased dendritic spine density and dendritic spine morphological abnormalities in the mPFC of VPA-treated mice may be indicative of PFC hypofunction, consistent with the observed behavioral differences. Since these types of long-lasting deficits are not exclusively found in ASD, early life exposure to VPA may reflect dysfunction of a neurobiological domain common to several developmental disorders, including ASD, ADHD, and conduct disorder., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.)

The gamma-aminobutyric acid (GABA)-shift hypothesis proposes that GABA agonist action is excitatory early in development and transitions to an inhibitory role later in life. In experiment 1, the nonspecific GABA agonist, valproic acid (VPA), was administered to pregnant C57BL/6 mice on embryonic day 13. Fetal and maternal brains were harvested 2 h post-VPA exposure and assayed for nuclear factor erythroid 2-related factor 2 (NRF2) and H3 expression through western blot analysis. In experiment 2, VPA was administered to neonatal pups on P14 and adult mice on P60. In both experiments, it was observed that NRF2 expression was increased in fetal and neonatal brains, but not in the adult brain. Because NRF2 expression is activated by oxidative stress, these results imply support of the GABA-shift hypothesis in that VPA may exert its developmental damage in the fetal and neonatal periods through excitotoxicity.

Cell replacement therapy is a promising treatment strategy for Parkinson's disease (PD); however, the poor survival rate of transplanted neurons is a critical barrier to functional recovery. In this study, we used self-assembling peptide nanofiber scaffolds (SAPNS) based on the peptide RADA16-I to support the in vitro maturation and in vivo post-transplantation survival of encapsulated human dopaminergic (DA) neurons derived from induced pluripotent stem cells. Neurons encapsulated within the SAPNS expressed mature neuronal and midbrain DA markers and demonstrated in vitro functional activity similar to neurons cultured in two dimensions. A microfluidic droplet generation method was used to encapsulate cells within monodisperse SAPNS microspheres, which were subsequently used to transplant adherent, functional networks of DA neurons into the striatum of a 6-hydroxydopamine-lesioned PD mouse model. SAPNS microspheres significantly increased the in vivo survival of encapsulated neurons compared with neurons transplanted in suspension, and they enabled significant recovery in motor function compared with control lesioned mice using approximately an order of magnitude fewer neurons than have been previously needed to demonstrate behavioral recovery. These results indicate that such biomaterial scaffolds can be used as neuronal transplantation vehicles to successfully improve the outcome of cell replacement therapies for PD. Impact Statement Transplantation of dopaminergic (DA) neurons holds potential as a treatment for Parkinson's disease (PD), but low survival rates of transplanted neurons is a barrier to successfully improving motor function. In this study, we used hydrogel scaffolds to transplant DA neurons into PD model mice. The hydrogel scaffolds enhanced survival of the transplanted neurons compared with neurons that were transplanted in a conventional manner, and they also improved recovery of motor function by using significantly fewer neurons than have typically been transplanted to see functional benefits. This cell transplantation technology has the capability to improve the outcome of neuron transplantation therapies.

Oxidative stress has been implicated in both the functional and cognitive decline associated with neuropsychiatric diseases and aging. A master regulator of the body's defense mechanism against oxidative stress is nuclear factor erythroid 2-related factor (NRF2). Here we investigated the effects of NRF2 deletion on motor and cognitive performance in "Aged" mice (17-25 months old) as compared to "Mature" mice (3-15 months old). We observed that the Aged Nrf2 -/- mice were hyperactive and exhibited impaired acquisition of an active avoidance response. Furthermore, the Mature mice also displayed a hyperactive phenotype and had impaired working memory in the probe trial of the water radial arm maze. Overall, it appears that NRF2 may be implicated in memory and activity functions and its deletion exacerbates deficits associated with aging. These observations provide a model for assessing the role of oxidative stress in age-related disorders., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Cleaning behavioral equipment between rodent subjects is important to prevent disease transmission and reduce odor cues from previous subjects. However, the reporting regarding the cleansing procedures used during such experiments is sporadic and often incomplete. In addition, some investigators are reluctant to clean devices between subjects because they are concerned that animals will react negatively to the smell of the cleansing agents. We hypothesized that mice tested on an elevated plus maze (EPM) soiled with excretions from conspecifics would test as being more stressed than mice tested on the same apparatus that was cleaned between animals. We tested the performance of C57BL/6J mice on an EPM sanitized with 3 common cleaning agents-isopropyl alcohol, chlorine dioxide, and bleach-and on an EPM soiled with rodent urine, feces, and presumably pheromones. We further tested the potentially aversive nature of the cleansing agents by using the classic light:dark box and a 2-choice light:dark box. Our data indicate that cleaning the EPM compared with leaving it soiled did not affect performance in male or female C57 mice, nor did cleaning agent choice. In addition, test subjects did not react to the presence of the cleaning agents when incorporated into the classic light:dark test. However, in the 2-choice light:dark test, mice given the option to avoid an area containing a cleaning agent showed aversion to all 3 agents, when all other conditions were equal. Given the lack of an observable effect of cleaning on EPM performance, we recommend cleaning of the EPM device between C57 mice to minimize the potential spread of disease.

Increased alcohol consumption and heightened aggression have been linked to social isolation. Furthermore, animals treated with alcohol following social separation showed higher aggression together with lower serotonin transmission. Although reduced serotonin transmission in the brain may be related to alcohol-induced heightened aggression and fluoxetine has been used to reduce alcohol intake and aggression, it remains unclear whether there are specific brain regions where changes in serotonin transmission are critical for animal aggression following the alcohol treatment. In the present study, we isolated mice for 4-6weeks and injected them with alcohol, fluoxetine and alcohol with fluoxetine. We studied their aggression by using two types of behavioral paradigms: isolation-induced attack behavior towards a naïve mouse in a neutral cage, or shock-induced target biting aggression. We observed that alcohol administered at 500mg/kg significantly increased animal attack behaviors towards naïve mice 30min after injections. This dose of alcohol co-administered with a low dose of fluoxetine (2mg/kg) further increased the attack behaviors, but with higher doses of fluoxetine, the attack behaviors were decreased. Alcohol administered at a dose of 1,000mg/kg significantly decreased the shock-induced target biting rates 24h after injections. Interestingly, 24h after injections, we observed a significant increase in target biting rates when alcohol was co-administered with fluoxetine at a dose of 16mg/kg. We also observed the same heightened target biting rates when animals were injected with fluoxetine alone. This heightened biting attack engendered by the fluoxetine (alone or in combination with the alcohol) occurred at a time when brain serotonin activity was reduced by these drugs in the frontal cortex and hypothalamus. These observations, in concordance with previous findings reported by others, indicate that heightened biting attack behavior may be associated with reduced serotonergic activity in brain regions regulating aggression., (Copyright © 2017 Elsevier B.V. All rights reserved.)

During development of the nervous system, molecular signals mediating cell-cell interactions play critical roles in the guidance of axonal growth and establishment of synaptic functions. The Eph family of tyrosine kinase receptors and their ephrin ligands has been shown to mediate neuronal interactions in the development of topographic axon projection maps in several brain regions, and the loss of Eph activities result in defects in select axonal pathways. However, effects of deficiencies of the Eph signals on animal behavior have not been well documented. In this study, we showed that inactivation of a ligand of the Eph receptors, ephrin-A5, resulted in defects in maternal behavior and alterations in anxiety. Female ephrin-A5 -/- mice show significant defects in nest building and pup retrieval. In addition, lower levels of anxiety were observed in both male and female null mice. These changes were not due to deficiencies in estradiol, progesterone or corticosterone levels. Our observations suggest that ephrin-A5 plays a key role in the development and/or function of neural pathways mediating mouse maternal care and anxiety., (© 2016 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

In mammals, changing daylength (photoperiod) is the main synchronizer of seasonal functions. The photoperiodic information is transmitted through the retino-hypothalamic tract to the suprachiasmatic nuclei (SCN), site of the master circadian clock. To investigate effects of day length change on the sheep SCN, we used in-situ hybridization to assess the daily temporal organization of expression of circadian clock genes (Per1, Per2, Bmal1 and Fbxl21) and neuropeptides (Vip, Grp and Avp) in animals acclimated to a short photoperiod (SP; 8h of light) and at 3 or 15 days following transfer to a long photoperiod (LP3, LP15, respectively; 16h of light), achieved by an acute 8-h delay of lights off. We found that waveforms of SCN gene expression conformed to those previously seen in LP acclimated animals within 3 days of transfer to LP. Mean levels of expression for Per1-2 and Fbxl21 were nearly 2-fold higher in the LP15 than in the SP group. The expression of Vip was arrhythmic and unaffected by photoperiod, while, in contrast to rodents, Grp expression was not detectable within the sheep SCN. Expression of the circadian output gene Avp cycled robustly in all photoperiod groups with no detectable change in phasing. Overall these data suggest that synchronizing effects of light on SCN circadian organisation proceed similarly in ungulates and in rodents, despite differences in neuropeptide gene expression.

The Eph family of receptor tyrosine kinases play key roles in both the patterning of the developing nervous system and neural plasticity in the mature brain. To determine functions of ephrin-A5, a GPI-linked ligand to the Eph receptors, in animal behavior regulations, we examined effects of its inactivation on male mouse aggression. When tested in the resident-intruder paradigm for offensive aggression, ephrin-A5-mutant animals (ephrin-A5(-/-)) exhibited severe reduction in conspecific aggression compared to wild-type controls. On the contrary, defensive aggression in the form of target biting was higher in ephrin-A5(-/-) mice, indicating that the mutant mice are capable of attacking behavior. In addition, given the critical role of olfaction in aggressive behavior, we examined the ability of the ephrin-A5(-/-) mice to smell and found no differences between the mutant and control animals. Testosterone levels in the mutant mice were also found to be within the normal range. Taken together, our data reveal a new role of ephrin-A5 in the regulation of aggressive behavior in mice., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Early exposure to valproic acid results in autism-like neural and behavioral deficits in humans and other animals through oxidative stress-induced neural damage. In the present study, valproic acid was administered to genetically altered mice lacking the Nrf2 (nuclear factor-erythroid 2 related factor 2) gene on postnatal day 14 (P14). Nrf2 is a transcription factor that induces genes that protect against oxidative stress. It was found that valproic acid-treated Nrf2 knockout mice were less active in open field activity chambers, less successful on the rotorod, and had deficits in learning and memory in the Morris water maze compared to the valproic acid-treated wild type mice. Given these results, it appears that Nrf2 knockout mice were more sensitive to the neural damage caused by valproic acid administered during early development., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Gastrointestinal (GI) dysfunctions are frequently reported by parents of children with autism spectrum disorders (ASD) and have been recently recognized as a comorbid condition. However, the clinical significance of these GI dysfunctions remains to be delineated. This study describes the clinical characteristics, associated comorbid disorders, and endoscopic and colonoscopic evaluation of GI dysfunction in a cohort of 164 children with ASD evaluated at a pediatric neurology practice. Symptoms of GI dysfunction were prevalent: 49% of the children reported one or more chronic GI complaints, 22% exhibited diarrhea, 26% suffered from constipation. Furthermore 13% of the parents reported their children to suffer from bloating and/or being gassy and while 10% of the parents reported vomiting or gastroesophageal reflux problems. Similar rates of GI symptoms were reported among pre-school and school-aged children. Inflammation of the gut was found in 6 of the 12 subjects who underwent endoscopic and colonoscopic evaluations, however clinical symptoms did not predict the results of the evaluation. GI dysfunction was significantly associated with sleep disorders and food intolerance, but not with irritability or aggressiveness. In summary, GI dysfunction was prevalent in this cohort of children with ASD, observations consistent with the reports of parents and other clinicians. We conclude that the GI dysfunction in ASD requires proper evaluation and treatment., (© 2014 International Society for Autism Research, Wiley Periodicals, Inc.)

Objectives: PAK5 and PAK6 are protein kinases highly expressed in the brain. Previously, we observed that Pak6 knockout mice gained significantly more weight during development than Pak5 knockout mice as well as wild-type controls and double-knockout mice lacking both Pak5 and Pak6. In this study, we assessed the effects of exercise on food intake and weight gain of these mice as well as their sensitivity to the stimulant effects of amphetamine., Methods: Mice of each genotype were placed in cages with free access to run wheel exercise or in cages without run wheels for a total of 74 days. Food and fluid intake as well as body weight of each mouse were measured on a weekly basis. Finally, mice were given a high dose of amphetamine and activity levels were observed immediately thereafter for 90 minutes. Brains and testes of mice were assayed for protein levels of the estrogen alpha and progesterone receptors., Results: While run wheel mice consumed significantly more food, they weighed less than non-run wheel mice. In addition, although Pak6 knockout mice consumed the same amount of food as wild-type mice, they were significantly heavier regardless of run wheel condition. Pak5 knockout mice were found to be more active than other genotypes after amphetamine treatment. Finally, protein levels of the progesterone and estrogen alpha receptors were altered in brain and testes of the Pak6 knockout mice., Discussion: Collectively, these data suggest that PAK6 play a role in weight gain unrelated to exercise and caloric intake and that Pak5 knockout mice are more sensitive to the stimulant effects of amphetamine.

The proper functions of cortical circuits are dependent upon both appropriate neuronal subtype specification and their maturation to receive appropriate signaling. These events establish a balanced circuit that is important for learning, memory, emotion, and complex motor behaviors. Recent research points to mRNA metabolism as a key regulator of this development and maturation process. Hu antigen D (HuD), an RNA-binding protein, has been implicated in the establishment of neuronal identity and neurite outgrowth in vitro. Therefore, we investigated the role of HuD loss of function on neuron specification and dendritogenesis in vivo using a mouse model. We found that loss of HuD early in development results in a defective early dendritic overgrowth phase and pervasive deficits in neuron specification in the lower neocortical layers and defects in dendritogenesis in the CA3 region of the hippocampus. Subsequent behavioral analysis revealed a deficit in performance of a hippocampus-dependent task: the Morris water maze. Further, HuD knock-out (KO) mice exhibited lower levels of anxiety than their wild-type counterparts and were overall less active. Last, we found that HuD KO mice are more susceptible to auditory-induced seizures, often resulting in death. Our findings suggest that HuD is necessary for the establishment of neocortical and hippocampal circuitry and is critical for their function.

The p21-activated kinases are effector proteins for Rho-family GTPases. PAK4, PAK5, and PAK6 are the group II PAKs associated with neurite outgrowth, filopodia formation, and cell survival. Pak4 knockout mice are embryonic lethal, while Pak5, Pak6, and Pak5/Pak6 double knockout mice are viable and fertile. Our previous work found that the double knockout mice exhibit locomotor changes and learning and memory deficits. We also found some differences with Pak5 and Pak6 single knockout mice and the present work further explores the potential differences of the Pak5 knockout and Pak6 knockout mice in comparison with wild type mice. The Pak6 knockout mice were found to weigh significantly more than the other genotypes. The double knockout mice were found to be less active than the other genotypes. The Pak5 knockout mice and the double knockout mice performed worse on the rotorod test. All the knockout genotypes were found to be less aggressive in the resident intruder paradigm. The double knockout mice were, once again, found to perform worse in the active avoidance assay. These results indicate, that although some behavioral differences are seen in the Pak5 and Pak6 single knockout mice, the double knockout mice exhibit the greatest changes in locomotion and learning and memory.

Oral administration of green tea, black tea, or caffeine (but not the decaffeinated teas) inhibited ultraviolet B radiation (UVB)-induced skin carcinogenesis in SKH-1 mice. Studies with caffeine indicated that its inhibitory effect on the ATR/Chk1 pathway is an important mechanism for caffeine's inhibition of UVB-induced carcinogenesis. The regular teas or caffeine increased locomotor activity and decreased tissue fat. In these studies, decreased dermal fat thickness was associated with a decrease in the number of tumors per mouse. Administration of caffeine, voluntary exercise, and removal of the parametrial fat pads all stimulated UVB-induced apoptosis, inhibited UVB-induced carcinogenesis, and stimulated apoptosis in UVB-induced tumors. These results suggest that caffeine administration, voluntary exercise, and removal of the parametrial fat pads inhibit UVB-induced carcinogenesis by stimulating UVB-induced apoptosis and by enhancing apoptosis in DNA-damaged precancer cells and in cancer cells. We hypothesize that tissue fat secretes antiapoptotic adipokines that have a tumor promoting effect.

Ultraviolet B (UVB)-pretreated SKH-1 mice were treated with water, caffeine (0.1 mg/ml), voluntary running wheel exercise (RW) or caffeine together with RW for 14 wk. Treatment of the mice with caffeine, RW, or caffeine plus RW decreased skin tumors per mouse by 27%, 35%, and 62%, respectively, and the tumor volume per mouse was decreased by 61%, 70%, and 85%, respectively. In mechanistic studies, mice were treated with water, caffeine, RW, or caffeine plus RW for 2 wk prior to a single irradiation with UVB. Caffeine plus RW increased RW activity by 22% when compared with RW alone. Caffeine ingestion was not significantly different between groups. Treatment of mice with caffeine plus RW for 2 wk decreased the weight of the parametrial fat pads and stimulated the formation of UVB-induced apoptosis to a greater extent than treatment with caffeine or RW alone. An antibody array revealed that caffeine plus RW administered to mice fed a high-fat diet and irradiated with UVB decreased the epidermal levels of lipopolysaccharide-induced CXC chemokine, soluble TNF alpha receptor-1, and macrophage inflammatory protein-1γ. Overall, caffeine during RW exerts a stronger effect than either treatment alone for decreasing tissue fat, increasing UVB-induced apoptosis, lowering the levels of cytokines associated with inflammation and for inhibiting UVB-induced carcinogenesis.

The Eph receptors and their ligands, the ephrins, play an important role during neural development. In particular, ephrin-A5 is highly expressed in the developing nervous system in several brain regions including the olfactory bulb, frontal cortex, striatum and hypothalamus. Although a number of studies have characterized the expression of ephrin-A5 in these regions, very little is known about the functional consequences that might follow alterations in the expression of this ligand. Previously, we demonstrated that ephrin-A5 acts as a guidance molecule regulating the trajectory of the ascending midbrain dopaminergic pathways. In light of this finding and the critical role of dopamine in modulating a number of behaviors, we sought to determine whether loss of ephrin-A5 altered neurobehavioral development. Our results indicate that ephrin-A5-null mice exhibit delays in reaching developmental milestones and in the maturation of motor skills. In addition, they exhibit increased locomotor activity and reduced levels of brain monoamines. Therefore, we conclude that ephrin-A5 expression appears to be critical for proper development of central monoaminergic pathways and that its loss results in a number of neurodevelopmental abnormalities. Because alterations in monoamine function are associated with a variety of neurodevelopmental disorders, these data suggest that further study on the potential role of ephrin-A5 in such disorders is warranted., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Removal of the parametrial fat pads (partial lipectomy) from female SKH-1 mice fed a high-fat diet inhibited UVB-induced carcinogenesis, but this was not observed in mice fed a low-fat chow diet. Partial lipectomy in high-fat-fed mice decreased the number of keratoacanthomas and squamous cell carcinomas per mouse by 76 and 79%, respectively, compared with sham-operated control mice irradiated with UVB for 33 wk. Immunohistochemical analysis indicated that partial lipectomy increased caspase 3 (active form) positive cells by 48% in precancerous epidermis away from tumors, by 68% in keratoacanthomas, and by 224% in squamous cell carcinomas compared with sham-operated control mice. In addition, partial lipectomy decreased cell proliferation away from tumors and in tumors. RT-PCR analysis for adipokines revealed that mRNAs for TIMP1, MCP1, and SerpinE1 (proinflammatory/antiapoptotic cytokines) in the parametrial fat pads of sham-operated control mice were 54- to 83-fold higher than levels in compensatory fat that returned after surgery in partially lipectomized mice at the end of the tumor study. Feeding mice high-fat diets for 2 wk increased levels of TIMP1 and other adipokines in serum and epidermis, and these increases were inhibited by removal of the parametrial fat pads. Our results are a unique demonstration that surgical removal of a specific tissue fat results in inhibition of carcinogenesis in obese mice. This inhibition was associated with an increase in apoptosis and a decrease in proliferation in tumors and in precancerous areas away from tumors.

A survey of sleep schedules, sleep health, and the impact on school performance was conducted in 585 adolescents in a high school in China. A high level of early and circadian-disadvantaged sleep/wake schedules during weekdays was observed. Significantly shorter sleep duration on weekdays was reported (P < 0.0001). Older teenagers slept significantly less than the younger teenagers (P < 0.0001). Complaints of inadequate sleep and sleepiness during weekdays were prevalent. Night awakenings were reported in 32.2% of students. Students with a sleep length of less than 7 hours, complaint of inadequate sleep, or excessive daytime sleepiness during weekdays were more likely to report an adverse effect of poor sleep on performance. The present observations are qualitatively similar to those reported in our study in American adolescents, particularly with respect to Chinese adolescents exhibiting a similar sleep deficiency on weekdays. We concluded that sleep deficiency and sleep health problems were prevalent in the participating adolescents in China, and were perceived to adversely affect school performance.

The effect of oral caffeine or voluntary running wheel exercise (RW) alone or in combination on the progression of human androgen-dependent LNCaP prostate tumors to androgen independence in male severe combined immunodeficiency mice was determined. The mice were injected subcutaneously with LNCaP cells, and when the tumors reached a moderate size, the mice were surgically castrated and treated with caffeine (0.40 mg/ml drinking water) or RW alone or in combination for 42 days. We found that caffeine administration or RW inhibited the progression and growth of androgen-dependent LNCaP tumors to androgen independence, and a combination of the 2 regimens was more effective than the individual regimens alone. The ratios of the percent mitotic cells/caspase-3 positive cells in tumors from the caffeine-treated, RW-treated, or combination-treated mice were decreased by 34%, 38%, and 52%, respectively. Caffeine treatment increased the percentage of mitotic tumor cells undergoing apoptosis (lethal mitosis) whereas RW inhibited the increase in interleukin-6 that occurred during the progression of LNCaP tumors from androgen dependence to androgen independence. Our results indicate that oral administration of caffeine in combination with voluntary exercise may be an effective strategy for the prevention of prostate cancer progression from androgen dependence to androgen independence.

Our previous studies reported that caffeine or voluntary exercise decreased skin tumor multiplicity, in part, by decreasing fat levels in the dermis. These data suggest that tissue fat may play an important role in regulating ultraviolet light (UV) B-induced skin tumor development. In the present study, we explored the effects of high-fat diets rich in either omega-3 or omega-6 fatty acids on UVB-induced skin carcinogenesis. SKH-1 mice were irradiated with 30 mJ/cm(2) of UVB once a day, two times per week for 39 weeks. During UVB treatment, one group of mice was given a high-fat fish oil (HFFO) diet rich in omega-3 fatty acids and the other group of mice was given a high-fat mixed-lipids (HFMLs) diet rich in omega-6 fatty acids. The results showed that, compared with HFML diet, HFFO treatment (i) increased latency for the development of UVB-induced skin tumors; (ii) decreased the formation of papilloma, keratoacanthoma and carcinoma by 64, 52 and 46%, respectively and (iii) decreased the size of papilloma, keratoacanthoma and carcinoma by 98, 80 and 83%, respectively. Mechanistic studies with antibody array revealed that compared with HFML diet, administration of HFFO to the mice significantly decreased the UVB-induced increases in the levels of TIMP-1, LIX and sTNF R1 as well as other several proinflammatory cytokines and stimulated the UVB-induced apoptosis in the epidermis. Our results indicate that omega-3 fatty acids in HFFO diet have beneficial effects against UVB-induced skin carcinogenesis, and these effects may be associated with an inhibition on UVB-induced inflammatory response.

We determined the inhibitory effect of dietary atorvastatin, dietary celecoxib and voluntary running wheel exercise (RW) alone or in combination on the formation and growth of androgen-independent LNCaP tumors in castrated SCID mice. Male SCID mice were injected subcutaneously with androgen-dependent prostate cancer LNCaP cells. When the tumors reached a moderate size, the mice were surgically castrated and treated with atorvastatin (0.02% in the diet), celecoxib (0.05% in the diet) or RW alone or in combination for 42 days. RW or celecoxib alone had a moderate inhibitory effect on the androgen-independent growth of LNCaP tumors, but atorvastatin alone had little or no effect on tumor growth. Combinations of atorvastatin and celecoxib had a stronger inhibitory effect on the formation and growth of androgen-independent LNCaP tumors than either drug alone. A combination of RW together with atorvastatin and celecoxib had the most potent inhibitory effect on the progression of LNCaP tumors to androgen independent growth. The serum concentration of atorvastatin after two weeks of oral administration of atorvastatin was 6.1 ng/ml. The serum concentration of celecoxib after treatment with dietary celecoxib for two weeks was 1090 ng/ml. The serum concentration of atorvastatin but not that of celecoxib was substantially reduced when the two drugs were given in combination. The drug concentrations observed in our animal studies are comparable or less than those commonly found in humans treated with atorvastatin or celecoxib. Our results indicate that administration of atorvastatin and celecoxib together with voluntary exercise may be an effective strategy for the prevention of prostate cancer progression from androgen dependence to androgen independence.

A survey on sleep schedule, sleep health, school performance and school start times was conducted in 1,941 adolescents. A high level of early and circadian-disadvantaged sleep/wake schedules during weekdays was observed. Shorter sleep duration on weekdays was reported, especially in upper classmen. Complaints of inadequate sleep and sleepiness during weekdays, alarm clock use, and napping were prevalent. Night awakening and prolonged sleep onset were common and associated with poor school performance. Students with a sleep length of less than 7 hours on both weekdays and weekends exhibited poorer performance, while those who made up this sleep loss on weekends did not. The total number of poor sleep factors in an individual also correlated with poor school performance. Earlier school start times were associated with a perception of poor sleep quality, shorter sleep duration and more sleep health problems. We conclude that sleep inadequacies and sleep health problems were prevalent in this population, especially in those who started school earlier in the morning, and that these poor sleep factors were associated with school performance.

In adults, migraine with aura is considered to be a risk factor for stroke, especially when other risk factors exist. However, the relationship between migraine with aura and risk of cerebral infarct in children has not been well established and requires further study. We describe four young patients who suffered from migraine with aura and focal neurological deficits. All four patients had migraine with aura and focal neurological deficits associated with headaches. Two of the four young patients had cerebral infarct during their migraine headaches. Detailed investigation did not reveal the etiology of the cerebral infarct in these two adolescents. No risk factor for stroke was apparent in any of the four patients and no specific risk factor or reliable clinical feature could be used to identify these young patients at risk for irreversible cerebral ischemia. Thus, our observations provide support that there may be an association between migraine with aura and risk of stroke in children. We, therefore, advocate aggressive treatment using prophylactic agents to prevent migraine attacks in children suffering from migraine with aura, especially when auras are prolonged.

Although the etiology of autism is unclear, disruptions of the dopaminergic and serotonergic systems have been associated with the disorder. Based on behavioral differences observed in the BALB/c strain of mice in comparison to other strains, notably, C57BL/6J mice, it has been suggested that the BALB/c strain may serve as an animal model of autism. However, to date, most work investigating neural and behavioral abnormalities in this strain has been performed in adult animals. Therefore, the present study was conducted to examine the development of the central dopaminergic and serotonergic systems of BALB/c mice as compared to C57BL/6J mice. Levels of dopamine, serotonin, and their metabolites in several different brain regions and at three ages during development were measured. Alterations in both monoaminergic systems associated with age and strain were detected across brain regions indicating that there are neurochemical differences between these strains early in life. However, despite these differences in the development of brain monoaminergic systems, it remains difficult to declare this strain as a valid model of autism., (Copyright 2010 Elsevier B.V. All rights reserved.)

Autism is a heterogeneous, behaviorally defined developmental disorder with unknown etiology but thought to be the result of environmental insult acting upon the developing brain of a genetically susceptible individual. Approximately 30% of individuals with autism have normal development up to the age of about 30 months after which they experience behavioral regression and lose previously acquired motor, cognitive and social skills. Early post-natal toxicant administration to mice has been used to model autistic regression. To test the hypothesis that genetically altered mice might be more sensitive to toxicant exposure early in life, mice with a deletion of glutathione-S-transferaseM1 (GSTM1; a gene associated with increased risk of autism that codes for an enzyme involved in the management of toxicant-induced oxidative stress) and wild-type controls were exposed to valproic acid (VPA; a toxicant known to cause autism-like behavioral deficits that, in part, are mediated through oxidative stress) on post-natal day 14. VPA treatment caused significant increases in apoptosis in granule cells of the hippocampus and cerebellum. There was a genotype by treatment by sex interaction with wild-type females exhibiting significantly fewer apoptotic cells in these regions compared to all other groups. VPA treatment also resulted in long-lasting deficits in social behaviors and significant alterations in brain chemistry. VPA-treated GSTM1 knockout animals performed significantly fewer crawl-under behaviors compared to saline-treated knockout animals as well as wild-type controls receiving either treatment. Collectively, these studies indicate that VPA-treatment causes cerebellar and hippocampal apoptosis and that having the wild-type GSTM1 genotype may confer protection against VPA-induced neuronal death in female mice., (Copyright 2010 Elsevier B.V. All rights reserved.)

Treatment of p53(-/-) mice orally with caffeine, voluntary exercise or their combination for 2 weeks prior to a single irradiation with UVB (i) decreased the weight of the epididymal fat pads by 22, 40 and 56%, (ii) decreased the thickness of the dermal fat layer by 10, 26 and 42%, (iii) increased the number of apoptotic sunburn cells by 29, 100 and 489%, (iv) increased the number of caspase-3-positive cells by 33, 117 and 667% and (v) increased the number of mitotic cells with cyclin B1-positive staining by 40, 210 and 510%, respectively. Pearson's correlation coefficient indicated a statistically significant inverse relationship between the level of tissue fat and the number of mitotic cells with cyclin B1 in p53(-/-) mice but not in p53(+/+) littermates. Western blot analysis indicated that treatment of p53(-/-) mice with caffeine together with exercise increased the level of cyclin B1 significantly more than in p53(+/+) mice. p53(-/-) mice, but not p53(+/+) mice, treated with caffeine during exercise exhibited a dramatic decrease in the level of survivin. Our results suggest that voluntary exercise in combination with oral caffeine may exert a synergistic increase in UVB-induced apoptosis and that tissue fat may be a more important modulator of apoptosis and carcinogenesis in p53-deficient mice than in p53-normal mice. The stimulatory effects on apoptosis in p53(-/-) mice by the combination treatment might be associated with increased levels of cyclin B1 and decreased levels of survivin.

Seasonal photoperiodic responses in mammals depend on the pineal hormone melatonin. The pars tuberalis (PT) region of the anterior pituitary has emerged as a principal melatonin target tissue, controlling endocrine responses. Rising melatonin levels acutely influence the expression of a small cluster of genes either positively (exemplified by cryptochrome-1, cry1) or negatively (exemplified by the type 1 melatonin receptor, mt1). The purpose of this study was to characterize the pathways through which these evening actions of melatonin are mediated. In vitro experiments showed that cAMP signaling in the PT directly influences mt1 but not cry1 expression. Analysis of nuclear extracts from sheep PT tissue collected 90 min after melatonin or saline control injections highlighted the response element for the immediate early gene egr1 (EGR1-RE) as a candidate for acute melatonin-dependent transcriptional regulation. We identified putative EGR1-RE's in the proximal promoter regions of the ovine cry1 and mt1 genes, and confirmed their functionality in luciferase reporter assays. Egr1 expression is suppressed by melatonin in PT cell cultures, and is rhythmic in the ovine PT with a nadir in the early night. We propose that melatonin-dependent effects on EGR1-RE's contribute to evening gene expression profiles in this pituitary melatonin target tissue.

High-dose administration of amphetamine-like compounds is associated with acute behavioral toxicity (including stereotypic and self-injurious behavior and schizophrenic-like psychoses) as well as long-lasting damage to dopaminergic neurons. Several mechanisms are thought to be responsible for methamphetamine-induced neurotoxicity including the formation of reactive oxygen species, dopamine quinones, glutamatergic activity, apoptosis, etc. Recently, new factors regarding glial cell line-derived neurotorophic factor, tumor necrosis factor-alpha, and interferon-gamma have also been associated with methamphetamine-induced neurotoxicity. The objective of this review is to link the behavioral and neurotoxic responses of the amphetamines, emphasizing their common underlying mechanism of monoaminergic release together with inhibition of monoamine oxidase activity. The amphetamine-induced release of dopamine and inhibition of monoamine oxidase increases both cytosolic and synaptic levels of dopamine leading to the acute manifestation of stereotypic and self-injurious behavior. In turn, the enhanced extravesicular levels of dopamine lead to oxidative stress through the generation of reactive oxygen species and dopamine quinones, and cause the long-lasting neuronal damage. Thus, we propose that acute behavioral observation of subjects immediately following methamphetamine administration may provide insight into the long-lasting toxicity to dopaminergic neurons.

Background: Epidemiological studies suggest that physical activity reduces the risk of colon cancer in humans. Results from animal studies, however, are inconclusive. The present study investigated the effects of voluntary exercise on intestinal tumor formation in two different animal models, Apc(Min/+) mice and azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated mice., Methods: In Experiments 1 and 2, five-week old female Apc(Min/+) mice were either housed in regular cages or cages equipped with a running wheel for 6 weeks (for mice maintained on the AIN93G diet; Experiment 1) or 9 weeks (for mice on a high-fat diet; Experiment 2). In Experiment 3, male CF-1 mice at 6 weeks of age were given a dose of AOM (10 mg/kg body weight, i.p.) and, 12 days later, 1.5% DSS in drinking fluid for 1 week. The mice were then maintained on a high-fat diet and housed in regular cages or cages equipped with a running wheel for 16 weeks., Results: In the Apc(Min/+) mice maintained on either the AIN93G or the high-fat diet, voluntary exercise decreased the number of small intestinal tumors. In the AOM/DSS-treated mice maintained on a high-fat diet, voluntary exercise also decreased the number of colon tumors. In Apc(Min/+) mice, voluntary exercise decreased the ratio of serum insulin like growth factor (IGF)-1 to IGF binding protein (BP)-3 levels. It also decreased prostaglandin E2 and nuclear beta-catenin levels, but increased E-cadherin levels in the tumors., Conclusion: These results indicate hat voluntary exercise inhibited intestinal tumorigenesis in Apc(Min/+) mice and AOM/DSS-treated mice, and the inhibitory effect is associated with decreased IGF-1/IGFBP-3 ratio, aberrant beta-catenin signaling, and arachidonic acid metabolism.

PAK6 is a member of the group B family of PAK serine/threonine kinases, and is highly expressed in the brain. The group B PAKs, including PAK4, PAK5, and PAK6, were first identified as effector proteins for the Rho GTPase Cdc42. They have important roles in filopodia formation, the extension of neurons, and cell survival. Pak4 knockout mice die in utero, and the embryos have several abnormalities, including a defect in the development of motor neurons. In contrast, Pak5 knockout mice do not have any noticeable abnormalities. So far nothing is known about the biological function of Pak6. To address this, we have deleted the Pak6 gene in mice. Since Pak6 and Pak5 are both expressed in the brain, we also generated Pak5/Pak6 double knockout mice. These mice were viable and fertile, but had several locomotor and behavioral deficits. Our results indicate that Pak5 and Pak6 together are not required for viability, but are required for a normal level of locomotion and activity as well as for learning and memory. This is consistent with a role for the group B PAKs in the nervous system.

It is believed that gene by environmental interactions contribute to the pathogenesis of autism spectrum disorders (ASD). We hypothesize that ASD are associated with early and repeated exposures to any of a number of toxicants or mixtures of toxicants. It is the cumulative effects of these repeated exposures acting upon genetically susceptible individuals that lead to the phenotypes of ASD. We report our initial observations of a considerable overlap of identified toxic landfills in the State of New Jersey and the residence of an ASD cohort, and a correlation between the identified toxic Superfund sites on each U.S. state and the total number of diagnosed cases of ASD in those states. The residence of 495 ASD patients in New Jersey by zip code and the toxic landfill sites were plotted on a map of Northern New Jersey. The area of highest ASD cases coincides with the highest density of toxic landfill sites while the area with lowest ASD cases has the lowest density of toxic landfill sites. Furthermore, the number of toxic Superfund sites and autism rate across 49 of the 50 states shows a statistically significant correlation (i.e. the number of identified superfund sites correlates with the rate of autism per 1000 residents in 49 of the states (p = 0.015; excluding the state of Oregon). These significant observations call for further organized studies to elucidate possible role(s) of environmental toxicants contributing to the pathogenesis of ASD.

Children with autism spectrum disorders (ASD) often exhibit sleep and behavioral disorders. Treatment of sleep disorders can be difficult in these children. Clonidine, an alpha2-adrenergic receptor agonist, has been shown to be effective in reducing impulsivity, inattention, and hyperactivity, as well as in serving as a sedative for medial procedures. An open labeled retrospective study of clonidine in treatment of insomnia, and/or hyperactivity, inattention, mood disorder, and aggressive behaviors was conducted using parent reports of sleep initiation and maintenance, as well as behaviors prior and during clonidine treatment. Clonidine was effective in reducing sleep initiation latency and night awakening, to a less degree in improving attention deficits hyperactivity, mood instability and aggressiveness in this cohort of 19 children with ASD. The side effects were largely tolerable. Further evaluation with placebo-controlled double-blind clinical trial of clonidine use in ASD will provide more insight into the clinical efficacy and safety of the medicine in ASD.

In the present study, we investigated the effect of voluntary exercise on the formation and growth of the human pancreas Panc-1 and prostate PC-3 tumors in immunodeficient mice. Female severe combined immunodeficient (SCID) mice were injected subcutaneously with human pancreatic cancer Panc-1 cells, and male SCID mice were injected subcutaneously with human prostate cancer PC-3 cells. Voluntary running wheel exercise for 63 days, starting one week before the subcutaneous injection of Panc-1 or PC-3 tumor cells into SCID mice, suppressed the growth of Panc-1 and PC-3 tumors. The exercise regimen increased the food and fluid consumption in the female and male mice. Exercise also decreased the size of the parametrial fat pads in the female mice and the paradidymis fat pads in the male mice, but there was no effect on the body weight. Mechanistic studies showed that voluntary running wheel exercise inhibited proliferation as reflected by a decreased mitosis, and the exercise regimen also stimulated apoptosis as reflected by the increased caspase-3 (active form) expression in the Panc-1 and PC-3 tumors. Voluntary running wheel exercise decreased the ratio of the percent mitotic cells/apoptotic cells in Panc-1 and PC-3 tumors by 38 and 32%, respectively. The present study demonstrated an inhibitory effect of voluntary exercise on the growth of pancreas and prostate tumors in a SCID mouse xenograft model.

During development, Eph tyrosine kinase receptors and their ephrin ligands function as axon guidance molecules while, in adults, these molecules appear to be involved in the regulation of neural plasticity and emotion. The absence of EphA5 receptor mediated forward signaling may cause alterations in connectivity of neural networks and boundary formation during development, including central monoaminergic systems. In the present studies, we demonstrated altered aggressive responses by animals lacking functional EphA5 receptors. These behavioral changes were accompanied by altered concentrations of serotonin (5-HT) and the metabolite, 5-HIAA, in the hypothalamus. The changes of serotonin activity in hypothalamus also result in increase of body weight in EphA5 knockout mice. Furthermore, EphA5 knockout mice exhibited a significant decrease in activity levels following exposure to naïve intruders in their home cages. We conclude that the EphA5 receptor may be involved in mediation of aggressive behavior regulated, in part, by hypothalamic serotonin.

Sodium valproate (VPA) administered to neonatal mice causes cognitive and motor deficits similar to those observed in humans with autism. In an effort to further evaluate similarities between early VPA exposure and autism, the present study examined treated mice for deficits in social behavior and neuronal damage. BALB/c mice injected on P14 with 400 mg/kg VPA engaged in fewer social interactions (including ano-genital sniffs, allogrooming, and crawl-under/over behaviors) than control mice. Treated mice also exhibited reduced motor activity in a social context but were not significantly different from controls when motor activity was assessed in non-social settings. A second set of BALB/c mice were treated with VPA on P14 and sacrificed at different times thereafter for histopathological analysis. At time-points 12 and 24 h following VPA, treated mice had up to a 30-fold increase in the number of TUNEL-positive cells in the external granule cell layer of the cerebellum and a 10-fold increase in TUNEL-positive cells in the dentate gyrus of the hippocampus. These observations may provide a histopathological correlate for the social deficits observed following post-natal VPA exposure and supports the use of early VPA administration as an animal model for the study of autism.

Various hypotheses have been proposed concerning the mechanisms responsible for methamphetamine (METH)-induced neurotoxicity including reactive oxygen species (ROS), dopamine quinones, glutamatergic activity, apoptosis, etc. Recently, new factors regarding glial cell line-derived neurotorophic factor, tumor necrosis factor-alpha, and alpha-synuclein contained in striatal interneural inclusions have also been associated with METH-induced neurotoxicity. In addition, METH-induced self-injurious behavior (SIB) has been proposed to be an acute or immediate behavioral marker predicting the long-lasting neurotoxicity induced by METH. Specifically, it has been proposed that the SIB response may accurately reflect the underlying mechanistic changes occurring in the neuron that eventually result in the long-lasting damage. Several studies have demonstrated that endogenous dopamine (DA) plays an important role in mediating METH-induced neuronal damage. DA release and redistribution from synaptic vesicles to cytoplasmic compartments is thought to involve METH-induced changes in both the vesicular monoamine transporter-2 and DA transporter function. In turn, the consequent elevation of cytosolic auto-oxidizable DA concentrations is thought generate ROS such as superoxide and hydroxyl radicals and cause the DA terminal injury. Finally, the inflammatory response of microglia and glutamatergic toxicity in astrocytes have been related to the METH-induced neurotoxicity. The objective of the present review will be to consolidate the new perspectives in an attempt to formulate a more cohesive explanation of the underlying mechanism responsible for METH-induced DA damage and its early biological markers.

Individuals with autism spectrum disorder are heterogeneous in clinical presentation, concurrent disorders, and developmental outcomes. This study characterized the clinical co-occurrences and potential subgroups in 160 children with autism spectrum disorders who presented to The Autism Center between 1999 and 2003. Medical and psychiatric co-occurrences included sleep disorders, epilepsy, food intolerance, gastrointestinal dysfunction, mood disorder, and aggressive and self-injurious behaviors. Sleep disorders were associated with gastrointestinal dysfunction (P < .05) and mood disorders (P < .01). Food intolerance was associated with gastrointestinal dysfunction (P = .001). Subjects with mood disorder tended to develop aggressive or self-injurious behaviors (P < .05). Developmental regression was not associated with increased co-occurrence of medical or psychiatric disorders. Medical co-occurrence did not present as a risk factor for psychiatric co-occurrence, and vice versa. These results showed a high prevalence of multiple medical and psychiatric co-occurrences. There may be common pathophysiologic mechanisms resulting in clinical subgroups of autism spectrum disorders. Recognition of the co-occurrence of concurrent disorders may provide insight into the therapeutic strategy.

At temperate latitudes, increases in day length in the spring promote the summer phenotype. In mammals, this long-day response is mediated by decreasing nightly duration of melatonin secretion by the pineal gland. This affects adenylate cyclase signal transduction and clock gene expression in melatonin-responsive cells in the pars tuberalis of the pituitary, which control seasonal prolactin secretion. To define the photoperiodic limits of the mammalian long day response, we transferred short day (8 h light per 24 h) acclimated Soay sheep to various longer photoperiods, simulating those occurring from spring to summer in their northerly habitat (57 degrees N). Locomotor activity and plasma melatonin rhythms remained synchronized to the light-dark cycle in all photoperiods. Surprisingly, transfer to 16-h light/day had a greater effect on prolactin secretion and oestrus activity than shorter (12 h) or longer (20 and 22 h) photoperiods. The 16-h photoperiod also had the largest effect on expression of circadian (per1) and neuroendocrine output (betaTSH) genes in the pars tuberalis and on kisspeptin gene expression in the arcuate nucleus of the hypothalamus, which modulates reproductive activity. This critical photoperiodic window of responsiveness to long days in mammals is predicted by a model wherein adenylate cyclase sensitization and clock gene phasing effects of melatonin combine to control neuroendocrine output. This adaptive mechanism may be related to the latitude of origin and the timing of the seasonal transitions.